FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Atwal, RS Desmond, CR Caron, N Maiuri, T Xia, JR Sipione, S Truant, R AF Atwal, Randy Singh Desmond, Carly R. Caron, Nicholas Maiuri, Tamara Xia, Jianrun Sipione, Simonetta Truant, Ray TI Kinase inhibitors modulate huntingtin cell localization and toxicity SO NATURE CHEMICAL BIOLOGY LA English DT Article ID KAPPA-B KINASE; MUTANT HUNTINGTIN; IKK-BETA; SELECTIVE INHIBITOR; SECONDARY STRUCTURE; TRANSGENIC MICE; IN-VIVO; DISEASE; PHOSPHORYLATION; AGGREGATION AB Two serine residues within the first 17 amino acid residues of huntingtin (N17) are crucial for modulation of mutant huntingtin toxicity in cell and mouse genetic models of Huntington's disease. Here we show that the stress-dependent phosphorylation of huntingtin at Ser13 and Ser16 affects N17 conformation and targets full-length huntingtin to chromatin-dependent sub-regions of the nucleus, the mitotic spindle and cleavage furrow during cell division. Polyglutamine-expanded mutant huntingtin is hypophosphorylated in N17 in both homozygous and heterozygous cell contexts. By high-content screening in live cells, we identified kinase inhibitors that modulated N17 phosphorylation and hence huntingtin subcellular localization. N17 phosphorylation was reduced by casein kinase-2 inhibitors. Paradoxically, IKK beta kinase inhibition increased N17 phosphorylation, affecting huntingtin nuclear and subnuclear localization. These data indicate that huntingtin phosphorylation at Ser13 and Ser16 can be modulated by small-molecule drugs, which may have therapeutic potential in Huntington's disease. C1 [Atwal, Randy Singh; Desmond, Carly R.; Caron, Nicholas; Maiuri, Tamara; Xia, Jianrun; Truant, Ray] McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON, Canada. [Sipione, Simonetta] Univ Alberta, Dept Pharmacol, Edmonton, AB, Canada. RP Atwal, RS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. EM truantr@mcmaster.ca FU Canadian Institutes of Health Research [MOP 165174]; Krembil Foundation; CHDI Foundation FX This work was supported by operating grants from the Canadian Institutes of Health Research (MOP 165174), the Krembil Foundation and the CHDI Foundation (to R. T.). We thank M. Prakesch (Ontario Institute for Cancer Research) for supplying multiple CK2 and IKK beta inhibitors, I. Bezprozvanny (University of Texas Southwestern) and G. Hajnocsky (Thomas Jefferson University) for the gift of huntingtin-null MEF cell lines, M. E. MacDonald (Massachusetts General Hospital) for the gift of mouse striatal STHdh cell lines, and Raquel and Richard Epand for assistance and advice with CD spectroscopy. NR 48 TC 61 Z9 62 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD JUL PY 2011 VL 7 IS 7 BP 453 EP 460 DI 10.1038/NCHEMBIO.582 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 785TF UT WOS:000292252100013 PM 21623356 ER PT J AU Hoglinger, GU Melhem, NM Dickson, DW Sleiman, PMA Wang, LS Klei, L Rademakers, R de Silva, R Litvan, I Riley, DE van Swieten, JC Heutink, P Wszolek, ZK Uitti, RJ Vandrovcova, J Hurtig, HI Gross, RG Maetzler, W Goldwurm, S Tolosa, E Borroni, B Pastor, P Cantwell, LB Han, MR Dillman, A van der Brug, MP Gibbs, JR Cookson, MR Hernandez, DG Singleton, AB Farrer, MJ Yu, CE Golbe, LI Revesz, T Hardy, J Lees, AJ Devlin, B Hakonarson, H Muller, U Schellenberg, GD AF Hoeglinger, Guenter U. Melhem, Nadine M. Dickson, Dennis W. Sleiman, Patrick M. A. Wang, Li-San Klei, Lambertus Rademakers, Rosa de Silva, Rohan Litvan, Irene Riley, David E. van Swieten, John C. Heutink, Peter Wszolek, Zbigniew K. Uitti, Ryan J. Vandrovcova, Jana Hurtig, Howard I. Gross, Rachel G. Maetzler, Walter Goldwurm, Stefano Tolosa, Eduardo Borroni, Barbara Pastor, Pau Cantwell, Laura B. Han, Mi Ryung Dillman, Allissa van der Brug, Marcel P. Gibbs, J. Raphael Cookson, Mark R. Hernandez, Dena G. Singleton, Andrew B. Farrer, Matthew J. Yu, Chang-En Golbe, Lawrence I. Revesz, Tamas Hardy, John Lees, Andrew J. Devlin, Bernie Hakonarson, Hakon Mueller, Ulrich Schellenberg, Gerard D. CA PSP Genetics Study Grp TI Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; UNFOLDED PROTEIN RESPONSE; ALZHEIMERS-DISEASE; CORTICOBASAL DEGENERATION; NEUROPATHOLOGIC CRITERIA; PARKINSONS-DISEASE; TAU-GENE; HAPLOTYPE; EXPRESSION; METAANALYSIS AB Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P <= 10(-3). We found significant previously unidentified signals (P < 5 x 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. C1 [Wang, Li-San; Cantwell, Laura B.; Han, Mi Ryung; Schellenberg, Gerard D.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Hoeglinger, Guenter U.] Univ Marburg, Dept Neurol, Marburg, Germany. [Melhem, Nadine M.; Klei, Lambertus; Devlin, Bernie] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Dickson, Dennis W.; Rademakers, Rosa] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Sleiman, Patrick M. A.; Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [de Silva, Rohan; Vandrovcova, Jana; Gibbs, J. Raphael; Hernandez, Dena G.; Hardy, John; Lees, Andrew J.] UCL, Inst Neurol, Reta Lila Weston Inst, London, England. [Litvan, Irene] Univ Louisville, Div Movement Disorders, Dept Neurol, Louisville, KY 40292 USA. [Riley, David E.] Case Western Reserve Univ, Dept Neurol, Univ Hosp, Cleveland, OH 44106 USA. [van Swieten, John C.] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Heutink, Peter] Vrije Univ VU Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, Netherlands. [Wszolek, Zbigniew K.; Uitti, Ryan J.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Hurtig, Howard I.; Gross, Rachel G.] Univ Penn Hlth Syst, Dept Neurol, Philadelphia, PA USA. [Maetzler, Walter] Univ Tubingen, Dept Neurodegenerat, Hertie Inst Clin Brain Res, Ctr Neurol, Tubingen, Germany. [Maetzler, Walter] Univ Tubingen, German Ctr Neurodegenerat Dis, Tubingen, Germany. [Goldwurm, Stefano] Ist Clin Perfezionamento, Parkinson Inst, Milan, Italy. [Tolosa, Eduardo] Univ Barcelona, IDIBAPS, CIBERNED, Neurol Serv,Hosp Clin, Barcelona, Spain. [Borroni, Barbara] Univ Brescia, Inst Neurol, Dept Med & Surg Sci, Brescia, Italy. [Pastor, Pau] Inst Salud Carlos III, CIBERNED, Madrid, Spain. [Pastor, Pau] Univ Navarra, Ctr Appl Med Res, Div Neurosci, Neurogenet Lab, E-31080 Pamplona, Spain. [Pastor, Pau] Univ Navarra, Clin Univ Navarra, Dept Neurol, E-31080 Pamplona, Spain. [Dillman, Allissa; Gibbs, J. Raphael; Cookson, Mark R.; Hernandez, Dena G.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [van der Brug, Marcel P.] Scripps Res Inst, Dept Neurosci, Jupiter, FL USA. [Farrer, Matthew J.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Yu, Chang-En] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Yu, Chang-En] Vet Affairs Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. [Golbe, Lawrence I.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Neurol, New Brunswick, NJ 08903 USA. [Revesz, Tamas; Lees, Andrew J.] UCL, UCL Inst Neurol, Dept Mol Neurosci, Queen Sq Brain Bank Neurol Disorders, London, England. [Mueller, Ulrich] Univ Giessen, Inst Humangenet, Giessen, Germany. RP Schellenberg, GD (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM ulrich.mueller@humangenetik.med.uni-giessen.de; gerardsc@mail.med.upenn.edu RI Silveira-Moriyama, Laura/G-4592-2014; Revesz, Tamas/A-8732-2010; Singleton, Andrew/C-3010-2009; Morris, Huw/B-8527-2008; Pastor, Pau/C-9834-2009; O'Sullivan, Sean/C-9333-2012; Hardy, John/C-2451-2009; Lees, Andrew/A-6605-2009; Ross, Owen/D-7573-2013; Melhem, Nadine/G-1510-2013; Troakes, Claire/K-4346-2015; Maetzler, Walter/A-6796-2011; Goldwurm, Stefano/Q-8978-2016 OI Silveira-Moriyama, Laura/0000-0002-8267-0977; Budka, Herbert/0000-0002-1933-1577; van Swieten, John /0000-0001-6278-6844; Geller, Evan/0000-0002-8035-8736; CILIA, ROBERTO/0000-0002-1990-1939; Pickering-Brown, Stuart/0000-0003-1561-6054; Litvan, Irene/0000-0002-3485-3445; Standaert, David/0000-0003-2921-8348; Revesz, Tamas/0000-0003-2501-0259; Morris, Huw/0000-0002-5473-3774; Pastor, Pau/0000-0002-7493-8777; Rohrer, Jonathan/0000-0002-6155-8417; Dickson, Dennis W/0000-0001-7189-7917; O'Sullivan, Sean/0000-0002-0583-7956; Goldwurm, Stefano/0000-0002-1651-567X FU CurePSP Foundation; Peebler PSP Research Foundation; US National Institutes of Health (NIH) (National Institute on Aging (NIA)/NIH) [R37 AG 11762, R01 PAS-03-092, P50 NS72187, P01 AG17216]; US National Institutes of Health (NIH) (National Institute of Mental Health (NIMH) [MH057881, MH077930]; NIA; German National Genome Research Network [01GS08136-4]; Deutsche Forschungsgemeinschaft [HO 2402/6-1]; Prinses Beatrix Fonds [01-0128]; Reta Lila Weston Trust; UK Medical Research Council [G0501560, G0400074]; Newcastle National Institute for Health Research (NIHR) Biomedical Research Centre in Ageing and Age Related Diseases; Alzheimer's Society; Alzheimer's Research Trust; TELETHON Italy [GTB07001]; Fondazione Grigioni per il Morbo di Parkinson; Wellcome Trust; Howard Hughes Medical Institute; Canadian Institute of Health Research; Federal Ministry of Education and Research (BMBF) [01GI0505]; PSP (Europe) Association; Cure PSP+; NIH/NINDS [1RC2NS070276, NS057567, P50NS072187]; Mayo Clinic Florida (MCF) Research Committee [90052030]; Government of Navarra; Division of Neuroscience, NIA; Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA; National Human Genome Research Institute (NHGRI) [U01HG004608]; National Institute for General Medical Sciences (NIGMS); Marshfield Clinic, Health Resources Service Administration Office of Rural Health Policy [D1A RH00025]; Wisconsin Department of Commerce [TDF FYO10718]; NIH [U01HG004438] FX We thank the subjects and their families that participated in this study. This work was funded by grants from the CurePSP Foundation, the Peebler PSP Research Foundation and US National Institutes of Health (NIH) grants R37 AG 11762, R01 PAS-03-092, P50 NS72187, P01 AG17216 (National Institute on Aging (NIA)/NIH), MH057881 and MH077930 (National Institute of Mental Health (NIMH)). Work was also supported in part by the NIA Intramural Research Program, the German National Genome Research Network (01GS08136-4) and the Deutsche Forschungsgemeinschaft (HO 2402/6-1), Prinses Beatrix Fonds (JCvS, 01-0128), the Reta Lila Weston Trust and the UK Medical Research Council (RdS: G0501560). The Newcastle Brain Tissue Resource provided tissue and is funded in part by a grant from the UK Medical Research Council (G0400074), by the Newcastle National Institute for Health Research (NIHR) Biomedical Research Centre in Ageing and Age Related Diseases to the Newcastle upon Tyne Hospitals National Health Service Foundation Trust and by a grant from the Alzheimer's Society and Alzheimer's Research Trust as part of the Brains for Dementia Research Project. We acknowledge the contribution of many tissue samples from the Harvard Brain Tissue Resource Center. We also acknowledge the 'Human Genetic Bank of Patients affected by Parkinson Disease and Parkinsonism' (http://www.parkinson.it/dnabank.html) of the Telethon Genetic Biobank Network, supported by TELETHON Italy (project no. GTB07001) and by Fondazione Grigioni per il Morbo di Parkinson. The University of Toronto sample collection was supported by grants from Wellcome Trust, Howard Hughes Medical Institute and the Canadian Institute of Health Research. Brain-Net-Germany is supported by the Federal Ministry of Education and Research (BMBF) (01GI0505). R.d.S., A.J.L. and J.A.H. are funded by the Reta Lila Weston Trust and the PSP (Europe) Association. R.d.S. is funded by the UK Medical Research Council (Grant G0501560) and Cure PSP+. Z.K.W. is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR programs (MCF #90052030 and MCF #90052030) and the gift from C. E. Bolch Jr. and S. B. Bolch (MCF #90052031/PAU # 90052). The Mayo Clinic College of Medicine would like to acknowledge M. Baker, R. Crook, M. DeJesus-Hernandez and N. Rutherford for their preparation of samples. P. P. was supported by a grant from the Government of Navarra ('Ayudas para la Realizacion de Proyectos de Investigacion' 2006-2007) and acknowledges the 'Iberian Atypical Parkinsonism Study Group Researchers': M. A. Pastor, M. R. Luquin, M. Riverol, J.A. Obeso and M. C. Rodriguez-Oroz (Department of Neurology, Clinica Universitaria de Navarra, University of Navarra, Pamplona, Spain), M. Blazquez (Neurology Department, Hospital Universitario Central de Asturias, Oviedo, Spain), A. Lopez de Munain, B. Indakoetxea, J. Olaskoaga, J. Ruiz, J. Felix Marti Masso (Servicio de Neurologia, Hospital Donostia, San Sebastian, Spain), V. Alvarez (Genetics Department, Hospital Universitario Central de Asturias, Oviedo, Spain), T. Tu on (Banco de Tejidos Neurologicos, CIBERNED, Hospital de Navarra, Navarra, Spain), F. Moreno (Servicio de Neurologia, Hospital Ntra. Sra. de la Antigua, Zumarraga, Gipuzkoa, Spain), A. Alzualde (Neurogenetics Department, Hospital Donostia, San Sebastian, Spain). E. T. wishes to acknowledge the Banco de Tejidos Neurologicos de la Universidad de Barcelona-Hospital Clinic, which provided many tissue samples for the project. We also acknowledge E.; Loomis for providng technical support.; The datasets used for older controls were obtained from Database for Genotypes and Phenotypes (dbGap) at http://www.ncbi.nlm.nih.gov/gap/. Funding support for the 'Genetic Consortium for Late Onset Alzheimer's Disease' was provided through the Division of Neuroscience, NIA. The Genetic Consortium for Late Onset Alzheimer's Disease (study accession number: phs000168.v1.p1) includes a genome-wide association study funded as part of the Division of Neuroscience, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Genetic Consortium for Late Onset Alzheimer's Disease. Funding support for the 'CIDR Visceral Adiposity Study' (study accession number: phs000169.v1.p1) was provided through the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. The CIDR Visceral Adiposity Study includes a genome-wide association study funded as part of the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Heath ABC Study Investigators. Funding support for the Personalized Medicine Research Project (PMRP) was provided through a cooperative agreement (U01HG004608) with the National Human Genome Research Institute (NHGRI), with additional funding from the National Institute for General Medical Sciences (NIGMS). The samples used for PMRP analyses were obtained with funding from Marshfield Clinic, Health Resources Service Administration Office of Rural Health Policy grant number D1A RH00025 and Wisconsin Department of Commerce Technology Development Fund contract number TDF FYO10718. Funding support for genotyping, which was performed at Johns Hopkins University, was provided by the NIH (U01HG004438). Assistance with phenotype harmonization and genotype cleaning was provided by the eMERGE Administrative Coordinating Center (U01HG004603) and the National Center for Biotechnology Information (NCBI). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000170.v1.p1. NR 46 TC 157 Z9 159 U1 2 U2 29 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 2011 VL 43 IS 7 BP 699 EP U125 DI 10.1038/ng.859 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 784UV UT WOS:000292184600017 PM 21685912 ER PT J AU Johnson, N Li, YC Walton, ZE Cheng, KA Li, DA Rodig, SJ Moreau, LA Unitt, C Bronson, RT Thomas, HD Newell, DR D'Andrea, AD Curtin, NJ Wong, KK Shapiro, GI AF Johnson, Neil Li, Yu-Chen Walton, Zandra E. Cheng, Katherine A. Li, Danan Rodig, Scott J. Moreau, Lisa A. Unitt, Christine Bronson, Roderick T. Thomas, Huw D. Newell, David R. D'Andrea, Alan D. Curtin, Nicola J. Wong, Kwok-Kin Shapiro, Geoffrey I. TI Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition SO NATURE MEDICINE LA English DT Article ID DNA-DAMAGE; POLY(ADP-RIBOSE) POLYMERASE; LUNG-CANCER; CELL-CYCLE; HOMOLOGOUS RECOMBINATION; REPAIR; PHOSPHORYLATION; TUMORS; CISPLATIN; LINES AB Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclindependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA-wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers. C1 [Johnson, Neil; Li, Yu-Chen; Walton, Zandra E.; Cheng, Katherine A.; Li, Danan; Wong, Kwok-Kin; Shapiro, Geoffrey I.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rodig, Scott J.; Unitt, Christine; Bronson, Roderick T.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Johnson, Neil; Wong, Kwok-Kin; Shapiro, Geoffrey I.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Rodig, Scott J.; Unitt, Christine] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Moreau, Lisa A.; D'Andrea, Alan D.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Moreau, Lisa A.; D'Andrea, Alan D.] Childrens Hosp, Dept Pediat, Boston, MA 02115 USA. [Thomas, Huw D.; Newell, David R.; Curtin, Nicola J.] Newcastle Univ, No Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Wong, Kwok-Kin] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA USA. RP Shapiro, GI (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM geoffrey_shapiro@dfci.harvard.edu OI wong, kwok kin/0000-0001-6323-235X FU US National Institutes of Health (NIH) [R01 CA090687, P50 CA089393]; Career Development Award; Susan G. Komen Post-Doctoral Fellowship [KG080773]; NIH [P50 CA090578, U01 CA141576, R01 AG2400401, R01 CA122794, R01 CA140594, 1RC2 CA147940-01]; Cancer Research U.K.; Uniting Against Lung Cancer grant FX This work was supported by US National Institutes of Health (NIH) Grants R01 CA090687 (G.I.S.), P50 CA089393 (Dana-Farber/Harvard Cancer Center (DF/HCC) Specialized Program of Research Excellence (SPORE) in Breast Cancer), including Developmental Project Funding (G.I.S.) and a Career Development Award (N.J.), as well as Susan G. Komen Post-Doctoral Fellowship Award KG080773 (N.J., G.I.S. and N.J. C.) and NIH Grant P50 CA090578 (DF/HCC SPORE in Lung Cancer) (G.I.S. and K.-K.W.). H.D.T., N.J.C. and D.R.N. were supported by a Programme Grant from Cancer Research U.K. K.-K. W. was also supported by a Uniting Against Lung Cancer grant and NIH grants U01 CA141576, R01 AG2400401, R01 CA122794, R01 CA140594 and 1RC2 CA147940-01. We thank M. Arora and J.D. Parvin for assistance with preliminary experiments; D. Skinner for technical assistance with tissue block and slide preparation; members of the Confocal and Light Microscopy Core Facility at the Dana-Farber Cancer Institute for technical assistance with acquisition of confocal microscopy images; M. Jasin (Memorial Sloan-Kettering Cancer Center) for U2OS pDR-GFP cells; and K. Hook, D. Madren and Z. Hostomsky of Pfizer for AG14361, AG014699 (PF-01367338) and AG024322 (PF-00176275). NR 36 TC 101 Z9 101 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2011 VL 17 IS 7 BP 875 EP U257 DI 10.1038/nm.2377 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 789FT UT WOS:000292500800043 PM 21706030 ER PT J AU Gather, MC Yun, SH AF Gather, Malte C. Yun, Seok Hyun TI Single-cell biological lasers SO NATURE PHOTONICS LA English DT Article ID GREEN FLUORESCENT PROTEIN; STIMULATED-EMISSION; MONOMERIC RED; MICROSCOPY; EXPRESSION; MUTANTS AB Since their invention some 50 years ago(1), lasers have made a tremendous impact on modern science and technology. Nevertheless, lasing has so far relied on artificial or engineered optical gain materials, such as doped crystals, semiconductors, synthetic dyes and purified gases(2,3). Here, we show that fluorescent proteins(4,5) in cells are a viable gain medium for optical amplification, and report the first successful realization of biological cell lasers based on green fluorescent protein (GFP). We demonstrate in vitro protein lasers using recombinant GFP solutions and introduce a laser based on single live cells expressing GFP. On optical pumping with nanojoule/nanosecond pulses, individual cells in a high-Q microcavity produce bright, directional and narrowband laser emission, with characteristic longitudinal and transverse modes. Lasing cells remained alive even after prolonged lasing action. Light amplification and lasing from and within biological systems pave the way to new forms of intracellular sensing, cytometry and imaging. C1 [Gather, Malte C.; Yun, Seok Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Gather, Malte C.; Yun, Seok Hyun] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02114 USA. [Yun, Seok Hyun] Korea Adv Inst Sci & Technol, WCU Grad Sch Nanosci & Technol, Taejon 305701, South Korea. [Yun, Seok Hyun] Harvard MIT Hlth Sci & Technol, Cambridge, MA USA. RP Yun, SH (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 55 Fruit St, Boston, MA 02114 USA. EM syun@hms.harvard.edu OI Gather, Malte/0000-0002-4857-5562 FU US National Science Foundation [ECCS-1101947]; Korea National Research Foundation [R31-2008-000-10071-0]; Bullock-Wellman Fellowship FX The authors thank Ji-Joon Song (KAIST, Korea) for providing recombinant eGFP solutions, S. Sassi and B. Seed (Harvard Medical School) for the donation of 293ETN cells and support with eGFP transfection, U. Shama for initial testing of a fluorescent protein and W. Farinelli for setting up the OPO system. This work was supported in part by the US National Science Foundation (ECCS-1101947) and the Korea National Research Foundation (R31-2008-000-10071-0). M.C.G. acknowledges financial support from the Bullock-Wellman Fellowship. NR 28 TC 104 Z9 104 U1 18 U2 113 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1749-4885 J9 NAT PHOTONICS JI Nat. Photonics PD JUL PY 2011 VL 5 IS 7 BP 406 EP 410 DI 10.1038/NPHOTON.2011.99 PG 5 WC Optics; Physics, Applied SC Optics; Physics GA 785PI UT WOS:000292240600014 ER PT J AU Wilson, BG Roberts, CWM AF Wilson, Boris G. Roberts, Charles W. M. TI SWI/SNF nucleosome remodellers and cancer SO NATURE REVIEWS CANCER LA English DT Review ID TUMOR-SUPPRESSOR GENE; EMBRYONIC STEM-CELLS; MALIGNANT RHABDOID TUMORS; TRITHORAX GROUP PROTEINS; SOFT-TISSUE SARCOMAS; TARGETING CYCLIN D1; SWI-SNF COMPLEX; LUNG-CANCER; ONCOGENIC TRANSFORMATION; FAMILIAL SCHWANNOMATOSIS AB SWI/SNF chromatin remodelling complexes use the energy of ATP hydrolysis to remodel nucleosomes and to modulate transcription. Growing evidence indicates that these complexes have a widespread role in tumour suppression, as inactivating mutations in several SWI/SNF subunits have recently been identified at a high frequency in a variety of cancers. However, the mechanisms by which mutations in these complexes drive tumorigenesis are unclear. In this Review we discuss the contributions of SWI/SNF mutations to cancer formation, examine their normal functions and discuss opportunities for novel therapeutic interventions for SWI/SNF-mutant cancers. C1 [Wilson, Boris G.; Roberts, Charles W. M.] Harvard Univ, Childrens Hosp Boston, Dana Farber Canc Inst,Dept Pediat, Dept Pediat Oncol,Div Hematol Oncol,Med Sch, Boston, MA 02115 USA. RP Roberts, CWM (reprint author), Harvard Univ, Childrens Hosp Boston, Dana Farber Canc Inst,Dept Pediat, Dept Pediat Oncol,Div Hematol Oncol,Med Sch, Boston, MA 02115 USA. EM Charles_Roberts@dfci.harvard.edu NR 141 TC 402 Z9 413 U1 8 U2 76 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD JUL PY 2011 VL 11 IS 7 BP 481 EP 492 DI 10.1038/nrc3068 PG 12 WC Oncology SC Oncology GA 782RP UT WOS:000292028300013 PM 21654818 ER PT J AU Ribas, A Flaherty, KT AF Ribas, Antoni Flaherty, Keith T. TI BRAF targeted therapy changes the treatment paradigm in melanoma SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID SMALL-CELL LUNG; CHRONIC MYELOID-LEUKEMIA; RAF INHIBITOR PLX4032; ONCOGENIC BRAF; METASTATIC MELANOMA; ACQUIRED-RESISTANCE; CUTANEOUS MELANOMA; SIGNALING PATHWAY; TYROSINE KINASE; HUMAN CANCER AB After decades of stagnation, recent therapeutic advances in melanoma seem on the horizon. The discovery of the genetic underpinnings of this historically refractory disease has exposed potential targets for therapy, BRAF mutations being principal among them. In the 8 years following the discovery of BRAF mutations in 50-60% of advanced melanomas, only recently have potent and selective inhibitors of this intracellular signaling molecule shown efficacy from early clinical testing. Vemurafenib (PLX4032) and GSK2118436, two orally available and well tolerated agents are on the verge of transforming the landscape of melanoma therapy based on the promising results of their respective phase I, II, and III trials. C1 [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Ribas, Antoni] Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. [Ribas, Antoni] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. RP Flaherty, KT (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM kflaherty@partners.org NR 61 TC 125 Z9 129 U1 2 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD JUL PY 2011 VL 8 IS 7 BP 426 EP 433 DI 10.1038/nrclinonc.2011.69 PG 8 WC Oncology SC Oncology GA 784WG UT WOS:000292188600009 PM 21606968 ER PT J AU de Gelder, B van Honk, J Tamietto, M AF de Gelder, Beatrice van Honk, Jack Tamietto, Marco TI Emotion in the brain: of low roads, high roads and roads less travelled SO NATURE REVIEWS NEUROSCIENCE LA English DT Letter ID AMYGDALA; EXPRESSIONS C1 [de Gelder, Beatrice; Tamietto, Marco] Tilburg Univ, Cognit & Affect Neurosci Lab, NL-5000 LE Tilburg, Netherlands. [de Gelder, Beatrice] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [van Honk, Jack] Univ Utrecht, Dept Expt Psychol, Utrecht, Netherlands. [van Honk, Jack] Univ Cape Town, Dept Psychiat & Mental Hlth, ZA-7700 Rondebosch, South Africa. RP de Gelder, B (reprint author), Tilburg Univ, Cognit & Affect Neurosci Lab, NL-5000 LE Tilburg, Netherlands. EM degelder@uvt.nl; M.Tamietto@uvt.nl OI Tamietto, Marco/0000-0002-8815-8499 NR 11 TC 23 Z9 23 U1 6 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD JUL PY 2011 VL 12 IS 7 DI 10.1038/nrn2920-c1 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 781MW UT WOS:000291937900015 PM 21673722 ER PT J AU Bednarz, B Chen, G Paganetti, H Han, B Ding, AP Xu, XG AF Bednarz, Bryan Chen, Gty Paganetti, Harald Han, Bin Ding, Aiping Xu, X. George TI COMPARISON OF PARTICLE-TRACKING FEATURES IN GEANT4 AND MCNPX CODES FOR APPLICATIONS IN MAPPING OF PROTON RANGE UNCERTAINTY SO NUCLEAR TECHNOLOGY LA English DT Article; Proceedings Paper CT 16th Biennial Topical Meeting of the American-Nuclear-Society-(ANS)-and-Radiation-Protection-and-Shielding-Di vision-(RPSD) CY APR, 2010 CL Univ Nevada, Las Vegas, NV SP Amer Nucl Soc, Radiation Protection Shielding Div HO Univ Nevada DE Monte Carlo; proton imaging; multiple coulomb scattering AB The accuracy of proton therapy is partially limited by uncertainties that result from changing pathological conditions in the patient such as tumor motion and shrinkage. These uncertainties can be minimized with the help of a time-resolved range telescope. Monte Carlo methods can help improve the performance of range telescopes by tracking proton interactions on a particle-by-particle basis thus broadening our understanding on the behavior of protons within the patient and the detector. This paper compared the proton multiple coulomb scattering algorithms in the Monte Carlo codes MCNPX and Geant4 to well-established scattering theories. We focus only on beam energies associated with proton imaging. Despite slight discrepancies between scattering algorithms, both codes appear to be capable of providing useful particle-tracking information for applications such as the proton range telescope. C1 [Bednarz, Bryan; Chen, Gty; Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Han, Bin; Ding, Aiping; Xu, X. George] Rensselaer Polytech Inst, Troy, NY 12180 USA. RP Bednarz, B (reprint author), Univ Wisconsin, Dept Med Phys, Madison, WI 53705 USA. EM bbednarz2@wisc.edu RI DING, AIPING/E-8338-2011; OI Han, Bin/0000-0001-8179-5762 FU NCI NIH HHS [P01 CA021239-33, P01 CA021239, R01 CA140735] NR 8 TC 1 Z9 1 U1 0 U2 0 PU AMER NUCLEAR SOC PI LA GRANGE PK PA 555 N KENSINGTON AVE, LA GRANGE PK, IL 60526 USA SN 0029-5450 J9 NUCL TECHNOL JI Nucl. Technol. PD JUL PY 2011 VL 175 IS 1 SI SI BP 2 EP 5 PG 4 WC Nuclear Science & Technology SC Nuclear Science & Technology GA 784PS UT WOS:000292169900002 PM 22389531 ER PT J AU Depauw, N Danto, S Bednarz, B Paganetti, H Fink, Y Seco, J AF Depauw, Nicolas Danto, Sylvain Bednarz, Bryan Paganetti, Harald Fink, Yoel Seco, Joao TI PRELIMINARY STUDY OF PROTON RADIOGRAPHY IMAGING QUALITIES USING GEANT4 MONTE CARLO SIMULATIONS SO NUCLEAR TECHNOLOGY LA English DT Article; Proceedings Paper CT 16th Biennial Topical Meeting of the American-Nuclear-Society-(ANS)-and-Radiation-Protection-and-Shielding-Di vision-(RPSD) CY APR, 2010 CL Univ Nevada, Las Vegas, NV SP Amer Nucl Soc, Radiation Protection Shielding Div HO Univ Nevada DE radiography; proton therapy; imaging ID THERAPY; TOOLKIT AB Proton radiography imaging qualities have been studied using Monte Carlo simulations. A specific phantom, made of different common tissues, was implemented for simulations using the Massachusetts General Hospital treatment proton beam, pure 230- and 490-MeV proton beams, and a pure 100-keV X-ray beam. Along with spatial resolution, the signal-to-noise ratio and the contrast-to-noise ratio were specified and compared for each tissue type and geometry, using filtered radiographs taking into account only primary proton interactions, both primary and secondary proton interactions, and both contributions while performing angular and energetic cuts. This work particularly highlights the faculty for proton radiography to image both low- and high-density tissues. This could play an important role in diagnosing specific tumor types, such as lung cancer, for which conventional radiography operates poorly. C1 [Depauw, Nicolas; Danto, Sylvain; Bednarz, Bryan; Paganetti, Harald; Fink, Yoel; Seco, Joao] Massachusetts Gen Hosp, Boston, MA 02116 USA. RP Depauw, N (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02116 USA. EM ndepauw@partners.org RI Seco, Joao/J-4451-2012; Danto, Sylvain/D-2259-2015 NR 11 TC 1 Z9 1 U1 0 U2 2 PU AMER NUCLEAR SOC PI LA GRANGE PK PA 555 N KENSINGTON AVE, LA GRANGE PK, IL 60526 USA SN 0029-5450 J9 NUCL TECHNOL JI Nucl. Technol. PD JUL PY 2011 VL 175 IS 1 SI SI BP 6 EP 10 PG 5 WC Nuclear Science & Technology SC Nuclear Science & Technology GA 784PS UT WOS:000292169900003 ER PT J AU Seco, J Depauw, N Danto, S Paganeti, H Fink, Y AF Seco, Joao Depauw, Nick Danto, Sylvain Paganeti, Harald Fink, Yoel TI QUALITATIVE EVALUATION OF PROTON RADIOGRAPHY FOR VIEWING DENSITY DIFFERENCES IN LUNG TUMORS: A MONTE CARLO STUDY SO NUCLEAR TECHNOLOGY LA English DT Article; Proceedings Paper CT 16th Biennial Topical Meeting of the American-Nuclear-Society-(ANS)-and-Radiation-Protection-and-Shielding-Di vision-(RPSD) CY APR, 2010 CL Univ Nevada, Las Vegas, NV SP Amer Nucl Soc, Radiation Protection Shielding Div HO Univ Nevada DE proton radiography; proton therapy; Monte Carlo AB Proton radiography is an imaging technique with potential application in proton radiation therapy. The ability of a proton radiograph to differentiate anatomical features in the thoracic region, such as heart, lung, rib cage, shoulder, etc., was qualitatively investigated using Monte Carlo simulations. A patient with a stage IIIA non-small cell lung cancer tumor located in the right upper lobe and mediastinum was considered for this study. The GEANT4 Monte Carlo toolkit was used to simulate proton transport through a proton nozzle and through the lung area of the patient, registering in a phase-space file the entry and exit energy, position, and motion direction of each proton. The Monte Carlo simulation ran a total of 10 million histories with the highest deliverable energy of 235 MeV at the Francis H. Burr Proton Therapy Center. The proton radiograph was then generated independently of the Monte Carlo simulation, using a numerical algorithm to input the proton position, direction of motion, and energy kept in the entry and exit phase-space files. The proton radiograph was compared to the standard portal X-ray image for tissue and tumor contrast, and for visibility relative to the background lung tissue. The preliminary results with GEANT4 showed that the proton radiography can produce images with good spatial resolution and excellent soft tissue contrast, resulting in better tumor edge localization within a soft tissue background region such as the lung. C1 [Seco, Joao; Depauw, Nick; Paganeti, Harald] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Seco, Joao; Depauw, Nick; Paganeti, Harald] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Danto, Sylvain; Fink, Yoel] MIT, Elect Res Lab, Cambridge, MA 02139 USA. RP Seco, J (reprint author), Harvard Univ, Sch Med, 30 Fruit St, Boston, MA 02114 USA. EM jseco@partners.org RI Seco, Joao/J-4451-2012; Danto, Sylvain/D-2259-2015 NR 14 TC 1 Z9 1 U1 0 U2 1 PU AMER NUCLEAR SOC PI LA GRANGE PK PA 555 N KENSINGTON AVE, LA GRANGE PK, IL 60526 USA SN 0029-5450 J9 NUCL TECHNOL JI Nucl. Technol. PD JUL PY 2011 VL 175 IS 1 SI SI BP 27 EP 31 PG 5 WC Nuclear Science & Technology SC Nuclear Science & Technology GA 784PS UT WOS:000292169900007 ER PT J AU Han, B Xu, XG Davidson, M Bednarz, B Sharp, GC Chen, GTY AF Han, Bin Xu, X. George Davidson, Matt Bednarz, Bryan Sharp, Gregory C. Chen, George T. Y. TI MONTE CARLO SIMULATION OF PERFORMANCE OF A TIME-RESOLVED RANGE TELESCOPE USING SELECTED IMAGE QUALITY ASSURANCE PHANTOMS SO NUCLEAR TECHNOLOGY LA English DT Article; Proceedings Paper CT 16th Biennial Topical Meeting of the American-Nuclear-Society-(ANS)-and-Radiation-Protection-and-Shielding-Di vision-(RPSD) CY APR, 2010 CL Univ Nevada, Las Vegas, NV SP Amer Nucl Soc, Radiation Protection Shielding Div HO Univ Nevada DE proton radiography; Monte Carlo; range telescope AB The superior dose conformation from protons is attributed to the Bragg peak near the end of the proton range. One challenge in proton cancer treatment is to assess the proton range fluctuations due to organ motion such as respiration. A time-resolved proton range telescope that measures coordinates, direction cosines, and the residual range of each proton can be useful in detecting and quantifying variations in radiological path length during the course of proton radiotherapy. In this paper, the Monte Carlo N-Particle eXtended (MCNPX) code was used to simulate the range telescope and study the image quality. To validate the MCNPX simulations, a simulated proton radiograph was compared with an experimentally acquired film for the same phantom. In addition, four quality assurance phantoms were simulated to investigate the quality of simulated proton radiography. Finally, the methods were applied to one phase of a patient four-dimensional computed tomography (4DCT) data set for proton radiography simulations. The results indicate that Monte Carlo simulations offer data that are useful in analyzing image spatial and temporal resolutions. Simulations show that it is useful to quantify the tumor position changes due to respiration by using a proton telescope. C1 [Han, Bin; Xu, X. George] Rensselaer Polytech Inst, Program Nucl Engn & Engn Phys, Troy, NY 12180 USA. [Davidson, Matt] MIT, Dept Nucl Sci & Engn, Cambridge, MA 02139 USA. [Bednarz, Bryan; Sharp, Gregory C.; Chen, George T. Y.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02140 USA. RP Han, B (reprint author), Rensselaer Polytech Inst, Program Nucl Engn & Engn Phys, Troy, NY 12180 USA. EM GCHEN@partners.org OI Han, Bin/0000-0001-8179-5762 NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER NUCLEAR SOC PI LA GRANGE PK PA 555 N KENSINGTON AVE, LA GRANGE PK, IL 60526 USA SN 0029-5450 J9 NUCL TECHNOL JI Nucl. Technol. PD JUL PY 2011 VL 175 IS 1 SI SI BP 58 EP 62 PG 5 WC Nuclear Science & Technology SC Nuclear Science & Technology GA 784PS UT WOS:000292169900012 ER PT J AU Askenazi, M Linial, M AF Askenazi, Manor Linial, Michal TI ARISTO: ontological classification of small molecules by electron ionization-mass spectrometry SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SPECTRAL LIBRARY; COMPOUND IDENTIFICATION; METABOLITES; SEARCH AB Gas chromatography-mass spectrometry (GC-MS) acquisitions routinely yield hundreds to thousands of Electron Ionization (EI) mass spectra. The chemical identification of these spectra typically involves a search protocol that seeks an exact match to a reference spectrum. Reference spectra are found in comprehensive libraries of small molecule EI spectra curated by commercial and public entities. We developed ARISTO (Automatic Reduction of Ion Spectra To Ontology), a webtool, which provides information regarding the general chemical nature of the compound underlying an input EI mass spectrum. Importantly, ARISTO can provide such annotation without necessitating an exact match to a specific compound. ARISTO provides assignments to a subset of the ChEBI (Chemical Entities of Biological Interest) dictionary, an ontology, which aims to cover biologically relevant small molecules. Our system takes as input a mass spectrum represented as a series of mass and intensity pairs; the system returns a graphical representation of the supported ontology as well as a detailed table of suggested annotations along with their associated statistical evidence. ARISTO is accessible at this URL: http://www.ionspectra.org/aristo. C1 [Askenazi, Manor; Linial, Michal] Hebrew Univ Jerusalem, Sudarsky Ctr Computat Biol, Dept Biol Chem, IL-91905 Jerusalem, Israel. [Askenazi, Manor] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. RP Askenazi, M (reprint author), Hebrew Univ Jerusalem, Sudarsky Ctr Computat Biol, Dept Biol Chem, IL-91905 Jerusalem, Israel. EM manoras@cs.huji.ac.il FU Binational Science Foundation (BSF) [2007-219]; Prospects consortium [EU FRVII] FX Binational Science Foundation (BSF) (2007-219); Prospects consortium [EU FRVII]. Funding for open access charge: Prospects consortium (EU FRVII). NR 12 TC 5 Z9 5 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2011 VL 39 SU 2 BP W505 EP W510 DI 10.1093/nar/gkr403 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 786RJ UT WOS:000292325300082 PM 21622952 ER PT J AU Ingram, KH Lara-Castro, C Gower, BA Makowsky, R Allison, DB Newcomer, BR Munoz, AJ Beasley, TM Lawrence, JC Lopez-Ben, R Rigsby, DY Garvey, WT AF Ingram, Katherine H. Lara-Castro, Cristina Gower, Barbara A. Makowsky, Robert Allison, David B. Newcomer, Bradley R. Munoz, A. Julian Beasley, T. Mark Lawrence, Jeannine C. Lopez-Ben, Robert Rigsby, Dana Y. Garvey, W. Timothy TI Intramyocellular Lipid and Insulin Resistance: Differential Relationships in European and African Americans SO OBESITY LA English DT Article ID TYPE-2 DIABETIC SUBJECTS; VISCERAL ADIPOSE-TISSUE; METABOLIC SYNDROME; SKELETAL-MUSCLE; WEIGHT-LOSS; ETHNIC-DIFFERENCES; ABDOMINAL FAT; WHITE WOMEN; SENSITIVITY; OBESITY AB Insulin resistance has been associated with the accumulation of fat within skeletal muscle fibers as intramyocellular lipid (IMCL). Here, we have examined in a cross-sectional study the interrelationships among IMCL, insulin sensitivity, and adiposity in European Americans (EAs) and African Americans (AAs). In 43 EA and 43 AA subjects, we measured soleus IMCL content with proton-magnetic resonance spectroscopy, insulin sensitivity with hyperinsulinemic-euglycemic clamp, and body composition with dual-energy X-ray absorptiometry. The AA and EA subgroups had similar IMCL content, insulin sensitivity, and percent fat, but only in EA was IMCL correlated with insulin sensitivity (r = -0.47, P < 0.01), BMI (r = 0.56, P < 0.01), percent fat (r = 0.35, P < 0.05), trunk fat (r = 0.47, P < 0.01), leg fat (r = 0.40, P < 0.05), and waist and hip circumferences (r = 0.54 and 0.55, respectively, P < 0.01). In a multiple regression model including IMCL, race, and a race by IMCL interaction, the interaction was found to be a significant predictor (t = 1.69, DF = 1, P = 0.0422). IMCL is related to insulin sensitivity and adiposity in EA but not in AA, suggesting that IMCL may not function as a pathophysiological factor in individuals of African descent. These results highlight ethnic differences in the determinants of insulin sensitivity and in the pathogenesis of the metabolic syndrome trait cluster. C1 [Ingram, Katherine H.; Makowsky, Robert; Allison, David B.; Beasley, T. Mark] Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. [Lara-Castro, Cristina; Gower, Barbara A.; Munoz, A. Julian; Lawrence, Jeannine C.; Rigsby, Dana Y.; Garvey, W. Timothy] Univ Alabama, Dept Nutr Sci, Birmingham, AL 35294 USA. [Lara-Castro, Cristina; Munoz, A. Julian] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Newcomer, Bradley R.] Univ Alabama, Dept Clin & Diagnost Sci, Birmingham, AL USA. [Lopez-Ben, Robert] Univ Alabama, Dept Radiol, Birmingham, AL USA. [Garvey, W. Timothy] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Ingram, KH (reprint author), Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. EM khingram@uab.edu OI Allison, David/0000-0003-3566-9399 FU National Institutes of Health [DK-038765, DK-083562, PO1 HL-55782]; T32 training grant [HL-007457, HL-072757]; Department of Veterans Affairs; UAB Center for Clinical and Translational Science [UL1 RR025777]; Diabetes Research and Training Center [P60 DK079626] FX We thank the research volunteers for their participation in this study. This work was supported from grants from the National Institutes of Health (DK-038765, DK-083562, PO1 HL-55782), the T32 training grant (HL-007457) entitled "Mechanisms of Hypertension and Cardiovascular Diseases" (PI: S. Oparil), the T32 training grant (HL-072757) entitled "UAB Statistical Genetics Post-Doctoral Training Program" (PI: D. B. A.), and by the Merit Review program of the Department of Veterans Affairs. We also acknowledge support from the UAB Center for Clinical and Translational Science (UL1 RR025777), and core facility support from the Clinical Nutrition Research Unit (P30-DK56336), and the Diabetes Research and Training Center (P60 DK079626). We further acknowledge Dr. Jan den Hollander at UAB for his assistance with IMCL measurements. NR 40 TC 24 Z9 24 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD JUL PY 2011 VL 19 IS 7 BP 1469 EP 1475 DI 10.1038/oby.2011.45 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 784CU UT WOS:000292132300022 PM 21436797 ER PT J AU Livhits, M Mercado, C Yermilov, I Parikh, JA Dutson, E Mehran, A Ko, CY Gibbons, MM AF Livhits, Masha Mercado, Cheryl Yermilov, Irina Parikh, Janak A. Dutson, Erik Mehran, Amir Ko, Clifford Y. Gibbons, Melinda Maggard TI Patient behaviors associated with weight regain after laparoscopic gastric bypass SO OBESITY RESEARCH & CLINICAL PRACTICE LA English DT Article DE Bariatric surgery; Weight regain; Behavioral factors ID TERM-FOLLOW-UP; BARIATRIC SURGERY; PSYCHIATRIC-DISORDERS; MORBID-OBESITY; IMPACT; PARTICIPATION; QUESTIONNAIRE; PREDICTORS; ATTENDANCE; OUTCOMES AB Background: Patients undergoing gastric bypass lose substantial weight, but 20% regain weight starting at 2 years after surgery. Our objective was to identify behavioral predictors of weight regain after laparoscopic Roux-en-Y gastric bypass (LRYGB). Methods: We retrospectively surveyed 197 patients for factors predictive of weight regain (>= 15% from lowest weight to weight at survey completion). Consecutive patients who had bariatric surgery from 1/2003 through 12/2008 were identified from an existing database. Response rate was 76%, with 150 patients completing the survey. Results: Follow-up after LRYGB was 45.0+/-12.7 months, 22% of patients had weight regain. After controlling for age, gender, and follow-up time, factors associated with weight regain included low physical activity (odds ratio (OR) 6.92, P=0.010), low self-esteem (OR 6.86, P=0.008), and Eating Inventory Disinhibition (OR 1.30, P=0.029). Conclusions: Physical activity, self-esteem, and maladaptive eating may be associated with weight regain after LRYGB. These factors should be addressed in prospective studies of weight loss following bariatric surgery, as they may identify patients at risk for weight regain who may benefit from tailored interventions. C1 [Livhits, Masha; Mercado, Cheryl; Yermilov, Irina; Parikh, Janak A.; Dutson, Erik; Mehran, Amir; Ko, Clifford Y.; Gibbons, Melinda Maggard] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Livhits, Masha; Yermilov, Irina; Parikh, Janak A.; Ko, Clifford Y.; Gibbons, Melinda Maggard] VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA 90073 USA. [Gibbons, Melinda Maggard] Olive View UCLA, Dept Surg, Sylmar, CA 91342 USA. RP Livhits, M (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, 10833 LeConte Ave,72-215 CHS, Los Angeles, CA 90095 USA. EM mlivhits@mednet.ucla.edu FU VA Department of Surgery, Robert Wood Johnson Physician Faculty Scholars Program FX VA Department of Surgery, Robert Wood Johnson Physician Faculty Scholars Program. NR 33 TC 2 Z9 2 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1871-403X J9 OBES RES CLIN PRACT JI Obes. Res. Clin. Pract. PD JUL-SEP PY 2011 VL 5 IS 3 BP E258 EP E265 DI 10.1016/j.orcp.2011.03.004 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 981GU UT WOS:000306955800010 ER PT J AU Berkowitz, LR Peyre, SE Johnson, NR AF Berkowitz, Lori R. Peyre, Sarah E. Johnson, Natasha R. TI Mobilizing Faculty for Simulation SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID OBSTETRIC SIMULATION AB Faculty involvement in simulation training is essential for curriculum development, utilization of their clinical expertise in teaching, and ultimately for validating the importance of the training program. Several barriers to faculty involvement exist, including competing demands on time, the challenges in developing curriculum, and teaching using simulation. Through our experiences in implementing a widely expansive program, we have identified several areas to encourage and engage faculty. Further discussion as a medical education community is needed to support the interaction and involvement of our faculty to support and promote ongoing simulation education. (Obstet Gynecol 2011;118:161-3) DOI: 10.1097/AOG.0b013e31821fd34d C1 [Berkowitz, Lori R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, STRATUS Ctr Med Simulat, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Berkowitz, LR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Obstet & Gynecol Serv, 55 Fruit St,YAW 4Boston, Boston, MA 02114 USA. EM lberkowitz@partners.org NR 12 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUL PY 2011 VL 118 IS 1 BP 161 EP 163 DI 10.1097/AOG.0b013e31821fd34d PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 780SY UT WOS:000291880600022 PM 21691175 ER PT J AU Cunnane, ME Hamberg, L Curtin, HD Goldstein, AJ Merchant, SN Halpin, CF AF Cunnane, Mary Elizabeth Hamberg, Leena Curtin, Hugh D. Goldstein, Allan J. Merchant, Saumil N. Halpin, Chris F. TI Radiologic and Audiologic Evidence of the Location of an Intracochlear Mass SO OTOLOGY & NEUROTOLOGY LA English DT Editorial Material C1 [Cunnane, Mary Elizabeth; Hamberg, Leena; Curtin, Hugh D.; Goldstein, Allan J.; Merchant, Saumil N.; Halpin, Chris F.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Cunnane, ME (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Mary_Beth_Cunnane@meei.harvard.edu NR 3 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD JUL PY 2011 VL 32 IS 5 BP E34 EP E35 DI 10.1097/MAO.0b013e3181ff73e1 PG 2 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 778DK UT WOS:000291679800002 PM 21068689 ER PT J AU Brunelle, CL Mulgrew, JA AF Brunelle, Cheryl L. Mulgrew, Jackie A. TI Exercise for Intermittent Claudication SO PHYSICAL THERAPY LA English DT Article ID SUPERVISED EXERCISE; REHABILITATION; MANAGEMENT; THERAPY; TRIAL AB << LEAP > highlights the findings and application of Cochrane reviews and other evidence pertinent to the practice of physical therapy. The Cochrane Library is a respected source of reliable evidence related to health care. Cochrane systematic reviews explore the evidence for and against the effectiveness and appropriateness of interventions-medications, surgery, education, nutrition, exercise-and the evidence for and against the use of diagnostic tests for specific conditions. Cochrane reviews are designed to facilitate the decisions of clinicians, patients, and others in health care by providing a careful review and interpretation of research studies published in the scientific literature.(1) Each article in this PTJ series summarizes a Cochrane review or other scientific evidence on a single topic and presents clinical scenarios based on real patients or programs to illustrate how the results of the review can be used to directly inform clinical decisions. This article focuses on an older patient with intermittent claudication. Could a supervised exercise program increase the distance he is able to walk before stopping because of pain? C1 [Brunelle, Cheryl L.; Mulgrew, Jackie A.] Massachusetts Gen Hosp, Phys Therapy Serv, Boston, MA 02114 USA. RP Brunelle, CL (reprint author), Massachusetts Gen Hosp, Phys Therapy Serv, 15 Parkman St, Boston, MA 02114 USA. EM cbrunelle@partners.org NR 16 TC 3 Z9 3 U1 0 U2 2 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD JUL PY 2011 VL 91 IS 7 BP 997 EP 1002 DI 10.2522/ptj.20100419 PG 6 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 786FL UT WOS:000292288700002 PM 21724596 ER PT J AU Evans, CT Rogers, TJ Burns, SP Lopansri, B Weaver, FM AF Evans, Charlesnika T. Rogers, Thea J. Burns, Stephen P. Lopansri, Bert Weaver, Frances M. TI Knowledge and Use of Antimicrobial Stewardship Resources by Spinal Cord Injury Providers SO PM&R LA English DT Article ID BLOOD-STREAM INFECTIONS; HEALTH-CARE EPIDEMIOLOGY; INSTITUTIONAL PROGRAM; REHABILITATION UNIT; AMERICA GUIDELINES; DISEASES SOCIETY; RESISTANCE; MORTALITY; PHYSICIAN; VETERANS AB Objective: To assess the knowledge and the use of antimicrobial stewardship resources, such as hospital antibiograms and infectious disease consultants, by spinal cord injury or disorder (SCI/D) providers. Design and Setting: Anonymous Internet-based, cross-sectional survey. Participants: A total of 314 SCI/D physicians, nurse practitioners, and physician assistants who prescribe antibiotics were invited to complete a survey. Main Outcome Measurements: Knowledge of and behaviors related to antibiograms and infectious disease (ID) consults. Results: A total of 118 providers (80 physicians, 20 nurse practitioners, 18 physician assistants) completed the survey (37.6% response rate). Approximately one-third of respondents indicated that they did not have access to (11.0%) or were unsure of (28.0%) the existence of facility antibiograms. Half of the providers indicated that they never used antibiograms to determine treatment for their SCI/D patients. Respondent factors associated with viewing facility antibiograms were older age, employment at SCI/D specialty centers, a longer duration since completion of training, and years of SCI/D patient care. Nearly all respondents (95%) indicated that they believed that improving access to antibiotic prescribing data or antibiograms would reduce antibiotic resistance. More than one-third reported that they never or seldom used ID consults. Conclusions: A significant portion of SCI/D providers who prescribe antibiotics do not have access to facility antibiograms or are unaware of their existence and thus could not use them for determining antibiotic treatment. Interventions could include formal education of providers on how to access antibiograms and the use of ID physicians as a resource, as well as providing technologic support, such as electronic facility-level antibiograms as part of the medical record system, which can be easily identified if a provider is making a decision on an antibiotic. PM R 2011;3:619-623 C1 [Evans, Charlesnika T.] Edward J Hines Jr VA Hosp 151H, Ctr Management Complex Chron Care, Hines, IL 60141 USA. [Evans, Charlesnika T.] Edward J Hines Jr VA Hosp 151H, Spinal Cord Injury Qual Enhancement Res Initiat, Dept Vet Affairs VA, Hines, IL 60141 USA. [Evans, Charlesnika T.] Northwestern Univ, Inst Healthcare Studies, Feinberg Sch Med, Chicago, IL 60611 USA. [Rogers, Thea J.; Weaver, Frances M.] Edward Hines Jr VA Hosp, Ctr Management Complex Chron Care, Hines, IL USA. [Rogers, Thea J.; Weaver, Frances M.] Edward Hines Jr VA Hosp, Spinal Cord Injury Qual Enhancement Res Initiat, Dept Vet Affairs VA, Hines, IL USA. [Burns, Stephen P.] VA Puget Sound Hlth Care Syst, Spinal Cord Injury Serv, Seattle, WA USA. [Burns, Stephen P.] Univ Washington, Seattle, WA 98195 USA. [Lopansri, Bert; Weaver, Frances M.] Loyola Univ Hlth Syst, Dept Med, Maywood, IL USA. [Lopansri, Bert] Edward Hines Jr VA Hosp, Dept Vet Affairs VA, Infect Dis Serv, Hines, IL USA. RP Evans, CT (reprint author), Edward J Hines Jr VA Hosp 151H, Ctr Management Complex Chron Care, 5th Ave & Roosevelt Rd,POB 5000,Rm D302, Hines, IL 60141 USA. EM Charlesnika.Evans@va.gov FU Department of Veterans Affairs; Office of Research and Development; Health Services Research and Development Service; SCI QUERI [98-000]; Paralyzed Veterans of America Research Foundation [2562] FX Supported by the Department of Veterans Affairs, Office of Research and Development, Health Services Research and Development Service, SCI QUERI (98-000) and the Paralyzed Veterans of America Research Foundation (Project 2562). NR 27 TC 4 Z9 4 U1 0 U2 5 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 2011 VL 3 IS 7 BP 619 EP 623 DI 10.1016/j.pmrj.2011.03.021 PG 5 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 961BC UT WOS:000305437900004 PM 21777860 ER PT J AU Basile, J AF Basile, Jan TI A New Approach to Glucose Control in Type 2 Diabetes: The Role of Kidney Sodium-Glucose Co-transporter 2 Inhibition SO POSTGRADUATE MEDICINE LA English DT Article DE diabetes; hyperglycemia; glucose reabsorption; SGLT2; pharmacotherapy; oral antidiabetics ID TRANSPORTER GENE-EXPRESSION; INADEQUATE GLYCEMIC CONTROL; SELECTIVE SGLT2 INHIBITOR; MICROVASCULAR COMPLICATIONS; THERAPEUTIC TARGET; RENAL GLUCOSURIA; HEALTHY-SUBJECTS; BLOOD-GLUCOSE; DOUBLE-BLIND; URIC-ACID AB Hyperglycemia is a defining characteristic of type 2 diabetes mellitus and is a major risk factor associated with the development of many microvascular complications. There are numerous therapies currently available to treat hyperglycemia, but glycemic control rates remain poor. One potential reason is the decline in beta-cell function over time, which decreases the effectiveness of therapies that rely on insulin action. The kidney occupies a central position in the control of glucose homeostasis by its role in gluconeogenesis and by regulating glucose excretion. Under normal conditions, glucose filtered by the kidney is virtually totally reabsorbed in the proximal tubule by the sodium-glucose co-transporter 2 (SGLT2). Inhibition of SGLT2 is an attractive, insulin-independent target for increasing glucose excretion in the setting of hyperglycemia. A number of SGLT2 inhibitors have been synthesized, and results from preclinical studies have shown that they increase glucose excretion and normalize plasma glucose in diabetic models. Initial clinical data are promising and suggest that SGLT2 inhibitors may be a new therapeutic option for treating type 2 diabetes mellitus. C1 Med Univ S Carolina, Div Gen Internal Med, Seinsheimer Cardiovasc Hlth Program, Ralph H Johnson VA Med Ctr, Charleston, SC 29403 USA. RP Basile, J (reprint author), Med Univ S Carolina, Div Gen Internal Med, Seinsheimer Cardiovasc Hlth Program, Ralph H Johnson VA Med Ctr, 109 Bee St, Charleston, SC 29403 USA. EM basilejn@musc.edu FU Bristol-Myers Squibb; AstraZeneca; National Heart, Lung and Blood Institute (ACCORD and SPRINT) FX Editorial support for the preparation of this manuscript was provided by Richard M. Edwards, PhD, and Janet E. Matsuura, PhD, from Complete Healthcare Communications, Inc., with funding from Bristol-Myers Squibb and AstraZeneca.; Jan Basile, MD has received grant/research support from the National Heart, Lung and Blood Institute (ACCORD and SPRINT). Dr Basile is a consultant for Daiichi-Sankyo, Forest, Novartis, and Takeda, and is on the speakers' bureaus for AstraZeneca, Daiichi-Sankyo, Forest, and Novartis. NR 75 TC 4 Z9 7 U1 0 U2 7 PU JTE MULTIMEDIA PI BERWYN PA 1235 WESTLAKES DR, STE 220, BERWYN, PA 19312 USA SN 0032-5481 J9 POSTGRAD MED JI Postgrad. Med. PD JUL PY 2011 VL 123 IS 4 BP 38 EP 45 DI 10.3810/pgm.2011.07.2302 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 983DO UT WOS:000307098600004 PM 21680987 ER PT J AU Beckley, EH Scibelli, AC Finn, DA AF Beckley, Ethan H. Scibelli, Angela C. Finn, Deborah A. TI Progesterone receptor antagonist CDB-4124 increases depression-like behavior in mice without affecting locomotor ability SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Premenstrual syndrome; Postpartum depression; CDB-4124; Mifepristone; Forced swim test; Progesterone receptors; Allopregnanolone ID FORCED-SWIM TEST; PREMENSTRUAL DYSPHORIC DISORDER; FEMALE RATS; GLUCOCORTICOID-RECEPTOR; GENE-EXPRESSION; SEX-DIFFERENCES; ESTROUS-CYCLE; WISTAR RATS; MIFEPRISTONE; WITHDRAWAL AB Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone's GABA(A) receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role of progesterone receptors. We administered the classic progesterone receptor antagonist mifepristone (RU-38486) and the specific progesterone receptor antagonist CDB-4124 to mice that had been primed with progesterone for five days, and found that both compounds induced FST immobility reliably, robustly, and in a dose-dependent fashion. Although CDB-4124 increased FST immobility, it did not suppress initial activity in a locomotor test. These findings suggest that decreased progesterone receptor activity contributes to depression-like behavior in mice, consistent with the hypothesis that progesterone withdrawal may contribute to the symptoms of premenstrual syndrome or postpartum depression. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Beckley, Ethan H.; Scibelli, Angela C.; Finn, Deborah A.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. [Finn, Deborah A.] Portland VA Med Ctr, Portland, OR 97239 USA. RP Beckley, EH (reprint author), Oregon Hlth & Sci Univ, Dept Behav Neurosci, 3181 SW Sam Jackson Pk Rd,Mail Code L-470, Portland, OR 97239 USA. EM beckleye@ohsu.edu FU National Institutes of Health [AA010760, AA012439, T32-AA07468, F31-MH081560, F31-AA018043]; Department of Veterans Affairs; N.L. Tartar Research Fellowship; American Psychological Foundation/Council of Graduate Departments of Psychology; ARCS Foundation FX Major funding was provided by grants AA010760, AA012439, T32-AA07468, F31-MH081560, and F31-AA018043 from the National Institutes of Health, and a Merit Review Grant from the Department of Veterans Affairs. Additional support was provided by the N.L. Tartar Research Fellowship, the American Psychological Foundation/Council of Graduate Departments of Psychology Graduate Research Scholarship, and by the Nancy and Dodd Fischer Scholarship from the ARCS Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health, the National Institute on Alcohol Abuse and Alcoholism, the National Institutes of Health, or other granting agencies. Granting agencies had no further role in experimental design, implementation, analysis, interpretation, or in any other aspect of the experiments reported currently. NR 63 TC 4 Z9 4 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD JUL PY 2011 VL 36 IS 6 BP 824 EP 833 DI 10.1016/j.psyneuen.2010.11.004 PG 10 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 785OE UT WOS:000292237500007 PM 21163582 ER PT J AU De Yang, F Wang, XQ Liu, XP Zhao, KX Fu, WH Hao, XR Zhang, XL Huang, GS Qu, SC Bai, JS Huang, XF Kosten, TR Zhang, XY AF De Yang, Fu Wang, Xiang Qun Liu, Xiu Ping Zhao, Ke Xin Fu, Wei Hong Hao, Xue Ru Zhang, Xing Li Huang, Guo Shu Qu, Sheng Cai Bai, Jing Shen Huang, Xu Feng Kosten, Thomas R. Zhang, Xiang Yang TI Sex difference in QTc prolongation in chronic institutionalized patients with schizophrenia on long-term treatment with typical and atypical antipsychotics SO PSYCHOPHARMACOLOGY LA English DT Article DE Schizophrenia; Antipsychotics; QT prolongation; Electrocardiography ID TORSADE-DE-POINTES; INTERVAL PROLONGATION; VENTRICULAR REPOLARIZATION; ANTIDEPRESSANT DRUGS; PSYCHIATRIC-PATIENTS; SUDDEN-DEATH; CLOZAPINE; ABNORMALITIES; ASSOCIATION; PARAMETERS AB Objective The rate-corrected electrocardiographic QT (QTc) interval may significantly increase in patients with schizophrenia taking antipsychotics. The objective of this naturalistic study was to assess the prevalence of prolonged QTc interval in a large population of inpatients with chronic schizophrenia and to explore QTc relationship with demographic variables and prescribed treatments. Materials and methods Electrocardiograms were obtained from age-and sex-matched 456 controls and 1,006 inpatients with schizophrenia (male/female= 689/317) taking antipsychotics. QTc prolongation was defined as a mean value of two standard deviations above the controls. The adjusted relative risk was calculated using logistic regression analysis. Results QTc prolongation was present in 45 (4.5%) of 1,006 patients overall. Fewer men (3.2%, 22 of 689) than women (7.3%, 23 of 317) displayed QTc prolongation (p<0.004). Moreover, QTc intervals were shorter in male (391 +/- 31 ms) than female subjects (400 +/- 37 ms) (p<0.001). Clozapine was found to produce a longer QTc intervals compared to risperidone and typical antipsychotics. Furthermore, multiple regression analysis showed that significant predictors for QTc prolongation were comorbid cardiovascular disease, antipsychotic types, sex, and age (all p<0.01). Conclusion Our present findings suggest that there are sex differences in the prevalence of QTc prolongation and QTc lengthening in schizophrenia. Antipsychotic types are risk factors for QTc prolongation, and risks are substantially higher for clozapine. C1 [De Yang, Fu; Wang, Xiang Qun; Liu, Xiu Ping; Zhao, Ke Xin; Fu, Wei Hong; Hao, Xue Ru; Zhang, Xing Li; Huang, Guo Shu; Qu, Sheng Cai; Bai, Jing Shen] Beijing HuiLongGuan Hosp, Beijing 100096, Peoples R China. [Huang, Xu Feng] Univ Wollongong, Sch Hlth Sci, Ctr Translat Neurosci, Wollongong, NSW, Australia. [Kosten, Thomas R.; Zhang, Xiang Yang] VA Med Ctr, Houston, TX 77030 USA. [Kosten, Thomas R.; Zhang, Xiang Yang] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. RP De Yang, F (reprint author), Beijing HuiLongGuan Hosp, Beijing 100096, Peoples R China. EM yangfd200@126.com; kosten@bcm.edu; xyzhang@bcm.edu RI Huang, Xu-Feng/D-6053-2013; Huang, Xu-Feng/H-7408-2015 OI Huang, Xu-Feng/0000-0002-5895-2253 FU Stanley Medical Research Institute [03T-459, 05T-726]; United States National Institute of Health [K05-DA0454, P50-DA18827, U01-MH79639] FX This study was funded by the Stanley Medical Research Institute (03T-459 and 05T-726) and the United States National Institute of Health (K05-DA0454, P50-DA18827, and U01-MH79639). NR 37 TC 1 Z9 1 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2011 VL 216 IS 1 BP 9 EP 16 DI 10.1007/s00213-011-2188-5 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 782WI UT WOS:000292043000002 ER PT J AU Tanabe, J Nyberg, E Martin, LF Martin, J Cordes, D Kronberg, E Tregellas, JR AF Tanabe, Jody Nyberg, Eric Martin, Laura F. Martin, Jesse Cordes, Dietmar Kronberg, Eugene Tregellas, Jason R. TI Nicotine effects on default mode network during resting state SO PSYCHOPHARMACOLOGY LA English DT Article DE Resting-state networks; Default mode network; Nicotine; Attention; Posterior cingulate; Extra-striate cortex ID FUNCTIONAL CONNECTIVITY; SPATIAL ATTENTION; VISUOSPATIAL ATTENTION; VISUAL-ATTENTION; CINGULATE CORTEX; PARIETAL CORTEX; TOP-DOWN; BRAIN; FMRI; SCHIZOPHRENIA AB The default mode network (DMN), one of several resting-state networks (RSN) in the brain, is thought to be involved in self-referential thought, awareness, and episodic memories. Nicotine improves cognitive performance, in part by improving attention. Nicotinic agonists have been shown to decrease activity in regions within DMN and increase activity in regions involved in visual attention during effortful processing of external stimuli. It is unknown if these pharmacological effects also occur in the absence of effortful processing. This study aims to determine if nicotine suppresses activity in default mode and enhances activity in extra-striate RSNs in the absence of an external visual task. Within-subject, single-blinded, counterbalanced study of 19 non-smoking subjects who had resting functional MRI scans after 7 mg nicotine or placebo patch. Group independent component analysis was performed. The DMN component was identified by spatial correlation with a reference DMN mask. A visual attention component was identified by spatial correlation with an extra-striate mask. Analyses were conducted using statistical parametric mapping. Nicotine was associated with decreased activity in regions within the DMN and increased activity in extra-striate regions. Suppression of DMN and enhancement of extra-striate resting-state activity in the absence of visual stimuli or effortful processing suggest that nicotine's cognitive effects may involve a shift in activity from networks that process internal to those that process external information. This is a potential mechanism by which cholinergic agonists may have a beneficial effect in diseases associated with altered resting-state activity. C1 [Tanabe, Jody; Nyberg, Eric; Cordes, Dietmar] Univ Colorado Denver, Sch Med, Dept Radiol, Denver, CO USA. [Tanabe, Jody; Martin, Laura F.; Martin, Jesse; Kronberg, Eugene; Tregellas, Jason R.] Univ Colorado Denver, Sch Med, Dept Psychiat, Denver, CO USA. [Martin, Laura F.; Tregellas, Jason R.] Denver VA Med Ctr, Res Serv, Denver, CO USA. RP Tanabe, J (reprint author), 12700 E 19th Ave,Mailstop C278, Aurora, CO 80045 USA. EM jody.tanabe@ucdenver.edu RI Tregellas, Jason/J-3637-2015 FU NIH [R21DA024104, R01DA027748]; VA Biomedical Laboratory and Clinical Science Research and Development Service FX This publication was made possible by NIH Grant Numbers R21DA024104, R01DA027748 and the VA Biomedical Laboratory and Clinical Science Research and Development Service. We thank Dr. Robert Freedman for his helpful discussion. NR 39 TC 46 Z9 47 U1 1 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2011 VL 216 IS 2 BP 287 EP 295 DI 10.1007/s00213-011-2221-8 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 782WL UT WOS:000292043300012 PM 21331518 ER PT J AU Wang, YB Alkasab, TK Narin, O Nazarian, RM Kaewlai, R Kay, J Abujudeh, HH AF Wang, Yingbing Alkasab, Tarik K. Narin, Ozden Nazarian, Rosalynn M. Kaewlai, Rathachai Kay, Jonathan Abujudeh, Hani H. TI Incidence of Nephrogenic Systemic Fibrosis after Adoption of Restrictive Gadolinium-based Contrast Agent Guidelines SO RADIOLOGY LA English DT Article ID GADOBENATE DIMEGLUMINE; DERMOPATHY; HEMODIALYSIS; INVOLVEMENT; TRIGGER; TISSUE AB Purpose: To retrospectively determine the incidence of nephrogenic systemic fibrosis (NSF) in a large academic medical center after the adoption of restrictive gadolinium-based contrast agent (GBCA) administration guidelines. Materials and Methods: For this retrospective HIPAA-compliant study, institutional review board approval was obtained and the requirement for informed consent was waived. Restrictive GBCA guidelines were adopted in May 2007. The guidelines (a) require a recent serum creatinine level measurement in any patient who is aged 60 years or older and/or at risk for renal disease, (b) limit the maximal weight-based GBCA dose administered to any patient with an estimated glomerular filtration rate (eGFR) lower than 60 mL/min/m(2) to 20 mL, and (c) prohibit the administration of any GBCA in patients who have an eGFR lower than 30 mL/min/m(2) and/or are undergoing chronic dialysis treatment (except in emergency situations). The electronic medical records were searched for all contrast material-enhanced magnetic resonance (MR) imaging examinations performed during the post-guidelines adoption period between January 2008 and March 2010 and the pre-guidelines adoption and transitional period between January 2002 and December 2007. Separate pathology records were searched for biopsy-confirmed cases of NSF during the same study periods. The incidences of NSF during the pre-guidelines adoption and transitional period and post-guidelines adoption period were compared by using the paired Z test. Results: A total of 52 954 contrast-enhanced MR examinations were performed during the post-guidelines adoption period. Of these 52 954 examinations, 46 464 (88%) were performed in adult patients with an eGFR of 60 mL/min/m(2) or higher or presumed normal renal function and 6454 (12%) were performed in patients with an eGFR of 3059 mL/min/m(2). Thirty-six patients with an eGFR lower than 30 mL/min/m(2) underwent contrast-enhanced MR imaging for emergent indications. Review of the pathology records for January 2008 to September 2010 revealed no new cases of NSF resulting from GBCA exposure. Conclusion: After restrictive guidelines regarding GBCA administration were instituted, no new cases of NSF were identified among 52 954 contrast-enhanced MR examinations, including those performed in patients with an eGFR lower than 60 mL/min/m(2). (C) RSNA, 2011 C1 [Wang, Yingbing; Alkasab, Tarik K.; Narin, Ozden; Kaewlai, Rathachai; Abujudeh, Hani H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Nazarian, Rosalynn M.] Massachusetts Gen Hosp, Dept Pathol, Dermatopathol Unit, Boston, MA 02114 USA. [Kay, Jonathan] UMass Mem Med Ctr, Dept Med, Div Rheumatol, Worcester, MA USA. [Kay, Jonathan] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Abujudeh, HH (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,FND 213B, Boston, MA 02114 USA. EM habujudeh@partners.org OI Kay, Jonathan/0000-0002-8970-4260; Alkasab, Tarik/0000-0002-4433-9482; Kaewlai, Rathachai/0000-0002-0650-9380 FU Bracco Diagnostics FX Y.W. No potential conflicts of interest to disclose. T. K. A. No potential conflicts of interest to disclose. O.N. No potential conflicts of interest to disclose. R.M.N. No potential conflicts of interest to disclose. R. K. No potential conflicts of interest to disclose. J.K. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: in October 2008 served as expert member of adjudication panel and received per diem honorarium for clinical trial of a gadolinium-containing contrast agent that was sponsored by Bracco Diagnostics; previously served as coinvestigator in a clinical trial sponsored by Bracco Diagnostics. Other relationships: none to disclose. H. H. A. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received a research grant from Bracco Diagnostics. Other relationships: none to disclose. NR 26 TC 59 Z9 62 U1 0 U2 6 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2011 VL 260 IS 1 BP 105 EP 111 DI 10.1148/radiol.11102340 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 781KZ UT WOS:000291932300012 PM 21586680 ER PT J AU Long, DT Raschle, M Joukov, V Walter, JC AF Long, David T. Raeschle, Markus Joukov, Vladimir Walter, Johannes C. TI Mechanism of RAD51-Dependent DNA Interstrand Cross-Link Repair SO SCIENCE LA English DT Article ID FANCONI-ANEMIA PATHWAY; DOUBLE-STRAND BREAKS; HOMOLOGOUS RECOMBINATION; REPLICATION; JUNCTIONS; PROTEIN; GENOME; CELLS AB DNA interstrand cross-links (ICLs) are toxic DNA lesions whose repair in S phase of eukaryotic cells is incompletely understood. In Xenopus egg extracts, ICL repair is initiated when two replication forks converge on the lesion. Dual incisions then create a DNA double-strand break (DSB) in one sister chromatid, whereas lesion bypass restores the other sister. We report that the broken sister chromatid is repaired via RAD51-dependent strand invasion into the regenerated sister. Recombination acts downstream of FANCI-FANCD2, yet RAD51 binds ICL-stalled replication forks independently of FANCI-FANCD2 and before DSB formation. Our results elucidate the functional link between the Fanconi anemia pathway and the recombination machinery during ICL repair. In addition, they demonstrate the complete repair of a DSB via homologous recombination in vitro. C1 [Long, David T.; Walter, Johannes C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Raeschle, Markus] Max Planck Inst Biochem, Dept Prote & Signal Transduct, D-82152 Martinsried, Germany. [Joukov, Vladimir] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Walter, JC (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM johannes_walter@hms.harvard.edu OI Long, David/0000-0001-9232-0316 FU NIH [GM GM80676, HL098316]; Department of Defense Breast Cancer Research [W81XWH-04-1-0524]; American Cancer Society [PF-10-146-01-DMC] FX We thank V. Costanzo for the BRCWT expression construct; T. V. Ho and O. Scharer for instruction on pICL preparation; P. Knipscheer for reagents and helpful discussions; and A. D'Andrea, K. J. Patel, R. Scully, and P. Knipscheer for critical reading of the manuscript. This work was supported by NIH grants GM GM80676 and HL098316 and a John and Virginia Kaneb award to J.C.W., Department of Defense Breast Cancer Research Program Award W81XWH-04-1-0524 to V. J., and American Cancer Society postdoctoral fellowship PF-10-146-01-DMC to D.T.L. M. R. made initial observation of X-arcs; V. J. generated x.l.RAD51 antibodies; D.T.L. and J.C.W. designed and analyzed experiments; D.T.L. performed experiments; and D.T.L. and J.C.W. prepared the manuscript. NR 17 TC 94 Z9 94 U1 2 U2 22 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 1 PY 2011 VL 333 IS 6038 BP 84 EP 87 DI 10.1126/science.1204258 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 785UF UT WOS:000292255400054 PM 21719678 ER PT J AU Kim, JH Chen, TC AF Kim, Julie H. Chen, Teresa C. TI Delayed Sterile Endophthalmitis after Glaucoma Drainage Implantation SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE sterile endophthalmitis; glaucoma drainage implant ID KRUPIN EYE VALVE; INFLAMMATORY RESPONSES; DIFFERENT BIOMATERIALS; MOLTENO IMPLANT; DEVICES; KERATOPROSTHESIS; COMPLICATIONS; SURGERY; BIOCOMPATIBILITY; SHUNT AB Glaucoma drainage devices are being used with increasing frequency for patients. Sterile endophthalmitis after implantation has been reported. Unlike traditional trabeculectomy surgery, the persistence of an implant may be contributory. As glaucoma specialists consider emerging technologies in implantable glaucoma drainage devices, it is important to understand that sterile endophthalmitis may be associated with these devices. C1 [Kim, Julie H.; Chen, Teresa C.] Massachusetts Eye & Ear Infirm, Glaucoma Serv, Boston, MA 02114 USA. RP Kim, JH (reprint author), 243 Charles St, Boston, MA 02114 USA. EM Julie_Kim@meei.harvard.edu NR 54 TC 3 Z9 4 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD JUL-SEP PY 2011 VL 26 IS 4-5 BP 290 EP 294 DI 10.3109/08820538.2011.588668 PG 5 WC Ophthalmology SC Ophthalmology GA 826VO UT WOS:000295383800009 PM 21958177 ER PT J AU Semenas, E Sharma, HS Nozari, A Basu, S Wiklund, L AF Semenas, Egidijus Sharma, Hari Shanker Nozari, Ala Basu, Samar Wiklund, Lars TI NEUROPROTECTIVE EFFECTS OF 17 beta-ESTRADIOL AFTER HYPOVOLEMIC CARDIAC ARREST IN IMMATURE PIGLETS: THE ROLE OF NITRIC OXIDE AND PEROXIDATION SO SHOCK LA English DT Article DE Cardiopulmonary resuscitation; hemorrhage; nitric oxide; sex; immaturity ID CATALYZED LIPID-PEROXIDATION; PERINATAL BRAIN-INJURY; CEREBRAL-BLOOD-FLOW; CARDIOPULMONARY-RESUSCITATION; SEX-DIFFERENCES; VENTRICULAR-FIBRILLATION; GENDER-DIFFERENCES; TRAUMA-HEMORRHAGE; ESTROGEN; SYNTHASE AB We recently reported that cerebral and cardiac injuries are mitigated in immature female piglets after severe hemorrhage with subsequent cardiac arrest. Female sex was also associated with a smaller increase in the cerebral expression of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS). In the current study, we tested the hypothesis that exogenously administered 17 beta-estradiol (E-2) can improve neurological outcome by NOS modulation. Thirty-nine sexually immature piglets were bled to a mean arterial pressure of 35 mmHg over 15 min. Fifty micrograms per kilogram of E-2 was then administered to 10 male and 10 female animals (estradiol group), whereas control animals (n = 10 males and 9 females) received equal volume of normal saline. The animals were then subjected to ventricular fibrillation (4 min) followed by up to 15 min of open-chest cardiopulmonary resuscitation. Vasopressin 0.4 U . kg(-1) and amiodarone 0.5 mg . kg(-1) were given, and 3 mL . kg(-1) of 7.5% saline with 6% dextran was administered over 20 min. All surviving animals were killed after 3 h, and their brains examined for histological injury and NOS expression. No significant differences were observed in survival or hemodynamics between the groups. Compared with the control group, animals in the E-2 group exhibited a significantly smaller increase in nNOS and iNOS expression, a smaller blood-brain-barrier disruption, and a mitigated neuronal injury. There was a significant correlation between nNOS and iNOS levels and neuronal injury. Interestingly, estradiol attenuated cerebral damage (including lower activation of nNOS and iNOS) both in male and female piglets. In conclusion, in our immature piglet model of hypovolemic cardiac arrest, E-2 downregulates iNOS and nNOS expression and results in decreased blood-brain-barrier permeability disruption and smaller neuronal injury. C1 [Semenas, Egidijus; Sharma, Hari Shanker; Wiklund, Lars] Univ Uppsala Hosp, Dept Surg Sci Anesthesiol & Intens Care, Fac Med, S-75185 Uppsala, Sweden. [Nozari, Ala] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. [Basu, Samar] Univ Uppsala Hosp, Dept Publ Hlth & Caring Sci Clin Nutr & Metab, Fac Med, S-75185 Uppsala, Sweden. RP Semenas, E (reprint author), Univ Uppsala Hosp, Dept Surg Sci Anesthesiol & Intens Care, Fac Med, S-75185 Uppsala, Sweden. EM egidijus.semenas@gmail.com RI Sharma, Hari/G-4508-2016 FU Laerdal Foundation for Acute Medicine, Stavanger, Norway FX The research was supported, in part, by the Laerdal Foundation for Acute Medicine, Stavanger, Norway. NR 35 TC 6 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1073-2322 EI 1540-0514 J9 SHOCK JI Shock PD JUL PY 2011 VL 36 IS 1 BP 30 EP 37 DI 10.1097/SHK.0b013e3182150f43 PG 8 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 778CC UT WOS:000291675800006 PM 21330940 ER PT J AU Lo, EH Fisher, M AF Lo, Eng H. Fisher, Marc TI Stroke Impact Beyond the Impact Factor? SO STROKE LA English DT Editorial Material C1 [Lo, Eng H.] Harvard Univ, Sch Med, MGH Harvard, Charlestown, MA 02129 USA. [Lo, Eng H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Lo, Eng H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Fisher, Marc] Mem Hosp, Worcester, MA 01605 USA. [Fisher, Marc] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Lo, EH (reprint author), Harvard Univ, Sch Med, MGH Harvard, MGH E 149-2401, Charlestown, MA 02129 USA. EM Lo@helix.mgh.harvard.edu; marc.fisher@umassmemorial.org NR 3 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2011 VL 42 IS 7 BP 1803 EP 1804 DI 10.1161/STROKEAHA.111.625541 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 783NQ UT WOS:000292090900011 ER PT J AU Kamalian, S Kamalian, S Maas, MB Goldmacher, GV Payabvash, S Akbar, A Schaefer, PW Furie, KL Gonzalez, RG Lev, MH AF Kamalian, Shahmir Kamalian, Shervin Maas, Matthew B. Goldmacher, Greg V. Payabvash, Seyedmehdi Akbar, Adnan Schaefer, Pamela W. Furie, Karen L. Gonzalez, R. Gilberto Lev, Michael H. TI CT Cerebral Blood Flow Maps Optimally Correlate With Admission Diffusion-Weighted Imaging in Acute Stroke but Thresholds Vary by Postprocessing Platform SO STROKE LA English DT Article DE acute stroke; cerebral blood flow; cerebral blood volume; CT perfusion ID ACUTE ISCHEMIC-STROKE; ACUTE HEMISPHERIC STROKE; INFARCT CORE; INTRAARTERIAL THROMBOLYSIS; COMPUTED-TOMOGRAPHY; PERFUSION; PENUMBRA; VOLUME; THERAPY; NEED AB Background and Purpose-Admission infarct core lesion size is an important determinant of management and outcome in acute (<9 hours) stroke. Our purposes were to: (1) determine the optimal CT perfusion parameter to define infarct core using various postprocessing platforms; and (2) establish the degree of variability in threshold values between these different platforms. Methods-We evaluated 48 consecutive cases with vessel occlusion and admission CT perfusion and diffusion-weighted imaging within 3 hours of each other. CT perfusion was acquired with a "second-generation" 66-second biphasic cine protocol and postprocessed using "standard" (from 2 vendors, "A-std" and "B-std") and "delay-corrected" (from 1 vendor, "A-dc") commercial software. Receiver operating characteristic curve analysis was performed comparing each CT perfusion parameter-both absolute and normalized to the contralateral uninvolved hemisphere-between infarcted and noninfarcted regions as defined by coregistered diffusion-weighted imaging. Results-Cerebral blood flow had the highest accuracy (receiver operating characteristic area under the curve) for all 3 platforms (P<0.01). The maximal areas under the curve for each parameter were: absolute cerebral blood flow 0.88, cerebral blood volume 0.81, and mean transit time 0.82 and relative Cerebral blood flow 0.88, cerebral blood volume 0.83, and mean transit time 0.82. Optimal receiver operating characteristic operating point thresholds varied significantly between different platforms (Friedman test, P<0.01). Conclusions-Admission absolute and normalized "second-generation" cine acquired CT cerebral blood flow lesion volumes correlate more closely with diffusion-weighted imaging-defined infarct core than do those of CT cerebral blood volume or mean transit time. Although limited availability of diffusion-weighted imaging for some patients creates impetus to develop alternative methods of estimating core, the marked variability in quantification among different postprocessing software limits generalizability of parameter map thresholds between platforms. (Stroke. 2011; 42: 1923-1928.) C1 [Lev, Michael H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Neuroradiol,Dept Radiol, Boston, MA 02114 USA. [Maas, Matthew B.; Furie, Karen L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Lev, MH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Neuroradiol,Dept Radiol, Gray B285,55 Fruit St, Boston, MA 02114 USA. EM mlev@partners.org RI Kamalian, Shervin/D-7667-2013; OI Kamalian, Shervin/0000-0001-8962-4773; Kamalian, Shahmir/0000-0002-9640-8144 FU National Institute of Health (NIH/National Institute of Neurological Disorders and Stroke) [1 P50 NS051343-01A2]; Agency for Healthcare Research and Quality [R01 HS11392-01A1]; Massachusetts General Hospital Clinical Research Center Harvard Clinical and Translational Science Center from the National Center for Research Resources [1 UL1 RR025758-01]; National Institutes of Health (NIH) [P50NS051343, R01NS050041]; GE Healthcare FX This work was supported by the Specialized Programs of Translational Research in Acute Stroke (SPOTRIAS) Network grant funded by the National Institute of Health (NIH/National Institute of Neurological Disorders and Stroke; 1 P50 NS051343-01A2), the Agency for Healthcare Research and Quality grant R01 HS11392-01A1, and the Massachusetts General Hospital Clinical Research Center (No. 1 UL1 RR025758-01) Harvard Clinical and Translational Science Center from the National Center for Research Resources.; K.L.F. received funding from National Institutes of Health (NIH) research grant P50NS051343. R. G. G. received funding from NIH research grant R01NS050041. M. H. L. received funding from NIH research grant P50NS051343. Research support was provided by GE Healthcare, a consultancy for Co-Axia, GE Healthcare, and Millennium Pharmaceuticals. NR 21 TC 70 Z9 70 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2011 VL 42 IS 7 BP 1923 EP 1928 DI 10.1161/STROKEAHA.110.610618 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 783NQ UT WOS:000292090900034 PM 21546490 ER PT J AU Ekundayo, OJ Vassar, SD Williams, LS Bravata, DM Cheng, EM AF Ekundayo, Olaniyi James Vassar, Stefanie D. Williams, Linda S. Bravata, Dawn M. Cheng, Eric M. TI Using Administrative Databases to Calculate Framingham Scores Within a Large Health Care Organization SO STROKE LA English DT Article DE administrative database; Framingham calculator; stroke ID TRANSIENT ISCHEMIC ATTACK; CARDIOVASCULAR RISK; VETERANS-AFFAIRS; STROKE RISK; ATHEROSCLEROSIS RISK; PREDICTION; VALIDATION; HYPERTENSION; ASSOCIATION; COMMUNITIES AB Background and Purpose-Framingham calculators are typically implemented in 1-on-1 settings to determine if a patient is at high risk for development of cardiovascular disease in the next 10 years. Because health care administrative datasets are including more clinical information, we explored how well administrative data-derived Framingham scores could identify persons who would have stroke develop in the next year. Methods-Using a nested case-control design, we compared all 313 persons who had a first-time stroke at 5 Veterans Administration Medical Centers with a random sample of 25 361 persons who did not have a first-time stroke in 2008. We compared Framingham scores and risk using administrative data available at the end of 2007. Results-Stroke patients had higher risk profile than controls: older age, higher systolic blood pressure and total cholesterol, more likely to have diabetes, cardiovascular disease, left ventricular hypertrophy, and more likely to use treatment for blood pressure (P<0.05). The mean Framingham generalized cardiovascular disease score (18.0 versus 14.5) as well as the mean Framingham stroke-specific score (13.2 versus 10.2) was higher for stroke cases than controls (both P<0.0001). The c-statistic for the generalized cardiovascular disease score was 0.68 (95% CI, 0.65-0.70) and for the stroke score was 0.64 (95% CI, 0.62-0.67). Conclusions-Persons who had a stroke develop in the next year had a worse Framingham risk profile, as determined by administrative data. Future studies should examine how to improve the stroke predictive tools and to identify the appropriate populations and uses for applying stroke risk predictive tools. (Stroke. 2011; 42: 1982-1987.) C1 [Cheng, Eric M.] VA Greater Los Angeles Healthcare Syst, Dept Neurol, Los Angeles, CA 90073 USA. [Ekundayo, Olaniyi James; Vassar, Stefanie D.; Cheng, Eric M.] Univ Calif Los Angeles, Los Angeles, CA USA. [Williams, Linda S.; Bravata, Dawn M.] VA HSR&D Ctr Excellence Implementing Evidence Bas, Richard L Roudebush VA Med Ctr, Indianapolis, IN USA. [Williams, Linda S.; Bravata, Dawn M.] Indiana Univ Sch Med, Indianapolis, IN USA. [Williams, Linda S.; Bravata, Dawn M.] Regenstrief Inst Hlth Care, Indianapolis, IN USA. RP Cheng, EM (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Neurol, 11301 Wilshire Blvd,ML 127, Los Angeles, CA 90073 USA. EM eric.cheng@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service Quality Enhancement Research Initiative [08-242]; National Institute of Health/National Institute of Neurological Disorders and Stroke [K23NS058571]; American Heart Association Pharmaceutical Roundtable and David and Stevie Spina FX The project reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service Quality Enhancement Research Initiative Project 08-242. Dr Cheng is supported by a career development award from National Institute of Health/National Institute of Neurological Disorders and Stroke (K23NS058571). Drs Cheng and Ekundayo are also supported by an award from the American Heart Association Pharmaceutical Roundtable and David and Stevie Spina. 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 21 TC 5 Z9 5 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD JUL PY 2011 VL 42 IS 7 BP 1982 EP 1987 DI 10.1161/STROKEAHA.110.603340 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 783NQ UT WOS:000292090900044 PM 21546488 ER PT J AU Fonarow, GC Smith, EE Schwamm, LH AF Fonarow, Gregg C. Smith, Eric E. Schwamm, Lee H. TI Response to Letter by Khan et al Regarding Article, "Hospital-Level Variation in Mortality and Rehospitalization for Medicare Beneficiaries With Acute Ischemic Stroke" SO STROKE LA English DT Letter ID CASE-FATALITY C1 [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA 90095 USA. [Smith, Eric E.] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada. [Schwamm, Lee H.] Massachusetts Gen Hosp, Div Neurol, Boston, MA 02114 USA. RP Fonarow, GC (reprint author), Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA 90095 USA. RI Smith, Eric/C-5443-2012; OI Smith, Eric/0000-0003-3956-1668; Schwamm, Lee/0000-0003-0592-9145 NR 6 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2011 VL 42 IS 7 BP E405 EP E405 DI 10.1161/STROKEAHA.111.614909 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 783NQ UT WOS:000292090900002 ER PT J AU Warshaw, AL Sarr, MG AF Warshaw, Andrew L. Sarr, Michael G. TI Social media in surgical education and practice SO SURGERY LA English DT Editorial Material C1 [Warshaw, Andrew L.; Sarr, Michael G.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Warshaw, AL (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,White 506, Boston, MA 02114 USA. EM swilliams7@partners.org NR 0 TC 5 Z9 5 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD JUL PY 2011 VL 150 IS 1 BP 1 EP 1 DI 10.1016/j.surg.2011.05.021 PG 1 WC Surgery SC Surgery GA 787DA UT WOS:000292355600001 PM 21683852 ER PT J AU Tilt, A Mermel, C Conrad, C AF Tilt, Alexandra Mermel, Craig Conrad, Claudius TI How surgical residents use social media SO SURGERY LA English DT Editorial Material C1 [Tilt, Alexandra; Mermel, Craig; Conrad, Claudius] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02108 USA. RP Conrad, C (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,GRB 425, Boston, MA 02108 USA. EM cconrad@partners.org NR 4 TC 7 Z9 7 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD JUL PY 2011 VL 150 IS 1 BP 5 EP 6 DI 10.1016/j.surg.2011.05.022 PG 2 WC Surgery SC Surgery GA 787DA UT WOS:000292355600003 PM 21683854 ER PT J AU Meisel, JA Fallon, EM Le, HD Nehra, D de Meijer, VE Rodig, SJ Puder, M AF Meisel, Jonathan A. Fallon, Erica M. Le, Hau D. Nehra, Deepika de Meijer, Vincent E. Rodig, Scott J. Puder, Mark TI Sunitinib inhibits postoperative adhesions in a rabbit model SO SURGERY LA English DT Article ID TYROSINE KINASE INHIBITOR; GROWTH-FACTORS; PREVENTION; REDUCTION; SURGERY; OBSTRUCTION; SEPRAFILM; MEMBRANE; SU11248 AB Background. Postoperative abdominal adhesions are a major cause of morbidity and mortality. We previously demonstrated the inhibitory effect of sunitinib, a receptor tyrosine kinase inhibitor; on adhesion formation in a murine model, and now investigate its effects in a rabbit model. Methods. Forty New Zealand White rabbits underwent a standard adhesion procedure. Preoperatively, animals were randomized to treatment with sunitinib or saline (control). Animals were treated with a total of 11 daily doses, 1 preoperative and 10 postoperative. One group of 20 animals (group 1) was humanely killed on postoperative day 10, and the other (group 2) on postoperative day 30. After killing, adhesions were scored and abdominal wounds were collected for tensile strength and microvessel density measurements. Results. Sunitinib-treated animals in group 1 had a mean tenacity score of 1.67 +/- 0.29 compared with 3.60 +/- 0.16 in control animals (P < .01). Similarly, the mean tenacity scores for sunitinib-treated and control animals in group 2 were 0.20 +/- 0.20 and 2.70 +/- 0.37 respectively (P < .01). The mean uterine involvement scores for sunitinib-treated and control animals in group 1 were 1.44 +/- 0.29 and 3.70 +/- 0.15, respectively (P < .01), and in group 2 were 0.10 +/- 0.10 and 2.70 +/- 0.45, respectively (P < .01). There were no differences in ultimate or modular wound tensile strength between sunitinib-treated and control animals. Conclusion. Sunitinib significantly reduces postoperative adhesions in a rabbit model. This therapy may improve postoperative adhesion-related morbidity and mortality. (Surgery 2011;150:32-8.) C1 [Meisel, Jonathan A.; Fallon, Erica M.; Le, Hau D.; Nehra, Deepika; de Meijer, Vincent E.; Puder, Mark] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Surg & Vasc Biol, Boston, MA USA. [Nehra, Deepika] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Puder, M (reprint author), 300 Longwood Ave,Fegan 3, Boston, MA 02115 USA. EM mark.puder@childrens.harvard.edu OI de Meijer, Vincent/0000-0002-7900-5917 FU Funded by a Congressionally Funded Project entitled "Angiogenesis and Tissue Engineering Research" [W81XWH-05-1-0115, 76344-01]; Children's Hospital Surgical Foundation; Vascular Biology Program (Boston, MA); Joshua Ryan Rappaport Fellowship; Massachusetts General Hospital; National Institutes of Health [T32 DK007754-12]; Stichting Prof. Michaelvan Vloten Fonds; VSBfonds; Gerrit Jan Mulder Stichting; Prins Bernhard Cultuurfonds; Dr Saal van Zwanenberg Stichting (The Netherlands) FX Funded by a Congressionally Funded Project entitled "Angiogenesis and Tissue Engineering Research," grant W81XWH-05-1-0115, fund 76344-01 (J.A.M., E.M.F., M.P.); the Children's Hospital Surgical Foundation and the Vascular Biology Program (Boston, MA; J.A.M., E.M.F., H.D.L., M.P.); the Joshua Ryan Rappaport Fellowship (E.M.F., H.D.L.); the Massachusetts General Hospital and the National Institutes of Health, grant T32 DK007754-12 (D.N.); the foundations Stichting Prof. Michaelvan Vloten Fonds, VSBfonds, Gerrit Jan Mulder Stichting, Prins Bernhard Cultuurfonds, and Dr Saal van Zwanenberg Stichting (The Netherlands; V.E.d.M.). NR 25 TC 14 Z9 14 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD JUL PY 2011 VL 150 IS 1 BP 32 EP 38 DI 10.1016/j.surg.2011.02.013 PG 7 WC Surgery SC Surgery GA 787DA UT WOS:000292355600010 PM 21507447 ER PT J AU Soldin, OP Brent, GA Kloos, RT AF Soldin, Offie P. Brent, Gregory A. Kloos, Richard T. TI Publication of Industry-Sponsored Medical Research: Guidelines from the Consortium of Laboratory Medicine Journal Editors SO THYROID LA English DT Editorial Material C1 [Soldin, Offie P.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Brent, Gregory A.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Endocrinol & Diabet Div,Dept Med, Los Angeles, CA 90095 USA. [Kloos, Richard T.] Ohio State Univ, Med Ctr, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Kloos, Richard T.] Ctr Comprehens Canc, Columbus, OH USA. RP Soldin, OP (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, LL S-166,3800 Reservoir Rd NW, Washington, DC 20057 USA. EM os35@georgetown.edu FU NIA NIH HHS [R01 AG033867] NR 2 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 1050-7256 J9 THYROID JI Thyroid PD JUL PY 2011 VL 21 IS 7 BP 693 EP 693 DI 10.1089/thy.2011.2107.ed2 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 784EW UT WOS:000292139300002 PM 21707435 ER PT J AU Phitayakorn, R Faquin, W Wei, N Barbesino, G Stephen, AE AF Phitayakorn, Roy Faquin, William Wei, Nancy Barbesino, Giuseppe Stephen, Antonia E. TI Thyroid-Associated Paragangliomas SO THYROID LA English DT Article ID OF-THE-LITERATURE; IMMUNOHISTOCHEMICAL FEATURES; GLAND; NODULE; CHEMODECTOMA; MUTATION; PATIENT; REGION; LARYNX; NECK AB Background: Paragangliomas in the region of the thyroid gland are rare tumors that can present a diagnostic challenge by mimicking follicular and c-cell derived thyroid tumors. Summary: Thyroid-associated paragangliomas are likely a subset of laryngeal paragangliomas and, although quite rare, should be considered in the differential diagnosis of a hypervascular thyroid nodule. The preoperative diagnosis of thyroid-associated paragangliomas can be challenging since the cytologic and histologic features overlap with more common primary thyroid neoplasms, in particular medullary carcinoma. Differential expression of a panel of immunohistochemical markers, including neuro-specific enolase, chromogranin A, synaptophysin, keratin, and S100, can be used to distinguish thyroid-associated paragangliomas from primary thyroid tumors. Intraoperatively, thyroid-associated paragangliomas may be associated with significant intraoperative bleeding and are often densely adherent to surrounding tissues, including the recurrent laryngeal nerve. Interestingly, the aggressive local behavior of these tumors does not correspond to potential formalignancy, as there are no patients with malignant thyroid-associated paragangliomas reported in the medical literature. Therefore, these tumors may be treated with limited resection. Postoperatively, patients with paragangliomas should receive hormonal evaluation for functional disease, imaging evaluation for multicentric and metastatic disease, and genetic counseling. Conclusion: Thyroid-associated paragangliomas are an important part of the differential diagnosis of a hypervascular thyroid nodule, especially in a patient with a fine-needle aspiration biopsy suggestive of medullary thyroid carcinoma, but with unremarkable serum calcitonin levels. Consideration of a thyroid-associated paraganglioma also has important operative and postoperative implications for determining the extent of thyroid resection as well as follow-up testing. C1 [Phitayakorn, Roy] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Gen & GI Surg, Boston, MA 02114 USA. [Faquin, William] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Wei, Nancy; Barbesino, Giuseppe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MGH Thyroid Unit, Boston, MA 02114 USA. RP Phitayakorn, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Gen & GI Surg, WACC 460,Suite 460,15 Parkman St, Boston, MA 02114 USA. EM rphitayakorn@partners.org OI Phitayakorn, Roy/0000-0002-8327-1484 NR 33 TC 11 Z9 11 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD JUL PY 2011 VL 21 IS 7 BP 725 EP 733 DI 10.1089/thy.2010.0362 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 784EW UT WOS:000292139300007 PM 21615305 ER PT J AU Paten, JA Zareian, R Saeidi, N Melotti, SA Ruberti, JW AF Paten, Jeffrey A. Zareian, Ramin Saeidi, Nima Melotti, Suzanna A. Ruberti, Jeffrey W. TI Design and Performance of an Optically Accessible, Low-Volume, Mechanobioreactor for Long-Term Study of Living Constructs SO TISSUE ENGINEERING PART C-METHODS LA English DT Article ID CYCLIC STRAIN; IN-VITRO; CORNEAL FIBROBLASTS; LIGAMENT FIBROBLASTS; ENGINEERED CARTILAGE; MATRIX ACCUMULATION; ARTICULAR-CARTILAGE; BIOREACTOR SYSTEM; ELASTIC-MODULUS; TISSUE AB Currently available bioreactor systems used by tissue engineers permit either direct, high-magnification observation of cell behavior or application of mechanical loads to growing tissue constructs, but not both simultaneously. Further, in most loading bioreactors, the volume of the dead space is not minimized to reduce the cost associated with perfusion media, exogenous stimulatory/inhibitory agents, proteases, and label. We have designed, developed, and tested a bioreactor that simultaneously satisfies the combined requirements of providing (i) controlled tensile mechanical stimulation, (ii) direct high-magnification imaging capability, and (iii) low dead-space volume. This novel mechanostimulatory (uniaxial tensile loading) bioreactor operates on an inverted microscope and permits continuous optical access (up to 600 X) to a loaded, growing construct for extended periods of time (weeks). The reactor employs an adjustable reaction chamber in which the dead space can be reduced to <2 mL. The device has been used to cultivate our human primary corneal fibroblast-derived, tissue-engineered system for up to 14 days. Using the instrument we have successfully recorded (i) the process of fibroblasts populating, growing to confluence, and stratifying on different substrates; (ii) recorded complex and organized cell sheet motions; and (iii) recorded the behavior of a subpopulation of what appear to be degradative/catabolic cells within our fibroblast culture. The device is capable of providing detailed, long-term, dynamic images of mechanically stimulated cell/matrix interaction that have not been observed previously. C1 [Paten, Jeffrey A.; Zareian, Ramin; Melotti, Suzanna A.; Ruberti, Jeffrey W.] Northeastern Univ, Boston, MA 02115 USA. [Saeidi, Nima] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA USA. RP Ruberti, JW (reprint author), Northeastern Univ, 360 Huntington Ave,334 Snell Engn Ctr, Boston, MA 02115 USA. EM j.ruberti@neu.edu FU Draper Laboratories; [NEI R01EY015500]; [NIBIB R21EB007317] FX The bioreactor was initially designed by undergraduates: Aaron Desjarlais, B. S., Jessica Kornfeld, B. S., Michael Lee, B. S., Matthew McGrath, B. S., and Jeffrey Perry, B. S., for their Capstone Senior Design Course at Northeastern University with the support of NEI R01EY015500 and NIBIB R21EB007317. The final device has been significantly modified by the authors with support from NEI R01EY015500. The first author (J.A.P.) has received support from Draper Laboratories during the period over which the device was developed. NR 47 TC 7 Z9 7 U1 1 U2 8 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3384 J9 TISSUE ENG PART C-ME JI Tissue Eng. Part C-Methods PD JUL PY 2011 VL 17 IS 7 BP 775 EP 788 DI 10.1089/ten.tec.2010.0642 PG 14 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 784VG UT WOS:000292185800008 PM 21413901 ER PT J AU Kaddurah-Daouk, R Boyle, SH Matson, W Sharma, S Matson, S Zhu, H Bogdanov, MB Churchill, E Krishnan, RR Rush, AJ Pickering, E Delnomdedieu, M AF Kaddurah-Daouk, R. Boyle, S. H. Matson, W. Sharma, S. Matson, S. Zhu, H. Bogdanov, M. B. Churchill, E. Krishnan, R. R. Rush, A. J. Pickering, E. Delnomdedieu, M. TI Pretreatment metabotype as a predictor of response to sertraline or placebo in depressed outpatients: a proof of concept SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE major depressive disorder; metabolomics; sertraline; placebo AB The purpose of this study was to determine whether the baseline metabolic profile (that is, metabotype) of a patient with major depressive disorder (MDD) would define how an individual will respond to treatment. Outpatients with MDD were randomly assigned to sertraline (up to 150 mg per day) (N = 43) or placebo (N = 46) in a double-blind 4-week trial. Baseline serum samples were profiled using the liquid chromatography electrochemical array; the output was digitized to create a 'digital map' of the entire measurable response for a particular sample. Response was defined as >= 50% reduction baseline to week 4 in the 17-item Hamilton Rating Scale for Depression total score. Models were built using the one-out method for cross-validation. Multivariate analyses showed that metabolic profiles partially separated responders and non-responders to sertraline or to placebo. For the sertraline models, the overall correct classification rate was 81% whereas it was 72% for the placebo models. Several pathways were implicated in separation of responders and non-responders on sertraline and on placebo including phenylalanine, tryptophan, purine and tocopherol. Dihydroxyphenylacetic acid, tocopherols and serotonin were common metabolites in separating responders and non-responders to both drug and placebo. Pretreatment metabotypes may predict which depressed patients will respond to acute treatment (4 weeks) with sertraline or placebo. Some pathways were informative for both treatments whereas other pathways were unique in predicting response to either sertraline or placebo. Metabolomics may inform the biochemical basis for the early efficacy of sertraline. C1 [Kaddurah-Daouk, R.; Boyle, S. H.; Churchill, E.; Krishnan, R. R.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Matson, W.; Sharma, S.; Matson, S.] Bedford VA Med Ctr, Dept Syst Biochem, Bedford, MA USA. [Matson, S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zhu, H.] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA. [Bogdanov, M. B.] Neurol & Neurosci Weill Cornell Med Coll, New York, NY USA. [Krishnan, R. R.; Rush, A. J.] Duke NUS Grad Med Sch, Singapore, Singapore. [Pickering, E.; Delnomdedieu, M.] Pfizer Global R&D, Groton, CT USA. RP Kaddurah-Daouk, R (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Box 3903, Durham, NC 27710 USA. EM rima.kaddurahdaouk@duke.edu OI Rush, Augustus/0000-0003-2004-2382 FU Pfizer corporation; NIGMS [GM078233] FX We would like to thank Dorothy Peters for her assistance in preparation of this manuscript and also acknowledge the editorial support of Jon Kilner (Pittsburgh, PA, USA). This work was done with funding from Pfizer corporation and from NIGMS grant GM078233, 'The Metabolomics Research Network for Drug Response Phenotype' (RKD, WM, SB, EC). NR 43 TC 31 Z9 33 U1 3 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JUL PY 2011 VL 1 AR e26 DI 10.1038/tp.2011.22 PG 7 WC Psychiatry SC Psychiatry GA V29SS UT WOS:000208768700010 ER PT J AU Choueiri, TK Schutz, FAB Hevelone, ND Nguyen, PL Lipsitz, SR Williams, SB Silverman, SG Hu, JC AF Choueiri, Toni K. Schutz, Fabio A. B. Hevelone, Nathanael D. Nguyen, Paul L. Lipsitz, Stuart R. Williams, Stephen B. Silverman, Stuart G. Hu, Jim C. TI Thermal Ablation vs Surgery for Localized Kidney Cancer: a Surveillance, Epidemiology, and End Results (SEER) Database Analysis SO UROLOGY LA English DT Article ID RENAL-CELL CARCINOMA; PARTIAL NEPHRECTOMY; RADIOFREQUENCY ABLATION; FOLLOW-UP; TUMORS; METAANALYSIS; OUTCOMES; MASSES; TRENDS AB OBJECTIVE To evaluate contemporary national practice pattern trends in the use of thermal ablation (radiofrequency ablation and cryoablation) in the management of stage I renal cell carcinoma (RCC), and the factors that lead to using thermal ablation (TA) vs partial (PN) or radical nephrectomy (RN) in the United States. METHODS Within the Surveillance, Epidemiology and End Results (SEER) database, we identified subjects with T1-N0M0 RCC treated with either PN, RN, or TA between 2004 and 2007. Proportions, trends, and multivariable logistic regression models tested the predictors of the use of TA. RESULTS In total, 15,145 patients underwent a procedure for an RCC that was organ-confined and <= 7 cm. Of these, 578 underwent TA, 4402 underwent PN, and 10,165 underwent RN. On unadjusted analyses, patients who received TA were more likely to be older, single, have smaller tumor size, be diagnosed in more recent years, and have more unspecified histologic subtype and tumor grade. In multivariable adjusted analyses, single status (P = .02), male gender (P = .01), increasing age (P < .01), year of diagnosis (P < .01), and smaller tumor size (P = .01) were strong independent predictors of TA use compared with surgery (PN or RN). Further adjusted analyses showed no statistical difference in cancer-specific or overall survival between TA vs PN or RN. CONCLUSIONS TA use for stage I RCC increased over a relatively short period and was performed more commonly in patients of older age and with smaller tumor size. Longer follow-up is needed to assess the comparative effectiveness of TA vs surgery. UROLOGY 78: 93-98, 2011. (C) 2011 Elsevier Inc. C1 [Choueiri, Toni K.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Choueiri, TK (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM Toni_Choueiri@dfci.harvard.edu OI Hevelone, Nathanael/0000-0003-4740-2085 FU Trust Family Research Fund for Kidney Cancer FX This work was supported by the Trust Family Research Fund for Kidney Cancer presented to Toni K. Choueiri. NR 27 TC 52 Z9 52 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD JUL PY 2011 VL 78 IS 1 BP 93 EP 98 DI 10.1016/j.urology.2011.01.068 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 783KE UT WOS:000292080300025 PM 21550636 ER PT J AU Psutka, SP Feldman, AS Rodin, D Olumi, AF Wu, CL McDougal, WS AF Psutka, Sarah P. Feldman, Adam S. Rodin, David Olumi, Aria F. Wu, Chin-Lee McDougal, W. Scott TI Men With Organ-confined Prostate Cancer and Positive Surgical Margins Develop Biochemical Failure at a Similar Rate to Men With Extracapsular Extension SO UROLOGY LA English DT Article ID RADICAL PROSTATECTOMY; ADJUVANT RADIOTHERAPY; PATHOLOGICAL STAGE; ANTIGEN RECURRENCE; NATURAL-HISTORY; PROGRESSION; IMPACT; SPECIMENS; DATABASE AB OBJECTIVES To define the role of positive surgical margins (PSMs) after radical retropubic prostatectomy as a predictor of biochemical failure (BCF) in prostate cancer with respect to pathologic stage. METHODS A retrospective cohort study of 300 patients who had undergone radical retropubic prostatectomy from 1993 to 1995 was performed. The role of margin status and the length of the PSM in the progression to BCF was defined after controlling for the preoperative prostate-specific antigen level, Gleason score, tumor stage, tumor volume, seminal vesical invasion, lymphovascular invasion, and perineural invasion using a multivariate regression model. The median follow-up time was 12 years. RESULTS The presence of PSMs correlated with a shorter time to BCF in men with Stage pT2 disease (P < .0001) but not in men with Stage pT3 disease (P = .66). Of the patients with Stage pT2 disease and PSMs, the PSM length did not correlate with progression to BCF. PSMs predicted a shorter time to progression to BCF in patients with high-and low-volume pT2 disease (P = .0261 and P = .0003, respectively). Only PSMs predicted a shorter time to BCF on multivariate analysis in patients with Stage pT2 cancer (hazard ratio 2.33, 95% confidence interval 1.495-3.723). In patients with Stage pT3 disease, PSMs were not associated with an increased risk of BCF (hazard ratio 0.747, 95% confidence interval 0.328-1.703). CONCLUSIONS Surgical margin status did not affect the risk of BCF in patients with Stage pT3a disease; however, it did affect patients with Stage pT2 disease, irrespective of PSM length or disease volume. During 12 years of follow-up, the patients with PSMs and Stage pT2 disease had a risk of BCF similar to that of the patients with Stage pT3 disease. UROLOGY 78: 121-125, 2011. (C) 2011 Elsevier Inc. C1 [McDougal, W. Scott] Harvard Univ, Massachusetts Gen Hosp, Dept Urol, Sch Med, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Dept Pathol, Sch Med, Boston, MA 02114 USA. RP McDougal, WS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Urol, Sch Med, 55 Fruit St,GRB 1102, Boston, MA 02114 USA. EM wmcdougal@partners.org NR 21 TC 17 Z9 18 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD JUL PY 2011 VL 78 IS 1 BP 121 EP 125 DI 10.1016/j.urology.2010.10.036 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 783KE UT WOS:000292080300031 PM 21411125 ER PT J AU Zivkovic, SA Peltier, AC Iacob, T Lacomis, D AF Zivkovic, S. A. Peltier, A. C. Iacob, T. Lacomis, D. TI Chronic inflammatory demyelinating polyneuropathy and ventilatory failure: report of seven new cases and review of the literature SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Editorial Material DE chronic inflammatory demyelinating polyneuropathy; ventilatory failure; phrenic nerve ID GUILLAIN-BARRE-SYNDROME; PHRENIC-NERVE; RESPIRATORY-FAILURE; POLYRADICULONEUROPATHY; CIDP AB Background - Ventilatory involvement is rarely reported in chronic inflammatory demyelinating polyneuropathy (CIDP), but small prospective studies showed frequent involvement of phrenic nerves, which is usually overshadowed by severe limb weakness. Objectives - To report the clinical features of CIDP associated with ventilatory failure. Results - There were seven patients (43% women), with a mean age of 58.6 (range 38-82). The clinical courses were relapsing in five and progressive in two. Four patients had an initial event simulating Guillain-Barre syndrome (GBS). Ventilatory failure was recurrent in three patients. Five patients had full or nearly complete recoveries; one still requires nocturnal ventilation; and one died (14%) of myocardial infarction while still requiring mechanical ventilation. Conclusions- Clinical ventilatory dysfunction in CIDP is usually not an indicator of poor prognosis, and many patients recover without significant permanent disability. The mortality rate is similar to intubated patients with GBS. Patients with cardiopulmonary comorbidities and acute GBS-like onset of CIDP may be at higher risk of ventilatory failure which typically responds to 'standard' treatments of CIDP. Larger prospective studies are needed to define the prevalence, clinical spectrum and significance of ventilatory involvement in CIDP and to establish guidelines for evaluation and treatment. C1 [Zivkovic, S. A.; Lacomis, D.] Univ Pittsburgh, Med Ctr, Dept Neurol, Pittsburgh, PA 15213 USA. [Zivkovic, S. A.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Peltier, A. C.] Vanderbilt Univ, Dept Neurol, Nashville, TN USA. [Iacob, T.] Gottlieb Mem Hosp, Melrose Pk, IL USA. [Lacomis, D.] Univ Pittsburgh, Med Ctr, Dept Pathol Neuropathol, Pittsburgh, PA 15213 USA. RP Zivkovic, SA (reprint author), Univ Pittsburgh, Med Ctr, Dept Neurol, 200 Lothrop St,PUH F878, Pittsburgh, PA 15213 USA. EM zivkovics@upmc.edu OI Peltier, Amanda/0000-0003-1097-7715 NR 22 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD JUL PY 2011 VL 124 IS 1 BP 59 EP 63 DI 10.1111/j.1600-0404.2010.01431.x PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 774QE UT WOS:000291400400009 PM 21649602 ER PT J AU Alfaro, EE Lauwers, GY AF Alfaro, Eduardo Enrique Lauwers, Gregory Y. TI Early Gastric Neoplasia: Diagnosis and Implications SO ADVANCES IN ANATOMIC PATHOLOGY LA English DT Review DE gastric dysplasia; gastric preneoplastic lesions; foveolar dysplasia; adenomatous dysplasia ID ENDOSCOPIC MUCOSAL RESECTION; LYMPH-NODE METASTASIS; HELICOBACTER-PYLORI INFECTION; FUNDIC GLAND POLYPS; FAMILIAL ADENOMATOUS POLYPOSIS; UPPER GASTROINTESTINAL-TRACT; PEUTZ-JEGHERS-SYNDROME; FOLLOW-UP; EPITHELIAL-DYSPLASIA; SUBMUCOSAL DISSECTION AB Early gastric neoplasia, which includes dysplasia and adenocarcinoma invading no more than the submucosa have been the subject of numerous studies in recent years. For example, different dysplastic phenotypes have been identified, in addition to the traditional adenomatous type, foveolar, pyloric, and tubule-neck dysplasia (associated with diffuse type carcinoma) have been recognized. Each subtype of dysplasia shows a different immuno-histochemical profile, and may vary in their risk of progression to adenocarcinoma. With regard to early gastric cancer the emergence of better diagnostic techniques allowed the development of endoscopic techniques such as endoscopic mucosal resection and endoscopic submucosal resection that nowadays allow optimal nonsurgical management. The purpose of this review is to discuss the current concepts in gastric dysplasia and early gastric cancer as they relate to diagnosis and management. C1 [Alfaro, Eduardo Enrique] Hosp Mexico, CCSS, Dept Pathol, San Jose, Costa Rica. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Gastrointestinal Pathol Serv, Boston, MA 02114 USA. RP Lauwers, GY (reprint author), Massachusetts Gen Hosp, Dept Pathol, Pathol Serv, 55 Fruit St,Warren 2, Boston, MA 02114 USA. EM glauwers@partners.org NR 161 TC 8 Z9 8 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-4109 J9 ADV ANAT PATHOL JI Adv. Anat. Pathol. PD JUL PY 2011 VL 18 IS 4 BP 268 EP 280 DI 10.1097/PAP.0b013e318220f792 PG 13 WC Pathology SC Pathology GA 774ZM UT WOS:000291425500002 PM 21654358 ER PT J AU Crilly, JF Keefe, RH Volpe, F AF Crilly, John F. Keefe, Robert H. Volpe, Fred TI Use of Electronic Technologies to Promote Community and Personal Health for Individuals Unconnected to Health Care Systems SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material ID PUBLIC-HEALTH; CHILDREN; IMPLEMENTATION; INFORMATION; ADHERENCE; VIOLENCE; PROGRAM AB Ensuring health care services for populations outside the mainstream health care system is challenging for all providers. But developing the health care infrastructure to better serve such unconnected individuals is critical to their health care status, to third-party payers, to overall cost savings in public health, and to reducing health disparities. Our increasingly sophisticated electronic technologies offer promising ways to more effectively engage this difficult to reach group and increase its access to health care resources. This process requires developing not only newer technologies but also collaboration between community leaders and health care providers to bring unconnected individuals into formal health care systems. We present three strategies to reach vulnerable groups, outline benefits and challenges, and provide examples of successful programs. (Am J Public Health. 2011;101:1163-1167. doi:10.2105/AJPH.2010. 300003) C1 [Crilly, John F.] Univ Rochester, Med Ctr, Dept Psychiat, Rochester, NY 14642 USA. [Crilly, John F.] US Dept Vet Affairs, Canandaigua, NY USA. [Keefe, Robert H.] SUNY Buffalo, Sch Social Work, Buffalo, NY 14260 USA. [Volpe, Fred] Substance Abuse & Mental Hlth Serv Adm, Drug Free Commun Program, Leesburg, VA USA. RP Keefe, RH (reprint author), SUNY Buffalo, Sch Social Work, 685 Baldy Hall, Buffalo, NY 14260 USA. EM rhkeefe@buffalo.edu NR 47 TC 8 Z9 9 U1 0 U2 6 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2011 VL 101 IS 7 BP 1163 EP 1167 DI 10.2105/AJPH.2010.300003 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 776DG UT WOS:000291514100007 PM 21566023 ER PT J AU Winickoff, JP McMillen, RC Vallone, DM Pearson, JL Tanski, SE Dempsey, JH Healton, C Klein, JD Abrams, D AF Winickoff, Jonathan P. McMillen, Robert C. Vallone, Donna M. Pearson, Jennifer L. Tanski, Susanne E. Dempsey, Janelle H. Healton, Cheryl Klein, Jonathan D. Abrams, David TI US Attitudes About Banning Menthol in Cigarettes: Results From a Nationally Representative Survey SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID ENVIRONMENTAL TOBACCO-SMOKE; NICOTINE DEPENDENCE; SOCIAL CLIMATE; UNITED-STATES; CESSATION; EXPOSURE; IMPACT AB Menthol is a cigarette flavoring that makes smoking more appealing to smokers. The US Food and Drug Administration (FDA) has regulatory authority to ban mentholated cigarettes to reduce youth uptake and encourage adult cessation. Survey findings indicate that more than half of all Americans (56.1%) and of Blacks alone (68.0% in one sample and 75.8% in another) support banning menthol. Endorsement of a ban especially by Blacks, who have the highest rates of menthol cigarette use would support FDA action to ban menthol to protect the public's health. (Am J Public Health. 2011;101:1234-1236. doi:10. 2105/AJPH.2011.300146) C1 [Winickoff, Jonathan P.; Dempsey, Janelle H.] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, Boston, MA 02114 USA. [Winickoff, Jonathan P.; McMillen, Robert C.; Tanski, Susanne E.; Klein, Jonathan D.] Amer Acad Pediat, Julius B Richmond Ctr Excellence, Elk Grove Village, IL USA. [Pearson, Jennifer L.; Abrams, David] Amer Legacy Fdn, Schroeder Inst Tobacco Res & Policy Studies, Washington, DC USA. [Vallone, Donna M.] Amer Legacy Fdn, Dept Res & Evaluat, Washington, DC USA. RP Winickoff, JP (reprint author), Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, 50 Stanford St,Suite 901, Boston, MA 02114 USA. EM jwinickoff@partners.org FU American Academy of Pediatrics Julius B. Richmond Center of Excellence; Flight Attendant Medical Research Institute; American Legacy Foundation FX This research was supported by the American Academy of Pediatrics Julius B. Richmond Center of Excellence and was funded by the Flight Attendant Medical Research Institute and a grant from the American Legacy Foundation. NR 21 TC 16 Z9 16 U1 1 U2 7 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2011 VL 101 IS 7 BP 1234 EP 1236 DI 10.2105/AJPH.2011.300146 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 776DG UT WOS:000291514100021 PM 21566038 ER PT J AU Lillemoe, KD AF Lillemoe, Keith D. TI Annals of Surgery The Next Generation SO ANNALS OF SURGERY LA English DT Editorial Material C1 [Lillemoe, Keith D.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lillemoe, Keith D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Lillemoe, KD (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM klillemoe@partners.org 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 0003-4932 J9 ANN SURG JI Ann. Surg. PD JUL PY 2011 VL 254 IS 1 BP 1 EP 1 DI 10.1097/SLA.0b013e318221c123 PG 1 WC Surgery SC Surgery GA 777BQ UT WOS:000291588600001 ER PT J AU Merkow, RP Bilimoria, KY McCarter, MD Cohen, ME Barnett, CC Raval, MV Caprini, JA Gordon, HS Ko, CY Bentrem, DJ AF Merkow, Ryan P. Bilimoria, Karl Y. McCarter, Martin D. Cohen, Mark E. Barnett, Carlton C. Raval, Mehul V. Caprini, Joseph A. Gordon, Howard S. Ko, Clifford Y. Bentrem, David J. TI Post-Discharge Venous Thromboembolism After Cancer Surgery Extending the Case for Extended Prophylaxis SO ANNALS OF SURGERY LA English DT Article ID QUALITY IMPROVEMENT PROGRAM; MAJOR ABDOMINAL-SURGERY; RISK-FACTORS; PULMONARY-EMBOLISM; THROMBOSIS; CHEMOTHERAPY; DEATH; COST AB Objective: To (1) define the frequency of overall and postdischarge venous thromboembolism (VTE) after cancer surgery, (2) identify VTE risk for individual cancer operations, and (3) assess mortality rates in patients who experienced a VTE. Summary and Background Data: Cancer is a known risk factor for VTE but less is known about VTE risk after specific cancer operations. Moreover, most cancer patients routinely receive VTE prophylaxis postoperatively while in the hospital, but few receive prolonged prophylaxis despite strong evidence it reduces postdischarge events. Methods: From 211 ACS NSQIP hospitals, 44,656 patients undergoing surgery for 9 cancers were identified (2006-2008). The frequency of VTE within 30-days of surgery was evaluated by cancer site and categorized as occurring before or after discharge. Multivariable logistic regression models were constructed to assess risk factors associated with VTE. Results: VTE occurred in 1.6% of all patients, most frequently after esophagogastric (4.2%) and hepatopancreaticobiliary (3.6%) surgery. Overall, 33.4% of VTEs occurred postdischarge (from 17.9% for esophagogastric to 100% for endocrine operations). Factors associated with VTE were age (>= 65 years), cancer/procedure type, metastatic disease, congestive heart failure, body mass index (BMI; >= 25 kg/m(2)), ascites, thrombocytosis (> 400,000 cells/mm(3)), albumin (< 3.0 g/dL), and operation duration (> 2 hours; all P < 0.001). Overall VTE was significantly more likely after gastrointestinal, lung, prostate, and ovarian/uterine operations (all P < 0.001). In those experiencing a VTE, mortality increased over 6-fold (8.0% vs. 1.3%; P < 0.001). Conclusion: One-third of VTE events in cancer surgery patients occurred postdischarge. Postoperative VTE was associated with operation type. Routine postdischarge VTE prophylaxis should be considered for high-risk patients. C1 [Merkow, Ryan P.; Bilimoria, Karl Y.; Raval, Mehul V.; Bentrem, David J.] Northwestern Univ, Feinberg Sch Med, Dept Surg, Jesse Brown VAMC, Chicago, IL 60611 USA. [Merkow, Ryan P.; McCarter, Martin D.; Barnett, Carlton C.] Univ Colorado, Dept Surg, Denver Sch Med, Aurora, CO USA. [Merkow, Ryan P.; Bilimoria, Karl Y.; Cohen, Mark E.; Raval, Mehul V.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Gordon, Howard S.] Univ Chicago, Pritzker Sch Med, Dept Surg, Chicago, IL 60637 USA. [Caprini, Joseph A.] Univ Illinois, Dept Med, Jesse Brown VAMC, Chicago, IL USA. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Merkow, RP (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Surg, Jesse Brown VAMC, 676 N St Clair St,Suite 650, Chicago, IL 60611 USA. EM R-Merkow@northwestern.edu RI Gordon, Howard/E-4420-2010; OI Gordon, Howard/0000-0002-6712-5954; Raval, Mehul/0000-0002-1527-2661 FU American College of Surgeons; Health Services Research Division, Department of Veterans Affairs FX Supported by the American College of Surgeons Clinical Scholars in Residence program (to R.P.M.) and Career Development Award from the Health Services Research Division, Department of Veterans Affairs (to D.J.B.). NR 33 TC 64 Z9 66 U1 1 U2 8 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 2011 VL 254 IS 1 BP 131 EP 137 DI 10.1097/SLA.0b013e31821b98da PG 7 WC Surgery SC Surgery GA 777BQ UT WOS:000291588600022 PM 21527843 ER PT J AU Martins, PNA AF Martins, Paulo Ney Aguiar TI Clinical Translation of Remote Ischemic Preconditioning of the Liver SO ANNALS OF SURGERY LA English DT Letter ID RANDOMIZED CONTROLLED-TRIAL; INJURY; OCCLUSION; SURGERY C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Transplantat, Boston, MA 02114 USA. RP Martins, PNA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Transplantat, 55 Fruit St, Boston, MA 02114 USA. EM pnmartins@partners.org NR 12 TC 1 Z9 1 U1 0 U2 4 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 2011 VL 254 IS 1 BP 180 EP 180 DI 10.1097/SLA.0b013e318221ff49 PG 1 WC Surgery SC Surgery GA 777BQ UT WOS:000291588600036 PM 21606830 ER PT J AU Carter, CS Barch, DM Bullmore, ET Breiling, J Buchanan, RW Butler, P Cohen, JD Geyer, M Gollub, R Green, MF Jaeger, J Krystal, JH Moore, H Nuechterlein, K Robbins, T Silverstein, S Smith, EE Strauss, M Wykes, T AF Carter, Cameron S. Barch, Deanna M. Bullmore, Edward T. Breiling, James Buchanan, Robert W. Butler, Pamela Cohen, Jonathan D. Geyer, Mark Gollub, Randy Green, Michael F. Jaeger, Judith Krystal, John H. Moore, Holly Nuechterlein, Keith Robbins, Trevor Silverstein, Steven Smith, Edward E. Strauss, Milton Wykes, Til TI Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia II: Developing Imaging Biomarkers to Enhance Treatment Development for Schizophrenia and Related Disorders SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Biomarker; CNTRICS; cognition; schizophrenia; treatment AB The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative, funded by an R13 from the National Institute of Mental Health, seeks to enhance translational research in treatment development for impaired cognition in schizophrenia by developing tools from cognitive neuroscience into useful measures of treatment effects on behavior and brain function. An initial series of meetings focused on the selection of a new set of tasks from cognitive neuroscience for the measurement of treatment effects on specific cognitive and neural systems. Subsequent validation and optimization studies are underway and a subset of validated measures with well-characterized psychometric properties will be generally available in 2011. This article describes results of the first meeting of the second phase of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia, which seeks to develop imaging biomarkers and improved animal models to enhance translational research. In this meeting, we considered issues related to the use of methods such as functional magnetic resonance imaging, electroencephalography, magnetoencephalography, and transcranial magnetic simulation as biomarkers for treatment development. We explored the biological nature of the signals measured by each method, their validity and reliability as measures of cognition-related neural activity, potential confounds related to drug effects on the signal of interest, and conceptual, methodological, and pragmatic issues related to their use in preclinical, first into human, and multicenter phase II and III studies. This overview article describes the background and goals of the meeting together with a summary of the major issues discussed in more detail in the accompanying articles appearing in this issue of Biological Psychiatry. C1 [Carter, Cameron S.] Univ Calif Davis, UC Davis Imaging Res Ctr, Dept Psychiat, Sacramento, CA 95816 USA. [Barch, Deanna M.] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Dept Psychiat, St Louis, MO USA. [Bullmore, Edward T.; Robbins, Trevor] Univ Cambridge, Dept Psychiat, Cambridge, England. GlaxoSmithKline, Cambridge, England. [Breiling, James] NIMH, Bethesda, MD 20892 USA. [Buchanan, Robert W.] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Butler, Pamela] SUNY, Dept Psychiat, New York, NY USA. [Cohen, Jonathan D.] Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. [Geyer, Mark] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Gollub, Randy] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Green, Michael F.] Univ Calif Los Angeles, Dept Psychiat, Semel Inst, Los Angeles, CA USA. [Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Jaeger, Judith] AstraZeneca, Wilmington, DE USA. [Krystal, John H.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Moore, Holly; Smith, Edward E.] Columbia Univ, Dept Psychiat, New York, NY USA. [Nuechterlein, Keith] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Silverstein, Steven] Univ Med & Dent New Jersey, Dept Psychiat, Newark, NJ 07103 USA. [Strauss, Milton] Univ New Mexico, Dept Psychiat, Albuquerque, NM 87131 USA. [Wykes, Til] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. RP Carter, CS (reprint author), Univ Calif Davis, UC Davis Imaging Res Ctr, Dept Psychiat, 4701 X St, Sacramento, CA 95816 USA. EM cameron.carter@ucdmc.ucdavis.edu RI Wykes, Til/B-3812-2011; Barch, Deanna/G-8638-2013; Bullmore, Edward/C-1706-2012; OI Wykes, Til/0000-0002-5881-8003; Bullmore, Edward/0000-0002-8955-8283; Gollub, Randy L./0000-0002-9434-4044 FU US Department of Veterans Affairs Alcohol Research Center; National Center for Posttraumatic Stress Disorder; Clinical Neurosciences Division, West Haven Connecticut; National Center for Research Resources, a component of the National Institutes of Health [UL1 RR024139]; National Institutes of Health Roadmap for Medical Research; GlaxoSmithKline; Allon; Novartis; Cambridge Enterprise Limited; University of Cambridge; Cypress Bioscience, Incorporated; Intracellular Therapeutics, Incorporated; Ortho-McNeil Janssen Scientific Affairs; Pfizer; Lundbeck; Eli Lilly FX Dr. Krystal acknowledges support from US Department of Veterans Affairs Alcohol Research Center, National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, West Haven, Connecticut, and Clinical and Translational Science Awards Grant Number UL1 RR024139 from the National Center for Research Resources, a component of the National Institutes of Health, and National Institutes of Health Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of National Center for Research Resources or National Institutes of Health.; Dr. Carter has served as a consultant for Pfizer, Roche, Lilly, Merck, and Servier and has received research funding from GlaxoSmithKline.; Dr. Barch has received grants from the Allon and Novartis.; Dr. Bullmore is an employee of the University of Cambridge (. 5 full-time equivalent) and GlaxoSmithKline (. 5 full-time equivalent); a stockholder in GlaxoSmithKline and the Brain Resource Company; and has received financial compensation resulting from a license agreement between Cambridge Enterprise Limited, University of Cambridge, and Cypress Bioscience, Incorporated.; Dr. Geyer has received contract research support from Intracellular Therapeutics, Incorporated, and compensation from Acadia, Addex, Amylin, Cerca Insights, Johnson & Johnson, Medivation, Merck, Omeros, Sepracor, Takeda, Teva, and Wyeth-Ayerst and holds an equity interest in San Diego Instruments.; Dr. Krystal is a consultant for Aisling Capital, LLC; AstraZeneca Pharmaceuticals; Brintnall & Nicolini, Incorporated; Easton Associates; Gilead Sciences, Incorporated; GlaxoSmithKline; Janssen Pharmaceuticals; Lundbeck Research USA; Medivation, Incorporated; Merz Pharmaceuticals; MK Medical Communications; Naurex, Incorporated; Pfizer Pharmaceuticals; F. Hoffmann-La Roche Ltd.; SK Holdings Company, Ltd.; TakedaIndustries; Teva Pharmaceutical Industries, Ltd.; and Transcept Pharmaceuticals and on the scientific advisory board of Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, and Lohocla Research Corporation. Dr. Krystal also has exercisable warrant options for Tetragenex Pharmaceuticals (value less than $150). Research support to Department of Veterans Affairs for Janssen Research Foundation (provided drug and some study support to the Department of Veterans Affairs); derives income greater than $10,000 as the Editor of Biological Psychiatry; Board Of Directors for Coalition for Translational Research in Alcohol and Substance Use Disorders; President Elect of the American College of Neuropsychopharmacology (12-2010); on the Editorial Board of the Shanghai Archives of Psychiatry; and has the following patents and inventions: 1) Seibyl JP, Krystal JH, Charney DS. Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia. Patent #: 5,447,948. September 5, 1995; 2) Dr. Krystal is aco-inventor with Dr. Gerard Sanacora on a filed patent application by Yale University related to targeting the glutamatergic system for the treatment of neuropsychiatric disorders (PCTWO06108055A1); and 3) Intranasal Administration of Ketamine to Treat Depression (pending).; Dr. Neuchterlein has received funding from Ortho-McNeil Janssen Scientific Affairs (the new name for Janssen, LP) and served as a consultant to Merck.; Dr. Robbins has stock options in Cambridge Cognition; serves as a consultant for Cambridge Cognition, Pfizer, Eli Lilly, GlaxoSmithKline, Wyeth, and Allon Therapeutics; and has received research Grants from Pfizer, GlaxoSmithKline, Lundbeck, and Eli Lilly.; Dr. Silverstein has received research funding from Pfizer and AstraZeneca. NR 10 TC 36 Z9 37 U1 0 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 1 PY 2011 VL 70 IS 1 BP 7 EP 12 DI 10.1016/j.biopsych.2011.01.041 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 776SX UT WOS:000291559300005 PM 21529781 ER PT J AU Wang, YN Irvine, DJ AF Wang, Yana Irvine, Darrell J. TI Engineering chemoattractant gradients using chemokine-releasing polysaccharide microspheres SO BIOMATERIALS LA English DT Article DE Alginate; Hydrogel; Microsphere; Chemokine; Chemotaxis; Leukocyte ID HIGH ENDOTHELIAL VENULES; ACTIVATED T-CELLS; DENDRITIC CELLS; LYMPH-NODES; IN-VIVO; B-CELLS; GLYCOSAMINOGLYCAN-BINDING; EBI1-LIGAND CHEMOKINE; IMMUNE-RESPONSE; ALGINATE BEADS AB Spatial and temporal concentration gradients of chemoattractants direct many biological processes, especially the guidance of immune cells to tissue sites during homeostasis and responses to infection. Such gradients are ultimately generated by secretion of attractant proteins from single cells or collections of cells. Here we describe cell-sized chemoattractant-releasing polysaccharide microspheres, capable of mimicking chemokine secretion by host cells and generating sustained bioactive chemokine gradients in their local microenvironment. Exploiting the common characteristic of net cationic charge and reversible glycosaminoglycan binding exhibited by many chemokines, we synthesized alginate hydrogel microspheres that could be loaded with several different chemokines (including CCL21, CCL19, CXCL12, and CXCL10) by electrostatic adsorption. These polysaccharide microspheres subsequently released the attractants over periods ranging from a few hours to at least 1 day when placed in serum-containing medium or collagen gels. The generated gradients were able to attract cells more than hundreds of microns away to make contact with individual microspheres. This versatile system for chemoattractant delivery could find applications in immunotherapy, vaccines and fundamental chemotaxis studies in vivo and in vitro. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Irvine, Darrell J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Wang, Yana] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Irvine, Darrell J.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Irvine, Darrell J.] Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02114 USA. [Irvine, Darrell J.] Harvard Univ, Boston, MA 02115 USA. [Irvine, Darrell J.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Irvine, DJ (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM djirvine@mit.edu FU Defense Advanced Research Projects Agency (DARPA); NIH [1R01EB007280] FX This work was supported in part by Defense Advanced Research Projects Agency (DARPA) and NIH (1R01EB007280). D.J.I. is an investigator of the Howard Hughes Medical Institute. NR 79 TC 27 Z9 27 U1 4 U2 33 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD JUL PY 2011 VL 32 IS 21 BP 4903 EP 4913 DI 10.1016/j.biomaterials.2011.03.027 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 776WT UT WOS:000291571400023 PM 21463892 ER PT J AU Liu, QS Wang, JH Kang, SA Thoreen, CC Hur, W Choi, HG Waller, DL Sim, T Sabatini, DM Gray, NS AF Liu, Qingsong Wang, Jinhua Kang, Seong A. Thoreen, Carson C. Hur, Wooyoung Choi, Hwan Geun Waller, David L. Sim, Taebo Sabatini, David M. Gray, Nathanael S. TI Discovery and optimization of potent and selective benzonaphthyridinone analogs as small molecule mTOR inhibitors with improved mouse microsome stability SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE mTOR; PI3K; Torin1 ID VIVO ANTITUMOR-ACTIVITY; MAMMALIAN TARGET; RAPAMYCIN MTOR; CANCER; 3-KINASE; THERAPY; PATHWAY AB Starting from small molecule mTOR inhibitor Torin1, replacement of the piperazine ring with a phenyl ring resulted in a new series of mTOR inhibitors (as exemplified by 10) that showed superior potency and selectivity for mTOR, along with significantly improved mouse liver microsome stability and a longer in vivo half-life. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Liu, Qingsong; Wang, Jinhua; Thoreen, Carson C.; Hur, Wooyoung; Choi, Hwan Geun; Waller, David L.; Sim, Taebo; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Liu, Qingsong; Wang, Jinhua; Thoreen, Carson C.; Hur, Wooyoung; Choi, Hwan Geun; Waller, David L.; Sim, Taebo; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Kang, Seong A.; Sabatini, David M.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Sabatini, David M.] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA. [Kang, Seong A.; Sabatini, David M.] MIT, Koch Ctr Integrat Canc Res, Cambridge, MA 02139 USA. RP Gray, NS (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM Nathanael_gray@dfci.harvard.edu OI liu, qing song/0000-0002-7829-2547 FU NCI NIH HHS [R01 CA129105, R01 CA129105-05] NR 22 TC 6 Z9 6 U1 2 U2 14 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 1 PY 2011 VL 21 IS 13 BP 4036 EP 4040 DI 10.1016/j.bmcl.2011.04.129 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 775PP UT WOS:000291474300041 PM 21621413 ER PT J AU Karajanagi, SS Yoganathan, R Mammucari, R Park, H Cox, J Zeitels, SM Langer, R Foster, NR AF Karajanagi, Sandeep S. Yoganathan, Roshan Mammucari, Raffaella Park, Hyoungshin Cox, Julian Zeitels, Steven M. Langer, Robert Foster, Neil R. TI Application of a Dense Gas Technique for Sterilizing Soft Biomaterials SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE dense CO(2); soft hydrogels; sterilization; bacteria; spores; PEG ID SUPERCRITICAL CARBON-DIOXIDE; TISSUE ENGINEERING APPLICATIONS; HIGH-PRESSURE CO2; BACTERIAL-SPORES; INACTIVATION; HYDROGELS; POLYMERS; BEHAVIOR; ULTRAFILTRATION; RADIATION AB Sterilization of soft biomaterials such as hydrogels is challenging because existing methods such as gamma irradiation, steam sterilization, or ethylene oxide sterilization, while effective at achieving high sterility assurance levels (SAL), may compromise their physicochemical properties and biocompatibility. New methods that effectively sterilize soft biomaterials without compromising their properties are therefore required. In this report, a dense-carbon dioxide (CO(2))-based technique was used to sterilize soft polyethylene glycol (PEG)-based hydrogels while retaining their structure and physicochemical properties. Conventional sterilization methods such as gamma irradiation and steam sterilization severely compromised the structure of the hydrogels. PEG hydrogels with high water content and low elastic shear modulus (a measure of stiffness) were deliberately inoculated with bacteria and spores and then subjected to dense CO(2). The dense CO(2)-based methods effectively sterilized the hydrogels achieving a SAL of 10(-7) without compromising the viscoelastic properties, pH, water-content, and structure of the gels. Furthermore, dense CO(2)-treated gels were biocompatible and non-toxic when implanted subcutaneously in ferrets. The application of novel dense CO(2)-based methods to sterilize soft biomaterials has implications in developing safe sterilization methods for soft biomedical implants such as dermal fillers and viscosupplements. Biotechnol. Bioeng. 2011; 108: 1716-1725. (C) 2011 Wiley Periodicals, Inc. C1 [Karajanagi, Sandeep S.; Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Karajanagi, Sandeep S.; Zeitels, Steven M.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Karajanagi, Sandeep S.; Zeitels, Steven M.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Yoganathan, Roshan; Mammucari, Raffaella; Foster, Neil R.] Univ New S Wales, Sch Chem Engn, Sydney, NSW, Australia. [Park, Hyoungshin] MIT, Harvard MIT Hlth Sci & Technol, Cambridge, MA USA. [Cox, Julian] Univ New S Wales, Fac Sci, Sydney, NSW, Australia. RP Karajanagi, SS (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA. EM skarajanagi@partners.org; n.foster@unsw.edu.au FU Eugene B. Casey Foundation FX Contract grant sponsor: Eugene B. Casey Foundation NR 42 TC 11 Z9 11 U1 4 U2 25 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD JUL PY 2011 VL 108 IS 7 BP 1716 EP 1725 DI 10.1002/bit.23105 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 775NV UT WOS:000291467600023 PM 21337339 ER PT J AU Ge, R Wang, Z Zeng, Q Xu, X Olumi, AF AF Ge, R. Wang, Z. Zeng, Q. Xu, X. Olumi, A. F. TI F-box protein 10, an NF-kappa B-dependent anti-apoptotic protein, regulates TRAIL-induced apoptosis through modulating c-Fos/c-FLIP pathway SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE c-FLIP; c-Fos; FBXL10; NF-kappa B; TRAIL; apoptosis ID PROSTATE-CANCER CELLS; CARCINOMA CELLS; DEATH RECEPTOR-5; GENE-EXPRESSION; TARGETING DEATH; LIGAND TRAIL; RESISTANCE; ACTIVATION; INHIBITOR; AP-1 AB Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces selective apoptotic death of human cancer cells while sparing normal human cells. Although TRAIL holds great promise as a potential anticancer agent, some tumors develop resistance to TRAIL. Previously, we have shown that the activator protein 1 (AP-1) family member, c-Fos, is an important modulator of apoptosis. Although F-box protein 10 (FBXL10) has been implicated to regulate an AP-1 family protein, c-Jun, its role in mediating apoptotic pathways has not been previously investigated. Here, we report that FBXL10 is a transcriptional repressor of c-Fos and a target gene of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B)-p65 in human cancers. We demonstrate that FBXL10 is an important anti-apoptotic molecule, which directly binds and represses c-Fos promoter in order for cancer cells to resist TRAIL-induced apoptosis. FBXL10 indirectly regulates c-FLIP(L) levels via c-Fos-dependent pathways. Silencing of FBXL10 sensitizes resistant cells to TRAIL, while, overexpression of FBXL10 represses TRAIL-induced apoptosis. Moreover, our results indicate that expression of FBXL10 functions via an NF-kappa B-dependent pathway, and TRAIL or proteasome inhibitors downregulate FBXL10 via inhibiting NF-kappa B signaling. Taken together, we find a novel functional role for FBXL10 as an anti-apoptotic molecule, and describe a new apoptotic-related pathway that involves NF-kappa B/FBXL10/c-Fos/c-FLIP. Therefore, silencing FBXL10 can help overcome resistant cancer cells for pro-apoptotic therapies. Cell Death and Differentiation (2011) 18, 1184-1195; doi:10.1038/cdd.2010.185; published online 21 January 2011 C1 [Ge, R.; Wang, Z.; Olumi, A. F.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Zeng, Q.; Xu, X.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02114 USA. RP Olumi, AF (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Urol, Yawkey Bldg,Suite 7E, Boston, MA 02114 USA. EM aolumi@partners.org FU New York Academy of Medicine FX This work was partially funded by support from the Edwin Beer Fellowship-New York Academy of Medicine to AFO. NR 40 TC 18 Z9 20 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD JUL PY 2011 VL 18 IS 7 BP 1184 EP 1195 DI 10.1038/cdd.2010.185 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 776RM UT WOS:000291555100011 PM 21252908 ER PT J AU Cadena, J Restrepo, MI AF Cadena, Jose Restrepo, Marcos I. TI Methicillin-Resistant Staphylococcus aureus Guidelines: A Myriad of Open Questions SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID CLINICAL-PRACTICE GUIDELINES; INFECTIOUS-DISEASES SOCIETY; VANCOMYCIN; PNEUMONIA; MULTICENTER; AMERICA C1 [Cadena, Jose] Univ Texas Hlth Sci Ctr San Antonio, S Texas Vet Hlth Care Syst, Dept Med, San Antonio, TX 78229 USA. [Cadena, Jose] S Texas Vet Hlth Care Syst, Dept Med, Hosp Epidemiol, San Antonio, TX USA. [Restrepo, Marcos I.] S Texas Vet Hlth Care Syst, Dept Med Pulm & Crit Care, VERDICT Res Ctr, San Antonio, TX USA. RP Cadena, J (reprint author), Univ Texas Hlth Sci Ctr San Antonio, S Texas Vet Hlth Care Syst, Dept Med, 7703 Floyd Curl Dr,MC 7881, San Antonio, TX 78229 USA. EM cadenazuluag@uthscsa.edu RI Restrepo, Marcos/H-4442-2014 FU NHLBI NIH HHS [K23 HL096054, K23HL096054] NR 9 TC 2 Z9 2 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2011 VL 53 IS 1 BP 97 EP U138 DI 10.1093/cid/cir278 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 776QA UT WOS:000291550700019 PM 21653313 ER PT J AU Borckardt, JJ Reeves, ST Beam, W Jensen, MP Gracely, RH Katz, S Smith, AR Madan, A Patterson, D George, MS AF Borckardt, Jeffrey J. Reeves, Scott T. Beam, Will Jensen, Mark P. Gracely, Richard H. Katz, Sophie Smith, Arthur R. Madan, Alok Patterson, David George, Mark S. TI A Randomized, Controlled Investigation of Motor Cortex Transcranial Magnetic Stimulation (TMS) Effects on Quantitative Sensory Measures in Healthy Adults Evaluation of TMS Device Parameters SO CLINICAL JOURNAL OF PAIN LA English DT Article DE transcranial magnetic stimulation; pain; motor cortex; TMS; thermal; theta ID CHRONIC NEUROPATHIC PAIN; THETA-BURST STIMULATION; BRAIN-STIMULATION; CORTICAL STIMULATION; RTMS; PERCEPTION; RELIEF; EXCITABILITY; THRESHOLDS; IMPROVEMENT AB Objectives: There is emerging evidence that transcranial magnetic stimulation (TMS) can produce analgesic effects in clinical samples and in healthy adults undergoing experimentally induced pain; and the field of minimally invasive brain stimulation for the management of pain is expanding rapidly. Although motor cortex is the most widely used cortical target for TMS in the management of neuropathic pain, few studies have systematically investigated the analgesic effects of a full range of device parameters to provide initial hints about what stimulation intensities and frequencies are most helpful (or even potentially harmful) to patients. Further, there is considerable inconsistency between studies with respect to laboratory pain measurement procedures, TMS treatment parameters, sophistication of the sham methods, and sample sizes. Methods: This study used a sham-controlled, within-subject, crossover design to examine the effects of 5 different TMS treatment parameters across several quantitative sensory measures in a sample of healthy adult volunteers. Sixty-five participants underwent quantitative sensory testing procedures pre and post-40-minutes of real and sham motor cortex TMS. TMS was delivered at 1 Hz 80% resting motor threshold (rMT), 1 Hz 100% rMT, 10 Hz 80% rMT, 10 Hz 100% rMT, or 50 Hz triplets at 90% of active motor threshold (intermittent theta-burst). Results: The mean painfulness rating of real TMS stimulation itself was 3.0 (SE = 0.36) out of 10 and was significantly greater than zero [t(64) = 8.17, P < 0.0001]. The sham TMS methods used permitted matching between real and sham TMS-induced scalp sensations and participants were successfully blinded to condition (real versus sham). Findings suggest that the effects of motor cortex TMS on quantitative sensory tests in healthy adults vary across different treatment parameters with the smallest observed effect for intermittent theta-burst stimulation (Cohen's d = 0.03) and the largest for 10 Hz 100% rMT (d = 0.34). Discussion: Overall, TMS was associated with statistically significant effects on warm and cool sensory thresholds, cold pain thresholds, suprathreshold stimulus unpleasantness ratings, and wind-up pain. With respect to device parameter effects, higher frequency stimulation seems to be associated with the most analgesic and antisensitivity effects with the exception of intermittent theta-burst stimulation. The present findings support several clinical research findings suggesting that higher TMS frequencies tend to be associated with the most clinical benefit in patients with chronic pain. C1 [Borckardt, Jeffrey J.; Katz, Sophie; Madan, Alok; George, Mark S.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Borckardt, Jeffrey J.; Reeves, Scott T.; Beam, Will; Smith, Arthur R.] Med Univ S Carolina, Dept Anesthesiol & Perioperat Med, Charleston, SC 29425 USA. [George, Mark S.] Med Univ S Carolina, Dept Neurol, Charleston, SC 29425 USA. [George, Mark S.] Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. [Jensen, Mark P.; Patterson, David] Univ Washington, Sch Med, Dept Rehabil Med, Seattle, WA 98195 USA. [Gracely, Richard H.] Univ N Carolina, Sch Dent, Dept Endodont, Ctr Neurosensory Disorders, Chapel Hill, NC USA. [George, Mark S.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Borckardt, JJ (reprint author), Med Univ S Carolina, Dept Psychiat & Behav Sci, 67 President St,IOP,5 North,518, Charleston, SC 29425 USA. EM borckard@musc.edu FU NINDS NIH HHS [K23 NS050485-01A2, K23 NS050485-03, K23 NS050485-02, K23 NS050485, K23 NS050485-04] NR 56 TC 18 Z9 20 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-8047 J9 CLIN J PAIN JI Clin. J. Pain PD JUL-AUG PY 2011 VL 27 IS 6 BP 486 EP 494 DI 10.1097/AJP.0b013e31820d2733 PG 9 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 774YR UT WOS:000291423200003 PM 21415720 ER PT J AU Banffy, MB Vrahas, MS Ready, JE Abraham, JA AF Banffy, Michael B. Vrahas, Mark S. Ready, John E. Abraham, John A. TI Nonoperative versus Prophylactic Treatment of Bisphosphonate-associated Femoral Stress Fractures SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID INSUFFICIENCY FRACTURES; ALENDRONATE THERAPY; INTERVENTION TRIAL; WOMEN; RISK AB Several studies have identified a specific fracture in the proximal diaphysis of the femur in patients treated with bisphosphonates. The fractures typically are sustained after a low-energy mechanism with the presence of an existing characteristic stress fracture. However, it is unclear whether these patients are best treated nonoperatively or operatively. What is the likelihood of nonoperatively treated bisphosphonate-associated femoral stress fractures progressing to completion and during what time period? If prophylactic fixation is performed, do patients have a shorter hospital length-of-stay compared with patients having surgical fixation after fracture completion? We retrospectively searched for patients older than 50 years receiving bisphosphonate therapy, with either incomplete, nondisplaced stress fractures or completed, displaced fractures in the proximal diaphysis of the femur between July 2002 and April 2009. After applying exclusion criteria, we identified 34 patients with a total of 40 bisphosphonate-associated fractures. The average duration of bisphosphonate use was 77 months. Twenty-eight of 40 (70%) fractures were completed, displaced fractures. Six of the 12 nondisplaced stress fractures initially were treated nonoperatively. The remaining six stress fractures were treated with prophylactic cephalomedullary nail fixation. The minimum followup was 12 months (mean, 36.5 months; range, 12-72 months). Five of the six stress fractures treated nonoperatively progressed to fracture completion and displacement at an average of 10 months (range, 3-18 months). The average hospital stay was 3.7 days for patients treated prophylactically and 6.0 days for patients treated after fracture completion. Our data suggest nonoperative treatment of bisphosphonate-related femoral stress fractures is not a reliable way to treat these fractures as the majority progress to fracture completion. Prophylactic fixation of femoral stress fractures also reduces total hospital admission time. Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. C1 [Banffy, Michael B.; Vrahas, Mark S.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Banffy, Michael B.; Vrahas, Mark S.; Ready, John E.; Abraham, John A.] Brigham & Womens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. RP Banffy, MB (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St WHT 535, Boston, MA 02114 USA. EM mbanffy@partners.org NR 23 TC 33 Z9 38 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUL PY 2011 VL 469 IS 7 BP 2028 EP 2034 DI 10.1007/s11999-011-1828-8 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 775SW UT WOS:000291484700035 PM 21350886 ER PT J AU Sackstein, R AF Sackstein, Robert TI The biology of CD44 and HCELL in hematopoiesis: the 'step 2-bypass pathway' and other emerging perspectives SO CURRENT OPINION IN HEMATOLOGY LA English DT Article DE bimolecular complex; CD44; HCELL; multistep paradigm; step 2-bypass pathway of cell migration ID L-SELECTIN LIGAND; CHONDROITIN SULFATE PROTEOGLYCAN; MEMBRANE-TYPE-1 MATRIX-METALLOPROTEINASE; HEPATOCYTE GROWTH-FACTOR; BONE-MARROW MACROPHAGES; HEPARIN-BINDING DOMAIN; CELL-ADHESION MOLECULE; ACUTE MYELOID-LEUKEMIA; HOMING RECEPTOR CD44; PROGENITOR CELLS AB Purpose of review The homing and egress of hematopoietic stem and progenitor cells (HSPCs) to and from marrow, respectively, and the proliferation and differentiation of HSPCs within marrow are complex processes critically regulated by the ordered expression and function of adhesion molecules that direct key cell-cell and cell-matrix interactions. The integral membrane molecule CD44, known primarily for its role in binding hyaluronic acid, is characteristically expressed on HSPCs. Conspicuously, human HSPCs uniquely display a specialized glycoform of CD44 known as hematopoietic cell E-/L-selectin ligand (HCELL), which is the most potent ligand for both E-selectin and L-selectin expressed on human cells. This review focuses on recent advances in our understanding of the biology of CD44 and HCELL in hematopoiesis. Recent findings New data indicate that CD44-mediated events in hematopoiesis are more complex than previously imagined. Ex-vivo glycan engineering has established that HCELL serves as a 'bone marrow homing receptor'. Moreover, biochemical studies now show that CD44 forms bimolecular complexes with a variety of membrane proteins, one of which is VLA-4. Engagement of CD44 or of HCELL directly induces VLA-4 activation via G-protein-dependent signaling, triggering a 'step 2-bypass pathway' of cell migration, and extravascular lodgment, in absence of chemokine receptor engagement. Summary Recent studies have further clarified the roles of CD44 and its glycoform HCELL in hematopoietic processes, providing key insights on how targeting these molecules may be beneficial in promoting hematopoiesis and in treating hematologic malignancies. C1 [Sackstein, Robert] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Sackstein, Robert] Harvard Univ, Sch Med, Harvard Skin Dis Res Ctr, Boston, MA USA. [Sackstein, Robert] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Sackstein, Robert] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Sackstein, R (reprint author), 77 Ave Louis Pasteur,Suite 671, Boston, MA 02115 USA. EM rsackstein@rics.bwh.harvard.edu FU National Institutes of Health [HL60528, HL073714, CA121335] FX I wish to thank my colleagues for their past and present landmark contributions to our understanding of CD44 biology, and express regret to those whose work could be not discussed nor cited because of space considerations. I am also forever grateful to my talented and devoted co-workers over the past three decades for their great assistance in helping me to elucidate the structure and biology of HCELL. This work was supported by National Institutes of Health grants HL60528, HL073714, and CA121335. NR 120 TC 24 Z9 25 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1065-6251 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD JUL PY 2011 VL 18 IS 4 BP 239 EP 248 DI 10.1097/MOH.0b013e3283476140 PG 10 WC Hematology SC Hematology GA 774ZP UT WOS:000291426000007 PM 21546828 ER PT J AU Issa, GC Leblebjian, H Roccaro, AM Ghobrial, IM AF Issa, Ghayas C. Leblebjian, Houry Roccaro, Aldo M. Ghobrial, Irene M. TI New insights into the pathogenesis and treatment of Waldenstrom macroglobulinemia SO CURRENT OPINION IN HEMATOLOGY LA English DT Article DE microenvironment; novel agents; pathogenesis; treatment; Waldenstrom ID PHASE-II TRIAL; CHRONIC LYMPHOCYTIC-LEUKEMIA; MULTIPLE-MYELOMA; IN-VITRO; WEEKLY BORTEZOMIB; TUMOR-SUPPRESSOR; B-LYMPHOCYTES; PLASMA-CELLS; CANCER; RITUXIMAB AB Purpose of review Waldenstrom macroglobulinemia is a distinct low-grade lymphoproliferative disease. There have been recent significant advances in understanding the underlying pathogenesis of this disease, including genetic and epigenetic regulators of tumor progression. Recent findings Current studies have shown that the tumor microenvironment plays a critical role in cell proliferation, dissemination, and drug resistance. Summary This review provides an update of the advances in the pathogenesis of factors both intrinsic (in the tumor clone) and extrinsic (in the bone marrow microenvironment) that regulate tumor progression in Waldenstrom macroglobulinemia. We next discuss novel agents that have been recently tested in clinical trials based on the advances observed in the pathogenesis of Waldenstrom macroglobulinemia. C1 [Leblebjian, Houry; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pharm, Boston, MA 02115 USA. RP Ghobrial, IM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pharm, 44 Binney St, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu OI Roccaro, Aldo/0000-0002-1872-5128 FU International Waldenstrom Macroglobulinemia Foundation (IWMF); Kirsch Lab for Waldenstrom; Heje Fellowship for Waldenstrom Macroglobulinemia; [1R01FD003743-01] FX This study was supported in part by 1R01FD003743-01, the International Waldenstrom Macroglobulinemia Foundation (IWMF), Kirsch Lab for Waldenstrom, and Heje Fellowship for Waldenstrom Macroglobulinemia. NR 70 TC 7 Z9 8 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1065-6251 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD JUL PY 2011 VL 18 IS 4 BP 260 EP 265 DI 10.1097/MOH.0b013e3283474e5b PG 6 WC Hematology SC Hematology GA 774ZP UT WOS:000291426000010 PM 21519243 ER PT J AU Motiwala, SR Wang, TJ AF Motiwala, Shweta R. Wang, Thomas J. TI Vitamin D and cardiovascular disease SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE blood pressure; cardiovascular disease; coronary artery disease; diabetes mellitus; hyperlipidemia; vitamin D ID CORONARY-ARTERY CALCIFICATION; NUTRITION EXAMINATION SURVEY; 25-HYDROXYVITAMIN D LEVELS; BETA-CELL FUNCTION; CALCIUM/VITAMIN-D SUPPLEMENTATION; RANDOMIZED CONTROLLED-TRIAL; TYPE-2 DIABETES-MELLITUS; RENIN-ANGIOTENSIN SYSTEM; INSULIN-RECEPTOR GENE; SMOOTH-MUSCLE-CELLS AB Purpose of review Vitamin D plays a role in many biochemical pathways outside of bone and calcium metabolism, including the cardiovascular system. Prior studies have linked vitamin D deficiency to hypertension, dyslipidemia, diabetes mellitus, and coronary artery disease. In this review, we summarize existing studies investigating these associations, specifically those addressing potential mechanisms, epidemiologic associations, and possible benefits of supplementation. Recent findings Experimental studies have demonstrated that activated vitamin D reduces neurohormonal activation, inhibits inflammation, and suppresses ventricular hypertrophy. Both retrospective and prospective observational studies have related vitamin D levels with cardiometabolic risk factors and outcomes. To date, there have been a small number of randomized controlled trials investigating the effects of vitamin D supplementation on cardiovascular structure and function, but results have been inconclusive or conflicting. Summary Experimental and clinical evidence suggests a link between vitamin D deficiency and cardiovascular disease. Nonetheless, it remains unclear how many of the reported associations are causal. Well designed prospective randomized controlled trials are necessary to further investigate the appropriate role of vitamin D supplementation for cardiovascular risk reduction. C1 [Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. [Motiwala, Shweta R.] Harvard Univ, Dept Med, Sch Med, Boston, MA 02114 USA. RP Wang, TJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM tjwang@partners.org FU NIH; American Heart Association; Diasorin Inc. FX T.J.W. has received research support from the NIH, the American Heart Association, and Diasorin Inc. and has participated on the scientific advisory board of Diasorin Inc. NR 92 TC 25 Z9 26 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD JUL PY 2011 VL 20 IS 4 BP 345 EP 353 DI 10.1097/MNH.0b013e3283474985 PG 9 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 774ZZ UT WOS:000291427100004 PM 21519252 ER PT J AU Colby, KA Koo, EB AF Colby, Kathryn A. Koo, Euna B. TI Expanding indications for the Boston keratoprosthesis SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article DE artificial cornea; Boston keratoprosthesis; corneal blindness; corneal transplant ID TYPE-1 KERATOPROSTHESIS; OUTCOMES; MULTICENTER; EXPERIENCE; KERATITIS; ANIRIDIA; GLAUCOMA; DISEASE; SURGERY AB Purpose of review To review emerging indications for the Boston keratoprosthesis (KPro) and to discuss current research underway to improve clinical outcomes. Recent findings In addition to multiple failed corneal grafts, other ocular conditions for which the Boston KPro has been used include herpetic keratitis, aniridia, autoimmune ocular disorders, and pediatric corneal opacities. In the recent years, the KPro has been implanted for various other conditions and has also been explored as a cost-effective treatment for severe corneal diseases internationally. Cicatricial and inflammatory ocular conditions remain the most difficult cases for KPro use but studies investigating various immunomodulators and biologic materials for improved retention are ongoing. Postoperative management of glaucoma is critical for preserving the visual gains achieved with the Boston KPro. Current studies are evaluating novel devices for intraocular pressure measurement. Summary Accrued experience with the Boston KPro has demonstrated its versatility but also the difficulties that remain in postoperative management. With many studies underway to improve cost-effectiveness, intra-operative and postoperative management, keratoprostheses will be made increasingly available to those countries most in need. C1 [Colby, Kathryn A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Sch Med, Boston, MA 02114 USA. [Koo, Euna B.] Univ Florida, Coll Med, Gainesville, FL USA. RP Colby, KA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Sch Med, 243 Charles St, Boston, MA 02114 USA. EM KAColby@meei.harvard.edu NR 42 TC 38 Z9 40 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8738 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD JUL PY 2011 VL 22 IS 4 BP 267 EP 273 DI 10.1097/ICU.0b013e3283477d0d PG 7 WC Ophthalmology SC Ophthalmology GA 775AQ UT WOS:000291429100010 PM 21537184 ER PT J AU Stolzmann, P Goetti, R Baumueller, S Plass, A Falk, V Scheffel, H Feuchtner, G Marincek, B Alkadhi, H Leschka, S AF Stolzmann, Paul Goetti, Robert Baumueller, Stephan Plass, Andre Falk, Volkmar Scheffel, Hans Feuchtner, Gudrun Marincek, Borut Alkadhi, Hatem Leschka, Sebastian TI Prospective and retrospective ECG-gating for CT coronary angiography perform similarly accurate at low heart rates SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE Dual-source CT; Coronary angiography; Diagnostic performance; Low heart rate; Prospectively ECG-gated; Retrospectively ECG-gated ID MULTISLICE COMPUTED-TOMOGRAPHY; DUAL-SOURCE CT; ARTERY-DISEASE; DIAGNOSTIC-ACCURACY; IMAGE QUALITY; SHOOT MODE AB Objective: To compare, in patients with suspicion of coronary artery disease (CAD) and low heart rates, image quality, diagnostic performance, and radiation dose values of prospectively and retrospectively electrocardiography (ECG)-gated dual-source computed tomography coronary angiography (CTCA) for the diagnosis of significant coronary stenoses. Materials and methods: Two-hundred consecutive patients with heart rates <= 70 bpm were retrospectively enrolled; 100 patients undergoing prospectively ECG-gated CTCA (group 1) and 100 patients undergoing retrospectively-gated CTCA (group 2). Coronary artery segments were assessed for image quality and significant luminal diameter narrowing. Sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), and accuracy of both CTCA groups were determined using conventional catheter angiography (CCA) as reference standard. Radiation dose values were calculated. Results: Both groups were comparable regarding gender, body weight, cardiovascular risk profile, severity of CAD, mean heart rate, heart rate variability, and Agatston score (all p > 0.05). There was no significant difference in the rate of non-assessable coronary segments between group 1 (1.6%, 24/1404) and group 2 (1.4%, 19/1385; p = 0.77); non-diagnostic image quality was significantly (p < 0.001) more often attributed to stair step artifacts in group 1. Segment-based sensitivity, specificity, PPV, NPV, and accuracy were 98%, 98%, 88%, 100%, and 100% among group 1; 96%, 99%, 90%, 100%, and 98% among group 2, respectively. Parameters of diagnostic performance were similar (all p > 0.05). Mean effective radiation dose of prospectively ECG-gated CTCA (2.2 +/- 0.4 mSv) was significantly (p < 0.0001) smaller than that of retrospectively ECG-gated CTCA (8.1 +/- 0.6 mSv). Conclusion: Prospectively ECG-gated CTCA yields similar image quality, performs as accurately as retrospectively ECG-gated CTCA in patients having heart rates <= 70 bpm while being associated with a lower mean effective radiation dose. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Stolzmann, Paul; Goetti, Robert; Baumueller, Stephan; Scheffel, Hans; Feuchtner, Gudrun; Marincek, Borut; Alkadhi, Hatem; Leschka, Sebastian] Univ Zurich Hosp, Inst Diagnost Radiol, CH-8091 Zurich, Switzerland. [Plass, Andre; Falk, Volkmar] Univ Zurich Hosp, Cardiovasc Surg Clin, CH-8091 Zurich, Switzerland. [Alkadhi, Hatem] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Alkadhi, Hatem] Harvard Univ, Sch Med, Boston, MA USA. RP Stolzmann, P (reprint author), Univ Zurich Hosp, Inst Diagnost Radiol, Raemistr 100, CH-8091 Zurich, Switzerland. EM paul.stolzmann@usz.ch RI Goetti, Robert/I-8961-2012 FU National Center of Competence in Research, Computer Aided and Image Guided Medical Interventions of the Swiss National Science Foundation FX This research has been supported by the National Center of Competence in Research, Computer Aided and Image Guided Medical Interventions of the Swiss National Science Foundation. NR 20 TC 20 Z9 27 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X J9 EUR J RADIOL JI Eur. J. Radiol. PD JUL PY 2011 VL 79 IS 1 BP 85 EP 91 DI 10.1016/j.ejrad.2009.12.016 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 775PC UT WOS:000291472300015 PM 20079993 ER PT J AU Schutz, FAB Bellmunt, J Rosenberg, JE Choueiri, TK AF Schutz, Fabio A. B. Bellmunt, Joaquim Rosenberg, Jonathan E. Choueiri, Toni K. TI Vinflunine: drug safety evaluation of this novel synthetic vinca alkaloid SO EXPERT OPINION ON DRUG SAFETY LA English DT Review DE antitubulin; bladder cancer; javlor; microtubule inhibitor; safety; transitional cell cancer; urothelial cancer; vinca alkaloid; vinflunine ID CELL LUNG-CANCER; PLATINUM-CONTAINING REGIMEN; PHASE-II TRIAL; METASTATIC UROTHELIAL CARCINOMA; EVERY 3 WEEKS; 2ND-LINE TREATMENT; BLADDER-CANCER; ANTITUMOR-ACTIVITY; SUPPORTIVE CARE; BREAST-CANCER AB Introduction: Vinca alkaloid agents have been widely used in several different types of malignancies. However, cancer cells, ultimately, develop resistance to these agents. Therefore, the development of new agents with improved efficacy is warranted. Recently, a new synthetic vinca alkaloid, vinflunine, was developed through the addition of two fluor molecules by superacidic chemistry. Areas covered: The authors describe the development of the new vinca alkaloid vinflunine from preclinical studies to the late-stage clinical trials, highlighting the most important clinical and safety data of vinflunine. In vitro and in vivo studies have shown a superior efficacy of vinflunine over other vinca alkaloids and with an improved safety profile. Early clinical trials have demonstrated a significant activity of vinflunine against different malignancies. Phase III trials showed that vinflunine increases survival in patients with advanced transitional cell carcinoma of the urothelium (TCCU) tract treated in the second-line and is as effective as docetaxel in second-line NSCLC. Expert opinion: Vinflunine is currently approved in Europe for the treatment of second-line TCCU and is currently being developed in other malignancies. It has been shown to have predictable and manageable adverse effects, such as neutropenia, anemia, constipation and fatigue. C1 [Bellmunt, Joaquim] Univ Hosp Mar, Dept Med Oncol, Barcelona 08003, Spain. [Schutz, Fabio A. B.; Rosenberg, Jonathan E.; Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Bellmunt, J (reprint author), Univ Hosp Mar, Dept Med Oncol, Passeig Maritim 25-29, Barcelona 08003, Spain. EM jbellmunt@imas.imim.es NR 37 TC 8 Z9 8 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1474-0338 J9 EXPERT OPIN DRUG SAF JI Expert Opin. Drug Saf. PD JUL PY 2011 VL 10 IS 4 BP 645 EP 653 DI 10.1517/14740338.2011.581660 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 776KR UT WOS:000291533800014 PM 21524237 ER PT J AU Pers, TH Hansen, NT Lage, K Koefoed, P Dworzynski, P Miller, ML Flint, TJ Mellerup, E Dam, H Andreassen, OA Djurovic, S Melle, I Borglum, AD Werge, T Purcell, S Ferreira, MA Kouskoumvekaki, I Workman, CT Hansen, T Mors, O Brunak, S AF Pers, Tune H. Hansen, Niclas Tue Lage, Kasper Koefoed, Pernille Dworzynski, Piotr Miller, Martin Lee Flint, Tracey J. Mellerup, Erling Dam, Henrik Andreassen, Ole A. Djurovic, Srdjan Melle, Ingrid Borglum, Anders D. Werge, Thomas Purcell, Shaun Ferreira, Manuel A. Kouskoumvekaki, Irene Workman, Christopher T. Hansen, Torben Mors, Ole Brunak, Soren TI Meta-Analysis of Heterogeneous Data Sources for Genome-Scale Identification of Risk Genes in Complex Phenotypes SO GENETIC EPIDEMIOLOGY LA English DT Article DE genome-wide association; meta-analysis; data integration; bipolar disorder; type 2 diabetes ID PROTEIN-INTERACTION NETWORK; CANDIDATE DISEASE GENES; 7 COMMON DISEASES; ETA CHAIN GENE; WIDE ASSOCIATION; BIPOLAR DISORDER; GLUCOCORTICOID-RECEPTOR; SUSCEPTIBILITY LOCI; PATHWAY ANALYSIS; TRYPTOPHAN-HYDROXYLASE AB Meta-analyses of large-scale association studies typically proceed solely within one data type and do not exploit the potential complementarities in other sources of molecular evidence. Here, we present an approach to combine heterogeneous data from genome-wide association (GWA) studies, protein-protein interaction screens, disease similarity, linkage studies, and gene expression experiments into a multi-layered evidence network which is used to prioritize the entire protein-coding part of the genome identifying a shortlist of candidate genes. We report specifically results on bipolar disorder, a genetically complex disease where GWA studies have only been moderately successful. We validate one such candidate experimentally, YWHAH, by genotyping five variations in 640 patients and 1,377 controls. We found a significant allelic association for the rs1049583 polymorphism in YWHAH (adjusted P = 5.6e-3) with an odds ratio of 1.28 [1.12-1.48], which replicates a previous case-control study. In addition, we demonstrate our approach's general applicability by use of type 2 diabetes data sets. The method presented augments moderately powered GWA data, and represents a validated, flexible, and publicly available framework for identifying risk genes in highly polygenic diseases. The method is made available as a web service at www.cbs.dtu.dk/services/metaranker. Genet. Epidemiol. 35 : 318-332, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Brunak, Soren] Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, DK-2800 Lyngby, Denmark. [Pers, Tune H.] Copenhagen Univ Hosp, Ctr Hlth & Soc, Inst Prevent Med, Copenhagen, Denmark. [Lage, Kasper] Massachusetts Gen Hosp, MassGeneral Hosp Children, Pediat Surg Res Labs, Boston, MA 02114 USA. [Lage, Kasper] Harvard Univ, Sch Med, Boston, MA USA. [Lage, Kasper; Purcell, Shaun; Ferreira, Manuel A.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Lage, Kasper; Brunak, Soren] Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark. [Koefoed, Pernille; Mellerup, Erling] Univ Copenhagen, Lab Neuropsychiat, Dept Neurosci & Pharmacol, Copenhagen, Denmark. [Koefoed, Pernille; Mellerup, Erling; Dam, Henrik] Rigshosp, Ctr Psychiat, DK-2100 Copenhagen, Denmark. [Flint, Tracey J.; Borglum, Anders D.; Mors, Ole] Aarhus Univ Hosp, Ctr Psychiat Res, Risskov, Denmark. [Andreassen, Ole A.; Djurovic, Srdjan; Melle, Ingrid] Univ Oslo, Oslo Univ Hosp, Div Mental Hlth & Addict, Top Project, Oslo, Norway. [Andreassen, Ole A.; Djurovic, Srdjan; Melle, Ingrid] Univ Oslo, Inst Clin Med, Oslo, Norway. [Borglum, Anders D.] Univ Aarhus, Inst Human Genet, Aarhus, Denmark. [Werge, Thomas] Copenhagen Univ Hosp, Mental Hlth Ctr Sct Hans, Res Inst Biol Psychiat, Roskilde, Denmark. [Purcell, Shaun; Ferreira, Manuel A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Hansen, Torben] Hagedorn Res Inst, Gentofte, Denmark. [Hansen, Torben] Univ Copenhagen, Marie Krogh Ctr Metab Res, Copenhagen, Denmark. RP Brunak, S (reprint author), Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, Bldg 208, DK-2800 Lyngby, Denmark. EM brunak@cbs.dtu.dk RI Ferreira, Manuel/D-3609-2013; Miller, Martin/D-4660-2009; Workman, Christopher/K-1066-2015; Melle, Ingrid /B-4858-2011; OI Workman, Christopher/0000-0002-2210-3743; Melle, Ingrid /0000-0002-9783-548X; Kouskoumvekaki, Irene/0000-0003-2333-8453; Miller, Martin L/0000-0003-3161-8690; Andreassen, Ole A./0000-0002-4461-3568 FU Danish Research Council for Technology and Production Sciences [274-06-0301]; Villum Kann Rasmussen Foundation; Danish Strategic Research Council; Danish Medical Research Council; Stanley Medical Research Institute; Lundbeck Foundation; Novo Nordisk Foundation; Research Council of Norway; South-Eastern Norway Health Authorities; EU [PIAP-GA-2008-218251] FX Contract grant sponsor: Danish Research Council for Technology and Production Sciences; Contract grant number: 274-06-0301; Contract grant sponsors: Villum Kann Rasmussen Foundation; Danish Strategic Research Council; Danish Medical Research Council; Stanley Medical Research Institute; Lundbeck Foundation; Novo Nordisk Foundation; Research Council of Norway; South-Eastern Norway Health Authorities; EU grant PsychGene; Contract grant number: PIAP-GA-2008-218251. NR 116 TC 20 Z9 20 U1 2 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUL PY 2011 VL 35 IS 5 BP 318 EP 332 DI 10.1002/gepi.20580 PG 15 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 777CI UT WOS:000291591100004 PM 21484861 ER PT J AU Billings, CJ Tremblay, KL Miller, CW AF Billings, Curtis J. Tremblay, Kelly L. Miller, Christi W. TI Aided cortical auditory evoked potentials in response to changes in hearing aid gain SO INTERNATIONAL JOURNAL OF AUDIOLOGY LA English DT Article DE Cortical auditory evoked potentials (CAEPs); Event-related potentials (ERPs); Signals in noise; Signal-to-noise ratio (SNR); N1; Auditory cortex; Hearing aids; Amplification ID TO-NOISE RATIO; STIMULUS-INTENSITY; SPEECH SOUNDS; INFANTS AB Objective : There is interest in using cortical auditory evoked potentials (CAEPs)to evaluate hearing aid fittings and experience-related plasticity associated with amplification; however, little is known about hearing aid signal processing effects on these responses. The purpose of this study was to determine the effect of clinically relevant hearing aid gain settings, and the resulting in-the-canal signal-to-noise ratios (SNRs), on the latency and amplitude of P1, N1, and P2 waves. Design & Sample : Evoked potentials and in-the-canal acoustic measures were recorded in nine normal-hearing adults in unaided and aided conditions. In the aided condition, a 40-dB signal was delivered to a hearing aid programmed to provide four levels of gain (0, 10, 20, and 30 dB). As a control, unaided stimulus levels were matched to aided condition outputs (i.e. 40, 50, 60, and 70 dB)for comparison purposes. Results : When signal levels are defined in terms of output level, aided CAEPs were surprisingly smaller and delayed relative to unaided CAEPs, probably resulting from increases to noise levels caused by the hearing aid. Discussion : These results reinforce the notion that hearing aids modify stimulus characteristics such as SNR, which in turn affects the CAEP in a way that does not reliably reflect hearing aid gain. C1 [Billings, Curtis J.] Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, Portland, OR 97239 USA. [Billings, Curtis J.] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97201 USA. [Tremblay, Kelly L.; Miller, Christi W.] Univ Washington, Dept Speech & Hearing Sci, Seattle, WA 98195 USA. RP Billings, CJ (reprint author), Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, 3710 SW US Vet Hosp Rd NCRAR, Portland, OR 97239 USA. EM curtis.billings2@va.gov FU National Institutes of Health through the National Institute on Deafness and Other Communication Disorders; Department of Veterans Affairs through the Rehabilitation Research and Development Service [F31-DC007296, C6971M, R01-DC007705, P30-DC004661] FX The authors wish to thank Pamela Souza for helpful discussions about these data, and Wendy Tolin for assistance with data processing. This work was supported by the National Institutes of Health through the National Institute on Deafness and Other Communication Disorders, and the Department of Veterans Affairs through the Rehabilitation Research and Development Service [F31-DC007296 and C6971M (CJB); R01-DC007705 (KLT); P30-DC004661]. NR 28 TC 14 Z9 19 U1 1 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1499-2027 J9 INT J AUDIOL JI Int. J. Audiol. PD JUL PY 2011 VL 50 IS 7 BP 459 EP 467 DI 10.3109/14992027.2011.568011 PG 9 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 776RB UT WOS:000291553800004 PM 21486122 ER PT J AU Clarke, BA Mulligan, AM Irving, JA McCluggage, WG Oliva, E AF Clarke, Blaise Alexander Mulligan, Anna Marie Irving, Julie A. McCluggage, W. Glenn Oliva, Esther TI Mullerian Adenosarcomas With Unusual Growth Patterns: Staging Issues SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Adenosarcoma; Staging; Federation of International Gynecologic Organization; Adenomyosis; Intramural; Synchronous ID ENDOMETRIAL ADENOCARCINOMA; CLINICOPATHOLOGICAL ANALYSIS; MYOMETRIAL INVASION; TAMOXIFEN THERAPY; ADENOMYOSIS; UTERUS; CARCINOMA; TUMOR AB Uterine adenosarcomas are uncommon mixed Mullerian neoplasms, most commonly arising in the uterine corpus. A new Federation of International Gynecologic Organization staging system for these tumors has recently been implemented. This staging system is an improvement on the earlier generic application of the 1988 Federation of International Gynecologic Organization staging system for endometrial cancer to adenosarcoma. Herein, we report 3 uterine adenosarcomas with unusual features. For 2 of these, no specific staging guidelines are provided by either the earlier or, more importantly, the new staging system. The first case is of an adenosarcoma arising in the eutopic endometrium with involvement of underlying adenomyosis without myometrial invasion; the second originated in a mural adenomyoma in the absence of eutopic endometrial involvement; and the third case encompassed synchronous endometrial and extrauterine (peritoneal) neoplasms. Such cases are rare, and there is insufficient evidence to be definitive about staging. Thus, we suggest a descriptive reporting strategy for adenosarcomas with these unusual features. We also propose a reporting nomenclature for such cases to ensure standardization such that they can be adequately recorded in synoptic reporting protocols. This will facilitate reliable data collection such that an evidence-based staging system for these scenarios may be derived. C1 [Clarke, Blaise Alexander] Univ Hlth Network, Dept Pathol, Toronto, ON M5G 2C4, Canada. [Mulligan, Anna Marie] Univ Toronto, St Michaels Hosp, Dept Lab Med, Toronto, ON M5B 1W8, Canada. [Irving, Julie A.] Royal Jubilee Hosp, Dept Pathol, Vancouver, BC, Canada. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [McCluggage, W. Glenn] Royal Grp Hosp Trust, Dept Pathol, Belfast, Antrim, North Ireland. [Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Clarke, BA (reprint author), Univ Hlth Network, Dept Pathol, 200 Elizabeth St,11th Floor,Eaton Wing, Toronto, ON M5G 2C4, Canada. EM blaise.clarke@uhn.on.ca NR 24 TC 7 Z9 7 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD JUL PY 2011 VL 30 IS 4 BP 340 EP 347 DI 10.1097/PGP.0b013e31820b341e PG 8 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA 774ZO UT WOS:000291425900004 PM 21623203 ER PT J AU Condray, R Dougherty, GG Keshavan, MS Reddy, RD Haas, GL Montrose, DM Matson, WR McEvoy, J Kaddurah-Daouk, R Yao, JK AF Condray, Ruth Dougherty, George G., Jr. Keshavan, Matcheri S. Reddy, Ravinder D. Haas, Gretchen L. Montrose, Debra M. Matson, Wayne R. McEvoy, Joseph Kaddurah-Daouk, Rima Yao, Jeffrey K. TI 3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Cognition; first-episode psychosis; 3-hydroxykynurenine; neuroleptic-naive; neurological symptoms; schizophrenia; tryptophan ID ENDOGENOUS KYNURENIC ACID; GLOBAL BIOCHEMICAL APPROACH; NMDA RECEPTOR; CEREBROSPINAL-FLUID; GLYCINE SITE; BRAIN; RAT; PSYCHOSIS; SCALE; SIGNS AB One branch of the tryptophan catabolic cascade is the kynurenine pathway, which produces neurotoxic [3-hydroxykynurenine (3-OHKY), quinolinic acid] and neuroinhibitory (kynurenic acid) compounds. Kynurenic acid acts as a competitive antagonist at the glycine site of N-methyl-D-asparate receptors at high concentrations and as a non-competitive antagonist on the alpha(7)-nicotinic acetylcholine receptor at low concentrations. Kynurenine compounds also influence cognitive functions known to be disrupted in schizophrenia. Alterations in tryptophan metabolism are therefore of potential significance for the pathophysiology of this disorder. In this paper, tryptophan metabolites were measured from plasma using high-pressure liquid chromatography coupled with electrochemical coulometric array detection, and relationships were tested between these metabolic signatures and clinical symptoms for 25 first-episode neuroleptic-naive schizophrenia patients. Blood samples were collected and clinical and neurological symptoms were rated at baseline and again at 4 wk following initiation of treatment. Level of 3-OHKY and total clinical symptom scores were correlated when patients were unmedicated and neuroleptic-naive, and this relationship differed significantly from the correlation observed for patients 4 wk after beginning treatment. Baseline psychosis symptoms were predicted only by neurological symptoms. Moreover, baseline 3-OHKY predicted clinical change at 4 wk, with the lowest concentrations of 3-OHKY being associated with the greatest improvement in symptoms. Taken together, our findings suggest a neurotoxic product of tryptophan metabolism, 3-OHKY, predicts severity of clinical symptoms during the early phase of illness and before exposure to antipsychotic drugs. Baseline level of 3-OHKY may also predict the degree of clinical improvement following brief treatment with antipsychotics. C1 [Condray, Ruth; Dougherty, George G., Jr.; Reddy, Ravinder D.; Haas, Gretchen L.; Yao, Jeffrey K.] VA Pittsburgh Healthcare Syst, Med Res Serv, Pittsburgh, PA USA. [Condray, Ruth; Dougherty, George G., Jr.; Keshavan, Matcheri S.; Reddy, Ravinder D.; Haas, Gretchen L.; Montrose, Debra M.; Yao, Jeffrey K.] Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA USA. [Keshavan, Matcheri S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Keshavan, Matcheri S.] Harvard Univ, Dept Psychiat, Boston, MA 02115 USA. [Matson, Wayne R.] Bedford VA Med Ctr, Med Res Serv, Bedford, MA USA. [McEvoy, Joseph] John Umstead Hosp, Dept Psychiat, Butner, NC USA. [McEvoy, Joseph; Kaddurah-Daouk, Rima] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. [Yao, Jeffrey K.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. RP Yao, JK (reprint author), VA Pittsburgh Healthcare Syst 151U II, Neurochem & Psychopharmacol Lab, Bldg 13,7180 Highland Dr, Pittsburgh, PA 15206 USA. EM jkyao@pitt.edu FU GlaxoSmithKline; Department of Veterans Affairs; Veterans Health Administration; Office of Research and Development, Biomedical Laboratory R D; VA Pittsburgh Healthcare System; National Institute of Mental Health [MH58141, MH64118, MH45203, MH84941]; National Institute of General Medical Sciences [R24 GM078233] FX This material is based on work supported by grants from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory R & D [Merit Reviews (J.K.Y.) and Senior Research Career Scientist Award (J.K.Y.)], VA Pittsburgh Healthcare System (J.K.Y., G.G.D., R.D.R.), National Institute of Mental Health [MH58141 (J.K.Y.), MH64118 (R. D. R.), MH45203 (M. S. K), and MH84941 (R. K. D.)], National Institute of General Medical Sciences [R24 GM078233 (R. K. D.)]. The authors are grateful to Dr Nina Schooler and Dr Cameron Carter, and the clinical core staff of the Center for the Neuroscience of Mental Disorders (MH45156, David Lewis, M. D., Director) for their assistance in diagnostic and psychopathological assessments, and to P. Cheng, C. Korbanic and J. Haflett for their technical assistance. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.; Dr McEvoy received honoraria from Lilly, and grant support from GlaxoSmithKline, Pfizer and Dainippon Sumitomo Pharmaceuticals America. Dr Kaddurah-Daouk is an equity holder in Metabolon Inc., a biotechnology company in the metabolomics domain, and also holds patent in this field. NR 66 TC 32 Z9 34 U1 2 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUL PY 2011 VL 14 IS 6 BP 756 EP 767 DI 10.1017/S1461145710001689 PG 12 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 777JF UT WOS:000291611000004 PM 21275080 ER PT J AU Prates, RA Kato, IT Ribeiro, MS Tegos, GP Hamblin, MR AF Prates, Renato A. Kato, Ilka T. Ribeiro, Martha S. Tegos, George P. Hamblin, Michael R. TI Influence of multidrug efflux systems on methylene blue-mediated photodynamic inactivation of Candida albicans SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE ABC transporters; major facilitator superfamily; photodynamic therapy; photosensitizer; verapamil ID STAPHYLOCOCCUS-AUREUS; PUMP INHIBITORS; TOLUIDINE-BLUE; ANTIMICROBIAL PHOTOINACTIVATION; PHOTOBACTERICIDAL ACTIVITY; ANTIFUNGAL AGENTS; ESCHERICHIA-COLI; THERAPY; RESISTANCE; BACTERIA AB Objectives: To investigate whether the major fungal multidrug efflux systems (MESs) affect the efficiency of methylene blue (MB)-mediated antimicrobial photodynamic inactivation (APDI) in pathogenic fungi and test specific inhibitors of these efflux systems to potentiate APDI. Methods: Candida albicans wild-type and mutants that overexpressed two classes of MESs [ATP-binding cassette (ABC) and major facilitator superfamily (MFS)] were tested for APDI using MB as the photosensitizer with and without addition of MES inhibitors. The uptake and cytoplasm localization of photosensitizer were achieved using laser confocal microscopy. Results: ABC MES overexpression reduced MB accumulation and APDI killing more than MFS MES overexpression. Furthermore, by combining MB APDI with the ABC inhibitor verapamil, fungal killing and MB uptake were potentiated, while by combining MB APDI with the MFS inhibitor INF(271), fungal killing and MB uptake were inhibited. This latter surprising finding may be explained by the hypothesis that the MFS channel can also serve as an uptake mechanism for MB. Conclusions: The ABC pumps are directly implicated in MB efflux from the cell cytoplasm. Both the influx and efflux of MB may be regulated by MFS systems, and blocking this gate before incubation with MB can decrease the uptake and APDI effects. An ABC inhibitor could be usefully combined with MB APDI for treating C. albicans infections. C1 [Tegos, George P.; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Prates, Renato A.; Kato, Ilka T.; Ribeiro, Martha S.] IPEN CNEN SP, Ctr Lasers & Applicat, BR-05508000 Sao Paulo, Brazil. [Tegos, George P.; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Tegos, George P.] Univ New Mexico, Sch Med, Dept Pathol, Albuquerque, NM 87131 USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu RI Prates, Renato/G-4872-2012; Ribeiro, Martha/G-3517-2012; Kato, Ilka/G-7644-2012; Prates, Renato/F-8235-2014; OI Ribeiro, Martha/0000-0002-4203-1134; Hamblin, Michael/0000-0001-6431-4605 FU Brazilian National Commission on Research (CNPq); FAPESP [2010/13313-9]; NIH [R01A1050875, R01CA137108]; US Air Force [FA9550-04-1-0079] FX This work was partially supported by the Brazilian National Commission on Research (CNPq) and FAPESP (2010/13313-9). Research in the Hamblin laboratory is supported by NIH grants (R01A1050875 to M. R. H. and R01CA137108 to Long Y. Chiang) and the US Air Force MFEL Program (FA9550-04-1-0079). NR 51 TC 37 Z9 38 U1 1 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD JUL PY 2011 VL 66 IS 7 BP 1525 EP 1532 DI 10.1093/jac/dkr160 PG 8 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 776LK UT WOS:000291536100013 PM 21525022 ER PT J AU Uzel, NG Teles, FR Teles, RP Song, XQ Torresyap, G Socransky, SS Haffajee, AD AF Uzel, Naciye G. Teles, Flavia R. Teles, Ricardo P. Song, Xiaoging Q. Torresyap, Gay Socransky, Sigmund S. Haffajee, Anne D. TI Microbial shifts during dental biofilm re-development in the absence of oral hygiene in periodontal health and disease SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE biofilms; health; oral bacteria; periodontal; periodontitis; subgingival; supragingival ID DNA-DNA HYBRIDIZATION; LIGHT PLAQUE FORMERS; SUBGINGIVAL PLAQUE; APATITIC SURFACES; ADHERENCE; HEAVY AB P>Aim To monitor microbial shifts during dental biofilm re-development. Materials and methods Supra- and subgingival plaque samples were taken separately from 28 teeth in 38 healthy and 17 periodontitis subjects at baseline and immediately after tooth cleaning. Samples were taken again from seven teeth in randomly selected quadrants during 1, 2, 4 and 7 days of no oral hygiene. Samples were analysed using checkerboard DNA-DNA hybridization. Species counts were averaged within subjects at each time point. Significant differences in the counts between healthy and periodontitis subjects were determined using the Mann-Whitney test. Results The total supra- and subgingival counts were significantly higher in periodontitis on entry and reached or exceeded the baseline values after day 2. Supragingival counts of Veillonella parvula, Fusobacterium nucleatum ss vincentii and Neisseria mucosa increased from 2 to 7 days. Subgingival counts were greater for Actinomyces, green and orange complex species. Significant differences between groups in supragingival counts occurred for 17 of 41 species at entry, 0 at day 7; for subgingival plaque, these values were 39/41 taxa at entry, 17/41 at day 7. Conclusions Supragingival plaque re-development was similar in periodontitis and health, but subgingival species recolonization was more marked in periodontitis. C1 [Uzel, Naciye G.; Teles, Flavia R.; Teles, Ricardo P.; Song, Xiaoging Q.; Torresyap, Gay; Socransky, Sigmund S.; Haffajee, Anne D.] Forsyth Inst, Dept Periodontol, Cambridge, MA 02142 USA. [Teles, Flavia R.; Teles, Ricardo P.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Teles, FR (reprint author), Forsyth Inst, Dept Periodontol, 245 1st St, Cambridge, MA 02142 USA. EM fteles@forsyth.org FU NIDCR [DE14368, T32-DE-07327] FX Supported by NIDCR grants DE14368 and T32-DE-07327 (F.R.T.). The authors declare that they have no conflict of interests. NR 28 TC 23 Z9 23 U1 0 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0303-6979 J9 J CLIN PERIODONTOL JI J. Clin. Periodontol. PD JUL PY 2011 VL 38 IS 7 BP 612 EP 620 DI 10.1111/j.1600-051X.2011.01730.x PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 774YM UT WOS:000291422700002 PM 21488936 ER PT J AU Clark, DG Kar, J AF Clark, David Glenn Kar, Jitesh TI Bias of quantifier scope interpretation is attenuated in normal aging and semantic dementia SO JOURNAL OF NEUROLINGUISTICS LA English DT Article DE Sentence comprehension; Semantic dementia; Aging; Quantifier scope ID PRIMARY-PROGRESSIVE-APHASIA; SENTENCE COMPREHENSION; LANGUAGE COMPREHENSION; EYE-MOVEMENTS; 3 VARIANTS; AMBIGUITIES; ABILITIES; DEFICITS; MEMORY AB Many sentences with two quantifiers exhibit a phenomenon known as "quantifier scope ambiguity." Consider the example A unicorn ran through every garden, which contains the quantifiers "a" and "every." Most speakers of English agree that it may refer to one or more than one unicorn. Very little previous work has evaluated the ability of brain-damaged or aphasic patients to interpret such sentences. We administered a sentence-reading task with picture verification to a group of semantic dementia patients (N = 5) and a matched group of cognitively normal controls (N = 23). Controls exhibited a tendency to interpret the word every as having wide scope regardless of the order of quantifiers, as evidenced by decreased reaction time and increased accuracy when verifying pictures that required this interpretation. This bias was attenuated by increasing age and by the presence of semantic dementia. Furthermore, higher FAS fluency scores were associated with slower responses and more errors, while higher semantic fluency scores were associated with the opposite pattern. These findings fit best with a model in which the initial products of linguistic analysis are underspecified and biases in their interpretation arise subsequently through frontally mediated logical or pragmatic reasoning. Published by Elsevier Ltd. C1 [Clark, David Glenn] Univ Alabama, Dept Neurol, Birmingham, AL 35294 USA. [Clark, David Glenn] Birmingham VA Med Ctr, Birmingham, AL USA. [Kar, Jitesh] New York Med Coll, Dept Med, Valhalla, NY 10595 USA. RP Clark, DG (reprint author), Univ Alabama, Dept Neurol, 1720 7th Ave S,SC 620C, Birmingham, AL 35294 USA. EM dgclark@uab.edu FU UAB McKnight Brain Research Institute FX This work was supported by a pilot grant from the UAB McKnight Brain Research Institute. The authors would like to thank Dr. David Basilico for insightful comments on an earlier version of the manuscript. NR 50 TC 2 Z9 2 U1 2 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0911-6044 J9 J NEUROLINGUIST JI J. Neurolinguist. PD JUL PY 2011 VL 24 IS 4 BP 401 EP 419 DI 10.1016/j.jneuroling.2011.01.002 PG 19 WC Linguistics; Neurosciences; Psychology, Experimental SC Linguistics; Neurosciences & Neurology; Psychology GA 776CL UT WOS:000291512000001 ER PT J AU Pugazhenthi, S Nair, S Velmurugan, K Liang, QL Mahalingam, R Cohrs, RJ Nagel, MA Gilden, D AF Pugazhenthi, Subbiah Nair, Sreekala Velmurugan, Kalpana Liang, Qiaoling Mahalingam, Ravi Cohrs, Randall J. Nagel, Maria A. Gilden, Don TI Varicella-Zoster Virus Infection of Differentiated Human Neural Stem Cells SO JOURNAL OF VIROLOGY LA English DT Article ID GANGLIA IN-VIVO; NEURONS; DNA; APOPTOSIS; QUANTITATION; EXPRESSION; LATENT; VZV AB Primary varicella-zoster virus (VZV) infection in humans produces varicella (chickenpox), after which the virus becomes latent in ganglionic neurons. Analysis of the physical state of viral nucleic acid and virus gene expression during latency requires postmortem acquisition of fresh human ganglia. To provide an additional way to study the VZV-host relationship in neurons, we developed an in vitro model of infected differentiated human neural stem cells (NSCs). NSCs were induced to differentiate in culture dishes coated with poly-L-lysine and mouse laminin in the presence of fibroblast growth factor 2 (FGF-2), nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), dibutyryl cyclic AMP, and retinoic acid. Immunostaining with neuronal (MAP2a and beta-tubulin), astrocyte (GFAP), and oligodendrocyte (CNPase) markers revealed that differentiated neurons constituted approximately 90% of the cell population. These neurons were maintained in culture for up to 8 weeks. No cytopathic effect (CPE) developed in neurons infected with cell-free VZV (Zostavax vaccine) compared to human fetal lung fibroblasts infected with VZV. Weeks later, VZV DNA virus-specific transcripts (open reading frames [ORFs] 21, 29, 62, and 63) were detected in infected neurons, and dual immunofluorescence staining revealed the presence of VZV IE63 and gE exclusively in healthy-appearing neurons, but not in astrocytes. Neither the tissue culture medium nor a homogenate prepared from VZV-infected neurons produced a CPE in fibroblasts. VZV induced apoptosis in fibroblasts, as shown by activation of caspase 3 and by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, but not in neurons. This model provides a unique in vitro system to study the VZV-neuronal relationship. C1 [Nair, Sreekala; Liang, Qiaoling; Mahalingam, Ravi; Cohrs, Randall J.; Nagel, Maria A.; Gilden, Don] Univ Colorado, Sch Med, Dept Neurol, Aurora, CO 80045 USA. [Mahalingam, Ravi; Cohrs, Randall J.; Gilden, Don] Univ Colorado, Sch Med, Dept Microbiol, Aurora, CO 80045 USA. [Pugazhenthi, Subbiah; Velmurugan, Kalpana] Univ Colorado, Sch Med, Dept Med, Aurora, CO 80045 USA. [Pugazhenthi, Subbiah; Velmurugan, Kalpana] Denver VA Med Ctr, Denver, CO USA. RP Gilden, D (reprint author), Univ Colorado, Sch Med, Dept Neurol, Mail Stop B182,12700 E 19th Ave, Aurora, CO 80045 USA. EM don.gilden@ucdenver.edu FU National Institutes of Health [AG006127, AG032958, NS067070]; Veterans Administration [NEUD-004-07F] FX This work was supported in part by Public Health Service grants AG006127 (D.G.), AG032958 (D.G., S.P., R.M., and R.J.C.), and NS067070 (M.A.N.) from the National Institutes of Health and Merit Review grant NEUD-004-07F from the Veterans Administration (S.P.). NR 22 TC 23 Z9 23 U1 0 U2 2 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 2011 VL 85 IS 13 BP 6678 EP 6686 DI 10.1128/JVI.00445-11 PG 9 WC Virology SC Virology GA 775CG UT WOS:000291434300054 PM 21525352 ER PT J AU Gewurz, BE Mar, JC Padi, M Zhao, B Shinners, NP Takasaki, K Bedoya, E Zou, JY Cahir-Mcfarland, E Quackenbush, J Kieff, E AF Gewurz, Benjamin E. Mar, Jessica C. Padi, Megha Zhao, Bo Shinners, Nicholas P. Takasaki, Kaoru Bedoya, Edward Zou, James Y. Cahir-Mcfarland, Ellen Quackenbush, John Kieff, Elliott TI Canonical NF-kappa B Activation Is Essential for Epstein-Barr Virus Latent Membrane Protein 1 TES2/CTAR2 Gene Regulation SO JOURNAL OF VIROLOGY LA English DT Article ID LYMPHOCYTE GROWTH TRANSFORMATION; NECROSIS-FACTOR-ALPHA; TRANSCRIPTION FACTOR-BINDING; RECEPTOR-ASSOCIATED FACTORS; HUMAN ENDOTHELIAL-CELLS; NASOPHARYNGEAL CARCINOMA; EXPRESSION PROGRAM; ENCODED LMP1; MEMBRANE-PROTEIN-1; TRAF6 AB Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) transforms rodent fibroblasts and is expressed in most EBV-associated malignancies. LMP1 (transformation effector site 2 [TES2]/C-terminal activation region 2 [CTAR2]) activates NF-kappa B, p38, Jun N-terminal protein kinase (JNK), extracellular signal-regulated kinase (ERK), and interferon regulatory factor 7 (IRF7) pathways. We have investigated LMP1 TES2 genome-wide RNA effects at 4 time points after LMP1 TES2 expression in HEK-293 cells. By using a false discovery rate (FDR) of <0.001 after correction for multiple hypotheses, LMP1 TES2 caused >2-fold changes in 1,916 mRNAs; 1,479 RNAs were upregulated and 437 were downregulated. In contrast to tumor necrosis factor alpha (TNF-alpha) stimulation, which transiently upregulates many target genes, LMP1 TES2 maintained most RNA effects through the time course, despite robust and sustained induction of negative feedback regulators, such as I kappa B alpha and A20. LMP1 TES2-regulated RNAs encode many NF-kappa B signaling proteins and secondary interacting proteins. Consequently, many LMP1 TES2-regulated RNAs encode proteins that form an extensive interactome. Gene set enrichment analyses found LMP1 TES2-upregulated genes to be significantly enriched for pathways in cancer, B- and T-cell receptor signaling, and Toll-like receptor signaling. Surprisingly, LMP1 TES2 and I kappa B alpha superrepressor coexpression decreased LMP1 TES2 RNA effects to only 5 RNAs, with FDRs of <0.001-fold and >2-fold changes. Thus, canonical NF-kappa B activation is critical for almost all LMP1 TES2 RNA effects in HEK-293 cells and a more significant therapeutic target than previously appreciated. C1 [Gewurz, Benjamin E.; Zhao, Bo; Shinners, Nicholas P.; Takasaki, Kaoru; Zou, James Y.; Cahir-Mcfarland, Ellen; Kieff, Elliott] Brigham & Womens Hosp, Channing Lab, Dept Med & Microbiol & Mol Genet, Boston, MA 02115 USA. [Gewurz, Benjamin E.; Zhao, Bo; Shinners, Nicholas P.; Takasaki, Kaoru; Zou, James Y.; Cahir-Mcfarland, Ellen; Kieff, Elliott] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Mar, Jessica C.; Padi, Megha; Bedoya, Edward; Quackenbush, John] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Mar, Jessica C.; Padi, Megha; Bedoya, Edward; Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Mar, Jessica C.; Padi, Megha; Bedoya, Edward; Quackenbush, John] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Kieff, E (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med & Microbiol & Mol Genet, 181 Longwood Ave, Boston, MA 02115 USA. EM ekieff@rics.bwh.harvard.edu FU NCI [RO1, 1K08CA140780-01, 5R01CA085180-10, 5P50HG004233-04]; T32 training grant [5T32CA009031-33] FX B.E.G. is a fellow of the Leukemia and Lymphoma Society and the Karin Grunebaum Cancer Foundation. This work was supported by NCI RO1, 1K08CA140780-01, 5R01CA085180-10, and 5P50HG004233-04. N.P.S. was supported by T32 training grant 5T32CA009031-33. NR 69 TC 19 Z9 19 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUL PY 2011 VL 85 IS 13 BP 6764 EP 6773 DI 10.1128/JVI.00422-11 PG 10 WC Virology SC Virology GA 775CG UT WOS:000291434300061 PM 21543491 ER PT J AU Hasserjian, RP Dal Cin, P AF Hasserjian, Robert P. Dal Cin, Paola TI Deletion of Chromosome 20q: Friend or foe? SO LEUKEMIA RESEARCH LA English DT Editorial Material DE Myelodysplastic syndrome; Cytogenetics; del(20q) ID CYTOGENETIC ABNORMALITIES; MYELODYSPLASTIC SYNDROME; MYELOID MALIGNANCIES; MULTIPLE-MYELOMA; DEL(20Q); DISORDERS; LEUKEMIA; PROTEIN C1 [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Dal Cin, Paola] Brigham & Womens Hosp, Ctr Adv Mol Diagnost, Boston, MA 02115 USA. RP Hasserjian, RP (reprint author), Massachusetts Gen Hosp, Dept Pathol, WRN244,55 Fruit St, Boston, MA 02114 USA. EM rhasserjian@partners.org NR 18 TC 5 Z9 6 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD JUL PY 2011 VL 35 IS 7 BP 844 EP 845 DI 10.1016/j.leukres.2011.03.031 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 775OS UT WOS:000291470800018 PM 21536329 ER PT J AU Kelly, TJ Souza, AL Clish, CB Puigserver, P AF Kelly, Timothy J. Souza, Amanda L. Clish, Clary B. Puigserver, Pere TI A Hypoxia-Induced Positive Feedback Loop Promotes Hypoxia-Inducible Factor 1 alpha Stability through miR-210 Suppression of Glycerol-3-Phosphate Dehydrogenase 1-Like SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROLYL HYDROXYLATION; TRANSCRIPTION FACTOR; SIGNAL-TRANSDUCTION; MICRORNA TARGETS; CANCER-THERAPY; BREAST-CANCER; HIF-ALPHA; HIF-1-ALPHA; RECRUITMENT; GENE AB Oxygen-dependent regulation of the transcription factor HIF-1 alpha relies on a family of prolyl hydroxylases (PHDs) that hydroxylate hypoxia-inducible factor 1 alpha (HIF-1 alpha) protein at two prolines during normal oxygen conditions, resulting in degradation by the proteasome. During low-oxygen conditions, these prolines are no longer hydroxylated and HIF-1 alpha degradation is blocked. Hypoxia-induced miRNA-210 (miR-210) is a direct transcriptional target of HIF-1 alpha, but its complete role and targets during hypoxia are not well understood. Here, we identify the enzyme glycerol-3-phosphate dehydrogenase 1-like (GPD1L) as a novel regulator of HIF-1 alpha stability and a direct target of miR-210. Expression of miR-210 results in stabilization of HIF-1 alpha due to decreased levels of GPD1L resulting in an increase in HIF-1 alpha target genes. Altering GPD1L levels by overexpression or knockdown results in a decrease or increase in HIF-1 alpha stability, respectively. GPD1L-mediated decreases in HIF-1 alpha stability can be reversed by pharmacological inhibition of the proteasome or PHD activity. When rescued from degradation by proteasome inhibition, elevated amounts of GPD1L cause hyperhydroxylation of HIF-1 alpha, suggesting increases in PHD activity. Importantly, expression of GPD1L attenuates the hypoxic response, preventing complete HIF-1 alpha induction. We propose a model in which hypoxia-induced miR-210 represses GPD1L, contributing to suppression of PHD activity, and increases of HIF-1 alpha protein levels. C1 [Kelly, Timothy J.; Puigserver, Pere] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Kelly, Timothy J.; Puigserver, Pere] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Kelly, Timothy J.] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA. [Souza, Amanda L.; Clish, Clary B.] Broad Inst MIT & Harvard, Metabolite Profiling Initiat, Cambridge Ctr 7, Cambridge, MA 02142 USA. RP Puigserver, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St,CLSB11144, Boston, MA 02115 USA. EM pere_puigserver@dfci.harvard.edu FU Ellison Medical Foundation; American Diabetes Association; U.S. Department of Defense; NIH [R01 DK069966] FX These studies were supported in part by an Ellison Medical Foundation New Scholar Award, American Diabetes Association, U.S. Department of Defense, and NIH grant R01 DK069966. NR 58 TC 66 Z9 71 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2011 VL 31 IS 13 BP 2696 EP 2706 DI 10.1128/MCB.01242-10 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 775BK UT WOS:000291431400013 PM 21555452 ER PT J AU Heinze, E Chan, G Mory, R Khavari, R Alavi, A Chung, SY Nishimura, RN Weisbart, RH AF Heinze, Emil Chan, Grace Mory, Rachel Khavari, Raz Alavi, Asif Chung, Sue Y. Nishimura, Robert N. Weisbart, Richard H. TI Tumor suppressor and T-regulatory functions of Foxp3 are mediated through separate signaling pathways SO ONCOLOGY LETTERS LA English DT Article DE transcription factors; apoptosis; immune regulation ID METASTASIS IN-VIVO; TRANSCRIPTIONAL REPRESSOR; CANCER; APOPTOSIS; P53; ONCOGENE; CELLS AB Foxp3 is a nuclear transcription factor that is both a tumor suppressor factor and regulator of T-regulatory cell (Treg) function, and is a potential therapeutic target in both autoimmunity and cancer. In order to distinguish molecular pathways responsible for these separate Foxp3 functions, deletion mutants of Foxp3 proteins were transduced and analyzed for cytotoxic activity in human cancer cell lines Skov3, MDA-MB-231, MCF-7 and Jurkat. Human Foxp3 cDNA mutants were amplified and ligated to produce plasmids for direct cell transfection. Constructs were produced and confirmed by DNA sequencing. Lipofectamine 2000 was used for plasmid transfection. Foxp3 cells were then examined. The results of our experiments reveal retention of tumor suppressor function in the absence of NFAT binding and transcriptional activation required for Treg function. Our results have significant implications for the design of autoimmune and cancer therapies that target Foxp3 and Treg cells. C1 [Heinze, Emil; Mory, Rachel; Khavari, Raz; Alavi, Asif; Chung, Sue Y.] Olive View UCLA Med Ctr, Dept Med, Sylmar, CA 91342 USA. [Chan, Grace; Weisbart, Richard H.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Res, Sepulveda, CA 91343 USA. [Nishimura, Robert N.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. RP Weisbart, RH (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst 1, Dept Res, 16111 Plummer St, North Hills, CA 91343 USA. EM rweisbar@ucla.edu FU Veterans Affairs FX This study was supported by a grant from the Veterans Affairs (RHW). NR 17 TC 1 Z9 1 U1 0 U2 5 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1792-1074 J9 ONCOL LETT JI Oncol. Lett. PD JUL-AUG PY 2011 VL 2 IS 4 BP 665 EP 668 DI 10.3892/ol.2011.307 PG 4 WC Oncology SC Oncology GA 775ZD UT WOS:000291503300015 ER PT J AU Hubbard, CS Ornitz, E Gaspar, JX Smith, S Amin, J Labus, JS Kilpatrick, LA Rhudy, JL Mayer, EA Naliboff, BD AF Hubbard, Catherine S. Ornitz, Edward Gaspar, John X. Smith, Suzanne Amin, Jenny Labus, Jennifer S. Kilpatrick, Lisa A. Rhudy, Jamie L. Mayer, Emeran A. Naliboff, Bruce D. TI Modulation of nociceptive and acoustic startle responses to an unpredictable threat in men and women SO PAIN LA English DT Article DE Aversive threat; Nociception; Pain; Anxiety; Sex differences ID FLEXION REFLEX NFR; SHOCK-INDUCED HYPERALGESIA; PAIN PERCEPTION; SEX-DIFFERENCES; ANTICIPATORY ANXIETY; SCORING CRITERIA; MENSTRUAL-CYCLE; HEALTHY WOMEN; FEAR; STIMULATION AB The present study examined whether a moderately aversive abdominal threat would lead to greater enhancement in affect-and pain-related defensive responding as indexed by the acoustic startle reflex (ASR) and nociceptive flexion reflex (NFR) in women compared to men. We also predicted sex differences in threat-related autonomic arousal measured by skin conductance responses (SCRs) to acoustic startle and noxious sural nerve stimulation. Unpredictable threat was manipulated by alternating 30-second safe ("no abdominal stimulation will be given'') and threat ("abdominal stimulation may occur at anytime'') periods. The experiment consisted of 2 blocks, each containing 4 safe and 4 threat periods in which the ASR or NFR was randomly probed 9-21 seconds following period onset. Unpredictable abdominal threat potentiated both ASR and NFR responses compared to periods signaling safety. SCRs to acoustic startle probes and noxious sural nerve stimulation were also significantly elevated during the threat vs safe periods. No sex differences in ASR or startle-evoked SCRs emerged. However, nociceptive responding was moderated by sex; females showed significant increases in NFR magnitudes across both safe and threat periods compared to males. Females also showed greater threat-potentiated SCRs to sural nerve stimulation than males. Our findings indicate that both affect-and pain-related defense and arousal systems are strongly influenced by threat of an aversive, unpredictable event, a situation associated with anticipatory anxiety. Females, compared to males, showed greater nociceptive responding and pain modulation when exposed to an unpredictable threatening context, whereas affect-driven ASR responses showed no such sex differentiation. Published by Elsevier B.V. on behalf of International Association for the Study of Pain. C1 [Naliboff, Bruce D.] Univ Calif Los Angeles, CNS, Div Digest Dis, Los Angeles, CA 90095 USA. [Hubbard, Catherine S.; Kilpatrick, Lisa A.; Mayer, Emeran A.] Univ Calif Los Angeles, Dept Med Digest Dis, Los Angeles, CA 90095 USA. [Hubbard, Catherine S.; Naliboff, Bruce D.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Ornitz, Edward; Labus, Jennifer S.; Mayer, Emeran A.; Naliboff, Bruce D.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Ornitz, Edward; Labus, Jennifer S.; Mayer, Emeran A.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA. [Rhudy, Jamie L.] Univ Tulsa, Dept Psychol, Tulsa, OK 74104 USA. [Mayer, Emeran A.] Univ Calif Los Angeles, Dept Physiol, Los Angeles, CA 90095 USA. RP Naliboff, BD (reprint author), Univ Calif Los Angeles, CNS, Div Digest Dis, CHS 47-122,MC 737818,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM naliboff@ucla.edu RI Kilpatrick, Lisa/E-6995-2015; OI Hubbard, Catherine/0000-0002-9139-2198 FU National Institutes of Health (NIH) [P50-DK64539, R24-AT002681, T32-DK07180-34]; VA Medical Research FX Special thanks to Bradford Lubell, Cathy Liu, Byron Alexander, and Melissa Alberto for their assistance. This research was supported by National Institutes of Health (NIH) Grants P50-DK64539, R24-AT002681, NIH GI Training Grant T32-DK07180-34, VA Medical Research, and a gift from the Virginia Friedhofer Charitable Trust. NR 51 TC 19 Z9 19 U1 4 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUL PY 2011 VL 152 IS 7 BP 1632 EP 1640 DI 10.1016/j.pain.2011.03.001 PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 775PM UT WOS:000291474000028 PM 21477924 ER PT J AU McCauley, JL Amstadter, AB Macdonald, A Danielson, CK Ruggiero, KJ Resnick, HS Kilpatrick, DG AF McCauley, Jenna L. Amstadter, Ananda B. Macdonald, Alexandra Danielson, Carla Kmett Ruggiero, Kenneth J. Resnick, Heidi S. Kilpatrick, Dean G. TI Non-medical use of prescription drugs in a national sample of college women SO ADDICTIVE BEHAVIORS LA English DT Article DE Non-medical use of prescription drugs; Substance use; Rape; Mental health; College women ID POSTTRAUMATIC-STRESS-DISORDER; SUBSTANCE USE; MENTAL-HEALTH; UNITED-STATES; RISK-FACTORS; ILLICIT USE; PREVALENCE; STUDENTS; RAPE; STIMULANTS AB Non-medical use of prescription drugs (NMUPD) is one of the fastest growing forms of illicit drug use, with research indicating that college students represent a particularly high risk population. The current study examined demographic characteristics, health/mental health, substance misuse, and rape experiences as potential risk correlates of NMUPD among a national sample of college women (N = 2000). Interviews were conducted via telephone using Computer-Assisted Telephone Interviewing technology. NMUPD was assessed by asking if, participants had used a prescription drug non-medically in the past year. NMUPD was endorsed by 7.8% of the sample (n = 155). Although incapacitated and drug-alcohol facilitated rape were associated with NMUPD in the initial model, the final multivariable model showed that only lifetime major depression and other forms of substance use/abuse were significantly uniquely associated with an increased likelihood of NMUPD. Implications for primary and secondary prevention and subsequent research are addressed. Published by Elsevier Ltd. C1 [McCauley, Jenna L.] Med Univ S Carolina, Natl Crime Victims Res & Treatment Ctr, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Amstadter, Ananda B.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. [Macdonald, Alexandra] Boston Vet Affairs Med Ctr, Natl Ctr PTSD, Behav Sci Div, Boston, MA USA. [Ruggiero, Kenneth J.] Ralph H Johnson Vet Adm Med Ctr, Charleston, SC USA. RP McCauley, JL (reprint author), Med Univ S Carolina, Natl Crime Victims Res & Treatment Ctr, Dept Psychiat & Behav Sci, POB 250852,67 President St, Charleston, SC 29425 USA. EM mccaule@musc.edu FU National Institute of Justice (NU) [2005-WG-BX-00060006] FX This research was supported by the National Institute of Justice (NU) Grant #2005-WG-BX-00060006 (PI: Dean G. Kilpatrick, Ph.D.). Views expressed in this article do not necessarily represent those of NU. NR 38 TC 21 Z9 21 U1 2 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD JUL PY 2011 VL 36 IS 7 BP 690 EP 695 DI 10.1016/j.addbeh.2011.01.020 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 771TA UT WOS:000291182400003 PM 21356576 ER PT J AU Vujanovic, AA Bonn-Miller, MO Marlatt, GA AF Vujanovic, Anka A. Bonn-Miller, Marcel O. Marlatt, G. Alan TI Posttraumatic stress and alcohol use coping motives among a trauma-exposed community sample: The mediating role of non-judgmental acceptance SO ADDICTIVE BEHAVIORS LA English DT Article DE Posttraumatic stress; Mindfulness; Acceptance; Alcohol; Coping ID SEXUAL ASSAULT SURVIVORS; MINDFULNESS MEDITATION; SELF-REPORT; DRINKING; DISORDER; PTSD; INDIVIDUALS; DEPENDENCE; SYMPTOMS; MODELS AB The current investigation evaluated (1) the incremental predictive validity of non-judgmental acceptance in terms of alcohol use coping motives and (2) the mediating role of non-judgmental acceptance in the association between posttraumatic stress symptom severity and alcohol use coping motives. Participants included 153 (79 women) adults who reported exposure to at least one DSM-IV PTSD Criterion A traumatic life event and alcohol use in the past month. Non-judgmental acceptance emerged as a significant incremental predictor of alcohol use coping motives. Furthermore, non-judgmental acceptance partially mediated the association between posttraumatic stress symptom severity and alcohol use coping motives. Theoretical and clinical implications of the findings are discussed with regard to better understanding the co-occurrence of posttraumatic stress and alcohol use disorders. Published by Elsevier Ltd. C1 [Vujanovic, Anka A.] VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA 02130 USA. [Vujanovic, Anka A.] Boston Univ, Sch Med, Boston, MA 02130 USA. [Bonn-Miller, Marcel O.] VA Palo Alto Hlth Care Syst, Natl Ctr PTSD, Disseminat & Training Div, Menlo Pk, CA 94025 USA. [Bonn-Miller, Marcel O.] VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk, CA 94025 USA. [Marlatt, G. Alan] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. RP Vujanovic, AA (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, 150 S Huntington Ave,116B-2, Boston, MA 02130 USA. EM anka.vujanovic@va.gov; marcel.bonn-miller@va.gov; marlatt@u.washington.edu FU National Research Service [1F31 DA21006-02]; Veterans Affairs Clinical Science Research and Development (CSRD) FX Data collection for this investigation was supported, in part, by a National Research Service Award (1F31 DA21006-02) granted to Dr. Vujanovic. The authors also acknowledge Dr. Michael J. Zvolensky for his contribution of a portion of the data used in the current study (1 R03 DA016566-01A2). This work was also supported, in part, by a Veterans Affairs Clinical Science Research and Development (CSR&D) Career Development Award - 2 granted to Dr. Bonn-Miller. NR 43 TC 8 Z9 8 U1 6 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD JUL PY 2011 VL 36 IS 7 BP 707 EP 712 DI 10.1016/j.addbeh.2011.01.033 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 771TA UT WOS:000291182400006 PM 21396785 ER PT J AU Jackson, DO Mrug, S Cook, F Beidleman, W Cropsey, KL AF Jackson, Dorothy O. Mrug, Sylvie Cook, Foster Beidleman, William Cropsey, Karen L. TI Factors predicting substance dependence and psychotropic medication use among offenders in community corrections SO ADDICTIVE BEHAVIORS LA English DT Article DE Substance dependence; Mental illness; Co-occurring disorders; Risk factors; Community corrections ID MENTAL-DISORDERS; SELF-MEDICATION; HYPOTHESIS; SERVICES; SUICIDE; RISK; COD AB Co-occurring substance abuse and mental illness is prevalent among criminal offenders, but little is mown about risk factors for these co-occurring disorders (COD) in community corrections population. To identify risk factors for COD in community corrections offenders, we analyzed assessment data from 5,595 offenders maintained under community supervision at a substance use diversion program. Three groups, offenders with substance use disorders who were taking psychotropic medications (SUPM), offenders with a substance use disorder (SUD) only and controls were compared. Logistic regressions were used to identify predictors of SUPM versus SUD only and controls. SUPM status was predicted by being White or Female, having some medical insurance (private or government aided), being unemployed, prior history of abuse/trauma. and prior history of suicidal ideation or behavior. Offenders with substance use disorders and co-occurring psychiatric problems face salient social risk that may need to be targeted through integrated services. Published by Elsevier Ltd. C1 [Jackson, Dorothy O.; Mrug, Sylvie] Univ Alabama, Dept Psychol, Birmingham, AL 35294 USA. [Cook, Foster; Cropsey, Karen L.] Univ Alabama, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35209 USA. [Beidleman, William] Birmingham Vet Affairs Med Ctr, Mental Hlth Clin, Birmingham, AL 35233 USA. RP Jackson, DO (reprint author), Univ Alabama, Dept Psychol, 1300 Univ Blvd,CH415, Birmingham, AL 35294 USA. EM ocky_888@hotmail.com FU UAB Department of Psychiatry; Jefferson County, Alabama FX This study was supported by UAB Department of Psychiatry internal funding and Jefferson County, Alabama, both of whom 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. NR 19 TC 3 Z9 3 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD JUL PY 2011 VL 36 IS 7 BP 755 EP 758 DI 10.1016/j.addbeh.2010.12.033 PG 4 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 771TA UT WOS:000291182400014 PM 21367532 ER PT J AU Park, ER Kleimann, S Youatt, EJ Lockhart, A Campbell, EG Levy, DE Halbert, CH Schmieder, E Krishna, R Shields, AE AF Park, Elyse R. Kleimann, Susan Youatt, Emily J. Lockhart, Abigail Campbell, Eric G. Levy, Douglas E. Halbert, Chanita Hughes Schmieder, Erin Krishna, Rasika Shields, Alexandra E. TI Black and White adults' perspectives on the genetics of nicotine addiction susceptibility SO ADDICTIVE BEHAVIORS LA English DT Article DE Racial differences; Genetic testing; Nicotine addiction; Addiction susceptibility; Smoking cessation ID TRYPTOPHAN-HYDROXYLASE GENE; SEROTONIN TRANSPORTER GENE; TOBACCO DEPENDENCE; SMOKING-CESSATION; LUNG-CANCER; REPLACEMENT THERAPY; CIGARETTE-SMOKING; UNITED-STATES; AFRICAN-AMERICANS; CLINICAL-TRIAL AB Aims: Emerging research may soon lead to improved quit rates via genetically-tailored smoking cessation treatment. The purpose of this study was to explore individuals' beliefs and attitudes about genetic testing in this context, and how these may differ across racial groups. Design: Two site qualitative study. Methods: Eleven focus groups were conducted in 2007 with 51 Black and 55 White adult participants in Montgomery, AL and Baltimore, MD. Measurements: Questions were asked about smoking as an addiction, the role of genetics in nicotine addiction susceptibility, and undergoing genetic testing to receive tailored smoking cessation treatment. Data were analyzed using content analysis. Findings: Most participants believed that smoking was an addiction yet were unwilling to endorse the notion that genetics played a role in nicotine addiction susceptibility. However, 91% of White participants and 62% of Black participants indicated that they would likely take a genetic test that would match them to their optimal smoking cessation treatment. The primary potential benefit was a vague sense that additional knowledge about oneself would be of value. Primary barriers included disinterest and skepticism about the test, unwillingness to believe that genetics played a role in nicotine addiction or treatment response, and concerns about psychological consequences. Conclusions: The majority of participants, particularly Black participants, did not believe that genetics played a significant role in nicotine addiction susceptibility but were willing to undergo genetic testing. Participants identified some benefit to tailoring smoking treatment by genotype. However, participants also expressed skepticism about the test and concerns about its consequences; these issues would need to be addressed in the clinical encounter. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Park, Elyse R.; Youatt, Emily J.; Lockhart, Abigail; Levy, Douglas E.; Shields, Alexandra E.] Harvard MGH Ctr Genom Vulnerable Populat & Hlth D, Boston, MA 02114 USA. [Park, Elyse R.; Campbell, Eric G.; Levy, Douglas E.; Shields, Alexandra E.] Harvard Univ, Sch Med, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Park, Elyse R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Kleimann, Susan; Schmieder, Erin; Krishna, Rasika] Kleimann Commun Grp, Washington, DC 20005 USA. [Halbert, Chanita Hughes] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Halbert, Chanita Hughes] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Park, ER (reprint author), Inst Hlth Policy, 50 Staniford St,Suite 901, Boston, MA 02114 USA. EM epark@partners.org FU National Institutes of Health [R01 HG003475-01A1]; American Cancer Society FX Funding for this study was provided by the National Institutes of Health [R01 HG003475-01A1 to A.E.S.] and the American Cancer Society Mentored Research Scholar Grant [E.R.P]. The National Institutes of Health and the American Cancer Society had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. NR 49 TC 8 Z9 8 U1 2 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD JUL PY 2011 VL 36 IS 7 BP 769 EP 772 DI 10.1016/j.addbeh.2011.02.007 PG 4 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 771TA UT WOS:000291182400018 PM 21406316 ER PT J AU Kashiwagi, A Fein, MJ Shimada, M AF Kashiwagi, Aki Fein, Mikaela J. Shimada, Masako TI Calpain Modulates Cyclin-Dependent Kinase Inhibitor 1B (p27(Kip1)) in Cells of the Osteoblast Lineage SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE Calpain; Calcium; Osteoblast; Osteoporosis ID PARATHYROID-HORMONE; SMALL-SUBUNIT; PROLIFERATION; DIFFERENTIATION; PROTEASE; BINDING; GROWTH; RECEPTOR; SYSTEM; CAPN4 AB The ubiquitously expressed calpains-1 and -2 belong to a family of calcium-dependent intracellular cysteine proteases. Both calpains are heterodimers consisting of a large catalytic subunit and a small regulatory subunit encoded by the gene Capn4. Ablation of the calpain small subunit eliminates calpain activity and leads to embryonic lethality. We previously created osteoblast-specific Capn4 knockout mice to investigate a physiological role for the calpain small subunit in cells of the osteoblast lineage. Deletion of Capn4 reduced trabecular and cortical bone, mainly due to impaired proliferation and differentiation of cells of the osteoblast lineage. To further investigate an underlining mechanism by which osteoblast-specific Capn4 knockout mice develop an osteoporotic bone phenotype, we established osteoblastic cell lines stably expressing either control or Capn4 RNA interference for this study. Capn4 knockdown cells showed reduced cell proliferation, accumulation of total and phosphorylated cyclin-dependent kinase inhibitor 1B (p27(Kip1)) on serine 10, and reduced phosphorylation of retinoblastoma protein on threonine 821. Moreover, ablation of Capn4 increased 27 (Kip1) mRNA levels, likely due to stabilized binding of Akt to protein phosphatase 2A, which presumably results in reduced phosphorylation of Akt on S473 and forkhead Box O (FoxO) 3A on T32. Collectively, calpain regulates cell proliferative function by modulating both transcription and degradation of p27(Kip1) in osteoblasts. In conclusion, calpain is a critical modulator for regulation of p27(Kip1) in cells of the osteoblast lineage. C1 [Kashiwagi, Aki; Fein, Mikaela J.; Shimada, Masako] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit,Dept Med, Boston, MA 02114 USA. RP Shimada, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit,Dept Med, Thier 10,50 Blossom St, Boston, MA 02114 USA. EM shimada@helix.mgh.harvard.edu FU National Institutes of Health [R01 DK072102]; William F. Milton Fund; MGH FX We thank Dr. Hanno Hock and Laura B. Prickett-Rice at the Center for Regenerative Medicine, Massachusetts General Hospital (MGH), for consultation and assistance with the flow-cytometric analysis. This work was partially supported by National Institutes of Health grant R01 DK072102, the William F. Milton Fund, and the MGH interim support fund (to M. S.). NR 27 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0171-967X J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD JUL PY 2011 VL 89 IS 1 BP 36 EP 42 DI 10.1007/s00223-011-9491-3 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 774MI UT WOS:000291390300005 PM 21544553 ER PT J AU Li, YX Berenji, GR AF Li, Yuxin Berenji, Gholam R. TI Cutaneous Sarcoidosis Evaluated by FDG PET SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE cutaneous sarcoidosis; positron emission tomography; FDG ID CLINICAL MANAGEMENT; SCINTIGRAPHY; TOMOGRAPHY AB A 50-year-old man presented with initial complaints of diffuse skin pain and pruritus. Physical examination revealed scattered skin plaques and subcutaneous nodules with mild tenderness throughout the body. Skin biopsy demonstrated noncaseating epithelioid granulomas. Patient soon developed cough, fever with hot flashes, and shortness of breath on exertion. FDG PET/CT demonstrated diffuse cutaneous involvement throughout the body. Follow-up FDG PET/CT after treatment revealed a decrease in FDG uptake suggesting a good response to therapy. C1 [Berenji, Gholam R.] VA Greater Los Angeles Healthcare Syst, Nucl Med Serv 115, Dept Nucl Med, Los Angeles, CA 90073 USA. RP Berenji, GR (reprint author), VA Greater Los Angeles Healthcare Syst, Nucl Med Serv 115, Dept Nucl Med, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Gholam.Berenji@va.gov NR 14 TC 11 Z9 11 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 2011 VL 36 IS 7 BP 584 EP 586 DI 10.1097/RLU.0b013e318217a67b PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 772XH UT WOS:000291271000026 PM 21637067 ER PT J AU Sockol, LE Epperson, CN Barber, JP AF Sockol, Laura E. Epperson, C. Neill Barber, Jacques P. TI A meta-analysis of treatments for perinatal depression SO CLINICAL PSYCHOLOGY REVIEW LA English DT Review DE Postpartum; Psychotherapy; Pregnancy; Treatment; Depression; Meta-analysis ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL THERAPY; POSTPARTUM DEPRESSION; POSTNATAL DEPRESSION; INTERPERSONAL PSYCHOTHERAPY; PSYCHOLOGICAL TREATMENT; PUBLICATION BIAS; PREGNANT-WOMEN; PREVALENCE; DISORDER AB This meta-analysis assessed efficacy of pharmacologic and psychological interventions for treatment of perinatal depression. A systematic review identified 27 studies, including open trials (n = 9), quasi-randomized trials (n = 2), and randomized controlled trials (n = 16) assessing change from pretreatment to posttreatment or comparing these interventions to a control group. Uncontrolled and controlled effect sizes were assessed in separate meta-analyses. There was significant improvement in depressive symptoms from pretreatment to posttreatment, with an uncontrolled overall effect size (Hedges' g) of 1.61 after removal of outliers and correction for publication bias. Symptom levels at posttreatment were below cutoff levels indicative of clinically significant symptoms. At posttreatment, intervention groups demonstrated significantly greater reductions in depressive symptoms compared to control groups, with an overall controlled effect size (Hedges' g) of 0.65 after removal of outliers. Individual psychotherapy was superior to group psychotherapy with regard to changes in symptoms from pretreatment to posttreatment. Interventions including an interpersonal therapy component were found to have greater effect sizes, compared to control conditions, than interventions including a cognitive-behavioral component. Implications of the findings for clinical practice and future research are discussed. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Sockol, Laura E.] Univ Penn, Dept Psychol, Philadelphia, PA 19104 USA. [Epperson, C. Neill; Barber, Jacques P.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Epperson, C. Neill] Univ Penn, Dept Obstet Gynecol, Philadelphia, PA 19104 USA. [Barber, Jacques P.] Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Sockol, LE (reprint author), Univ Penn, Dept Psychol, 3815 Walnut St, Philadelphia, PA 19104 USA. EM lsockol@sas.upenn.edu FU NIDA NIH HHS [K24 DA030301] NR 75 TC 76 Z9 76 U1 9 U2 55 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0272-7358 J9 CLIN PSYCHOL REV JI Clin. Psychol. Rev. PD JUL PY 2011 VL 31 IS 5 BP 839 EP 849 DI 10.1016/j.cpr.2011.03.009 PG 11 WC Psychology, Clinical SC Psychology GA 771VM UT WOS:000291188800012 PM 21545782 ER PT J AU Baker-LePain, JC Nakamura, MC Lane, NE AF Baker-LePain, Julie C. Nakamura, Mary C. Lane, Nancy E. TI Effects of inflammation on bone: an update SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE BMP pathway; bone loss; cytokine; inflammation; osteoblast; osteoclast; therapy; WNT pathway ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; EARLY RHEUMATOID-ARTHRITIS; COLLAGEN-INDUCED ARTHRITIS; INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY; GROWTH-FACTOR-BETA; MINERAL-DENSITY; ANKYLOSING-SPONDYLITIS; TNF-ALPHA; RADIOGRAPHIC PROGRESSION; INTERFERON-BETA AB Purpose of review To present an updated summary of the relationship between inflammation and localized and generalized bone loss in the rheumatic diseases. Recent findings In addition to the well established role of inflammatory cytokines in promoting enhanced osteoclast function and bone loss, recent work has discovered the cytokine milieu may also inhibit osteoblast function and bone repair. The WNT and bone morphogenetic protein pathways provide molecular links between inflammation and altered bone homeostasis in chronic inflammatory states. These pathways and others have been the targets of emerging therapies for the management of inflammatory bone loss. Summary Inflammation and bone loss are linked through a number of molecular pathways. Both of these processes need to be addressed when designing an effective treatment strategy for the rheumatic diseases. C1 [Lane, Nancy E.] Univ Calif Davis, Med Ctr, Dept Internal Med, Ctr Healthy Aging, Sacramento, CA 95817 USA. [Nakamura, Mary C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Nakamura, Mary C.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Lane, NE (reprint author), Univ Calif Davis, Med Ctr, Dept Internal Med, Ctr Healthy Aging, Sacramento, CA 95817 USA. EM nelane@ucdavis.edu FU NIH [AR007304]; SOF; REF; UCSF [Lane K24, Lane R01, Lane R13 - AR04884, AR052000, AR043052]; Nakamura VA Merit Review, Department of Veteran's Affairs [R01 AR050038-01] FX This work was supported by the NIH Academic Rheumatology and Clinical Immunology Training Grant AR007304 to J.C.B. and by SOF, REF, UCSF training grant, Lane K24, Lane R01, Lane R13 - AR04884, AR052000, and AR043052 to N.E.L. Nakamura R01 AR050038-01 VA Merit Review, Department of Veteran's Affairs. NR 79 TC 23 Z9 24 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 J9 CURR OPIN RHEUMATOL JI Curr. Opin. Rheumatol. PD JUL PY 2011 VL 23 IS 4 BP 389 EP 395 DI 10.1097/BOR.0b013e3283474dbe PG 7 WC Rheumatology SC Rheumatology GA 772OU UT WOS:000291244200012 PM 21532485 ER PT J AU Rotkopf, S Hamberg, Y Aigaki, T Snapper, SB Shilo, BZ Schejter, ED AF Rotkopf, Shay Hamberg, Yuval Aigaki, Toshiro Snapper, Scott B. Shilo, Ben-Zion Schejter, Eyal D. TI The WASp-based actin polymerization machinery is required in somatic support cells for spermatid maturation and release SO DEVELOPMENT LA English DT Article DE Energy storage; Kinematics; Resilin; Drosophila ID DROSOPHILA-MELANOGASTER; MYOBLAST FUSION; SELF-RENEWAL; ARP2/3 COMPLEX; N-WASP; SPERMATOGENESIS; GENE; CYTOSKELETON; EXPRESSION; ADHESION AB WASp family proteins serve as conserved regulators of branched microfilament array formation via the Arp2/3 actin polymerization machinery. We have identified a specific role during spermatogenesis for the Drosophila WASp homolog (Wsp) and associated elements. Spermatogenesis within the fly testis is carried out in cysts, where a pair of somatic cyst cells encloses differentiating sperm. The final phase of the process involves the attachment of matured cysts to a specialized epithelium at the base of the testis, followed by release of individual motile spermatids into the adjoining seminal vesicle. Wsp mutant cysts contain fully mature sperm, but spermatid release does not occur, resulting in male sterility. Our data suggest that the Wsp-Arp2/3-based machinery acts in the cyst cells to influence proper microfilament organization and to enable cyst attachment to the base of the testis. Wsp activity in this context is mediated by the small GTPase Cdc42. Involvement of the cell surface protein Sticks and stones and the Wsp adapter protein D-WIP (Vrp1) is also crucial. In parallel, we demonstrate that N-WASp (Wasl), the major mammalian WASp family protein, is required in the somatic Sertoli cells of the mouse testis for sperm maturation. A requirement for WASp-based activity in somatic support cells therefore appears to be a universal feature of spermatogenesis. C1 [Rotkopf, Shay; Hamberg, Yuval; Shilo, Ben-Zion; Schejter, Eyal D.] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. [Aigaki, Toshiro] Tokyo Metropolitan Univ, Dept Biol Sci, Tokyo 1920397, Japan. [Snapper, Scott B.] 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 FX We thank Susan Abmayr, Elizabeth Chen, Steve DiNardo, George Enders, Therese Eriksson, Dies Meijer, Ruth Palmer, Mar Ruiz-Gomes, Mireille Schafer and Ronen Schweitzer, as well as the Bloomington, VDRC (Vienna) and DGRC (Kyoto) Drosophila stock centers for providing fly and mouse reagents; R'ada Massarwa for generating the embryonic D-WIP-GFP flies; Moshe Grunspan for images used in Fig. 6; Eli Arama and members of his lab for technical assistance, reagents and advice; the Weizmann Institute Veterinary Resources Department for housing and handling of mice strains; Tamara Berkutzki and Ori Brenner for instruction in preparation and interpretation of histological sections; Julie Brill (Hospital for Sick Children, Toronto) and Sandra Kleinman (Sourasky Medical Center, Tel Aviv) for many helpful discussions; our colleagues Inbal Mor and Eli Arama for critical reading of the manuscript; and all B.-Z. S. lab members for their advice and support. Our research was supported by a grant from the Israel Science Foundation to B.-Z. S. and E. D. S. B.-Z. S. is an incumbent of the Hilda and Cecil Lewis Chair in Molecular Genetics. NR 57 TC 10 Z9 10 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUL 1 PY 2011 VL 138 IS 13 BP 2729 EP 2739 DI 10.1242/dev.059865 PG 11 WC Developmental Biology SC Developmental Biology GA 773YS UT WOS:000291348700010 PM 21652648 ER PT J AU Missmer, SA Pearson, KR Ryan, LM Meeker, JD Cramer, DW Hauser, R AF Missmer, Stacey A. Pearson, Kimberly R. Ryan, Louise M. Meeker, John D. Cramer, Daniel W. Hauser, Russ TI Analysis of Multiple-cycle Data From Couples Undergoing In Vitro Fertilization Methodologic Issues and Statistical Approaches SO EPIDEMIOLOGY LA English DT Article ID OUTCOMES; MODELS AB The number of in vitro fertilization (IVF) cycles in the United States increased from fewer than 46,000 in 1995 to more than 120,000 in 2005. IVF and other assisted reproductive technology (ART) data are routinely collected and used to identify outcome predictors. However, researchers do not always make full use of the data due to their complexity. Design approaches have included restriction to first-cycle attempts only, which reduces power and identifies effects only of those factors associated with initial success. Many statistical techniques have been used or proposed for analysis of IVF data, ranging from simple t tests to sophisticated models designed specifically for IVF. We applied several of these methods to data from a prospective cohort of 2687 couples undergoing ART from 1994 through 2003. Results across methods are compared and the appropriateness of the various methods is discussed with the intent to illustrate methodologic validity. We observed a remarkable similarity of coefficient estimates across models. However, each method for dealing with multiple cycle data relies on assumptions that may or may not be expected to hold in a given IVF study. The robustness and reported magnitude of effect for individual predictors of IVF success may be inflated or attenuated due to violation of statistical assumptions, and should always be critically interpreted. Given that risk factors associated with IVF success may also advance our understanding of the physiologic processes underlying conception, implantation, and gestation, the application of valid methods to these complex data is critical. C1 [Missmer, Stacey A.; Cramer, Daniel W.] Harvard Univ, Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Sch Med, Boston, MA 02115 USA. [Missmer, Stacey A.; Cramer, Daniel W.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Missmer, Stacey A.] Harvard Univ, Brigham & Womens Hosp, Channing Lab, Dept Med,Med Sch, Boston, MA 02115 USA. [Pearson, Kimberly R.; Ryan, Louise M.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Meeker, John D.] Univ Michigan, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Massachusetts Gen Hosp, Vincent Mem Obstet & Gynecol Serv, Androl Lab, Boston, MA 02114 USA. [Hauser, Russ] Massachusetts Gen Hosp, Vitro Fertilizat Unit, Boston, MA 02114 USA. RP Missmer, SA (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Sch Med, 75 Francis St, Boston, MA 02115 USA. EM stacey.missmer@channing.harvard.edu RI Ryan, Louise/A-4562-2009; OI Ryan, Louise/0000-0001-5957-2490; Meeker, John/0000-0001-8357-5085 FU National Institutes of Health [HD32153, ES13967] FX Supported by the National Institutes of Health (grants HD32153 and ES13967). NR 23 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 2011 VL 22 IS 4 BP 497 EP 504 DI 10.1097/EDE.0b013e31821b5351 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 772RJ UT WOS:000291252100011 PM 21558857 ER PT J AU Ahearn, EP Juergens, T Cordes, T Becker, T Krahn, D AF Ahearn, Eileen P. Juergens, Timothy Cordes, Timothy Becker, Tara Krahn, Dean TI A review of atypical antipsychotic medications for posttraumatic stress disorder SO INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY LA English DT Review DE atypical antipsychotics; pharmacologic treatment; posttraumatic stress disorder ID DOUBLE-BLIND; COMBAT VETERANS; OPEN-LABEL; ADULT-RAT; ADJUNCTIVE RISPERIDONE; PSYCHOTIC SYMPTOMS; OPEN TRIAL; OLANZAPINE; PLACEBO; PTSD AB Posttraumatic stress disorder (PTSD) can be a chronic and disabling illness with a limited response to antidepressant treatment, particularly in the case of combat-induced PTSD. The purpose of this study is to review randomized controlled and open-label trials of atypical antipsychotics for the treatment of PTSD. We conducted PUBMED and PILOTS database searches for clinical trials of atypical antipsychotic medications for PTSD in May 2010. Eighteen clinical trials (10 double-blind placebo-controlled, eight open-label) of atypical antipsychotics for PTSD were found and reviewed. Effect sizes of double-blind placebo-controlled trials were small, but were positive for risperidone and quetiapine. Intrusive and hypervigilance symptom subscales showed the most improvement. We concluded that atypical antipsychotic medications have a modest benefit for the treatment of PTSD. Larger randomized controlled trials are needed to clarify the potential utility of these medications in the treatment of PTSD and more rigorous examination of metabolic side effects is warranted. Int Clin Psychopharmacol 26:193-200 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Ahearn, Eileen P.; Juergens, Timothy; Krahn, Dean] Univ Wisconsin, William S Middleton Mem Vet Hosp, Madison, WI 53705 USA. [Ahearn, Eileen P.; Juergens, Timothy; Cordes, Timothy; Krahn, Dean] Univ Wisconsin, Dept Psychiat, Madison, WI 53705 USA. [Becker, Tara] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53705 USA. RP Ahearn, EP (reprint author), Univ Wisconsin, VA Hosp, 2500 Overlook Terrace, Madison, WI 53705 USA. EM eileen.ahearn@va.gov NR 51 TC 13 Z9 14 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0268-1315 J9 INT CLIN PSYCHOPHARM JI Int. Clin. Psychopharmacol. PD JUL PY 2011 VL 26 IS 4 BP 193 EP 200 DI 10.1097/YIC.0b013e3283473738 PG 8 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 774KD UT WOS:000291383200002 PM 21597381 ER PT J AU Bitran, S Farabaugh, AH Ameral, VE LaRocca, RA Clain, AJ Fava, M Mischoulon, D AF Bitran, Stella Farabaugh, Amy H. Ameral, Victoria E. LaRocca, Rachel A. Clain, Alisabet J. Fava, Maurizio Mischoulon, David TI Do early changes in the HAM-D-17 anxiety/somatization factor items affect the treatment outcome among depressed outpatients? Comparison of two controlled trials of St John's wort (Hypericum perforatum) versus a SSRI SO INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE antidepressants; anxiety; depression; predictors; remission; St John's wort ID MAJOR DEPRESSION; EARLY IMPROVEMENT; ANTIDEPRESSANT TREATMENT; ALTERNATIVE MEDICINE; FLUOXETINE TREATMENT; TREATMENT RESPONSE; CLINICAL-TRIALS; DRUG RESPONSE; METAANALYSIS; DISORDER AB To assess whether early changes in Hamilton Depression Rating Scale-17 anxiety/somatization items predict remission in two controlled studies of Hypericum perforatum (St John's wort) versus selective serotonin reuptake inhibitors for major depressive disorder. The Hypericum Depression Trial Study Group (National Institute of Mental Health) randomized 340 patients to Hypericum, sertraline, or placebo for 8 weeks, whereas the Massachusetts General Hospital study randomized 135 patients to Hypericum, fluoxetine, or placebo for 12 weeks. The investigators examined whether remission was associated with early changes in anxiety/somatization symptoms. In the National Institute of Mental Health study, significant associations were observed between remission and early improvement in the anxiety (psychic) item (sertraline arm), somatic (gastrointestinal item; Hypericum arm), and somatic (general) symptoms (placebo arm). None of the three treatment arms of the Massachusetts General Hospital study showed significant associations between anxiety/somatization symptoms and remission. When both study samples were pooled, we found associations for anxiety (psychic; selective serotonin reuptake inhibitors arm), somatic (gastrointestinal), and hypochondriasis (Hypericum arm), and anxiety (psychic) and somatic (general) symptoms (placebo arm). In the entire sample, remission was associated with the improvement in the anxiety (psychic), somatic (gastrointestinal), and somatic (general) items. The number and the type of anxiety/somatization items associated with remission varied depending on the intervention. Early scrutiny of the Hamilton Depression Rating Scale-17 anxiety/somatization items may help to predict remission of major depressive disorder. Int Clin Psychopharmacol 26:206-212 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Bitran, Stella; Farabaugh, Amy H.; Ameral, Victoria E.; LaRocca, Rachel A.; Clain, Alisabet J.; Fava, Maurizio; Mischoulon, David] Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, Boston, MA 02114 USA. RP Mischoulon, D (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, 1 Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM dmischoulon@partners.org FU MGH; National Institute of Mental Health (NIMH); National Center for Complementary and Alternative Medicine (NCCAM); Lichtwer Pharma AG (Berlin, Germany) FX Support: this re-analysis is supported by the MGH Depression Clinical and Research Program's clinical practice revenues. The authors thank the members of the Hypericum Depression Trial Study Group for allowing us access to the original database from their clinical trial.; The placebo-controlled clinical trial of a standardized extract of Hypericum perforatum in the major depressive disorder was conducted and supported by the National Institute of Mental Health (NIMH) and the National Center for Complementary and Alternative Medicine (NCCAM) in collaboration with the study investigators. This manuscript reflects the views of the authors and may not reflect the opinions or views of all the study investigators, the NIMH, or the NCCAM. The double blind, randomized trial of St John's Wort, fluoxetine, and placebo in major depressive disorder was supported by a grant of Lichtwer Pharma AG (Berlin, Germany) to the Massachusetts General Hospital. NR 36 TC 3 Z9 4 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0268-1315 J9 INT CLIN PSYCHOPHARM JI Int. Clin. Psychopharmacol. PD JUL PY 2011 VL 26 IS 4 BP 206 EP 212 DI 10.1097/YIC.0b013e328343ba08 PG 7 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 774KD UT WOS:000291383200004 PM 21278577 ER PT J AU Fueki, K Igarashi, Y Maeda, Y Baba, K Koyano, K Akagawa, Y Sasaki, K Kuboki, T Kasugai, S Garrett, NR AF Fueki, K. Igarashi, Y. Maeda, Y. Baba, K. Koyano, K. Akagawa, Y. Sasaki, K. Kuboki, T. Kasugai, S. Garrett, N. R. TI Factors related to prosthetic restoration in patients with shortened dental arches: a multicentre study SO JOURNAL OF ORAL REHABILITATION LA English DT Article DE shortened dental arch; prosthetic treatment; occlusal unit; multicentre study ID REMOVABLE PARTIAL DENTURES; QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; MISSING OCCLUSAL UNITS; MASTICATORY PERFORMANCE; ORAL FUNCTION; SATISFACTION; ABILITY; 5-YEAR AB P>The aim of this study was to identify the factors related to prosthetic restoration in patients with shortened dental arches (SDA). SDA patients with 2-12 missing occlusal units were consecutively enrolled from seven university-based dental hospitals in Japan. Of the 145 subjects (mean age; 63 center dot 4 years), 41% chose no treatment and 59% sought to replace their edentulous spaces with removable partial dentures or implant-supported fixed partial dentures. Restoration decisions were related to tooth loss patterns. Only 3% of subjects missing just second molar(s) sought to receive prosthetic treatment, while the percentage increased to 58% in subjects who were missing first and second molars and 93% in subjects missing premolar(s). Logistic regression analyses found that young age, increased number of missing occlusal units, asymmetric arch and presence of chewing complaint were significant predictors for prosthetic restoration (P < 0 center dot 05). Increased number of missing occlusal units and asymmetric arch were significant predictors for the presence of chewing complaint (P < 0 center dot 05). These results suggest that perceived impairment of chewing ability owing to missing occlusal units is a critical factor for prosthetic restoration in SDA patients. C1 [Fueki, K.; Igarashi, Y.] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Sect Removable Partial Denture Prosthodont, Tokyo 1138549, Japan. [Maeda, Y.] Osaka Univ, Grad Sch Dent, Div Oromaxillofacial Regenerat, Osaka, Japan. [Baba, K.] Showa Univ, Sch Dent, Dept Prosthodont, Tokyo 142, Japan. [Koyano, K.] Kyushu Univ, Div Oral Rehabil, Grad Sch Dent, Sect Removable Prosthodont, Kyushu, Japan. [Akagawa, Y.] Hiroshima Univ, Grad Sch Biomed Sci, Dept Adv Prosthodont, Hiroshima, Japan. [Sasaki, K.] Tohoku Univ, Grad Sch Dent, Div Adv Prosthet Dent, Sendai, Miyagi 980, Japan. [Kuboki, T.] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Oral Rehabil & Regenerat Med, Okayama, Japan. [Kasugai, S.] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Sect Oral Implantol & Regenerat Dent Med, Tokyo, Japan. [Garrett, N. R.] Univ Calif Los Angeles, Sch Dent, Jane & Jerry Weintraub Ctr Reconstruct Biotechnol, Los Angeles, CA 90024 USA. [Garrett, N. R.] Univ Calif Los Angeles, Sch Dent, Div Adv Prosthodont Biomat & Hosp Dent, Los Angeles, CA 90024 USA. [Garrett, N. R.] Vet Adm Greater Angeles Healthcare Syst, Los Angeles, CA USA. RP Fueki, K (reprint author), Tokyo Med & Dent Univ, Grad Sch, Sect Removable Partial Denture Prosthodont, Bunkyo Ku, 1-5-45 Yushima, Tokyo 1138549, Japan. EM kunfu.rpro@tmd.ac.jp RI Fueki, Kenji/A-9909-2008 OI Fueki, Kenji/0000-0002-5885-2447 FU Ministry of Education, Culture, Sports, Science and Technology of Japan [20249077] FX The authors thank collaborative researchers of this study, Drs. E. Yoshida, T. Sugiura, K. Ikebe, H. Tukasaki, Y. Ogino, S. Koyama, K. Koretake, and H. Arakawa for their kind assistance with data collection and analyses. This study was supported by a Grant-in-Aid for Scientific Research (A) (No. 20249077) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. There are no potential conflicts of interest. NR 27 TC 10 Z9 11 U1 0 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0305-182X J9 J ORAL REHABIL JI J. Oral Rehabil. PD JUL PY 2011 VL 38 IS 7 BP 525 EP 532 DI 10.1111/j.1365-2842.2010.02183.x PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 772ZK UT WOS:000291276600007 PM 21091529 ER PT J AU Mullen, JT Savarese, DMF AF Mullen, John T. Savarese, Diane M. F. TI Carcinoid Tumors of the Appendix: A Population-Based Study SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE appendix; carcinoid; lymph node metastasis; survival; SEER ID RIGHT HEMICOLECTOMY; DISTANT METASTASIS AB Background: Carcinoid tumors of the appendix are rare, and as such there are few data guiding their optimal treatment. Methods: The analysis included all patients with malignant, typical carcinoid tumor of the appendix for whom complete data were available in the Surveillance, Epidemiology, and End Results database between 1988 and 2003. Clinicopathologic factors predicting lymph node (LN) involvement and survival were determined. Results: LN metastases were present in 44 of 89 patients (49%), including 4 of 27 patients (15%) with tumors <= 1.0 cm, 16 of 34 patients (47%) with tumors > 1.0 cm but <= 2.0 cm, and 24 of 28 patients (86%) with tumors > 2.0 cm. Increasing tumor size predicted LN involvement, whereas age, gender, and depth of tumor invasion did not. Excluding patients with distant metastasis (DM), the 10-year overall survival rates of patients with positive LNs and tumor sizes <= 1.0 cm, > 1.0 cm but <= 2.0 cm, and > 2.0 cm were 100%, 92%, and 91%, respectively. Conclusions: Right hemicolectomy should be considered for patients with appendiceal carcinoid tumors > 1.0 cm in size given their high incidence of LN metastases and limited data concerning the natural history of unresected LN metastases. J. Surg. Oncol. 2011;104:41-44. (C) 2011 Wiley-Liss, Inc. C1 [Mullen, John T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, Boston, MA 02114 USA. [Savarese, Diane M. F.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02114 USA. RP Mullen, JT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM jmullen@partners.org NR 20 TC 27 Z9 31 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-4790 J9 J SURG ONCOL JI J. Surg. Oncol. PD JUL 1 PY 2011 VL 104 IS 1 BP 41 EP 44 DI 10.1002/jso.21888 PG 4 WC Oncology; Surgery SC Oncology; Surgery GA 773YI UT WOS:000291347600008 PM 21294132 ER PT J AU Arvold, ND Chen, MH Moul, JW Moran, BJ Dosoretz, DE Banez, LL Katin, MJ Braccioforte, MH D'Amico, AV AF Arvold, Nils D. Chen, Ming-Hui Moul, Judd W. Moran, Brian J. Dosoretz, Daniel E. Banez, Lionel L. Katin, Michael J. Braccioforte, Michelle H. D'Amico, Anthony V. TI Risk of Death From Prostate Cancer After Radical Prostatectomy or Brachytherapy in Men With Low or Intermediate Risk Disease SO JOURNAL OF UROLOGY LA English DT Article DE prostatectomy; brachytherapy; prostatic neoplasms; mortality; risk ID EXTERNAL-BEAM RADIOTHERAPY; ADJUVANT RADIOTHERAPY; HORMONAL-THERAPY; COMPETING RISK; FOLLOW-UP; SURVIVAL; FAILURE; RADIATION; OUTCOMES; TRIAL AB Purpose: Radical prostatectomy and brachytherapy are widely used treatments for favorable risk prostate cancer. We estimated the risk of prostate cancer specific mortality following radical prostatectomy or brachytherapy in men with low or intermediate risk prostate cancer using prospectively collected data. Materials and Methods: The study cohort comprised 5,760 men with low risk prostate cancer (prostate specific antigen 10 ng/ml or less, clinical category T1c or 2a and Gleason score 6 or less), and 3,079 with intermediate risk prostate cancer (prostate specific antigen 10 to 20 ng/ml, clinical category T2b or T2c, or Gleason score 7). Competing risks multivariable regression was performed to assess the risk of prostate cancer specific mortality after radical prostatectomy or brachytherapy, adjusting for age, year of treatment, cardiovascular comorbidity and known prostate cancer prognostic factors. Results: After a median followup of 4.2 years (IQR 2.0 - 7.4) for low risk and 4.8 years (IQR 2.2-8.1) for intermediate risk men, there was no significant difference in the risk of prostate cancer specific mortality among low risk (adjusted hazard ratio 1.62, 95% CI 0.59-4.45, p = 0.35) or intermediate risk men (AHR 2.30, 95% CI 0.95-5.58, p = 0.07) treated with brachytherapy compared with radical prostatectomy. The only factor associated with an increased risk of prostate cancer specific mortality (AHR 1.05, 95% CI 1.01-1.10, p = 0.03) was increasing age at treatment in intermediate risk men. Conclusions: The risk of prostate cancer specific mortality in men with low or intermediate risk prostate cancer was not significantly different following radical prostatectomy vs brachytherapy. C1 [Arvold, Nils D.] Brigham & Womens Hosp, Harvard Radiat Oncol Program, Dept Radiat Oncol, Boston, MA 02115 USA. [Arvold, Nils D.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Moul, Judd W.; Banez, Lionel L.] Duke Univ, Div Urol Surg, Durham, NC USA. [Moul, Judd W.; Banez, Lionel L.] Duke Univ, Dept Surg, Duke Prostate Ctr, Durham, NC USA. [Moran, Brian J.; Braccioforte, Michelle H.] Prostate Canc Fdn Chicago, Westmont, IL USA. [Dosoretz, Daniel E.; Katin, Michael J.] 21st Century Oncol, Ft Myers, FL USA. RP Arvold, ND (reprint author), Brigham & Womens Hosp, Harvard Radiat Oncol Program, Dept Radiat Oncol, L-2 Level,75 Francis St, Boston, MA 02115 USA. EM narvold@partners.org NR 29 TC 12 Z9 14 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2011 VL 186 IS 1 BP 91 EP 96 DI 10.1016/j.juro.2011.03.003 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 775PH UT WOS:000291472900026 PM 21571341 ER PT J AU Page, ST Hirano, L Gilchriest, J Dighe, M Amory, JK Marck, BT Matsumoto, AM AF Page, Stephanie T. Hirano, Lianne Gilchriest, Janet Dighe, Manjiri Amory, John K. Marck, Brett T. Matsumoto, Alvin M. TI Dutasteride Reduces Prostate Size and Prostate Specific Antigen in Older Hypogonadal Men With Benign Prostatic Hyperplasia Undergoing Testosterone Replacement Therapy SO JOURNAL OF UROLOGY LA English DT Article DE testosterone; prostate; 5-alpha reductase inhibitors; dihydrotestosterone ID LOW SERUM TESTOSTERONE; LOWER URINARY-TRACT; EXOGENOUS TESTOSTERONE; ANDROGEN DEFICIENCY; CANCER; 5-ALPHA-REDUCTASE; FINASTERIDE; SYMPTOMS; PROGRESSION; PREDICTORS AB Purpose: Benign prostatic hyperplasia and hypogonadism are common disorders in aging men. There is concern that androgen replacement in older men may increase prostate size and symptoms of benign prostatic hyperplasia. We examined whether combining dutasteride, which inhibits testosterone to dihydrotestosterone conversion, with testosterone treatment in older hypogonadal men with benign prostatic hyperplasia reduces androgenic stimulation of the prostate compared to testosterone alone. Materials and Methods: We conducted a double-blind, placebo controlled trial of 53 men 51 to 82 years old with symptomatic benign prostatic hyperplasia, prostate volume 30 cc or greater and serum total testosterone less than 280 ng/dl (less than 9.7 nmol/l). Subjects were randomized to daily transdermal 1% T gel plus oral placebo or dutasteride for 6 months. Testosterone dosing was adjusted to a serum testosterone of 500 to 1,000 ng/dl. The primary outcomes were prostate volume measured by magnetic resonance imaging, serum prostate specific antigen and androgen levels. Results: A total of 46 subjects completed all procedures. Serum testosterone increased similarly into the mid-normal range in both groups. Serum dihydrotestosterone increased in the testosterone only but decreased in the testosterone plus dutasteride group. In the testosterone plus dutasteride group prostate volume and prostate specific antigen (mean +/- SEM) decreased 12% +/- 2.5% and 35% +/- 5%, respectively, compared to the testosterone only group in which prostate volume and prostate specific antigen increased 7.5% +/- 3.3% and 19% +/- 7% (p = 0.03 and p = 0.008), respectively, after 6 months of treatment. Prostate symptom scores improved in both groups. Conclusions: Combined treatment with testosterone plus dutasteride reduces prostate volume and prostate specific antigen compared to testosterone only. Coadministration of a 5 alpha-reductase inhibitor with testosterone appears to spare the prostate from androgenic stimulation during testosterone replacement in older, hypogonadal men with symptomatic benign prostatic hyperplasia. C1 [Page, Stephanie T.] Univ Washington, Sch Med, Div Metab Endocrinol & Nutr, Dept Med, Seattle, WA 98195 USA. [Dighe, Manjiri] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Hirano, Lianne; Gilchriest, Janet; Marck, Brett T.; Matsumoto, Alvin M.] Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Seattle, WA 98108 USA. [Hirano, Lianne; Gilchriest, Janet; Marck, Brett T.; Matsumoto, Alvin M.] Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Seattle, WA USA. RP Page, ST (reprint author), Univ Washington, Sch Med, Div Metab Endocrinol & Nutr, Dept Med, Box 3547138,1959 NE Pacific St, Seattle, WA 98195 USA. EM page@u.washington.edu FU GlaxoSmithKline FX Supported by an investigator initiated grant from GlaxoSmithKline. NR 26 TC 18 Z9 19 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2011 VL 186 IS 1 BP 191 EP 197 DI 10.1016/j.juro.2011.03.026 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 775PH UT WOS:000291472900058 PM 21575967 ER PT J AU Ogilvy, CS Khalessi, AA Hauck, EF Shannon, LR Hopkins, LN Levy, EI Siddiqui, AH AF Ogilvy, Christopher S. Khalessi, Alexander A. Hauck, Erik F. Shannon, Larry R., II Hopkins, L. Nelson Levy, Elad I. Siddiqui, Adnan H. TI Delayed Endovascular Revascularization in a Patient With Progressive Neurological Deterioration From Bilateral Intracranial Vertebral Artery Occlusions: Case Report SO NEUROSURGERY LA English DT Article DE Intracranial vertebral artery occlusion; Revascularization; Stenting; Stroke ID ACUTE ISCHEMIC-STROKE; MECHANICAL EMBOLUS REMOVAL; INTERNAL CAROTID-ARTERY; CEREBRAL-ISCHEMIA; RECANALIZATION; TRIAL; THROMBOLYSIS; MANAGEMENT; PERFUSION; THERAPY AB BACKGROUND AND IMPORTANCE: This article describes delayed endovascular revascularization in a patient with clinical and radiographic evidence of posterior circulation hemodynamic failure in the setting of intracranial occlusive lesions. CLINICAL PRESENTATION: A 48-year-old man presented with a 6-week history of progressive headache, nausea, and ataxia. Bilateral intracranial vertebral artery occlusions and a left posterior inferior cerebellar artery stroke were diagnosed, and the patient began warfarin therapy. Despite these measures, the patient developed dense lower cranial neuropathies, including severe dysarthria, decreased left-sided hearing acuity, and left facial droop. He presented at this point for endovascular evaluation. The patient underwent successful revascularization with intravascular Wingspan stents (Boston Scientific, Natick, Massachusetts) in a delayed fashion (approximately 6 weeks after his initial stroke presentation). His neurological syndrome stabilized and began to improve slowly. CONCLUSION: Patients with arterial occlusion should be evaluated acutely for potential revascularization. In the posterior circulation, clinical progression may supplant physiological imaging in the assessment of hemodynamic collapse. A subpopulation of patients will present with progressive deficits distinct from extracranial manifestations of vertebrobasilar insufficiency; these patients should be considered for delayed revascularization. C1 [Ogilvy, Christopher S.] Massachusetts Gen Hosp, Neurovasc Serv, Boston, MA 02114 USA. [Ogilvy, Christopher S.; Khalessi, Alexander A.; Hauck, Erik F.; Shannon, Larry R., II; Hopkins, L. Nelson; Levy, Elad I.; Siddiqui, Adnan H.] SUNY Buffalo, Dept Neurosurg, Buffalo, NY 14260 USA. SUNY Buffalo, Toshiba Stroke Res Ctr, Buffalo, NY 14260 USA. [Hopkins, L. Nelson; Levy, Elad I.; Siddiqui, Adnan H.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Radiol, Buffalo, NY 14260 USA. [Ogilvy, Christopher S.; Khalessi, Alexander A.; Hauck, Erik F.; Shannon, Larry R., II; Hopkins, L. Nelson; Levy, Elad I.; Siddiqui, Adnan H.] Millard Fillmore Gates Hosp, Dept Neurosurg, Buffalo, NY USA. RP Ogilvy, CS (reprint author), Massachusetts Gen Hosp, Neurovasc Serv, Wang 745,55 Fruit St, Boston, MA 02114 USA. EM cogilvy@partners.org FU Toshiba; Boston Scientific; Codman & Shurtleff, Inc.; ev3/Covidien Vascular Therapies; Abbott Vascular; National Institutes of Health [1R01NS064592-01A1]; University at Buffalo FX Dr Ogilvy serves as a consultant to Mizuho America. Dr Hopkins receives research support from Toshiba; serves as a consultant to Abbott, Boston Scientific, Cordis, Micrus, and W. L. Gore; holds a financial interest in AccessClosure, Boston Scientific, Claret Medical Inc., Micrus, and Valor Medical; has a board/trustee/officer position with AccessClosure, Claret Medical Inc., and Micrus (until September 2010); belongs to the Abbott Vascular speakers' bureau; and receives honoraria from Bard, Boston Scientific, Cordis, Memorial Healthcare System, Complete Conference Management, SCAI, and Cleveland Clinic (Boston Scientific's neurovascular business was acquired by Stryker in 2011). Dr Levy receives research grant support (principal investigator: Stent-Assisted Recanalization in acute Ischemic Stroke, SARIS), other research support (devices), and honoraria from Boston Scientific and research support from Codman & Shurtleff, Inc. and ev3/Covidien Vascular Therapies; has ownership interests in Intratech Medical Ltd. and Mynx/Access Closure; serves as a consultant on the board of Scientific Advisors to Codman & Shurtleff, Inc.; serves as a consultant per project and/or per hour for Codman & Shurtleff, Inc., ev3/Covidien Vascular Therapies, and TheraSyn Sensors, Inc.; and receives fees for carotid stent training from Abbott Vascular and ev3/Covidien Vascular Therapies. Dr Levy receives no consulting salary arrangements. All consulting is per project and/or per hour (Boston Scientific's neurovascular business was acquired by Stryker in 2011). Dr Siddiqui has received research grants from the National Institutes of Health (co-investigator: NINDS 1R01NS064592-01A1, Hemodynamic induction of pathologic remodeling leading to intracranial aneurysms) and the University at Buffalo (Research Development Award); holds financial interests in Hotspur, Intratech Medical, StimSox, and Valor Medical; serves as a consultant to Codman & Shurtleff, Inc., Concentric Medical, ev3/Covidien Vascular Therapies, GuidePoint Global Consulting, and Penumbra; belongs to the speakers' bureaus of Codman & Shurtleff, Inc. and Genentech; serves on an advisory board for Codman & Shurtleff; and has received honoraria from American Association of Neurological Surgeons' courses, an Emergency Medicine Conference (7th Annual Contemporary Issues in Emergency Medicine, Upstate Medical School of Medicine, March 2007, Syracuse, New York, New York), Genentech, Neocure Group LLC, and from Abbott Vascular and Codman & Shurtleff, Inc. for training other neurointerventionists in carotid stenting and for training physicians in endovascular stenting for aneurysms. Dr Siddiqui receives no consulting salary arrangements. All consulting is per project and/or per hour. Drs Khalessi, Hauck, and Shannon have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. NR 20 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD JUL PY 2011 VL 69 IS 1 BP E251 EP E256 DI 10.1227/NEU.0b013e3182186811 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 773XK UT WOS:000291344700009 PM 21796070 ER PT J AU Spiliopoulos, K Williams, Z AF Spiliopoulos, Konstantinos Williams, Ziv TI Brachial Plexus Reconstruction Following Resection of a Malignant Peripheral Nerve Sheath Tumor: Case Report SO NEUROSURGERY LA English DT Article DE Brachial; Malignancy; Nerve; Neurotization; Peripheral; Plexus; Transfer ID SOFT-TISSUE SARCOMAS; HEALTH-SCIENCES-CENTER; POSTOPERATIVE RADIOTHERAPY; SUPRASCAPULAR NERVE; REGION TUMORS; MANAGEMENT; OUTCOMES; SURGERY; SERIES; RESTORATION AB BACKGROUND AND IMPORTANCE: The main therapeutic approach for malignant peripheral nerve sheath tumors (MPNSTs) of the brachial plexus is wide local excision. Sacrifice of some-occasionally all-elements of the brachial plexus often is required to obtain complete resection, and therefore can be associated with significant morbidity. While peripheral nerve repair is commonly used in the setting of traumatic nerve injury, little is known about its potential use in the treatment of MPNST. CLINICAL PRESENTATION: We present a patient with an enlarging right neck mass who was diagnosed with MPNST of the brachial plexus. The patient underwent gross total resection of the tumor, requiring sectioning of the upper trunk of the brachial plexus, as well as associated divisions. Following resection, sural nerve grafts were used to connect the C5 nerve root to the anterior division of the upper trunk and the spinal accessory nerve to the suprascapular nerve, whereas a triceps branch of the radial nerve was coapted directly to the anterior division of the axillary nerve. CONCLUSION: By 20 months after surgery, the patient had regained significant strength in her upper trunk distribution and demonstrated no evidence of tumor recurrence. Brachial plexus reconstruction offers a potentially valuable surgical adjunct to MPNST treatment. C1 [Spiliopoulos, Konstantinos; Williams, Ziv] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Williams, Z (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,WAC 745K, Boston, MA 02114 USA. EM zwilliams@partners.org NR 41 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD JUL PY 2011 VL 69 IS 1 BP E245 EP E250 DI 10.1227/NEU.0b013e31821867de PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 773XK UT WOS:000291344700007 PM 21796069 ER PT J AU Cote, CJ AF Cote, Charles J. TI Risk, Error, Outcome, and Prevention in Pediatric Anesthesia: so many issues, lots of good solutions, but where do we find the resources? SO PEDIATRIC ANESTHESIA LA English DT Editorial Material C1 Harvard Univ, MassGen Hosp Children, Dept Anesthesia Crit Care & Pain Management, Div Pediat Anesthesia,Sch Med,Massachusetts Gen H, Boston, MA 02115 USA. RP Cote, CJ (reprint author), Harvard Univ, MassGen Hosp Children, Dept Anesthesia Crit Care & Pain Management, Div Pediat Anesthesia,Sch Med,Massachusetts Gen H, 55 Fruit St, Boston, MA 02115 USA. EM cjcote@partners.org NR 0 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1155-5645 J9 PEDIATR ANESTH JI Pediatr. Anesth. PD JUL PY 2011 VL 21 IS 7 BP 713 EP 715 DI 10.1111/j.1460-9592.2011.03620.x PG 3 WC Anesthesiology; Pediatrics SC Anesthesiology; Pediatrics GA 772HC UT WOS:000291223900001 PM 21627713 ER PT J AU Singh, JA Yang, S Strand, V Simon, L Forsythe, A Hamburger, S Chen, L AF Singh, Jasvinder A. Yang, Shuo Strand, Vibeke Simon, Lee Forsythe, Anna Hamburger, Steve Chen, Lang TI Validation of pain and patient global scales in chronic gout: data from two randomised controlled trials SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID CLINICALLY IMPORTANT DIFFERENCES; QUALITY-OF-LIFE; RHEUMATOID-ARTHRITIS; IMPORTANT DIFFERENCE; DEFINITION AB Objective To assess validity of pain and patient global scales in gout. Methods The authors used data from pegloticase clinical trials in chronic refractory gout to examine the validity of visual analogue scale (VAS) pain, Short-Form 36 (SF-36) bodily pain subscale and VAS patient global assessment (all scales 0-100). Convergent/divergent validity with clinical characteristics was tested by using Spearman's correlation coefficient. For discriminant ability, the authors compared the change at 6 months between placebo and pegloticase arms and calculated effect size (ES) and standardised response mean (SRM). Results 212 patients (mean age, 55.4 years, 82% men; 73% with tophaceous gout) provided data. VAS pain was statistically significantly correlated with tender joints (r = 0.42), swollen joints (r = 0.30), SF-36 physical (r = -0.56) and Mental Component Summary (r = -0.36) and Health Assessment Questionnaire scores (r = 0.54; all p-values <0.0001), but not disease duration (r = -0.01; p = 0.84), gout flares (r = 0.12; p = 0.08), comorbidities (r = 0.05; p = 0.47) or plasma urate (r = 0.01; p = 0.89). Similar and significant correlation coefficients with tender and swollen joints were noted for VAS patient global assessment (r = 0.35 and 0.23; p<0.0012 for both) and SF-36 pain subscale (r = -0.27 and -0.19; p<0.006 for both). Pegloticase group had significantly more improvement than placebo at 6 months, mean (SD): VAS pain, -9.2 (29.3) versus 1.9 (26.4), p = 0.0002; SF-36 pain, 14.6 (25.6) versus -0.04 (21.1), p<0.0001; and patient global, -9.3 (26.5) versus 3.4 (22.8), p<0.0001. ES and SRMs in pegloticase group were as follows: VAS pain, 0.34 and 0.30; SF-36 pain, 0.69 and 0.57; patient global, 0.49 and 0.44. Conclusion VAS pain, SF-36 pain and patient global VAS are valid outcome measures in patients with chronic gout. C1 [Singh, Jasvinder A.; Yang, Shuo; Chen, Lang] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Ctr Surg Med Acute Care Res & Transit, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama, Sch Publ Hlth, Div Epidemiol, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Mayo Clin, Sch Med, Dept Orthoped Surg, Rochester, MN USA. [Strand, Vibeke] Stanford Univ, Palo Alto, CA 94304 USA. [Simon, Lee] SDG LLC, Cambridge, MA USA. [Forsythe, Anna; Hamburger, Steve] Savient Pharmaceut Inc, E Brunswick, NJ USA. RP Singh, JA (reprint author), Univ Alabama, Dept Med, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. EM jasvinder.md@gmail.com RI YANG, SHUO/D-2695-2014; OI YANG, SHUO/0000-0002-4999-0506; singh, jasvinder/0000-0003-3485-0006 FU University of Alabama; CRADA; Allergan; Takeda; Savient; Wyeth; Amgen FX This material is the result of work supported with University of Alabama grant to JAS and the resources and the use of facilities at the Birmingham VA Medical Center, Alabama, USA. Savient Pharmaceuticals and UAB are parties to a Clinical Research and Development Agreement (CRADA) that pertains to health-related quality of life studies in the area of gout. Funding from the CRADA was not used to support this project.; JAS has received speaker honoraria from Abbott; research and travel grants from Allergan, Takeda, Savient, Wyeth and Amgen; and consultant fees from Savient, URL Pharmaceuticals and Novartis. VS is a consultant for Savient and Novartis. LS is a consultant for Takeda, Horizon Pharma, Savient, Wyeth, Pfizer, Merck and Genzyme and is a member of the Board of Directors of Savient. SH and AF are employees of Savient Pharmaceuticals, Inc. SY and LC has no financial conflicts. NR 15 TC 9 Z9 10 U1 0 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2011 VL 70 IS 7 BP 1277 EP 1281 DI 10.1136/ard.2010.144022 PG 5 WC Rheumatology SC Rheumatology GA 769PG UT WOS:000291028800017 PM 21622774 ER PT J AU Wilens, TE Morrison, NR AF Wilens, Timothy E. Morrison, Nicholas R. TI The intersection of attention-deficit/hyperactivity disorder and substance abuse SO CURRENT OPINION IN PSYCHIATRY LA English DT Article DE attention-deficit/hyperactivity disorder; prevention treatment; substance use disorder; treatment ID DEFICIT HYPERACTIVITY DISORDER; PROSPECTIVE FOLLOW-UP; CONTROLLED-TRIAL; EXAMINING PHARMACOKINETICS; ADULT ADHD; ATOMOXETINE; SMOKING; RISK; METHYLPHENIDATE; ADOLESCENTS AB Purpose of review The link between attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) continues to be an area of great interest. In this report more recent work exploring the developmental relationship between ADHD and SUDs and associated concurrent disorders is discussed. Recent findings Recent work highlights the role of treatment of ADHD in children on subsequent cigarette smoking and SUDs in adolescence and adulthood. Contemporary data suggest that ADHD may be underdiagnosed in SUD populations. Studies in patients with ADHD and SUDs suggest that SUDs treatment needs to be sequenced initially with ADHD treatment quickly thereafter. Recent studies also highlight concerns associated with the misuse and diversion of prescription stimulants in ADHD adolescents and young adults and indicate that extended-release stimulants may reduce the likelihood for abuse. Summary Practitioners are increasingly recognizing the overlap between ADHD and SUDs, and treatment modalities including cognitive behavioral therapy and pharmacotherapy demonstrate mixed results in the treatment of these comorbid disorders. Areas in need of further investigation include the mechanism(s) by which ADHD leads to SUDs, diagnostic criteria associated with ADHD in SUD individuals, and prevention and treatment strategies for these populations. C1 [Wilens, Timothy E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Pediat Psychopharmacol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Ctr Addict Med, Boston, MA 02114 USA. RP Wilens, TE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Pediat Psychopharmacol Unit, YAW 6A,55 Fruit St, Boston, MA 02114 USA. EM TWilens@partners.org FU NIH [R01 DA14419, K24 DA016264]; Abbott; McNeil; Lilly; Nextwave; NIH (NIDA); Merck; Shire FX This research was supported by NIH R01 DA14419 and K24 DA016264 to T.E.W. T.E.W. is receiving or has received grant support from Abbott, McNeil, Lilly, Nextwave, NIH (NIDA), Merck, and Shire; has been a speaker for Eli Lilly, McNeil, Novartis, and Shire, and is or has been a consultant for Abbott, AstraZeneca, McNeil, Nextwave, NIH, Lilly, Novartis, Merck, and Shire. T.E.W. has published a book with Guilford Press; Straight Talk About Psychiatric Medications for Kids. NR 35 TC 26 Z9 28 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7367 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD JUL PY 2011 VL 24 IS 4 BP 280 EP 285 DI 10.1097/YCO.0b013e328345c956 PG 6 WC Psychiatry SC Psychiatry GA 769PS UT WOS:000291030800004 PM 21483267 ER PT J AU Trinh, NHT Youn, SJ Sousa, J Regan, S Bedoya, CA Chang, TE Fava, M Yeung, A AF Trinh, Nhi-Ha T. Youn, Soo Jeong Sousa, Jessica Regan, Susan Bedoya, C. Andres Chang, Trina E. Fava, Maurizio Yeung, Albert TI Using electronic medical records to determine the diagnosis of clinical depression SO INTERNATIONAL JOURNAL OF MEDICAL INFORMATICS LA English DT Article DE Depression; Electronic medical records; Clinical research methods ID OPERATING CHARACTERISTIC CURVES; CARE; EPIDEMIOLOGY; DISORDER; NETWORK; BIAS AB Objective: To investigate the validity of using electronic medical records (EMR) database in a large health organization for identifying patients with clinical depression. Method: The Massachusetts General Hospital EMR system was used to generate a sample of primary care patients seen in the primary care clinic in 2007. Using this sample, the validity of using certain fields in the EMR database (i.e., billing diagnosis, problem list, and medication list) to identify patients with clinical depression was compared to primary care physician (PCP) assessment by a written questionnaire. Based on this standard, the sensitivity, specificity, positive predictive value, negative predictive value, and the areas under receiver operating characteristic curve (AUC) of three specific EMR fields - individually and in combination - were calculated to identify which EMR field best predicted PCP classification. Results: The EMR fields "billing diagnosis", "problem list" and antidepressant in "medication list", were all able to identify patients' diagnosis of depression by their PCPs reasonably well. Having one or more "billing diagnosis" of depression had the highest sensitivity and highest AUC (77% sensitivity, 76% specificity, AUC 0.77) among any of the fields used alone. Conclusion: The AUC for "billing diagnosis" of depression performed the best of the three single fields tested, with an AUC of 0.77, corresponding to a test with moderate accuracy. This analysis demonstrates that specific EMR fields can be used as a proxy for PCP assessment of depression for this EMR system. Limitations to our analysis include the physician response rate to our survey as well as the quality of the data, which is collected primarily for administrative and clinical purposes. When using administrative and clinical data in mental health studies, researchers must first assess the accuracy of choosing specific fields within their EMR system in order to determine the level of accuracy for them to be used as proxies for clinical diagnoses. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Trinh, Nhi-Ha T.; Youn, Soo Jeong; Sousa, Jessica; Chang, Trina E.; Fava, Maurizio; Yeung, Albert] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Regan, Susan] Massachusetts Gen Hosp, Div Internal Med, Boston, MA 02114 USA. [Bedoya, C. Andres] Massachusetts Gen Hosp, Behav Med Serv, Boston, MA 02114 USA. [Yeung, Albert] S Cove Community Hlth Ctr, Boston, MA 02111 USA. RP Trinh, NHT (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, 1 Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM ntrinh@partners.org OI Regan, Susan/0000-0003-0940-2017 FU NIMH NIH HHS [T32 MH017119-25, T32 MH017119] NR 19 TC 10 Z9 11 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1386-5056 J9 INT J MED INFORM JI Int. J. Med. Inform. PD JUL PY 2011 VL 80 IS 7 BP 533 EP 540 DI 10.1016/j.ijmedinf.2011.03.014 PG 8 WC Computer Science, Information Systems; Health Care Sciences & Services; Medical Informatics SC Computer Science; Health Care Sciences & Services; Medical Informatics GA 769VW UT WOS:000291047400008 PM 21514880 ER PT J AU Porter, JE AF Porter, Janet E. TI What Hat Are You Wearing? SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE LA English DT Editorial Material C1 Dana Farber Canc Inst, Boston, MA 02215 USA. RP Porter, JE (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. NR 2 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-4659 J9 J PUBLIC HEALTH MAN JI J. Public Health Manag. Pract. PD JUL-AUG PY 2011 VL 17 IS 4 BP 393 EP 395 DI 10.1097/PHH.0b013e31821e0dc6 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 769NK UT WOS:000291022300024 PM 21617421 ER PT J AU Goebel-Stengel, M Stengel, A Tache, Y Reeve, JR AF Goebel-Stengel, Miriam Stengel, Andreas Tache, Yvette Reeve, Joseph R., Jr. TI The importance of using the optimal plasticware and glassware in studies involving peptides SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Test tube surface; Endocrine peptide; Radioimmunoassay; Iodinated peptide ID PROTEIN; PURIFICATION; ADSORPTION; GHRELIN; HORMONE; LOSSES; RATS AB The unpredictable nature of peptide binding to surfaces requires optimization of experimental containers to be used. To demonstrate the variable recoveries of peptides from multiple surfaces commonly employed in peptide research, we tested the recovery of radiolabeled 125I endocrine peptides under different conditions and provide guidelines for determining the surfaces to use for other peptides. (125)I-labeled peptides (ghrelin, sulfated cholecystokinin-8, corticotropin-releasing factor, glucagon-like peptide-1 [GLP-1], insulin, leptin, nesfatin-1, and peptide YY), representing a wide spectrum in net charge, size, end group, and modification, were incubated for 48 h in glass and plastic tubes untreated or coated with siliconizing fluid. Best surfaces were chosen and peptides were incubated with bovine serum albumin (BSA, 1%) with or without subsequent lyophilization. Recovery of (125)I-labeled peptides was determined by gamma counting. Important differences in (125)I-labeled peptide binding capacities to various types of surfaces exist. Siliconization decreased, whereas the addition of BSA improved recovery from surfaces tested. Lyophilizing solutions containing (125)I-labeled peptides and BSA in the tubes best suited for individual peptides rendered more than 89% recovery for all peptides. Ghrelin specifically displaced (125)I-ghrelin from borosilicate glass, whereas GLP-1 and Fmoc-arginine did not. Choosing the appropriate experimental container avoids unpredictable peptide loss that results in inaccurate measurements and false conclusions. (C) 2011 Elsevier Inc. All rights reserved. C1 [Goebel-Stengel, Miriam; Stengel, Andreas; Tache, Yvette; Reeve, Joseph R., Jr.] VA Greater Los Angeles Healthcare Syst, Peptid Radioimmunoassay & Prote Lab, CURE Digest Dis Res Ctr, Los Angeles, CA 90073 USA. [Goebel-Stengel, Miriam] Martin Luther Hosp, Dept Med, D-14193 Berlin, Germany. [Goebel-Stengel, Miriam] Martin Luther Hosp, Inst Neurogastroenterol, D-14193 Berlin, Germany. [Goebel-Stengel, Miriam; Stengel, Andreas; Tache, Yvette; Reeve, Joseph R., Jr.] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Los Angeles, CA 90095 USA. [Stengel, Andreas] Univ Med Berlin, Dept Med, Div Psychosomat Med & Psychotherapy, D-10117 Berlin, Germany. RP Reeve, JR (reprint author), VA Greater Los Angeles Healthcare Syst, Peptid Radioimmunoassay & Prote Lab, CURE Digest Dis Res Ctr, Los Angeles, CA 90073 USA. EM jreeve@mednet.ucla.edu FU National Institutes of Health [DK-41301, RO1 DK-83449] FX This work was supported by National Institutes of Health Center Grant: CURE/Digestive Diseases Research Center Grant DK-41301 (Peptidomic RIA Proteomic Core (J.R.R. Jr.) and Animal Core (Y.T.)) and RO1 DK-83449 (J.R.R. Jr.). NR 16 TC 30 Z9 30 U1 5 U2 37 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUL 1 PY 2011 VL 414 IS 1 BP 38 EP 46 DI 10.1016/j.ab.2011.02.009 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 765KK UT WOS:000290704300006 PM 21315060 ER PT J AU Suarez, A Huber, RJ Myre, MA O'Day, DH AF Suarez, Andres Huber, Robert J. Myre, Michael A. O'Day, Danton H. TI An extracellular matrix, calmodulin-binding protein from Dictyostelium with EGF-like repeats that enhance cell motility SO CELLULAR SIGNALLING LA English DT Article DE Calmodulin binding protein; Cysteine-rich; Extracellular matrix; EGF-like repeats; Cell motility; Extracellular calmodulin; Dictyostelium ID EPIDERMAL-GROWTH-FACTOR; POTENTIAL TARGETS; DISCOIDEUM; RECEPTOR; CHEMOTAXIS; CYTOTACTIN; MIGRATION; CLEAVAGE; KINASE; FAMILY AB CyrA is a novel cysteine-rich protein with four EGFL repeats that was isolated using the calmodulin (CaM) binding overlay technique (CaMBOT), suggesting it is a CaM-binding protein (CaMBP). The full-length 63 kDa cyrA is cleaved into two major C-terminal fragments, cyrA-C45 and cyrA-C40. A putative CaM-binding domain was detected and both CaM-agarose binding and CaM immunoprecipitation verified that cyrA-C45 and cyrA-C40 each bind to CaM in both a Ca(2+)-dependent and -independent manner. cyrA-C45 was present continuously throughout growth and development but was secreted at high levels during the multicellular slug stage of Dictyostelium development. At this time, cyrA localizes to the extracellular matrix (ECM). ECM purification verified the presence of cyrA-C45. An 18 amino acid peptide (DdEGFL1) from the first EGFL repeat sequence of cyrA (EGFL1) that is present in both cyrA-C45 and -C40 enhances both random cell motility and cAMP-mediated chemotaxis. Here we reveal that the dose-dependent enhancement of motility by DdEGFL1 is related to the time of cell starvation. Addition of DdEGFL1 also inhibits cyrA proteolysis. The status of cyrA as an extracellular CaMBP was further clarified by the demonstration that CaM is secreted during development. Antagonism of CaM with W7 resulted in enhanced cyrA proteolysis suggesting a functional role for extracellular CaM in protecting CaMBPs from proteolysis. cyrA is the first extracellular CaMBP identified in Dictyostelium and since it is an ECM protein with EGF-like repeats that enhance cell motility and it likely also represents the first matricellular protein identified in a lower eukaryote. (C) 2011 Elsevier Inc. All rights reserved. C1 [Suarez, Andres; O'Day, Danton H.] Univ Toronto, Dept Biol, Mississauga, ON L5L 1C6, Canada. [Huber, Robert J.; O'Day, Danton H.] Univ Toronto, Dept Cell & Syst Biol, Toronto, ON, Canada. [Myre, Michael A.] Massachusetts Gen Hosp, Mol Neurogenet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. RP O'Day, DH (reprint author), Univ Toronto, Dept Biol, Mississauga, ON L5L 1C6, Canada. EM danton.oday@utoronto.ca FU Natural Sciences and Engineering Council of Canada FX We would like to thank Christopher Henley and Ray Lim for technical assistance on cyrA gene isolation. Karsten Suhre is thanked for helping us with protein sequence comparisons. The pDXA plasmid used for cyrA-FLAG was provided by Dr. Tom Egelhoff, through the Dicty Stock Centre. We also thank Wei Luo and Dr. Yali Wang for peptide synthesis. This work was supported by a grant from the Natural Sciences and Engineering Council of Canada (DHO'D). NR 57 TC 13 Z9 13 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD JUL PY 2011 VL 23 IS 7 BP 1197 EP 1206 DI 10.1016/j.cellsig.2011.03.008 PG 10 WC Cell Biology SC Cell Biology GA 766KH UT WOS:000290780500016 PM 21402150 ER PT J AU Paraskar, A Soni, S Basu, S Amarasiriwardena, CJ Lupoli, N Srivats, S Roy, RS Sengupta, S AF Paraskar, Abhimanyu Soni, Shivani Basu, Sudipta Amarasiriwardena, Chitra J. Lupoli, Nicola Srivats, Shyam Roy, Rituparna Sinha Sengupta, Shiladitya TI Rationally engineered polymeric cisplatin nanoparticles for improved antitumor efficacy SO NANOTECHNOLOGY LA English DT Article ID CANCER; DNA; CARBOPLATIN; DELIVERY; DRUGS AB The use of cisplatin, a first line chemotherapy for most cancers, is dose-limited due to nephrotoxicity. While this toxicity can be addressed through nanotechnology, previous attempts at engineering cisplatin nanoparticles have been limited by the impact on the potency of cisplatin. Here we report the rational engineering of a novel cisplatin nanoparticle by harnessing a novel polyethylene glycol-functionalized poly-isobutylene-maleic acid (PEG-PIMA) copolymer, which can complex with cis-platinum (II) through a monocarboxylato and a coordinate bond. We show that this complex self-assembles into a nanoparticle, and exhibits an IC(50) = 0.77 +/- 0.11 mu M comparable to that of free cisplatin (IC(5)0 = 0.44 +/- 0.09 mu M). The nanoparticles are internalized into the endolysosomal compartment of cancer cells, and release cisplatin in a pH-dependent manner. Furthermore, the nanoparticles exhibit significantly improved antitumor efficacy in a 4T1 breast cancer model in vivo, with limited nephrotoxicity, which can be explained by preferential biodistribution in the tumor with reduced kidney concentrations. Our results suggest that the PEG-PIMA-cisplatin nanoparticle can emerge as an attractive solution to the challenges in cisplatin chemotherapy. C1 [Paraskar, Abhimanyu; Soni, Shivani; Basu, Sudipta; Srivats, Shyam; Roy, Rituparna Sinha; Sengupta, Shiladitya] Harvard Univ, Sch Med, BWH HST Ctr Biomed Engn, Cambridge, MA 02139 USA. [Amarasiriwardena, Chitra J.; Lupoli, Nicola; Sengupta, Shiladitya] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Lab,Dept Med, Cambridge, MA 02139 USA. [Amarasiriwardena, Chitra J.; Lupoli, Nicola; Sengupta, Shiladitya] Harvard Univ, Sch Med, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Sengupta, Shiladitya] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Sengupta, S (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Lab,Dept Med, 65 Landsdowne St, Cambridge, MA 02139 USA. EM ssengupta2@partners.org FU US Department of Defense (DOD) [W81XWH-07-1-0482]; DOD; National Institutes of Health [1R01CA135242-01A2]; BCRP [W81XWH-09-1-0728]; Charles A King Trust FX S Sengupta is supported by US Department of Defense (DOD) Breast Cancer Research Program (BCRP) Era of Hope Scholar Award (W81XWH-07-1-0482), a DOD Collaborative Innovator Grant, and National Institutes of Health Grant R01 (1R01CA135242-01A2). AP is supported by a BCRP postdoctoral fellowship award (W81XWH-09-1-0728). SB is supported by a Charles A King Trust fellowship. NR 18 TC 11 Z9 11 U1 4 U2 26 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0957-4484 J9 NANOTECHNOLOGY JI Nanotechnology PD JUL 1 PY 2011 VL 22 IS 26 AR 265101 DI 10.1088/0957-4484/22/26/265101 PG 8 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA 765OY UT WOS:000290719500002 PM 21576779 ER PT J AU Loftis, JM Choi, D Hoffman, W Huckans, MS AF Loftis, Jennifer M. Choi, Dongseok Hoffman, William Huckans, Marilyn S. TI Methamphetamine Causes Persistent Immune Dysregulation: A Cross-Species, Translational Report SO NEUROTOXICITY RESEARCH LA English DT Article DE Methamphetamine; Substance abuse; Adhesion molecules; Cytokines; Neuroinflammation; Chemokines ID PRO-INFLAMMATORY CYTOKINES; RECEPTOR MESSENGER-RNA; LONG-TERM POTENTIATION; NECROSIS-FACTOR-ALPHA; BLOOD-BRAIN-BARRIER; CHRONIC HEPATITIS-C; RECOGNITION MEMORY; STRUCTURAL ABNORMALITIES; REGIONAL HETEROGENEITY; DEPENDENT INDIVIDUALS AB Methamphetamine (MA) dependence causes serious cognitive impairments that can persist during abstinence and negatively affect recovery outcomes. Evidence suggests that immune factors, such as cytokines, chemokines, and cellular adhesion molecules, contribute to MA-induced immune dysfunction, neuronal injury, and persistent cognitive impairments, yet the role of MA-induced brain inflammation remains unclear. To address this question, we used a cross-species, translational approach. Thirty-two male C57BL/6J mice were administered MA (1 mg/kg) or saline subcutaneously for seven consecutive days. Mice were euthanized at 72 h or 3 weeks after the last drug dose, and blood and brain samples were collected. In addition, 20 adults in remission from MA dependence and 20 non-dependent controls completed neuropsychological assessments and a blood draw. Multiplex assays were used to measure cytokine, chemokine, and intercellular adhesion molecule (ICAM-1) expression in mouse and human samples. A number of significant MA-induced changes in neuroimmune factors were observed. Of particular interest were the chemokine monocyte chemoattractant protein 1 (MCP-1) and the cellular adhesion molecule ICAM-1, which were similarly increased in the plasma of MA exposed mice as well as humans. In human participants, MA-induced changes in the cytokine and chemokine milieu were accompanied by increased cognitive impairments. Mice showing MA-induced changes in peripheral immune molecule expression also had significant brain-region specific changes in pro-inflammatory cytokines, chemokines, and ICAM-1. This cross-species, translational study suggests that chronic CNS immune dysregulation may in part contribute to the longlasting neuropsychiatric consequences of MA dependence. C1 [Loftis, Jennifer M.; Hoffman, William; Huckans, Marilyn S.] Portland VA Med Ctr, Res & Dev Serv, Portland, OR 97239 USA. [Choi, Dongseok] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA. [Loftis, Jennifer M.; Hoffman, William; Huckans, Marilyn S.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97239 USA. RP Loftis, JM (reprint author), Portland VA Med Ctr, Res & Dev Serv, 3710 SW US Vet Hosp Rd,R&D 16, Portland, OR 97239 USA. EM loftisj@ohsu.edu; Marilyn.huckans@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Office of Research, and Development and Clinical Sciences Research and Development; National Institute on Drug Abuse [P50 DA18165]; Methamphetamine Abuse Research Center at Oregon Health & Science University; Portland VAMC FX This material is based upon research in part supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research, and Development and Clinical Sciences Research and Development. Additional funding for this study was provided by the National Institute on Drug Abuse (P50 DA18165). The authors would like to thank the Methamphetamine Abuse Research Center at Oregon Health & Science University, and the Portland VAMC for providing research and administrative support. NR 68 TC 35 Z9 35 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 J9 NEUROTOX RES JI Neurotox. Res. PD JUL PY 2011 VL 20 IS 1 BP 59 EP 68 DI 10.1007/s12640-010-9223-x PG 10 WC Neurosciences SC Neurosciences & Neurology GA 760IT UT WOS:000290318700007 PM 20953917 ER PT J AU Park, J Werner, RM AF Park, Jeongyoung Werner, Rachel M. TI CHANGES IN THE RELATIONSHIP BETWEEN NURSING HOME FINANCIAL PERFORMANCE AND QUALITY OF CARE UNDER PUBLIC REPORTING SO HEALTH ECONOMICS LA English DT Article DE nursing homes; financial performance; quality of care; report cards; pay-for-performance ID MEDICAID REIMBURSEMENT; CASE-MIX; OWNERSHIP; COMPETITION; TRENDS; IMPACT; PROFIT; COSTS AB The relationship between financial performance and quality of care in nursing homes is not well defined and prior work has been mixed. The recent focus on improving the quality of nursing homes through market-based incentives such as public reporting may have changed this relationship, as public reporting provides nursing homes with increased incentives to engage in quality-based competition. If quality improvement activities require substantial production costs, nursing home profitability may become a more important predictor of quality under public reporting. This study explores the relationship between financial performance and quality of care and test whether this relationship changes under public reporting. Using a 10-year (fiscal years 1997-2006) panel data set of 9444 skilled nursing facilities in the US, this study employs a facility fixed-effects with and without instrumental variables approach to test the effect of finances on quality improvement and correct for potential endogeneity. The results show that better financial performance, as reflected by the 1-year lagged total profit margin, is modestly associated with higher quality but only after public reporting is initiated. These findings have important policy implications as federal and state governments use market-based incentives to increase demand for high-quality care and induce providers to compete based on quality. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Park, Jeongyoung] Amer Board Internal Med, Philadelphia, PA 19106 USA. [Werner, Rachel M.] Philadelphia VAMC, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Werner, Rachel M.] Univ Penn, Div Gen Internal Med, Philadelphia, PA 19104 USA. RP Park, J (reprint author), Amer Board Internal Med, 510 Walnut St,Suite 1700, Philadelphia, PA 19106 USA. EM jpark@abim.org FU Agency for Healthcare Research and Quality [R01 HS016478-01]; VA HSRD FX This research was funded by a grant from the Agency for Healthcare Research and Quality (R01 HS016478-01). Rachel M. Werner is supported in part by a VA HSR&D Career Development Award. We are grateful to Sally Stearns, Daniel Polsky, and Ryan Mutter for their helpful comments on an earlier draft of this manuscript. NR 39 TC 6 Z9 7 U1 1 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1057-9230 J9 HEALTH ECON JI Health Econ. PD JUL PY 2011 VL 20 IS 7 BP 783 EP 801 DI 10.1002/hec.1632 PG 19 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 748HB UT WOS:000289379800003 PM 20578255 ER PT J AU Naranjo, A Parisi, MT Shulkin, BL London, WB Matthay, KK Kreissman, SG Yanik, GA AF Naranjo, Arlene Parisi, Marguerite T. Shulkin, Barry L. London, Wendy B. Matthay, Katherine K. Kreissman, Susan G. Yanik, Gregory A. TI Comparison of I-123-Metaiodobenzylguanidine (MIBG) and I-131-MIBG Semi-Quantitative Scores in Predicting Survival in Patients With Stage 4 Neuroblastoma: A Report From the Children's Oncology Group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE COG A3973; Curie score ID HIGH-RISK NEUROBLASTOMA; PROSPECTIVE MULTICENTER TRIAL; BONE-MARROW-TRANSPLANTATION; EVENT-FREE SURVIVAL; METASTATIC NEUROBLASTOMA; METAIODOBENZYLGUANIDINE SCINTIGRAPHY; I-123-MIBG SCINTIGRAPHY; INDUCTION CHEMOTHERAPY; COMPUTED-TOMOGRAPHY; IV NEUROBLASTOMA AB Background. I-123-metaiodobenzylguanidine (MIBG) scans are preferable to I-131-MIBG for neuroblastoma imaging as they deliver less patient radiation yet have greater sensitivity in disease detection. Both I-123-MIBG and I-131-MIBGscans were used for disease assessments of neuroblastoma patients enrolled on Children's Oncology Group (COG) high-risk study A3973. The hypothesis was that I-123-MIBG and I-131-MIBGscans were sufficiently similar for clinical purposes in terms of ability to predict survival. Procedure. Patients enrolled on COG A3973 with stage 4 disease who completed I-123-MIBG or I-131-MIBGscans at diagnosis, post-induction, posttransplant, or post-biotherapy were analyzed. The performance of the Curie score for each MIBG scan type in predicting survival was evaluated. At each time point, survival curves for I-123-MIBG versus I-131-MIBGwere compared using the log-rank test. Results. Of the 413 patients on A3973 with at least one MIBG scan, 350 were stage 4. The 5-year event-free survival (EFS) and overall survival (OS) rates were 33.4 +/- 3.6% and 45.6 +/- 4.0% (N = 350). At post-induction, EFS (P = 0.3501) and OS (P = 0.5337) for I-123-MIBG versus I-131-MIBGwere not significantly different. Similarly, comparisons at the three other time points were non-significant. Conclusions. We found no evidence of a statistically significant difference in outcome by type of scan. For future survival analyses of MIBG Curie scores, I-123-MIBG and I-131-MIBGresults may be combined and analyzed overall, without adjustment for scan type. Pediatr Blood Cancer 2011; 56: 1041-1045. (C) 2011 Wiley-Liss, Inc. C1 [Naranjo, Arlene] Univ Florida, Childrens Oncol Grp COG, Gainesville, FL 32601 USA. [Parisi, Marguerite T.] Univ Washington, Sch Med, Dept Radiol & Pediat, Seattle, WA USA. [Parisi, Marguerite T.] Seattle Childrens Hosp, Seattle, WA USA. [Shulkin, Barry L.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [London, Wendy B.] Childrens Hosp, Dana Farber Canc Inst, Childrens Oncol Grp, Boston, MA 02115 USA. [Matthay, Katherine K.] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA. [Matthay, Katherine K.] UCSF Childrens Hosp, San Francisco, CA USA. [Kreissman, Susan G.] Duke Univ, Med Ctr, Durham, NC USA. [Yanik, Gregory A.] Univ Michigan, CS Mott Childrens Hosp, Ann Arbor, MI 48109 USA. RP Naranjo, A (reprint author), Univ Florida, Childrens Oncol Grp COG, 104 N Main St,Suite 600, Gainesville, FL 32601 USA. EM anaranjo@cog.ufl.edu FU Children's Oncology Group [U10 CA98413, U10 CA98543] FX Grant sponsor: Children's Oncology Group; Grant numbers: U10 CA98413, U10 CA98543. NR 35 TC 25 Z9 26 U1 0 U2 2 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2011 VL 56 IS 7 BP 1041 EP 1045 DI 10.1002/pbc.22991 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 749CX UT WOS:000289440800008 PM 21328522 ER PT J AU Winkfield, KM Tsai, HK Yao, XP Larson, E Neuberg, D Pomeroy, SL Ullrich, NJ Cohen, LE Kieran, MW Scott, RM Goumnerova, LC Marcus, KJ AF Winkfield, Karen M. Tsai, Henry K. Yao, Xiaopan Larson, Elysia Neuberg, Donna Pomeroy, Scott L. Ullrich, Nicole J. Cohen, Laurie E. Kieran, Mark W. Scott, R. Michael Goumnerova, Liliana C. Marcus, Karen J. TI Long-term Clinical Outcomes Following Treatment of Childhood Craniopharyngioma SO PEDIATRIC BLOOD & CANCER LA English DT Article DE craniopharyngioma; pediatrics; brain tumor; treatment-related morbidity ID CONFORMAL RADIATION-THERAPY; PHASE-II TRIAL; PEDIATRIC-PATIENTS; CHILDREN; RADIOTHERAPY; SURGERY; EXPERIENCE; MANAGEMENT; IRRADIATION; ENDOCRINE AB Purpose. To review our institution's experience with treatment of craniopharyngioma in children, and to report long-term treatment outcomes stratified by treatment era to assess whether modern treatment techniques result in improvements in local control and survival. Materials and Methods. We retrospectively reviewed the records of 100 children who underwent surgery for craniopharygioma at Children's Hospital Boston (CHB) from August 1976 to March 2003. Of these, 79 children (median age 8.5 years) had initial treatment at CHB and sufficient follow-up data to be included in this analysis. We report their treatment course, recurrence rates, and treatment-related morbidity. We compared the results in two different treatment eras based on changes in surgical approach at CHB. Results. Thirty-six patients underwent initial treatment with surgery alone; 63% treated prior to 1988 recurred and 36% treated after 1988 recurred. Recurrence rates following combined modality therapy (CMT) with limited surgery followed by radiation were 21 and 5% in the pre- and post-1988 eras, respectively. Accounting for treatment era, patients treated with surgery alone were 7.7 times as likely to recur as those treated with CMT (95% CI: 2.0, 28.7). In the Cox regression model, there was no significant difference in local control or overall survival based on treatment era; initial treatment remained the only statistically significant variable (P = 0.02). Conclusions. Advancements in treatment techniques have improved local control in children diagnosed with craniopharyngioma. The excellent survival rates necessitate long-term patient follow-up to identify and manage any treatment-related effects, including second tumors, vascular abnormalities, and endocrinopathies. Pediatr Blood Cancer 2011;56:1120-1126. (C) 2010 Wiley-Liss, Inc. C1 [Winkfield, Karen M.] Harvard Univ, Dept Radiat Oncol, Harvard Radiat Oncol Program, Sch Med, Boston, MA 02114 USA. [Winkfield, Karen M.; Tsai, Henry K.; Marcus, Karen J.] Childrens Hosp Boston, Dept Radiat Oncol, Boston, MA USA. [Yao, Xiaopan; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Larson, Elysia] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Pomeroy, Scott L.; Ullrich, Nicole J.] Childrens Hosp Boston, Dept Neurol, Boston, MA USA. [Cohen, Laurie E.] Childrens Hosp Boston, Dept Endocrinol, Boston, MA USA. [Kieran, Mark W.] Childrens Hosp Boston, Dept Pediat Oncol, Boston, MA USA. [Scott, R. Michael; Goumnerova, Liliana C.] Childrens Hosp Boston, Dept Neurosurg, Boston, MA USA. RP Winkfield, KM (reprint author), Harvard Univ, Dept Radiat Oncol, Harvard Radiat Oncol Program, Sch Med, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM kwinkfield@partners.org OI Kieran, Mark/0000-0003-2184-7692 NR 37 TC 14 Z9 15 U1 0 U2 0 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2011 VL 56 IS 7 BP 1120 EP 1126 DI 10.1002/pbc.22884 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 749CX UT WOS:000289440800021 PM 21488157 ER PT J AU Patenaude, AF Grootenhuis, M Noll, R AF Patenaude, Andrea Farkas Grootenhuis, Martha Noll, Robert TI Pediatric Psycho-Oncology Comes of Age: SIOP 2010 SO PEDIATRIC BLOOD & CANCER LA English DT Editorial Material C1 [Patenaude, Andrea Farkas] Harvard Univ, Dana Farber Canc Inst, Dept Pediat Oncol, Dept Psychiat,Med Sch, Boston, MA 02215 USA. [Grootenhuis, Martha] Univ Amsterdam, Acad Med Ctr, Emmas Childrens Hosp, Pediat Psychosocial Dept, NL-1105 AZ Amsterdam, Netherlands. [Noll, Robert] Univ Pittsburgh, Dept Pediat Psychiat & Psychol, Pittsburgh, PA USA. RP Patenaude, AF (reprint author), Harvard Univ, Dana Farber Canc Inst, Dept Pediat Oncol, Dept Psychiat,Med Sch, 450 Brookline Ave, Boston, MA 02215 USA. EM andrea_patenaude@dfci.harvard.edu NR 0 TC 2 Z9 2 U1 1 U2 2 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2011 VL 56 IS 7 BP 1154 EP 1154 DI 10.1002/pbc.23118 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 749CX UT WOS:000289440800033 PM 21425235 ER PT J AU Recklitis, CJ AF Recklitis, Christopher J. TI PSYCHOLOGICAL DISTRESS IN ADULT SURVIVORS OF CHILDHOOD CANCER: SHOULD WE BE SCREENING? SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Recklitis, Christopher J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Recklitis, Christopher J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2011 VL 56 IS 7 BP 1155 EP 1156 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 749CX UT WOS:000289440800038 ER PT J AU Wiener, L Friebert, S Mullins, LL Elkin, D Madan-Swain, A Phipps, S Sherman-Bien, S Patenaude, A Battles, H Zadeh, S Pao, M AF Wiener, Lori Friebert, Sarah Mullins, Larry L. Elkin, David Madan-Swain, Avi Phipps, Sean Sherman-Bien, Sandra Patenaude, Andrea Battles, Haven Zadeh, Sima Pao, Maryland TI CHARACTERIZING LONE PARENTING: A MULTI-INSTITUTIONAL PILOT STUDY OF THE PERCEPTIONS OF SUPPORT AND PERCEIVED STRESS OF LONE PARENTS OF CHILDREN WITH CANCER SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Wiener, Lori; Battles, Haven; Zadeh, Sima] NCI, NIH, Bethesda, MD 20892 USA. [Mullins, Larry L.] Oklahoma State Univ, Stillwater, OK 74078 USA. [Elkin, David] Univ Mississippi, Med Ctr, University, MS 38677 USA. [Madan-Swain, Avi] Univ Alabama, Div Pediat Hematol Oncol, Childrens Hosp, Tuscaloosa, AL 35487 USA. [Phipps, Sean] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Patenaude, Andrea] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pao, Maryland] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2011 VL 56 IS 7 BP 1157 EP 1157 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 749CX UT WOS:000289440800043 ER PT J AU Casey, R Zwemer, E Recklitis, C AF Casey, Robert Zwemer, Eric Recklitis, Christopher TI IS SURVIVOR IDENTITY ASSOCIATED WITH PHYSICAL AND BEHAVIORAL HEALTH?: RESULTS FROM PROJECT REACH SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Casey, Robert] Childrens Hosp, Ctr Canc & Blood Disorders, Denver, CO 80218 USA. [Zwemer, Eric; Recklitis, Christopher] Harvard Univ, Sch Med, Dana Farber Canc Inst, Perini Family Survivors Ctr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2011 VL 56 IS 7 BP 1159 EP 1159 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 749CX UT WOS:000289440800052 ER PT J AU Parsons, SK Ratichek, SJ Rodday, AM Davies, S Bingen, K Kupst, MJ Schwartz, L Guinan, EC Syrjala, KL Patel, S Mayer, DK McTavish, F Gustafson, DH AF Parsons, Susan K. Ratichek, Sara J. Rodday, Angie M. Davies, Stella Bingen, Kristin Kupst, Mary Jo Schwartz, Lisa Guinan, Eva C. Syrjala, Karen L. Patel, Sunita Mayer, Deborah K. McTavish, Fiona Gustafson, David H. TI CARING FOR THE CAREGIVER: EHEALTH INTERVENTIONS FOR PARENTS OF PEDIATRIC HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Parsons, Susan K.; Ratichek, Sara J.; Rodday, Angie M.] Tufts Med Ctr, Boston, MA USA. [Parsons, Susan K.] Tufts Univ, Sch Med, Medford, MA 02155 USA. [Davies, Stella] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Bingen, Kristin; Kupst, Mary Jo] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Schwartz, Lisa] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Guinan, Eva C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Syrjala, Karen L.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Patel, Sunita] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Mayer, Deborah K.] Univ N Carolina, Chapel Hill, NC USA. [McTavish, Fiona; Gustafson, David H.] Univ Wisconsin, Ctr Hlth Enhancement Syst Studies, Madison, WI 53706 USA. NR 0 TC 5 Z9 5 U1 1 U2 2 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2011 VL 56 IS 7 BP 1159 EP 1159 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 749CX UT WOS:000289440800053 ER PT J AU Salley, CG Hewitt, LL Patenaude, AF Yeates, KO Gerhardt, CA Vannatta, K AF Salley, Christina G. Hewitt, Larissa L. Patenaude, Andrea Farkas Yeates, Keith O. Gerhardt, Cynthia A. Vannatta, Kathryn TI SOCIAL COGNITIVE DIFFERENCES IN PEDIATRIC BRAIN TUMOR SURVIVORS AND COMPARISON PEERS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Salley, Christina G.; Yeates, Keith O.; Gerhardt, Cynthia A.; Vannatta, Kathryn] Ohio State Univ, Columbus, OH 43210 USA. [Hewitt, Larissa L.; Patenaude, Andrea Farkas] Dana Farber Canc Inst, Boston, MA 02115 USA. [Patenaude, Andrea Farkas] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RI Vannatta, Kathryn/E-4237-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2011 VL 56 IS 7 BP 1161 EP 1161 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 749CX UT WOS:000289440800062 ER PT J AU Rey-Casserly, C Diver, T Liptak, C Chordas, C Delaney, B Manley, P AF Rey-Casserly, Celiane Diver, Tanya Liptak, Cori Chordas, Christine Delaney, Brian Manley, Peter TI NEUROPSYCHOLOGICAL AND ADAPTIVE OUTCOMES IN CHILDREN TREATED FOR MEDULLOBLASTOMA SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Rey-Casserly, Celiane; Diver, Tanya] Childrens Hosp, Boston, MA 02115 USA. [Liptak, Cori; Chordas, Christine; Delaney, Brian; Manley, Peter] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2011 VL 56 IS 7 BP 1162 EP 1162 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 749CX UT WOS:000289440800066 ER PT J AU Vannatta, K Barrera, M Gerhardt, CA Fairclough, D Kupst, MJ Meyer, EA Patenaude, AF Turner, C AF Vannatta, Kathryn Barrera, Maru Gerhardt, Cynthia A. Fairclough, Diane Kupst, Mary Jo Meyer, Eugene A. Patenaude, Andrea F. Turner, Christopher TI SOCIAL AND BEHAVIORAL ADJUSTMENT OF PEDIATRIC BRAIN TUMOR SURVIVORS: EXAMINATION OF FACTORS THAT MAY MODIFY RISK SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Vannatta, Kathryn; Gerhardt, Cynthia A.] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. [Vannatta, Kathryn; Gerhardt, Cynthia A.] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Barrera, Maru] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Fairclough, Diane] Univ Colorado Denver, Denver, CO USA. [Kupst, Mary Jo] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Meyer, Eugene A.] Childrens Hosp Milwaukee, Milwaukee, WI USA. [Meyer, Eugene A.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Patenaude, Andrea F.; Turner, Christopher] Schneider Childrens Hosp, Long Isl City, NY USA. [Patenaude, Andrea F.; Turner, Christopher] Albert Einstein Coll Med, Long Isl City, NY USA. RI Vannatta, Kathryn/E-4237-2011 NR 0 TC 2 Z9 2 U1 0 U2 0 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL PY 2011 VL 56 IS 7 BP 1162 EP 1162 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 749CX UT WOS:000289440800064 ER PT J AU Lambrechts, G Van Leeuwen, K Boonen, H Maes, B Noens, I AF Lambrechts, Greet Van Leeuwen, Karla Boonen, Hannah Maes, Bea Noens, Ilse TI Parenting behaviour among parents of children with autism spectrum disorder SO RESEARCH IN AUTISM SPECTRUM DISORDERS LA English DT Article DE Parenting behaviour; Autism spectrum disorder ID PRESCHOOL-CHILDREN; COGNITIVE-STYLE; WEAK COHERENCE; MOTHERS; STRESS; FATHERS; MIND AB Contrary to the extensive amount of empirical findings about parental perceptions, parenting cognitions, and coping in families with a child with autism spectrum disorder (ASD), research about parenting itself is very scarce. A first goal of this study was to examine the factor structure and internal consistency of two scales to measure parenting behaviour: the Parental Behaviour Scale-short version (PBS, Van Leeuwen, 2002; Van Leeuwen & Vermulst, 2004, 2010) and a new scale to measure parenting behaviours more specifically relevant to children with ASD. A second goal was to compare general and more specific parenting behaviour among parents of children with and without ASD. The participants were 305 parents of a child with ASD between 8 and 18 years old and 325 parents of a typically developing child between 8 and 18 years old. Parents completed both scales. Exploratory factor analysis of the new scale resulted in two factors: Stimulating the Development and Adapting the Environment. Multisample confirmatory factor analyses showed good fit indices for the noninvariant model of both the PBS and the new scale. Mean level analyses revealed significant main effects of group with higher mean scores for the control group in comparison with the experimental group for the subscale Harsh Punishment and the reversed effect for the subscale Stimulating the Development. We concluded that it is possible to use the parenting constructs of the PBS-short version to investigate parenting behaviour of parents with and without children with ASD. Furthermore, the new scale showed a relatively stable two factor structure for the control group as well as for the experimental group. The two factors 'Stimulating the child's Development' and 'Adapting the child's Environment' were also convincing as regards content. A first indication was found that parents of children with ASD indeed use more specifically relevant parenting behaviours. It is self-evident that more research is needed to gain further insight into the nature of these behaviours. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Lambrechts, Greet; Van Leeuwen, Karla; Boonen, Hannah; Maes, Bea; Noens, Ilse] Katholieke Univ Leuven, Parenting & Special Educ Res Grp, B-3000 Louvain, Belgium. [Lambrechts, Greet; Boonen, Hannah; Noens, Ilse] Katholieke Univ Leuven, Leuven Autism Res Consortium LAuRes, B-3000 Louvain, Belgium. [Noens, Ilse] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. RP Lambrechts, G (reprint author), Katholieke Univ Leuven, Parenting & Special Educ Res Grp, Vesaliusstr 2,POB 3765, B-3000 Louvain, Belgium. EM Greet.Lambrechts@ped.kuleuven.be; Karla.Vanleeuwen@ped.kuleuven.be; Hannah.Boonen@ped.kuleuven.be; Bea.Maes@ped.kuleuven.be; Ilse.Noens@ped.kuleuven.be NR 44 TC 7 Z9 7 U1 4 U2 34 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1750-9467 J9 RES AUTISM SPECT DIS JI Res. Autism Spectr. Disord. PD JUL-SEP PY 2011 VL 5 IS 3 BP 1143 EP 1152 DI 10.1016/j.rasd.2010.12.011 PG 10 WC Education, Special; Psychology, Developmental; Psychiatry; Rehabilitation SC Education & Educational Research; Psychology; Psychiatry; Rehabilitation GA 747NR UT WOS:000289327200021 ER PT J AU Bell, D Berchuck, A Birrer, M Chien, J Cramer, DW Dao, F Dhir, R DiSaia, P Gabra, H Glenn, P Godwin, AK Gross, J Hartmann, L Huang, M Huntsman, DG Iacocca, M Imielinski, M Kalloger, S Karlan, BY Levine, DA Mills, GB Morrison, C Mutch, D Olvera, N Orsulic, S Park, K Petrelli, N Rabeno, B Rader, JS Sikic, BI Smith-McCune, K Sood, AK Bowtell, D Penny, R Testa, JR Chang, K Dinh, HH Drummond, JA Fowler, G Gunaratne, P Hawes, AC Kovar, CL Lewis, LR Morgan, MB Newsham, IF Santibanez, J Reid, JG Trevino, LR Wu, YQ Wang, M Muzny, DM Wheeler, DA Gibbs, RA Getz, G Lawrence, MS Cibulskis, K Sivachenko, AY Sougnez, C Voet, D Wilkinson, J Bloom, T Ardlie, K Fennell, T Baldwin, J Gabriel, S Lander, ES Ding, L Fulton, RS Koboldt, DC McLellan, MD Wylie, T Walker, J O'Laughlin, M Dooling, DJ Fulton, L Abbott, R Dees, ND Zhang, Q Kandoth, C Wendl, M Schierding, W Shen, D Harris, CC Schmidt, H Kalicki, J Delehaunty, KD Fronick, CC Demeter, R Cook, L Wallis, JW Lin, L Magrini, VJ Hodges, JS Eldred, JM Smith, SM Pohl, CS Vandin, F Raphael, BJ Weinstock, GM Mardis, R Wilson, RK Meyerson, M Winckler, W Getz, G Verhaak, RGW Carter, SL Mermel, CH Saksena, G Nguyen, H Onofrio, RC Lawrence, MS Hubbard, D Gupta, S Crenshaw, A Ramos, AH Ardlie, K Chin, L Protopopov, A Zhang, JH Kim, TM Perna, I Xiao, Y Zhang, H Ren, G Sathiamoorthy, N Park, RW Lee, E Park, PJ Kucherlapati, R Absher, DM Waite, L Sherlock, G Brooks, JD Li, JZ Xu, J Myers, RM Laird, PW Cope, L Herman, JG Shen, H Weisenberger, DJ Noushmehr, H Pan, F Triche, T Berman, BP Van den Berg, DJ Buckley, J Baylin, SB Spellman, PT Purdom, E Neuvial, P Bengtsson, H Jakkula, LR Durinck, S Han, J Dorton, S Marr, H Choi, YG Wang, V Wang, NJ Ngai, J Conboy, JG Parvin, B Feiler, HS Speed, TP Gray, JW Levine, DA Socci, ND Liang, Y Taylor, BS Schultz, N Borsu, L Lash, AE Brennan, C Viale, A Sander, C Ladanyi, M Hoadley, KA Meng, S Du, Y Shi, Y Li, L Turman, YJ Zang, D Helms, EB Balu, S Zhou, X Wu, J Topal, MD Hayes, DN Perou, CM Getz, G Voet, D Saksena, G Zhang, JNH Zhang, H Wu, CJ Shukla, S Cibulskis, K Lawrence, MS Sivachenko, A Jing, R Park, RW Liu, Y Park, PJ Noble, M Chin, L Carter, H Kim, D Karchin, R Spellman, PT Purdom, E Neuvial, P Bengtsson, H Durinck, S Han, J Korkola, JE Heiser, LM Cho, RJ Hu, Z Parvin, B Speed, TP Gray, JW Schultz, N Cerami, E Taylor, BS Olshen, A Reva, B Antipin, Y Shen, R Mankoo, P Sheridan, R Ciriello, G Chang, WK Bernanke, JA Borsu, L Levine, DA Ladanyi, M Sander, C Haussler, D Benz, CC Stuart, JM Benz, SC Sanborn, JZ Vaske, CJ Zhu, J Szeto, C Scott, GK Yau, C Hoadley, KA Du, Y Balu, S Hayes, DN Perou, CM Wilkerson, MD Zhang, N Akbani, R Baggerly, KA Yung, WK Mills, GB Weinstein, JN Penny, R Shelton, T Grimm, D Hatfield, M Morris, S Yena, P Rhodes, P Sherman, M Paulauskis, J Millis, S Kahn, A Greene, JM Sfeir, R Jensen, MA Chen, J Whitmore, J Alonso, S Jordan, J Chu, A Zhang, JH Barker, A Compton, C Eley, G Ferguson, M Fielding, P Gerhard, DS Myles, R Schaefer, C Shaw, KRM Vaught, J Vockley, JB Good, PJ Guyer, MS Ozenberger, B Peterson, J Thomson, E AF Bell, D. Berchuck, A. Birrer, M. Chien, J. Cramer, D. W. Dao, F. Dhir, R. DiSaia, P. Gabra, H. Glenn, P. Godwin, A. K. Gross, J. Hartmann, L. Huang, M. Huntsman, D. G. Iacocca, M. Imielinski, M. Kalloger, S. Karlan, B. Y. Levine, D. A. Mills, G. B. Morrison, C. Mutch, D. Olvera, N. Orsulic, S. Park, K. Petrelli, N. Rabeno, B. Rader, J. S. Sikic, B. I. Smith-McCune, K. Sood, A. K. Bowtell, D. Penny, R. Testa, J. R. Chang, K. Dinh, H. H. Drummond, J. A. Fowler, G. Gunaratne, P. Hawes, A. C. Kovar, C. L. Lewis, L. R. Morgan, M. B. Newsham, I. F. Santibanez, J. Reid, J. G. Trevino, L. R. Wu, Y. -Q. Wang, M. Muzny, D. M. Wheeler, D. A. Gibbs, R. A. Getz, G. Lawrence, M. S. Cibulskis, K. Sivachenko, A. Y. Sougnez, C. Voet, D. Wilkinson, J. Bloom, T. Ardlie, K. Fennell, T. Baldwin, J. Gabriel, S. Lander, E. S. Ding, L. Fulton, R. S. Koboldt, D. C. McLellan, M. D. Wylie, T. Walker, J. O'Laughlin, M. Dooling, D. J. Fulton, L. Abbott, R. Dees, N. D. Zhang, Q. Kandoth, C. Wendl, M. Schierding, W. 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Szeto, C. Scott, G. K. Yau, C. Hoadley, K. A. Du, Y. Balu, S. Hayes, D. N. Perou, C. M. Wilkerson, M. D. Zhang, N. Akbani, R. Baggerly, K. A. Yung, W. K. Mills, G. B. Weinstein, J. N. Penny, R. Shelton, T. Grimm, D. Hatfield, M. Morris, S. Yena, P. Rhodes, P. Sherman, M. Paulauskis, J. Millis, S. Kahn, A. Greene, J. M. Sfeir, R. Jensen, M. A. Chen, J. Whitmore, J. Alonso, S. Jordan, J. Chu, A. Zhang, Jinghui Barker, A. Compton, C. Eley, G. Ferguson, M. Fielding, P. Gerhard, D. S. Myles, R. Schaefer, C. Shaw, K. R. Mills Vaught, J. Vockley, J. B. Good, P. J. Guyer, M. S. Ozenberger, B. Peterson, J. Thomson, E. CA Canc Genome Atlas Res Network TI Integrated genomic analyses of ovarian carcinoma SO NATURE LA English DT Article ID HIGH-THROUGHPUT ANNOTATION; GYNECOLOGIC-ONCOLOGY-GROUP; GRADE SEROUS CARCINOMA; BRCA MUTATION CARRIERS; CLEAR-CELL CARCINOMA; SOMATIC MUTATIONS; CANCER STATISTICS; DRIVER MUTATIONS; HYBRID SELECTION; MUTANT-CELLS AB A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology. C1 Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. [Bell, D.] Mayo Clin, Div Anat Pathol, Rochester, MN 55905 USA. [Berchuck, A.] Duke Univ, Div Gynecol Oncol, Dept Obstet & Gynecol, Med Ctr, Durham, NC 27708 USA. [Berchuck, A.] Duke Univ, Duke Inst Genome Sci & Policy, Med Ctr, Durham, NC 27708 USA. [Birrer, M.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Birrer, M.; Imielinski, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chien, J.] Mayo Clin, Div Expt Pathol, Rochester, MN 55905 USA. [Cramer, D. W.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Epidemiol Ctr, Boston, MA 02115 USA. [Levine, D. A.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Dhir, R.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [DiSaia, P.] Univ Calif Irvine, Gynecol Oncol Grp, Irvine, CA 92697 USA. [Gabra, H.] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, Ovarian Canc Act Res Ctr, London W12 0NN, England. [Glenn, P.; Smith-McCune, K.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Serv, San Francisco, CA 94143 USA. [Godwin, A. K.] Fox Chase Canc Ctr, Dept Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA. [Gross, J.; Karlan, B. Y.; Orsulic, S.] Univ Calif Los Angeles, Canc Res Inst, Samuel Oschin Comprehens Canc Inst, Cedars Sinai Med Ctr,Geffen Sch Med, Los Angeles, CA 90048 USA. [Hartmann, L.] Mayo Clin, Div Med Oncol, Rochester, MN 55905 USA. [Huang, M.] Fox Chase Canc Ctr, Dept Pathol, Philadelphia, PA 19111 USA. [Huntsman, D. G.; Kalloger, S.] British Columbia Canc Agcy, Ctr Translat & Appl Genom, Vancouver, BC V5Z 1G1, Canada. [Iacocca, M.; Rabeno, B.] Christiana Care Hlth Syst, Dept Pathol, Newark, DE 19718 USA. [Karlan, B. Y.] Univ Calif Los Angeles, Dept Obstet & Gynecol, Cedars Sinai Med Ctr, Geffen Sch Med, Los Angeles, CA 90048 USA. [Mills, G. B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. Univ Texas MD Anderson Canc Ctr, Kleberg Ctr Mol Markers, Houston, TX 77030 USA. [Morrison, C.] Roswell Pk Canc Inst, Dept Pathol & Lab Med, Buffalo, NY 14263 USA. [Morrison, C.] Roswell Pk Canc Inst, Div Mol Pathol, Buffalo, NY 14263 USA. [Mutch, D.] Washington Univ, Div Gynecol Oncol, Dept Obstet & Gynecol, Sch Med St Louis, St Louis, MO 63110 USA. [Park, K.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Petrelli, N.] Helen F Graham Canc Ctr Christina Care, Dept Surg, Newark, DE 19713 USA. [Rader, J. S.] Med Coll Wisconsin, Human & Mol Genet Ctr, Dept Obstet & Gynecol, Milwaukee, WI 53226 USA. [Sikic, B. I.] Stanford Univ, Dept Med, Div Oncol, Sch Med, Palo Alto, CA 94304 USA. [Sood, A. K.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77230 USA. [Sood, A. K.] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNA, Houston, TX 77230 USA. [Bowtell, D.] Peter MacCallum Canc Ctr, Div Res, Melbourne, Vic 8006, Australia. [Penny, R.; Shelton, T.; Grimm, D.; Hatfield, M.; Morris, S.; Yena, P.; Rhodes, P.; Sherman, M.; Paulauskis, J.; Millis, S.] Internat Genom Consortium, Phoenix, AZ 85004 USA. [Testa, J. R.] Fox Chase Canc Ctr, Canc Biol Program, Philadelphia, PA 19111 USA. [Chang, K.; Dinh, H. H.; Drummond, J. A.; Fowler, G.; Gunaratne, P.; Hawes, A. C.; Kovar, C. L.; Lewis, L. R.; Morgan, M. B.; Newsham, I. F.; Santibanez, J.; Reid, J. G.; Trevino, L. R.; Wu, Y. -Q.; Wang, M.; Muzny, D. M.; Wheeler, D. A.; Gibbs, R. A.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Sougnez, C.; Winckler, W.; Getz, G.] MIT, Eli & Edythe L Broad Inst, Canc Genome Project, Cambridge, MA 02142 USA. [Sougnez, C.; Winckler, W.; Getz, G.] MIT, Eli & Edythe L Broad Inst, Med Resequencing Project, Cambridge, MA 02142 USA. [Cibulskis, K.; Sougnez, C.; Wilkinson, J.; Bloom, T.; Fennell, T.; Baldwin, J.; Gabriel, S.; Winckler, W.; Getz, G.; Crenshaw, A.] Harvard Univ, Cambridge, MA 02142 USA. [Lander, E. S.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Lander, E. S.] Harvard Univ, Dept Syst Biol, Boston, MA 02115 USA. [Ding, L.; Fulton, R. S.; Koboldt, D. C.; McLellan, M. D.; Wylie, T.; Walker, J.; O'Laughlin, M.; Dooling, D. J.; Fulton, L.; Abbott, R.; Dees, N. D.; Zhang, Q.; Kandoth, C.; Wendl, M.; Schierding, W.; Shen, D.; Harris, C. C.; Schmidt, H.; Kalicki, J.; Delehaunty, K. D.; Fronick, C. C.; Demeter, R.; Cook, L.; Wallis, J. W.; Lin, L.; Magrini, V. J.; Hodges, J. S.; Eldred, J. M.; Smith, S. M.; Pohl, C. S.; Weinstock, G. M.; Mardis, R.; Wilson, R. K.] Washington Univ, Sch Med St Louis, Genome Ctr, Dept Genet, St Louis, MO 63108 USA. [Vandin, F.; Raphael, B. J.] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA. [Vandin, F.; Raphael, B. J.] Brown Univ, Ctr Computat Mol Biol, Providence, RI 02912 USA. [Mardis, R.; Wilson, R. K.] Washington Univ, Siteman Canc Ctr, Sch Med St Louis, St Louis, MO 63108 USA. [Meyerson, M.; Verhaak, R. G. W.; Carter, S. L.; Mermel, C. H.; Hubbard, D.; Ramos, A. H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Meyerson, M.; Hubbard, D.; Ramos, A. H.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Chin, L.; Protopopov, A.; Zhang, Juinhua; Perna, I.; Xiao, Y.; Zhang, H.; Ren, G.; Zhang, Junihua; Wu, C. J.; Shukla, S.; Liu, Y.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Dept Med Oncol, Boston, MA 02115 USA. [Chin, L.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Kim, T. M.; Park, R. W.; Lee, E.; Park, P. J.; Park, R. W.] Harvard Univ, Ctr Biomed Informat, Sch Med, Boston, MA 02115 USA. [Sathiamoorthy, N.] Partners Ctr Personalized Genet Med, Cambridge, MA 02139 USA. Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Kucherlapati, R.] Harvard Univ, Dept Genet, Sch Med, Boston, MA 02115 USA. [Absher, D. M.; Waite, L.; Myers, R. M.; Speed, T. P.] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Brooks, J. D.; Sander, C.] Stanford Univ, Dept Urol, Sch Med, Stanford, CA 94305 USA. [Li, J. Z.; Xu, J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Laird, P. W.; Shen, H.; Weisenberger, D. J.; Noushmehr, H.; Pan, F.; Triche, T., Jr.; Berman, B. P.; Van den Berg, D. J.; Buckley, J.] Univ So Calif, Epigenome Ctr, Los Angeles, CA 90089 USA. [Cope, L.] Johns Hopkins Univ, Biometry & Clin Trials Div, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Herman, J. G.; Baylin, S. B.] Johns Hopkins Univ, Div Canc Biol, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Purdom, E.; Neuvial, P.; Bengtsson, H.] Univ Calif Berkeley, Dept Stat, Berkeley, CA 95720 USA. [Choi, Y. G.; Ngai, J.] Univ Calif Berkeley, Dept Mol & Cellular Biol, Berkeley, CA 95720 USA. [Wang, V.] Univ Houston, Dept Biol & Biochem, Houston, TX 77004 USA. [Speed, T. P.] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. [Socci, N. D.; Liang, Y.; Taylor, B. S.; Schultz, N.; Lash, A. E.; Sander, C.; Cerami, E.; Reva, B.; Antipin, Y.; Mankoo, P.; Sheridan, R.; Ciriello, G.] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Borsu, L.; Ladanyi, M.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, Dept Pathol, New York, NY 10065 USA. [Brennan, C.] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA. [Viale, A.] Mem Sloan Kettering Canc Ctr, Genom Core Lab, New York, NY 10065 USA. Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Topal, M. D.] Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Meng, S.; Du, Y.; Shi, Y.; Li, L.; Turman, Y. J.; Zang, D.; Helms, E. B.; Balu, S.; Zhou, X.; Wu, J.; Topal, M. D.; Hayes, D. N.; Wilkerson, M. D.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Hayes, D. N.] Univ N Carolina, Dept Internal Med, Div Med Oncol, Chapel Hill, NC 27599 USA. [Carter, H.; Kim, D.; Karchin, R.] Johns Hopkins Univ, Dept Biomed Engn, Inst Computat Med, Baltimore, MD 21231 USA. [Olshen, A.; Shen, R.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. Weill Cornell Grad Sch Med Sci, Dept Physiol & Biophys, New York, NY 10065 USA. [Bernanke, J. A.] Cornell Univ, Weill Med Coll, New York, NY 10065 USA. [Benz, S. C.; Sanborn, J. Z.] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Benz, S. C.; Sanborn, J. Z.] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. [Benz, C. C.; Yau, C.] Buck Inst Age Res, Novato, CA 94945 USA. Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Zhang, N.; Akbani, R.; Baggerly, K. A.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Yung, W. K.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Kahn, A.; Greene, J. M.; Sfeir, R.; Jensen, M. A.; Chen, J.; Whitmore, J.; Alonso, S.; Jordan, J.; Chu, A.] SRAInternational, Fairfax, VA 22033 USA. St Jude Childrens Res Hosp, Dept Biotechnol, Memphis, TN 38105 USA. [Compton, C.; Eley, G.; Fielding, P.; Gerhard, D. S.; Myles, R.; Schaefer, C.; Shaw, K. R. Mills; Vaught, J.; Vockley, J. B.] NCI, NIH, Bethesda, MD 20892 USA. [Ferguson, M.] MLF Consulting, Arlington, MA 02474 USA. [Good, P. J.; Guyer, M. S.; Ozenberger, B.; Peterson, J.; Thomson, E.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Spellman, PT (reprint author), Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. EM spellmap@ohsu.edu RI sander, chris/H-1452-2011; Karchin, Rachel/A-3385-2010; Lester, Jenny/B-5933-2012; Meyerson, Matthew/E-7123-2012; Sherlock, Gavin/E-9110-2012; Laird, Peter/G-8683-2012; Weinstock, George/C-6314-2013; Noushmehr, Houtan/C-9692-2013; Vaske, Charles/D-6018-2013; Reva, Boris/B-6436-2014; Berman, Benjamin/D-5942-2014; Bowtell, David/H-1007-2016 OI Benz, Stephen/0000-0002-4067-0602; Triche, Tim/0000-0001-5665-946X; Park, Kay/0000-0001-8989-2938; Brennan, Cameron/0000-0003-4064-8891; Hayes, D. Neil/0000-0001-6203-7771; Kandoth, Cyriac/0000-0002-1345-3573; Lash, Alex/0000-0003-3787-1590; Sherlock, Gavin/0000-0002-1692-4983; Perou, Charles/0000-0001-9827-2247; Chien, Jeremy/0000-0003-4744-8374; Schultz, Nikolaus/0000-0002-0131-4904; Weinstock, George/0000-0002-2997-4592; Noushmehr, Houtan/0000-0003-4051-8114; Vaske, Charles/0000-0001-8151-6612; Reva, Boris/0000-0002-8805-389X; Bowtell, David/0000-0001-9089-7525 FU USA National Institutes of Health [U24CA143840, U24CA143882, U24CA143731, U24CA143835, U24CA143845, U24CA143858, U24CA144025, U24CA143866, U24CA143867, U24CA143848, U24CA143843, R21CA135877] FX We thank J. Palchik, A. Mirick and Julia Zhang for administrative coordination of TCGA activities. This work was supported by the following grants from the USA National Institutes of Health: U54HG003067, U54HG003079, U54HG003273, U24CA126543, U24CA126544, U24CA126546, U24CA126551, U24CA126554, U24CA126561, U24CA126563, U24CA143840, U24CA143882, U24CA143731, U24CA143835, U24CA143845, U24CA143858, U24CA144025, U24CA143882, U24CA143866, U24CA143867, U24CA143848, U24CA143843 and R21CA135877. NR 51 TC 1448 Z9 1467 U1 27 U2 295 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 JUN 30 PY 2011 VL 474 IS 7353 BP 609 EP 615 DI 10.1038/nature10166 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 785CF UT WOS:000292204300032 ER PT J AU Zhou, Y Cashman, TJ Nevis, KR Obregon, P Carney, SA Liu, Y Gu, AH Mosimann, C Sondalle, S Peterson, RE Heideman, W Burns, CE Burns, CG AF Zhou, Yong Cashman, Timothy J. Nevis, Kathleen R. Obregon, Pablo Carney, Sara A. Liu, Yan Gu, Aihua Mosimann, Christian Sondalle, Samuel Peterson, Richard E. Heideman, Warren Burns, Caroline E. Burns, C. Geoffrey TI Latent TGF-beta binding protein 3 identifies a second heart field in zebrafish SO NATURE LA English DT Article ID ARTERIAL POLE; OUTFLOW TRACT; MOUSE HEART; CELLS; GROWTH; DIFFERENTIATION; ORIGIN AB The four-chambered mammalian heart develops from two fields of cardiac progenitor cells distinguished by their spatiotemporal patterns of differentiation and contributions to the definitive heart(1-3). The first heart field differentiates earlier in lateral plate mesoderm, generates the linear heart tube and ultimately gives rise to the left ventricle. The second heart field (SHF) differentiates later in pharyngeal mesoderm, elongates the heart tube, and gives rise to the outflow tract and much of the right ventricle. Because hearts in lower vertebrates contain a rudimentary outflow tract but not a right ventricle(4), the existence and function of SHF-like cells in these species has remained a topic of speculation(4-10). Here we provide direct evidence from Cre/Lox-mediated lineage tracing and loss-of-function studies in zebrafish, a lower vertebrate with a single ventricle, that latent TGF-beta binding protein 3 (ltbp3) transcripts mark a field of cardiac progenitor cells with defining characteristics of the anterior SHF in mammals. Specifically, ltbp3(+) cells differentiate in pharyngeal mesoderm after formation of the heart tube, elongate the heart tube at the outflow pole, and give rise to three cardiovascular lineages in the outflow tract and myocardium in the distal ventricle. In addition to expressing Ltbp3, a protein that regulates the bioavailability of TGF-beta ligands(11), zebrafish SHF cells co-express nkx2.5, an evolutionarily conserved marker of cardiac progenitor cells in both fields(4). Embryos devoid of ltbp3 lack the same cardiac structures derived from ltbp3(+) cells due to compromised progenitor proliferation. Furthermore, small-molecule inhibition of TGF-beta signalling phenocopies the ltbp3-morphant phenotype whereas expression of a constitutively active TGF-beta type I receptor rescues it. Taken together, our findings uncover a requirement for ltbp3-TGF-beta signalling during zebrafish SHF development, a process that serves to enlarge the single ventricular chamber in this species. C1 [Zhou, Yong; Cashman, Timothy J.; Nevis, Kathleen R.; Obregon, Pablo; Gu, Aihua; Sondalle, Samuel; Burns, Caroline E.; Burns, C. Geoffrey] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Zhou, Yong; Cashman, Timothy J.; Nevis, Kathleen R.; Obregon, Pablo; Liu, Yan; Gu, Aihua; Mosimann, Christian; Sondalle, Samuel; Burns, Caroline E.; Burns, C. Geoffrey] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Carney, Sara A.; Peterson, Richard E.; Heideman, Warren] Univ Wisconsin, Sch Pharm, Div Pharmaceut Sci, Madison, WI 53705 USA. [Liu, Yan] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA. [Gu, Aihua] Nanjing Med Univ, Sch Publ Hlth, Nanjing 210029, Peoples R China. [Mosimann, Christian] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Mosimann, Christian] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Sondalle, Samuel; Burns, Caroline E.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Burns, CE (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. EM cburns6@partners.org; gburns@cvrc.mgh.harvard.edu RI Sondalle, Samuel/C-1283-2014 OI Sondalle, Samuel/0000-0002-4144-9897 FU NIH, National Institute of Environmental Health Sciences [R01 ES012716]; EMBO long-term fellowship; HFSP long-term fellowship; Cardiovascular Research Center at Massachusetts General Hospital; Claflin Distinguished Scholar Award; Harvard Stem Cell Institute; National Heart Lung and Blood Institute [5R01HL096816]; American Heart Association [10GRNT4270021] FX We thank M. Whitman for advice on pSmad2 staining, D. Hami and M. Kirby for providing Eln2 antisera and their immunohistochemistry protocol, R. Cornell for providing tfAP2a and tfAP2c morpholinos, M. Whitman, A. Srinivasan, D. Langenau, E. Provost, S. Leach, R. Anderson, D. Stainier, I. Woods, and A. Schier for providing plasmids. J. W. Xiong for providing clom39 fish, B. Barut and L. Zon for providing bacterial artificial chromosomes (BACs), and the MGH Nephrology Division for access to their confocal microscopy facilities. S. C., R. E. P. and W. H. were supported by NIH grant R01 ES012716 from the National Institute of Environmental Health Sciences. C. M. received support through an EMBO long-term fellowship and an HFSP long-term fellowship. This work was funded by the Cardiovascular Research Center at Massachusetts General Hospital, a Claflin Distinguished Scholar Award and Harvard Stem Cell Institute Seed Grant to C. E. B., and by awards from the National Heart Lung and Blood Institute (5R01HL096816), American Heart Association (Grant in Aid no. 10GRNT4270021), and Harvard Stem Cell Institute (Seed Grant) to C. G. B. NR 24 TC 82 Z9 82 U1 2 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 30 PY 2011 VL 474 IS 7353 BP 645 EP 648 DI 10.1038/nature10094 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 785CF UT WOS:000292204300040 PM 21623370 ER PT J AU Yuan, CM Wang, Z Inslicht, SS McCaslin, SE Metzler, TJ Henn-Haase, C Apfel, BA Tong, HQ Neylan, TC Fang, YR Marmar, CR AF Yuan, Chengmei Wang, Zhen Inslicht, Sabra S. McCaslin, Shannon E. Metzler, Thomas J. Henn-Haase, Clare Apfel, Brigitte A. Tong, Huiqi Neylan, Thomas C. Fang, Yiru Marmar, Charles R. TI Protective factors for posttraumatic stress disorder symptoms in a prospective study of police officers SO PSYCHIATRY RESEARCH LA English DT Article DE PTSD; Critical incident; World assumption; Social adjustment; Social support; Personality ID PSYCHOLOGICAL RESILIENCE; PERSONALITY-TRAITS; SOCIAL SUPPORT; MENTAL-HEALTH; RISK-FACTORS; WORLD ASSUMPTIONS; TRAUMA EXPOSURE; PTSD SYMPTOMS; PREDICTORS; ADULTS AB Although police officers are frequently exposed to potentially traumatic incidents. only a minority will develop chronic posttraumatic stress disorder (FTSD). Identifying and understanding protective factors could inform the development of preventive interventions; however, few studies have examined this. In the present prospective study, 233 police officers were assessed during academy training and again following 2 years of police service. Caucasian race, less previous trauma exposure, and less critical incident exposure during police service as well as greater sense of self-worth, beliefs of greater benevolence of the world, greater social support and better social adjustment, all assessed during academy training, were associated with lower PTSD symptoms after 2 years of service. Positive personality attributes assessed during training with the NEO Five-Factor Personality Inventory were not associated with lower PTSD symptoms. In a hierarchical linear regression model, only Caucasian race, lower critical incident exposure during police service, greater assumptions of benevolence of the world and better social adjustment during training remained predictive of lower PTSD symptoms after 2 years of police service. These results suggest that positive world assumptions and better social functioning during training may protect police officers from critical incident related PTSD. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Yuan, Chengmei; Fang, Yiru] Shanghai Jiao Tong Univ, Sch Med, Shanghai Mental Hlth Ctr, Div Mood Disorder, Shanghai 200030, Peoples R China. [Yuan, Chengmei; Wang, Zhen; Inslicht, Sabra S.; McCaslin, Shannon E.; Metzler, Thomas J.; Apfel, Brigitte A.; Tong, Huiqi; Neylan, Thomas C.] San Francisco VA Med Ctr, Mental Hlth Serv, San Francisco, CA USA. [Yuan, Chengmei; Wang, Zhen; Inslicht, Sabra S.; McCaslin, Shannon E.; Apfel, Brigitte A.; Neylan, Thomas C.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Henn-Haase, Clare; Marmar, Charles R.] NYU, Dept Psychiat, New York, NY 10016 USA. [Wang, Zhen] Shanghai Jiao Tong Univ, Sch Med, Shanghai Mental Hlth Ctr, Dept Clin Psychol, Shanghai 200030, Peoples R China. RP Apfel, BA (reprint author), Vet Adm Med Ctr, Mental Hlth Serv, 4150 Clement St 116P, San Francisco, CA 94121 USA. EM brigitte.apfel@ucsf.edu; yirufang@yahoo.com.cn FU National Institute of Mental Health [5R01-MH056350-10] FX This research was supported by National Institute of Mental Health Grant No. 5R01-MH056350-10. NR 54 TC 13 Z9 14 U1 2 U2 35 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUN 30 PY 2011 VL 188 IS 1 BP 45 EP 50 DI 10.1016/j.psychres.2010.10.034 PG 6 WC Psychiatry SC Psychiatry GA 780DO UT WOS:000291834900009 PM 21095622 ER PT J AU Bennett, CL Fallah-Arani, F Conlan, T Trouillet, C Goold, H Chorro, L Flutter, B Means, TK Geissmann, F Chakraverty, R AF Bennett, Clare L. Fallah-Arani, Farnaz Conlan, Thomas Trouillet, Celine Goold, Hugh Chorro, Laurent Flutter, Barry Means, Terry K. Geissmann, Frederic Chakraverty, Ronjon TI Langerhans cells regulate cutaneous injury by licensing CD8 effector cells recruited to the skin SO BLOOD LA English DT Article ID LANGERIN(+) DENDRITIC CELLS; GRAFT-VERSUS-LEUKEMIA; TOLL-LIKE RECEPTOR; T-CELLS; CONTACT HYPERSENSITIVITY; STEADY-STATE; HOST-DISEASE; IN-VIVO; ANTIGEN; RESPONSES AB Langerhans cells (LCs) are a distinct population of dendritic cells that form a contiguous network in the epidermis of the skin. Although LCs possess many of the properties of highly proficient dendritic cells, recent studies have indicated that they are not necessary to initiate cutaneous immunity. In this study, we used a tractable model of cutaneous GVHD, induced by topical application of a Toll-like receptor agonist, to explore the role of LCs in the development of tissue injury. By adapting this model to permit inducible and selective depletion of host LCs, we found that GVHD was significantly reduced when LCs were absent. However, LCs were not required either for CD8 T-cell activation within the draining lymph node or subsequent homing of effector cells to the epidermis. Instead, we found that LCs were necessary for inducing transcription of IFN-gamma and other key effector molecules by donor CD8 cells in the epidermis, indicating that they license CD8 cells to induce epithelial injury. These data demonstrate a novel regulatory role for epidermal LCs during the effector phase of an inflammatory immune response in the skin. (Blood. 2011;117(26):7063-7069) C1 [Bennett, Clare L.; Fallah-Arani, Farnaz; Conlan, Thomas; Goold, Hugh; Flutter, Barry; Chakraverty, Ronjon] UCL, Dept Haematol, Div Canc Studies, Transplantat Immunol Grp, London NW3 2PF, England. [Trouillet, Celine; Chorro, Laurent; Geissmann, Frederic] Kings Coll London, Div Immunobiol Infect & Inflammatory Dis, Ctr Mol & Cellular Biol Inflammat, London, England. [Means, Terry K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. RP Bennett, CL (reprint author), UCL, Dept Haematol, Div Canc Studies, Transplantat Immunol Grp, UCL Royal Free Campus,Rowland Hill St, London NW3 2PF, England. EM c.bennett@medsch.ucl.ac.uk RI bennett, clare/J-5249-2013; OI bennett, clare/0000-0001-9146-2347; geissmann, frederic/0000-0001-5029-2468 FU Leukemia and Lymphoma Research, United Kingdom FX This work was supported by Leukemia and Lymphoma Research, United Kingdom. NR 35 TC 18 Z9 19 U1 0 U2 3 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 JUN 30 PY 2011 VL 117 IS 26 BP 7063 EP 7069 DI 10.1182/blood-2011-01-329185 PG 7 WC Hematology SC Hematology GA 785QO UT WOS:000292244000014 PM 21566096 ER PT J AU Salles, G de Jong, D Xie, WL Rosenwald, A Chhanabhai, M Gaulard, P Klapper, W Calaminici, M Sander, B Thorns, C Campo, E Molina, T Lee, A Pfreundschuh, M Horning, S Lister, A Sehn, LH Raemaekers, J Hagenbeek, A Gascoyne, RD Weller, E AF Salles, Gilles de Jong, Daphne Xie, Wanling Rosenwald, Andreas Chhanabhai, Mukesh Gaulard, Philippe Klapper, Wolfram Calaminici, Maria Sander, Birgitta Thorns, Christoph Campo, Elias Molina, Thierry Lee, Abigail Pfreundschuh, Michael Horning, Sandra Lister, Andrew Sehn, Laurie H. Raemaekers, John Hagenbeek, Anton Gascoyne, Randy D. Weller, Edie TI Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell lymphoma: a study from the Lunenburg Lymphoma Biomarker Consortium SO BLOOD LA English DT Article ID CHEMOTHERAPY PLUS RITUXIMAB; 3-WEEKLY CHOP CHEMOTHERAPY; NON-HODGKINS-LYMPHOMA; GERMINAL CENTER; ELDERLY-PATIENTS; TISSUE MICROARRAY; PREDICTS SURVIVAL; R-CHOP; AGGRESSIVE LYMPHOMAS; EXPRESSION PREDICTS AB The Lunenburg Lymphoma Biomarker Consortium (LLBC) evaluated the prognostic value of IHC biomarkers in a large series of patients with diffuse large B-cell lymphoma (DLBCL). Clinical data and tumor samples were retrieved from 12 studies from Europe and North America, with patients treated before or after the rituximab era. Using tissue microarrays from 1514 patients, IHC for BCL2, BCL6, CD5, CD10, MUM1, Ki67, and HLA-DR was performed and scored according to previously validated protocols. Optimal cut points predicting overall survival of patients treated in the rituximab era could only be determined for CD5 (P = .003) and Ki67 (P = .02), whereas such cut points for BCL2, BCL6, HLA-DR, and MUM1 could only be defined in patients not receiving rituximab. A prognostic model for patients treated in the rituximab era identified 4 risk groups using BCL2, Ki67, and International Prognostic Index (IPI) with improved discrimination of low-risk patients. Newly recognized correlations between specific biomarkers and IPI highlight the importance of carefully controlling for clinical and biologic factors in prognostic models. These data demonstrate that the IPI remains the best available index in patients with DLBCL treated with rituximab and chemotherapy. (Blood. 2011;117(26):7070-7078) C1 [Salles, Gilles] Hosp Civils Lyon, Lyon, France. [Salles, Gilles] Univ Lyon 1, Lyon, France. [de Jong, Daphne] Netherlands Canc Inst, Amsterdam, Netherlands. [Xie, Wanling; Weller, Edie] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA USA. [Rosenwald, Andreas] Univ Wurzburg, Inst Pathol, D-8700 Wurzburg, Germany. [Chhanabhai, Mukesh; Sehn, Laurie H.; Gascoyne, Randy D.] Univ British Columbia, Dept Pathol & Med Oncol, BC Canc Agcy, Vancouver, BC V5Z 1M9, Canada. [Gaulard, Philippe] Hop Henri Mondor, Dept Pathol, F-94010 Creteil, France. [Klapper, Wolfram] Univ Hosp Schleswig Holstein, Hematopathol Sect, Dept Pathol, Kiel, Germany. [Calaminici, Maria; Lee, Abigail; Lister, Andrew] St Bartholomews Hosp, Canc Res UK Med Oncol Unit, London, England. [Sander, Birgitta] Karolinska Inst, Stockholm, Sweden. [Thorns, Christoph] Univ Klinkum Schleswig Holstein, Dept Pathol, Lubeck, Germany. [Campo, Elias] Univ Barcelona, Hosp Clin, Barcelona, Spain. [Molina, Thierry] Univ Paris 05, Assistance Publ Hop Paris, Paris, France. [Pfreundschuh, Michael] Univ Saarland, Dept Internal Med 1, D-6650 Homburg, Germany. [Horning, Sandra] Stanford Univ, Med Ctr, Dept Med, Palo Alto, CA 94304 USA. [Raemaekers, John] Radboud Univ Nijmegen, Med Ctr, Dept Hematol, Nijmegen, Netherlands. [Hagenbeek, Anton] Univ Amsterdam, Acad Med Ctr, Dept Haematol, NL-1105 AZ Amsterdam, Netherlands. RP Salles, G (reprint author), Hosp Civils Lyon, Lyon, France. EM gilles.salles@chu-lyon.fr RI Thorns, Christoph/E-2945-2010; Klapper, Wolfram/S-6314-2016; OI Campo, elias/0000-0001-9850-9793 FU Bayer-Schering-Pharma; Eli-Lilly; Genentech; Millennium; Roche FX This study was supported by unrestricted grants from Bayer-Schering-Pharma, Eli-Lilly, Genentech, Millennium, and Roche. NR 49 TC 94 Z9 104 U1 1 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 JUN 30 PY 2011 VL 117 IS 26 BP 7070 EP 7078 DI 10.1182/blood-2011-04-345256 PG 9 WC Hematology SC Hematology GA 785QO UT WOS:000292244000015 PM 21536860 ER PT J AU Tinetti, ME Studenski, SA AF Tinetti, Mary E. Studenski, Stephanie A. TI Comparative Effectiveness Research and Patients with Multiple Chronic Conditions SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID OLDER PERSONS C1 [Tinetti, Mary E.] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Tinetti, Mary E.] Yale Univ, Sch Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Studenski, Stephanie A.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Studenski, Stephanie A.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Tinetti, ME (reprint author), Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. NR 5 TC 77 Z9 78 U1 1 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 JUN 30 PY 2011 VL 364 IS 26 BP 2478 EP 2481 DI 10.1056/p1100535 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 785AM UT WOS:000292199800003 PM 21696327 ER PT J AU Bejar, R Stevenson, K Abdel-Wahab, O Galili, N Nilsson, B Garcia-Manero, G Kantarjian, H Raza, A Levine, RL Neuberg, D Ebert, BL AF Bejar, Rafael Stevenson, Kristen Abdel-Wahab, Omar Galili, Naomi Nilsson, Bjoern Garcia-Manero, Guillermo Kantarjian, Hagop Raza, Azra Levine, Ross L. Neuberg, Donna Ebert, Benjamin L. TI Clinical Effect of Point Mutations in Myelodysplastic Syndromes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PROGNOSTIC SCORING SYSTEM; ACUTE MYELOID-LEUKEMIA; TP53 MUTATIONS; OF-FUNCTION; GENE; RISK; NEOPLASMS; CANCERS; TET2; CBL AB BACKGROUND Myelodysplastic syndromes are clinically heterogeneous disorders characterized by clonal hematopoiesis, impaired differentiation, peripheral-blood cytopenias, and a risk of progression to acute myeloid leukemia. Somatic mutations may influence the clinical phenotype but are not included in current prognostic scoring systems. METHODS We used a combination of genomic approaches, including next-generation sequencing and mass spectrometry-based genotyping, to identify mutations in samples of bone marrow aspirate from 439 patients with myelodysplastic syndromes. We then examined whether the mutation status for each gene was associated with clinical variables, including specific cytopenias, the proportion of blasts, and overall survival. RESULTS We identified somatic mutations in 18 genes, including two, ETV6 and GNAS, that have not been reported to be mutated in patients with myelodysplastic syndromes. A total of 51% of all patients had at least one point mutation, including 52% of the patients with normal cytogenetics. Mutations in RUNX1, TP53, and NRAS were most strongly associated with severe thrombocytopenia (P < 0.001 for all comparisons) and an increased proportion of bone marrow blasts (P < 0.006 for all comparisons). In a multivariable Cox regression model, the presence of mutations in five genes retained independent prognostic significance: TP53 (hazard ratio for death from any cause, 2.48; 95% confidence interval [CI], 1.60 to 3.84), EZH2 (hazard ratio, 2.13; 95% CI, 1.36 to 3.33), ETV6 (hazard ratio, 2.04; 95% CI, 1.08 to 3.86), RUNX1 (hazard ratio, 1.47; 95% CI, 1.01 to 2.15), and ASXL1 (hazard ratio, 1.38; 95% CI, 1.00 to 1.89). CONCLUSIONS Somatic point mutations are common in myelodysplastic syndromes and are associated with specific clinical features. Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with myelodysplastic syndromes, independently of established risk factors. (Funded by the National Institutes of Health and others.) C1 [Bejar, Rafael; Nilsson, Bjoern; Ebert, Benjamin L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bejar, Rafael; Nilsson, Bjoern; Ebert, Benjamin L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Bejar, Rafael; Ebert, Benjamin L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Stevenson, Kristen; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Abdel-Wahab, Omar; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Abdel-Wahab, Omar; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Leukemia Serv, Dept Med, New York, NY 10021 USA. [Galili, Naomi; Raza, Azra] Columbia Univ, New York Presbyterian Hosp, Med Ctr, Dept Hematol, New York, NY USA. [Garcia-Manero, Guillermo; Kantarjian, Hagop] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. RP Ebert, BL (reprint author), Brigham & Womens Hosp, Karp Res Bldg,CHRB 05-211,1 Blackfan Cir, Boston, MA 02115 USA. EM bebert@partners.org FU National Institutes of Health (NIH) [5R01 HL082945, P01 CA108631, T32 HL007623]; Starr Cancer Consortium; Burroughs-Wellcome Fund; Huber-Foster Fellowship FX Supported by grants from the National Institutes of Health (NIH) (5R01 HL082945 and P01 CA108631), the Starr Cancer Consortium, and the Burroughs-Wellcome Fund (Career Awards for Medical Scientists) (all to Dr. Ebert) and a grant from the NIH (T32 HL007623) and a Huber-Foster Fellowship (both to Dr. Bejar). NR 37 TC 572 Z9 598 U1 2 U2 32 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 JUN 30 PY 2011 VL 364 IS 26 BP 2496 EP 2506 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 785AM UT WOS:000292199800005 PM 21714648 ER PT J AU Chapman, PB Hauschild, A Robert, C Haanen, JB Ascierto, P Larkin, J Dummer, R Garbe, C Testori, A Maio, M Hogg, D Lorigan, P Lebbe, C Jouary, T Schadendorf, D Ribas, A O'Day, SJ Sosman, JA Kirkwood, JM Eggermont, AMM Dreno, B Nolop, K Li, J Nelson, B Hou, J Lee, RJ Flaherty, KT McArthur, GA AF Chapman, Paul B. Hauschild, Axel Robert, Caroline Haanen, John B. Ascierto, Paolo Larkin, James Dummer, Reinhard Garbe, Claus Testori, Alessandro Maio, Michele Hogg, David Lorigan, Paul Lebbe, Celeste Jouary, Thomas Schadendorf, Dirk Ribas, Antoni O'Day, Steven J. Sosman, Jeffrey A. Kirkwood, John M. Eggermont, Alexander M. M. Dreno, Brigitte Nolop, Keith Li, Jiang Nelson, Betty Hou, Jeannie Lee, Richard J. Flaherty, Keith T. McArthur, Grant A. CA BRIM-3 Study Grp TI Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID METASTATIC MELANOMA; PHASE-III; MALIGNANT-MELANOMA; RAF KINASE; DACARBAZINE; INHIBITION; RESISTANCE; SORAFENIB; PATHWAY AB BACKGROUND Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. METHODS We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. RESULTS At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P < 0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. CONCLUSIONS Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.) C1 [Chapman, Paul B.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Hauschild, Axel] Univ Kiel, Kiel, Germany. [Schadendorf, Dirk] Univ Hosp Essen, Essen, Germany. [Garbe, Claus] Univ Tubingen, Tubingen, Germany. [Robert, Caroline; Eggermont, Alexander M. M.] Inst Gustave Roussy, Paris, France. [Lebbe, Celeste] Hop St Louis, Serv Dermatol, F-75475 Paris, France. [Haanen, John B.] Netherlands Canc Inst, Amsterdam, Netherlands. [Ascierto, Paolo] Ist Nazl Tumori Fdn Pascale, Naples, Italy. [Maio, Michele] Ist Toscano Tumori, Florence, Italy. [Larkin, James] Royal Marsden Hosp, Dept Med Oncol, London, England. [Dummer, Reinhard] Univ Zurich, Dept Dermatol, Zurich, Switzerland. [Testori, Alessandro] Ist Europeo Oncol, Milan, Italy. [Hogg, David] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Hogg, David] Univ Hlth Network, Toronto, ON, Canada. [Lorigan, Paul] Univ Manchester, Manchester, Lancs, England. [Jouary, Thomas] St Andre Hosp, Bordeaux, France. [Dreno, Brigitte] Nantes Univ Hosp, Dept Dermatol, Nantes, France. [Ribas, Antoni] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [O'Day, Steven J.] Angeles Clin & Res Inst, Los Angeles, CA USA. [Sosman, Jeffrey A.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Kirkwood, John M.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Nolop, Keith] Plexxikon, Berkeley, CA USA. [Li, Jiang; Lee, Richard J.] Hoffmann La Roche, Nutley, NJ USA. [Nelson, Betty; Hou, Jeannie] Genentech Inc, San Francisco, CA USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [McArthur, Grant A.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. RP Chapman, PB (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10065 USA. EM chapmanp@mskcc.org RI Ottensmeier, Christian/E-8131-2012; Lorigan, Paul/J-6898-2015; Del Vecchio, Michele/K-1584-2016; OI Ottensmeier, Christian/0000-0003-3619-1657; Lorigan, Paul/0000-0002-8875-2164; Del Vecchio, Michele/0000-0001-9060-2512; coral, sandra/0000-0002-1308-3082 FU Hoffmann-La Roche; Roche; GlaxoSmithKline; Abraxis/Celgene; AstraZeneca; Bayer; Biovex; Bristol-Myers Squibb; Boehringer Ingleheim; Eisai; Merck; Novartis; Bayer and Merck; Schering-Plough; Plexxikon; Roche/Genentech; Millennium; Vical; Imedex; Pfizer FX Supported by Hoffmann-La Roche.; Dr. Chapman reports receiving consulting fees, payment for serving on scientific advisory boards, and grant support from Roche and consulting fees from GlaxoSmithKline; Dr. Hauschild, receiving consulting fees from Abraxis/Celgene, AstraZeneca, Bayer, Biovex, Bristol-Myers Squibb, Boehringer Ingleheim, Eisai, GlaxoSmithKline, Merck, Novartis, and Roche, grant support from Bayer and Merck, and lecture fees from Abraxis/Celgene, AstraZeneca, Biovex, Bristol-Myers Squibb, Merck, Novartis, and Roche; Dr. Robert, receiving consulting fees from Roche, Bristol-Myers Squibb, GlaxoSmithKline, and Merck and travel payments from Bristol-Myers Squibb; Dr. Ascierto, serving as a board member for Bristol-Myers Squibb, GlaxoSmithKline, Schering-Plough, Merck, and Roche and lecture fees from Schering-Plough and Merck; Dr. Garbe, receiving consulting fees from Bristol-Myers Squibb, Merck, GlaxoSmithKline, and Philogen, grant support from Bristol-Myers Squibb, Philogen, and Swedish Orphan, and travel payments from Bristol- Myers Squibb, Roche, and Merck; Dr. Maio, serving on advisory boards for Bristol-Myers Squibb and Pfizer and receiving lecture fees from Bristol-Myers Squibb; Dr. Hogg, receiving consulting fees from Roche, GlaxoSmithKline, and Bristol-Myers Squibb and lecture fees from Roche; Dr. Lorigan, receiving consulting fees from Roche and an educational grant from Roche; Dr. Lebbe, serving on paid advisory boards for Roche and Bristol- Myers Squibb and receiving payments for the development of educational presentations and travel payments from Bristol-Myers Squibb; Dr. Jouary, serving on an advisory board for Bristol-Myers Squibb and receiving consulting fees from Bristol-Myers Squibb and Schering-Plough; Dr. Schadendorf, receiving consulting fees from Roche, GlaxoSmithKline, Bristol-Myers Squibb, and Merck, serving on advisory boards for Roche, GlaxoSmithKline, Bristol-Myers Squibb, Merck, and Schering-Plough, receiving grant support from Schering-Plough and Plexxikon, receiving lecture fees from Bristol-Myers Squibb, Merck, Schering-Plough, and Roche, and receiving payment for developing presentations for Bristol-Myers Squibb; Dr. Ribas, receiving consulting fees from Roche/Genentech; Dr. O'Day, receiving consulting fees from Glaxo-SmithKline, receiving consulting fees, grant support, lecture fees, and payment for the development of educational presentations from Bristol-Myers Squibb, and serving as an expert witness in a private lawsuit; Dr. Sosman, receiving grant support from Roche, Millennium, and GlaxoSmithKline and consulting fees from Roche and Millennium; Dr. Kirkwood, serving as a board member for Morphotek and receiving consulting fees from GlaxoSmithKline and Vical, lecture fees from Merck, and payment for the development of educational presentations from Imedex; Dr. Eggermont, receiving consulting fees from Bristol-Myers Squibb, Merck, and GlaxoSmithKline; Dr. Dreno, receiving consulting fees from Roche; Dr. Nolop, being an employee of and having an equity interest in Plexxikon; Mrs. Li and Dr. Lee, being employees of Roche; Miss Nelson and Dr. Hou, being employees of Genentech and having an equity interest in Roche; Dr. Flaherty, receiving consulting fees from GlaxoSmithKline; and Dr. McArthur, receiving grant support from Pfizer. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. NR 28 TC 3239 Z9 3312 U1 43 U2 302 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 JUN 30 PY 2011 VL 364 IS 26 BP 2507 EP 2516 DI 10.1056/NEJMoa1103782 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 785AM UT WOS:000292199800006 PM 21639808 ER PT J AU Ryan, ET Madoff, LC Ferraro, MJ AF Ryan, Edward T. Madoff, Lawrence C. Ferraro, Mary Jane TI A Man with Diarrhea after a Trip to the Dominican Republic Vibrio cholerae, serogroup O1 (toxigenic), serotype Ogawa, biotype El Tor. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ANTIBIOTIC-TREATMENT; TRAVELERS DIARRHEA C1 [Ryan, Edward T.] Massachusetts Gen Hosp, Dept Infect Dis, Boston, MA 02114 USA. [Ferraro, Mary Jane] Massachusetts Gen Hosp, Dept Pathol & Microbiol, Boston, MA 02114 USA. [Ryan, Edward T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Ferraro, Mary Jane] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Madoff, Lawrence C.] Massachusetts Dept Publ Hlth, Boston, MA USA. [Madoff, Lawrence C.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. RP Ryan, ET (reprint author), Massachusetts Gen Hosp, Dept Infect Dis, Boston, MA 02114 USA. NR 17 TC 1 Z9 1 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 JUN 30 PY 2011 VL 364 IS 26 BP 2536 EP 2541 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 785AM UT WOS:000292199800011 PM 21714651 ER PT J AU Smart-Halajko, MC Kelley-Hedgepeth, A Montefusco, MC Cooper, JA Kopin, A McCaffrey, JM Balasubramanyam, A Pownall, HJ Nathan, DM Peter, I Talmud, PJ Huggins, GS AF Smart-Halajko, Melissa C. Kelley-Hedgepeth, Alyson Montefusco, Maria Claudia Cooper, Jackie A. Kopin, Alan McCaffrey, Jeanne M. Balasubramanyam, Ashok Pownall, Henry J. Nathan, David M. Peter, Inga Talmud, Philippa J. Huggins, Gordon S. CA Look AHEAD Study TI ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels in Non-Hispanic White Americans from the Look AHEAD Clinical Trial SO BMC MEDICAL GENETICS LA English DT Article ID ANGIOPOIETIN-LIKE PROTEIN-4; CORONARY-HEART-DISEASE; LIPOPROTEIN-LIPASE; CARDIOVASCULAR-DISEASE; ADIPOSE-TISSUE; RISK; HDL; PREVENTION; REDUCTION; WEIGHT AB Background: Elevated triglyceride levels are a risk factor for cardiovascular disease. Angiopoietin-like protein 4 (Angptl4) is a metabolic factor that raises plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). In nondiabetic individuals, the ANGPTL4 coding variant E40K has been associated with lower plasma triglyceride levels while the T266M variant has been associated with more modest effects on triglyceride metabolism. The objective of this study was to determine whether ANGPTL4 E40K and T266M are associated with triglyceride levels in the setting of obesity and T2D, and whether modification of triglyceride levels by these genetic variants is altered by a lifestyle intervention designed to treat T2D. Methods: The association of ANGPTL4 E40K and T266M with fasting triglyceride levels was investigated in 2,601 participants from the Look AHEAD Clinical Trial, all of whom had T2D and were at least overweight. Further, we tested for an interaction between genotype and treatment effects on triglyceride levels. Results: Among non-Hispanic White Look AHEAD participants, ANGPTL4 K40 carriers had mean triglyceride levels of 1.61 +/- 0.62 mmol/L, 0.33 mmol/L lower than E40 homozygotes (p = 0.001). Individuals homozygous for the minor M266 allele (MAF 30%) had triglyceride levels of 1.75 +/- 0.58 mmol/L, 0.24 mmol/L lower than T266 homozygotes (p = 0.002). The association of the M266 with triglycerides remained significant even after removing K40 carriers from the analysis (p = 0.002). There was no interaction between the weight loss intervention and genotype on triglyceride levels. Conclusions: This is the first study to demonstrate that the ANGPTL4 E40K and T266M variants are associated with lower triglyceride levels in the setting of T2D. In addition, our findings demonstrate that ANGPTL4 genotype status does not alter triglyceride response to a lifestyle intervention in the Look AHEAD study. C1 [Smart-Halajko, Melissa C.; Cooper, Jackie A.; Talmud, Philippa J.] Royal Free & UCL Med Sch, Div Cardiovasc Genet, Dept Med, British Heart Fdn Labs, London, England. [Kelley-Hedgepeth, Alyson; Montefusco, Maria Claudia; Kopin, Alan; Huggins, Gordon S.] Tufts Med Ctr, Mol Cardiol Res Inst, MCRI Ctr Translat Genom, Boston, MA USA. [McCaffrey, Jeanne M.] Brown Med Sch, Providence, RI USA. [McCaffrey, Jeanne M.] Miriam Hosp, Weight Control & Diabet Res Ctr, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Balasubramanyam, Ashok; Pownall, Henry J.] Baylor Coll Med, Houston, TX 77030 USA. [Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Diabet Unit, Boston, MA USA. [Peter, Inga] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. RP Smart-Halajko, MC (reprint author), Royal Free & UCL Med Sch, Div Cardiovasc Genet, Dept Med, British Heart Fdn Labs, London, England. EM m.smart-halajko@qmul.ac.uk; ghuggins@tuftsmedicalcenter.org OI Talmud, Philippa/0000-0002-5560-1933; Smart, Melissa/0000-0002-2655-3880 FU National Institutes of Health [R01 DK072497]; British Heart Foundation [PG20057014]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center [M01-RR-01066]; University of Colorado Health Sciences Center General Clinical Research Center [M01 RR00051]; Clinical Nutrition Research Unit [P30 DK48520]; University of Tennessee at Memphis General Clinical Research Center [M01RR00211-40]; University of Pittsburgh General Clinical Research Center [M01 RR000056 44]; NIH [DK 046204, 5T32HL069770]; Unilever/BBSRC FX We gratefully acknowledge the contributions of the Look AHEAD Study Group members [4]. This study is supported by the National Institutes of Health (R01 DK072497), the British Heart Foundation (PG20057014) and additional sources listed below. This manuscript is based on a subset of the baseline data set from participants enrolled from the Look AHEAD sites at Pennington Biomedical Research Center; Massachusetts General Hospital; University of Colorado Health Sciences Center; Baylor College of Medicine; The University of Tennessee Health Science Center, University of Tennessee; University of Minnesota; St. Luke's Roosevelt Hospital Center; University of Pennsylvania; University of Pittsburgh; and Brown University. Additional support was received from the Massachusetts General Hospital Mallinckrodt General Clinical Research Center (M01-RR-01066); the University of Colorado Health Sciences Center General Clinical Research Center (M01 RR00051) and Clinical Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR00211-40); the University of Pittsburgh General Clinical Research Center (M01 RR000056 44) and NIH grant (DK 046204). Author AKH was supported by the Training Program in Cardiovascular Research (NIH, 5T32HL069770) and MCS is supported by a Unilever/BBSRC Case studentship. NR 18 TC 18 Z9 19 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JUN 29 PY 2011 VL 12 AR 89 DI 10.1186/1471-2350-12-89 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 799KL UT WOS:000293285500001 PM 21714923 ER PT J AU Cao, K Graziotto, JJ Blair, CD Mazzulli, JR Erdos, MR Krainc, D Collins, FS AF Cao, Kan Graziotto, John J. Blair, Cecilia D. Mazzulli, Joseph R. Erdos, Michael R. Krainc, Dimitri Collins, Francis S. TI Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID AGGREGATE-PRONE PROTEINS; CHRONOLOGICAL LIFE-SPAN; CONJUGATION SYSTEM; AUTOPHAGY; LAMIN; DEGRADATION; DISEASE; TARGET; MTOR; LAMINOPATHIES AB Hutchinson-Gilford progeria syndrome (HGPS) is a lethal genetic disorder characterized by premature aging. HGPS is most commonly caused by a de novo single-nucleotide substitution in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11, producing an abnormal lamin A protein termed progerin. Accumulation of progerin in dividing cells adversely affects the integrity of the nuclear scaffold and leads to nuclear blebbing in cultured cells. Progerin is also produced in normal cells, increasing in abundance as senescence approaches. Here, we report the effect of rapamycin, a macrolide antibiotic that has been implicated in slowing cellular and organismal aging, on the cellular phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells. Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts. Our findings suggest an additional mechanism for the beneficial effects of rapamycin on longevity and encourage the hypothesis that rapamycin treatment could provide clinical benefit for children with HGPS. C1 [Graziotto, John J.; Mazzulli, Joseph R.; Krainc, Dimitri] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Cao, Kan; Blair, Cecilia D.; Erdos, Michael R.; Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Cao, Kan] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. RP Krainc, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. EM krainc@helix.mgh.harvard.edu; francis.collins@nih.gov FU Progeria Research Foundation; National Human Genome Research Institute; [R00AG029761]; [R01NS051303] FX This work was supported by grants R00AG029761 (K.C.) and R01NS051303 (D.K.), The Progeria Research Foundation (J.J.G. and D.K.), and the intramural program of the National Human Genome Research Institute (F.S.C.). NR 38 TC 93 Z9 96 U1 7 U2 39 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 JUN 29 PY 2011 VL 3 IS 89 AR 89ra58 DI 10.1126/scitranslmed.3002346 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 795NY UT WOS:000292982100005 PM 21715679 ER PT J AU Xiang, ZM Valenza, M Cui, LB Leoni, V Jeong, HK Brilli, E Zhang, JY Peng, Q Duan, WZ Reeves, SA Cattaneo, E Krainc, D AF Xiang, Zhongmin Valenza, Marta Cui, Libin Leoni, Valerio Jeong, Hyun-Kyung Brilli, Elisa Zhang, Jiangyang Peng, Qi Duan, Wenzhen Reeves, Steven A. Cattaneo, Elena Krainc, Dimitri TI Peroxisome-Proliferator-Activated Receptor Gamma Coactivator 1 alpha Contributes to Dysmyelination in Experimental Models of Huntington's Disease SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; MOUSE MODEL; TRANSCRIPTIONAL ACTIVITY; MUTANT HUNTINGTIN; ENERGY-METABOLISM; TRANSGENIC MICE; CHOLESTEROL; MYELIN; PGC-1-ALPHA; DYSFUNCTION AB The peroxisome-proliferator-activated receptor gamma coactivator 1 alpha (PGC1 alpha) has been implicated in the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Recent data demonstrating white matter abnormalities in PGC1 alpha knock-out (KO) mice prompted us to examine the role of PGC1 alpha in CNS myelination and its relevance to HD pathogenesis. We found deficient postnatal myelination in the striatum of PGC1 alpha KO mice, accompanied by a decrease in myelin basic protein (MBP). In addition, brain cholesterol, its precursors, and the rate-limiting enzymes for cholesterol synthesis, HMG CoA synthase (HMGCS1) and HMG CoA reductase (HMGCR), were also reduced in PGC1 alpha KO mice. Moreover, knockdown of PGC1 alpha in oligodendrocytes by lentiviral shRNA led to a decrease in MBP, HMGCS1, and Hmgcr mRNAs. Chromatin immunoprecipitations revealed the recruitment of PGC1 alpha to MBP promoter in mouse brain, and PGC1 alpha over-expression increased MBP and SREBP-2 promoter activity, suggesting that PGC1 alpha regulates MBP and cholesterol synthesis at the transcriptional level. Importantly, expression of mutant huntingtin (Htt) in primary oligodendrocytes resulted in decreased expression of PGC1 alpha and its targets HmgcS1, Hmgcr, and MBP. Decreased expression of MBP and deficient myelination were found postnatally and in adult R6/2 mouse model of HD. Diffusion tensor imaging detected white matter abnormalities in the corpus callosum of R6/2 mice, and electron microscopy revealed thinner myelin sheaths and increased myelin periodicity in BACHD [bacterial artificial chromosome (BAC)-mediated transgenic model for Huntington's disease] mice expressing full-length mutant Htt. Together, these data suggest that PGC1 alpha plays a role in postnatal myelination and that deficient PGC1 alpha activity in oligodendrocytes may contribute to abnormal myelination in HD. C1 [Xiang, Zhongmin; Cui, Libin; Jeong, Hyun-Kyung; Reeves, Steven A.; Krainc, Dimitri] Harvard Univ, Sch Med, MassGen Inst Neurodegenerat Dis, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Valenza, Marta; Brilli, Elisa; Cattaneo, Elena] Univ Milan, Dept Pharmaceut Sci, I-20133 Milan, Italy. [Valenza, Marta; Brilli, Elisa; Cattaneo, Elena] Univ Milan, Ctr Stem Cell Res, I-20133 Milan, Italy. [Leoni, Valerio] Inst Neurol IRCCS C Besta, Lab Clin Pathol & Med Genet, I-20133 Milan, Italy. [Zhang, Jiangyang] Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21287 USA. [Duan, Wenzhen] Johns Hopkins Univ, Div Neurobiol, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. RP Krainc, D (reprint author), Harvard Univ, Sch Med, MassGen Inst Neurodegenerat Dis, Massachusetts Gen Hosp, 114 16th St, Charlestown, MA 02129 USA. EM dkrainc@partners.org FU National Institutes of Health [R01NS050352, R01 NS035996]; Fondazione Cariplo (Italy) [2008/2406]; Ministero della Salute and Fondi per giovani Ricercatori (Italy) [GR-2008-1145270]; CHDI Foundation; Huntington's Disease Coalition for the Cure (USA) FX This work was supported by National Institutes of Health Grants to D.K. (R01NS050352) and S.R. (R01 NS035996), by Fondazione Cariplo (Italy; 2008/2406) to M.V., by Ministero della Salute and Fondi per giovani Ricercatori (Italy; GR-2008-1145270) to L.V., by CHDI Foundation to W.D., and by Huntington's Disease Coalition for the Cure (USA) and CHDI (Cure Huntington's Disease Initiative) Foundation to E.C. We thank William Yang and Xiaofeng Gu for BACHD brain samples, and Marian Difiglia and Ellen Sapp for assistance with electron microscopy. NR 53 TC 50 Z9 50 U1 1 U2 4 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 JUN 29 PY 2011 VL 31 IS 26 BP 9544 EP 9553 DI 10.1523/JNEUROSCI.1291-11.2011 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 784WP UT WOS:000292189500012 PM 21715619 ER PT J AU Adatto, I Lawrence, C Thompson, M Zon, LI AF Adatto, Isaac Lawrence, Christian Thompson, Michael Zon, Leonard I. TI A New System for the Rapid Collection of Large Numbers of Developmentally Staged Zebrafish Embryos SO PLOS ONE LA English DT Article ID DANIO-RERIO; VERTEBRATE; BEHAVIOR AB The zebrafish is an excellent genetic and developmental model system used to study biology and disease. While the zebrafish model is associated with high fecundity, its reproductive potential has not been completely realized by scientists. One major issue is that embryo collection is inefficient. Here, we have developed an innovative breeding vessel designed to stimulate the natural reproductive behavior of the fish. This novel apparatus allows us to collect large numbers of developmentally synchronized embryos in brief and defined windows of time, and with minimal investments in labor and space. To demonstrate the efficacy of this approach, we placed three separate groups (n = 180) of fish in the vessel and allowed them to spawn for 10-minute intervals. During these trials, which were repeated three times, the fish produced 8600 +/- 917, 8400 +/- 794, and 6800 +/- 1997 embryos, respectively. This level of embryo production is nearly twice what we were able to achieve when using conventional crossing equipment with some of the same fish, and it required significantly less room and time to set up and break down. This system overcomes major space and labor restrictions inherent in spawning equipment currently used in the field, and will greatly accelerate efforts to improve the scale and throughput of experiments. C1 [Adatto, Isaac; Zon, Leonard I.] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Adatto, Isaac; Zon, Leonard I.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Adatto, Isaac; Zon, Leonard I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Adatto, Isaac; Zon, Leonard I.] Harvard Stem Cell Inst, Boston, MA USA. [Zon, Leonard I.] Harvard Univ, Sch Med, Boston, MA USA. [Zon, Leonard I.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Lawrence, Christian] Childrens Hosp, Aquat Resources Program, Boston, MA 02115 USA. [Thompson, Michael] Plast Concepts Inc, Billerica, MA USA. RP Adatto, I (reprint author), Childrens Hosp, Stem Cell Program, 300 Longwood Ave, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu FU National Institutes of Health (NIH) [2P30DK049216-17]; Howard Hughes Medical Institute FX I.A. is supported by the National Institutes of Health (NIH) grant # 2P30DK049216-17. L.I.Z. is supported by the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. M. T. is the owner and president of Plastics Concepts, Inc. and supervised fabrication of the breeding vessel prototype. NR 11 TC 26 Z9 26 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 29 PY 2011 VL 6 IS 6 AR e21715 DI 10.1371/journal.pone.0021715 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 786FZ UT WOS:000292290100062 PM 21738776 ER PT J AU Du, SX Xu, L Zhang, WG Tang, S Boenig, RI Chen, H Mariano, EB Zwick, MB Parren, PWHI Burton, DR Wrin, T Petropoulos, CJ Ballantyne, JA Chambers, M Whalen, RG AF Du, Sean X. Xu, Li Zhang, Wenge Tang, Susan Boenig, Rebecca I. Chen, Helen Mariano, Ellaine B. Zwick, Michael B. Parren, Paul W. H. I. Burton, Dennis R. Wrin, Terri Petropoulos, Christos J. Ballantyne, John A. Chambers, Michael Whalen, Robert G. TI A Directed Molecular Evolution Approach to Improved Immunogenicity of the HIV-1 Envelope Glycoprotein SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZING ANTIBODY-RESPONSES; HUMAN MONOCLONAL-ANTIBODIES; SUBTYPE-B ENVELOPE; CD4 BINDING-SITE; MONOMERIC GP120; VACCINE DESIGN; INFECTION; PROTEIN; MACAQUES AB A prophylactic vaccine is needed to slow the spread of HIV-1 infection. Optimization of the wild-type envelope glycoproteins to create immunogens that can elicit effective neutralizing antibodies is a high priority. Starting with ten genes encoding subtype B HIV-1 gp120 envelope glycoproteins and using in vitro homologous DNA recombination, we created chimeric gp120 variants that were screened for their ability to bind neutralizing monoclonal antibodies. Hundreds of variants were identified with novel antigenic phenotypes that exhibit considerable sequence diversity. Immunization of rabbits with these gp120 variants demonstrated that the majority can induce neutralizing antibodies to HIV-1. One novel variant, called ST-008, induced significantly improved neutralizing antibody responses when assayed against a large panel of primary HIV-1 isolates. Further study of various deletion constructs of ST-008 showed that the enhanced immunogenicity results from a combination of effective DNA priming, an enhanced V3-based response, and an improved response to the constant backbone sequences. C1 [Du, Sean X.; Xu, Li; Zhang, Wenge; Tang, Susan; Boenig, Rebecca I.; Chen, Helen; Mariano, Ellaine B.; Whalen, Robert G.] Maxygen Inc, Dept Infect Dis, Redwood City, CA USA. [Zwick, Michael B.; Parren, Paul W. H. I.; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp, MIT, Boston, MA USA. [Burton, Dennis R.] Harvard, Boston, MA USA. [Wrin, Terri; Petropoulos, Christos J.] Monogram Biosci, San Francisco, CA USA. [Ballantyne, John A.; Chambers, Michael] Aldevron LLC, Fargo, ND USA. RP Du, SX (reprint author), Simcere Pharmaceut Grp, Nanjing, Peoples R China. EM robert.whalen@altravax.com OI Parren, Paul/0000-0002-4365-3859 FU NIH [P01 AI56375]; DOD [W9113M-05-C-0198]; Double Bottom Line Ventures FX This work was funded by the NIH (P01 AI56375), DOD (contract W9113M-05-C-0198), and Double Bottom Line Ventures. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 87 TC 11 Z9 11 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 JUN 29 PY 2011 VL 6 IS 6 AR e20927 DI 10.1371/journal.pone.0020927 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 786FZ UT WOS:000292290100009 PM 21738594 ER PT J AU Huso, DL Edie, S Levine, MA Schwindinger, W Wang, YL Juppner, H Germain-Lee, EL AF Huso, David L. Edie, Sarah Levine, Michael A. Schwindinger, William Wang, Yingli Jueppner, Harald Germain-Lee, Emily L. TI Heterotopic Ossifications in a Mouse Model of Albright Hereditary Osteodystrophy SO PLOS ONE LA English DT Article ID STIMULATORY G-PROTEIN; GS-ALPHA GENE; PROGRESSIVE OSSEOUS HETEROPLASIA; TOTAL HIP-ARTHROPLASTY; ECTOPIC BONE-FORMATION; PSEUDOHYPOPARATHYROIDISM TYPE-1A; INACTIVATING MUTATIONS; TARGETED DISRUPTION; HORMONE RESISTANCE; SUBUNIT G(S)ALPHA AB Albright hereditary osteodystrophy (AHO) is characterized by short stature, brachydactyly, and often heterotopic ossifications that are typically subcutaneous. Subcutaneous ossifications (SCO) cause considerable morbidity in AHO with no effective treatment. AHO is caused by heterozygous inactivating mutations in those GNAS exons encoding the alpha-subunit of the stimulatory G protein (G alpha(s)). When inherited maternally, these mutations are associated with obesity, cognitive impairment, and resistance to certain hormones that mediate their actions through G protein-coupled receptors, a condition termed pseudohypoparathyroidism type 1a (PHP1a). When inherited paternally, GNAS mutations cause only AHO but not hormonal resistance, termed pseudopseudohypoparathyroidism (PPHP). Mice with targeted disruption of exon 1 of Gnas (Gnas(E1-/+)) replicate human PHP1a or PPHP phenotypically and hormonally. However, SCO have not yet been reported in Gnas(E1+/-) mice, at least not those that had been analyzed by us up to 3 months of age. Here we now show that Gnas(E1-/+) animals develop SCO over time. The ossified lesions increase in number and size and are uniformly detected in adult mice by one year of age. They are located in both the dermis, often in perifollicular areas, and the subcutis. These lesions are particularly prominent in skin prone to injury or pressure. The SCO comprise mature bone with evidence of mineral deposition and bone marrow elements. Superficial localization was confirmed by radiographic and computerized tomographic imaging. In situ hybridization of SCO lesions were positive for both osteonectin and osteopontin. Notably, the ossifications were much more extensive in males than females. Because Gnas(E1-/+) mice develop SCO features that are similar to those observed in AHO patients, these animals provide a model system suitable for investigating pathogenic mechanisms involved in SCO formation and for developing novel therapeutics for heterotopic bone formation. Moreover, these mice provide a model with which to investigate the regulatory mechanisms of bone formation. C1 [Huso, David L.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21218 USA. [Edie, Sarah] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Levine, Michael A.] Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. [Levine, Michael A.] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Schwindinger, William] Weis Ctr Res, Geisinger Clin, Danville, PA 17822 USA. [Wang, Yingli] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Jueppner, Harald] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Jueppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. [Jueppner, Harald] Harvard Univ, Sch Med, Boston, MA USA. [Germain-Lee, Emily L.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Germain-Lee, Emily L.] Kennedy Krieger Inst, Albright Clin, Baltimore, MD USA. [Germain-Lee, Emily L.] Hugo W Moser Res Inst Kennedy Krieger, Baltimore, MD USA. RP Huso, DL (reprint author), Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21218 USA. EM germainlee@kennedykrieger.org OI Levine, Michael/0000-0003-0036-7809 FU Bosworth Family; Friedman Family FX This work was supported by generous donations to the research of E.L.G.-L. by the Bosworth Family, the Friedman Family, and the families/friends of patients with Albright hereditary osteodystrophy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 13 Z9 14 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 29 PY 2011 VL 6 IS 6 AR e21755 DI 10.1371/journal.pone.0021755 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 786FZ UT WOS:000292290100067 PM 21747923 ER PT J AU Rothe, F Ignatiadis, M Chaboteaux, C Haibe-Kains, B Kheddoumi, N Majjaj, S Badran, B Fayyad-Kazan, H Desmedt, C Harris, AL Piccart, M Sotiriou, C AF Rothe, Francoise Ignatiadis, Michail Chaboteaux, Carole Haibe-Kains, Benjamin Kheddoumi, Naima Majjaj, Samira Badran, Bassam Fayyad-Kazan, Hussein Desmedt, Christine Harris, Adrian L. Piccart, Martine Sotiriou, Christos TI Global MicroRNA Expression Profiling Identifies MiR-210 Associated with Tumor Proliferation, Invasion and Poor Clinical Outcome in Breast Cancer SO PLOS ONE LA English DT Article ID MOLECULAR SUBTYPES; PROGNOSIS; SIGNATURE; METASTASIS; SURVIVAL; HYPOXIA; TARGETS; TRANSCRIPTION; GRADE; MIRNA AB Purpose: Aberrant microRNA (miRNA) expression is associated with cancer and has potential diagnostic and prognostic value in various malignancies. In this study, we investigated miRNA profiling as a complementary tool to improve our understanding of breast cancer (BC) biology and to assess whether miRNA expression could predict clinical outcome of BC patients. Experimental Design: Global miRNA expression profiling using microarray technology was conducted in 56 systemically untreated BC patients who had corresponding mRNA expression profiles available. Results were further confirmed using qRT-PCR in an independent dataset of 89 ER-positive BC patients homogeneously treated with tamoxifen only. MiR-210 functional analyses were performed in MCF7 and MDA-MB-231 BC cell lines using lentiviral transduction. Results: Estrogen receptor (ER) status, tumor grade and our previously developed gene expression grade index (GGI) were associated with distinct miRNA profiles. Several miRNAs were found to be clinically relevant, including miR-210, its expression being associated with tumor proliferation and differentiation. Furthermore, miR-210 was associated with poor clinical outcome in ER-positive, tamoxifen-treated BC patients. Interestingly, the prognostic performance of miR-210 was similar to several reported multi-gene signatures, highlighting its important role in BC differentiation and tumor progression. Functional analyses in BC cell lines revealed that miR-210 is involved in cell proliferation, migration and invasion. Conclusions: This integrated analysis combining miRNA and mRNA expression demonstrates that miRNA expression provides additional biological information beyond mRNA expression. Expression of miR-210 is linked to tumor proliferation and appears to be a strong potential biomarker of clinical outcome in BC. C1 [Rothe, Francoise; Ignatiadis, Michail; Chaboteaux, Carole; Kheddoumi, Naima; Majjaj, Samira; Desmedt, Christine; Piccart, Martine; Sotiriou, Christos] Univ Libre Bruxelles, Inst Jules Bordet, Translat Res Unit, Brussels, Belgium. [Haibe-Kains, Benjamin] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02115 USA. [Badran, Bassam; Fayyad-Kazan, Hussein] Univ Libre Bruxelles, Inst Jules Bordet, Lab Expt Hematol, Brussels, Belgium. [Harris, Adrian L.] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Canc Res UK Mol Oncol Labs, Oxford OX3 9DU, England. RP Rothe, F (reprint author), Univ Libre Bruxelles, Inst Jules Bordet, Translat Res Unit, Brussels, Belgium. EM christos.sotiriou@bordet.be RI Haibe-Kains, Benjamin/D-3702-2011; OI Haibe-Kains, Benjamin/0000-0002-7684-0079; Desmedt, Christine/0000-0002-5223-5579; Harris, Adrian/0000-0003-1376-8409 FU Belgian National Foundation for Cancer Research, FNRS; Breast Cancer Research Foundation; Brussels Region; MEDIC Foundation FX This work was supported by the Belgian National Foundation for Cancer Research, FNRS (CS); by The Breast Cancer Research Foundation (FR, CS); the Brussels Region (CD) and by the MEDIC Foundation (FR, CS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 114 Z9 117 U1 4 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 29 PY 2011 VL 6 IS 6 AR e20980 DI 10.1371/journal.pone.0020980 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 786FZ UT WOS:000292290100011 PM 21738599 ER PT J AU Bhatt, RS Zurita, AJ O'Neill, A Norden-Zfoni, A Zhang, L Wu, HK Wen, PY George, D Sukhatme, VP Atkins, MB Heymach, JV AF Bhatt, R. S. Zurita, A. J. O'Neill, A. Norden-Zfoni, A. Zhang, L. Wu, H. K. Wen, P. Y. George, D. Sukhatme, V. P. Atkins, M. B. Heymach, J. V. TI Increased mobilisation of circulating endothelial progenitors in von Hippel-Lindau disease and renal cell carcinoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE circulating endothelial cells; von Hippel-Lindau (VHL) disease; renal cancer; biomarker; angiogenesis ID SURROGATE MARKER; CANCER-PATIENTS; TUMOR; THERAPY; ANGIOGENESIS; BIOMARKERS; INHIBITOR; SUNITINIB; BLOOD AB BACKGROUND: Circulating endothelial cells (CECs) are a candidate biomarker for monitoring angiogenesis in cancer. Circulating endothelial cell subsets are mobilised by angiogenic mediators. Because of the highly angiogenic phenotype of renal cell carcinoma (RCC), we sought to assess the potential of CECs as a marker of RCC in patients with von Hippel-Lindau (VHL) disease and those with sporadic RCC. METHODS: We performed multicolour flow cytometry to enumerate CECs in patients with RCC, patients with VHL disease with and without RCC, and normal subjects. Two subsets of CECs were evaluated: mature CECs (mCECs) and circulating endothelial progenitors (CEPs). RESULTS: In patients with VHL disease and RCC and those with sporadic RCC (N = 10), CEPs and the CEP:mCEC ratio were higher than in normal subjects (N = 17) (median CEPs: 0.97 vs 0.19 cells mu l(-1), respectively, P<0.01; median CEP:mCEC:0.92 vs 0.58, respectively, P = 0.04). However, in patients with VHL without RCC, CECs were not increased. In paired pre- and post-nephrectomy RCC patient samples (N = 20), CEPs decreased after surgery (median difference 0.02 cells mu l(-1), -0.06 to 1.2; P = 0.05). CONCLUSION: Circulating endothelial progenitors were elevated in RCC, but not in patients with VHL without RCC. Circulating endothelial progenitor enumeration merits further investigation as a monitoring strategy for patients with VHL. British Journal of Cancer (2011) 105, 112-117. doi:10.1038/bjc.2011.186 www.bjcancer.com Published online 14 June 2011 (C) 2011 Cancer Research UK C1 [Bhatt, R. S.; Zhang, L.; Atkins, M. B.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol & Canc Biol, Boston, MA 02215 USA. [Zurita, A. J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [O'Neill, A.] Harvard Univ, Sch Med, Childrens Hosp, Dept Biostat & Computat Biol,Dana Farber Canc Ins, Boston, MA 02215 USA. [Norden-Zfoni, A.; Wu, H. K.; Heymach, J. V.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. [Norden-Zfoni, A.; Wu, H. K.; Heymach, J. V.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Canc Biol, Houston, TX 77030 USA. [Wen, P. Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. [George, D.] Duke Univ, Med Ctr, Div Med Oncol & Urol, Durham, NC 27705 USA. [Sukhatme, V. P.] Beth Israel Deaconess Med Ctr, Dept Med, Div Interdisciplinary Med & Biotechnol, Boston, MA 02215 USA. RP Bhatt, RS (reprint author), Beth Israel Deaconess Med Ctr, Div Hematol Oncol & Canc Biol, 375 Longwood Ave,MASCO 426, Boston, MA 02215 USA. EM rbhatt@bidmc.harvard.edu FU Beth Israel Deaconess Medical Center-Harvard/MIT Health Sciences and Technology; AstraZeneca/MD Anderson Strategic Alliance; National Institutes of Health through the Dana-Farber-Harvard Cancer Center [P50 CA101942]; Damon-Runyon Clinical Investigator Award [CI-24-04]; MD Anderson's Cancer Center [CA016672]; National Institutes of Health, National Center for Research Resource [KL2 RR0224149] FX This work was supported in part by the Clinical Investigator Training Program, Beth Israel Deaconess Medical Center-Harvard/MIT Health Sciences and Technology (to RSB); by the AstraZeneca/MD Anderson Strategic Alliance (to AJZ); and by the National Institutes of Health through the Dana-Farber-Harvard Cancer Center Kidney Cancer SPORE grant, P50 CA101942, Damon-Runyon Clinical Investigator Award to JVH (CI-24-04) and MD Anderson's Cancer Center Support Grant, CA016672. AJZ was partially supported by the Center for Clinical and Translational Sciences, which is funded by the National Institutes of Health Clinical and Translational Award KL2 RR0224149 from the National Center for Research Resource. NR 24 TC 17 Z9 18 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 28 PY 2011 VL 105 IS 1 BP 112 EP 117 DI 10.1038/bjc.2011.186 PG 6 WC Oncology SC Oncology GA 784TZ UT WOS:000292182400017 PM 21673679 ER PT J AU Lagergren, J Mattsson, F El-Serag, H Nordenstedt, H AF Lagergren, J. Mattsson, F. El-Serag, H. Nordenstedt, H. TI Increased risk of hepatocellular carcinoma after cholecystectomy SO BRITISH JOURNAL OF CANCER LA English DT Article DE liver cancer; gall bladder; epidemiology; risk ID CANCER; LIVER AB BACKGROUND: The association between gall bladder removal (cholecystectomy) and hepatocellular carcinoma warrants investigation. An increased intrahepatic bile duct pressure following cholecystectomy might cause chronic inflammation in the surrounding liver tissue, which might induce cancer development. METHODS: A nationwide Swedish population-based cohort study in 1965-2008 included 345 251 patients undergoing cholecystectomy because of gallstone. The number of observed hepatocellular carcinoma cases was divided by the expected number, calculated from the corresponding background Swedish population, thus providing standardised incidence ratios (SIRs) with 95% confidence intervals (CIs). RESULTS: During follow-up of 4 854 969 person-years, 333 new cases of hepatocellular carcinoma were identified, rendering an overall increased risk (SIR 1.24, 95% CI: 1.11-1.38). The risk increased with longer follow-up (P for trend = 0.003). Among patients who underwent cholecystectomy 30-43 years earlier, SIR was 2.00 (95% CI: 1.32-2.87). The results were similar after exclusion of 15 634 patients with any recorded risk factor, that is, diabetes, obesity, hepatitis, liver cirrhosis, alcoholism, or blood transfusion. CONCLUSION: Cholecystectomy might be associated with a long-term increased risk of hepatocellular carcinoma. British Journal of Cancer (2011) 105, 154-156. doi:10.1038/bjc.2011.181 www.bjcancer.com Published online 24 May 2011 (C) 2011 Cancer Research UK C1 [Lagergren, J.; Mattsson, F.; Nordenstedt, H.] Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden. [Lagergren, J.] Kings Coll London, London WC2R 2LS, England. [El-Serag, H.] Baylor Coll Med, Houston Ctr Qual Care & Utilizat Studies, Houston, TX 77030 USA. [El-Serag, H.] Michael E DeBakey Vet Adm Med Ctr, Houston, TX 77030 USA. RP Lagergren, J (reprint author), Karolinska Inst, Dept Mol Med & Surg, Norra Stationsgatan 67,Level 2, S-17176 Stockholm, Sweden. EM Jesper.Lagergren@ki.se OI Lagergren, Jesper/0000-0002-5143-5448 FU Swedish Research Council (SIMSAM); Swedish Cancer Society FX This study was supported by project grants from the Swedish Research Council (SIMSAM) and the Swedish Cancer Society. NR 10 TC 9 Z9 11 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 28 PY 2011 VL 105 IS 1 BP 154 EP 156 DI 10.1038/bjc.2011.181 PG 3 WC Oncology SC Oncology GA 784TZ UT WOS:000292182400023 PM 21610710 ER PT J AU Win, AK Dowty, JG English, DR Campbell, PT Young, JP Winship, I Macrae, FA Lipton, L Parry, S Young, GP Buchanan, DD Martinez, ME Jacobs, ET Ahnen, DJ Haile, RW Casey, G Baron, JA Lindor, NM Thibodeau, SN Newcomb, PA Potter, JD Le Marchand, L Gallinger, S Hopper, JL Jenkins, MA AF Win, A. K. Dowty, J. G. English, D. R. Campbell, P. T. Young, J. P. Winship, I. Macrae, F. A. Lipton, L. Parry, S. Young, G. P. Buchanan, D. D. Martinez, M. E. Jacobs, E. T. Ahnen, D. J. Haile, R. W. Casey, G. Baron, J. A. Lindor, N. M. Thibodeau, S. N. Newcomb, P. A. Potter, J. D. Le Marchand, L. Gallinger, S. Hopper, J. L. Jenkins, M. A. TI Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes SO BRITISH JOURNAL OF CANCER LA English DT Article DE body mass index; colorectal cancer; mismatch repair gene ID LYNCH-SYNDROME; COLON-CANCER; MICROSATELLITE INSTABILITY; FAMILY REGISTRY; BREAST-CANCER; OBESITY; METAANALYSIS; WEIGHT; COHORT; MEN AB BACKGROUND: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers. METHODS: A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry. RESULTS: During 122 304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kgm(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P = 0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P = 0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P = 0.50). For MLH1 and PMS2 (MutL alpha heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P = 0.02). For MSH2 and MSH6 (MutS alpha heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P = 0.09). There was no significant difference between the HRs for MutLa and MutSa heterodimer carriers (P = 0.56). CONCLUSION: Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers. British Journal of Cancer (2011) 105, 162-169. doi:10.1038/bjc.2011.172 www.bjcancer.com Published online 10 May 2011 (C) 2011 Cancer Research UK C1 [Win, A. K.; Dowty, J. G.; English, D. R.; Hopper, J. L.; Jenkins, M. A.] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Parkville, Vic 3010, Australia. [English, D. R.] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Campbell, P. T.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Campbell, P. T.; Newcomb, P. A.; Potter, J. D.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. [Young, J. P.; Buchanan, D. D.] Queensland Inst Med Res, Familial Canc Lab, Herston, Qld 4006, Australia. [Winship, I.] Univ Melbourne, Parkville, Vic 3052, Australia. [Macrae, F. A.] Royal Melbourne Hosp, Dept Colorectal Med & Genet, Parkville, Vic 3050, Australia. [Lipton, L.] Royal Melbourne Hosp, Ludwig Inst Canc Res, Parkville, Vic 3050, Australia. [Parry, S.] Auckland City Hosp, New Zealand Familial Gastrointestinal Canc Regist, Auckland, New Zealand. [Parry, S.] Middlemore Hosp, Dept Gastroenterol, Auckland 6, New Zealand. [Young, G. P.] Flinders Univ S Australia, Flinders Ctr Canc Prevent & Control, Adelaide, SA 5001, Australia. [Martinez, M. E.; Jacobs, E. T.] Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. [Martinez, M. E.; Jacobs, E. T.] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. [Ahnen, D. J.] Univ Colorado, Denver Sch Med, Denver, CO 80202 USA. [Ahnen, D. J.] Denver VA Med Ctr, Denver, CO USA. [Haile, R. W.; Casey, G.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Baron, J. A.] Dartmouth Med Sch, Dept Med, Lebanon, NH USA. [Baron, J. A.] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Lindor, N. M.; Thibodeau, S. N.] Mayo Clin, Dept Med Genet, Rochester, MN USA. [Le Marchand, L.] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Gallinger, S.] Canc Care Ontario, Toronto, ON, Canada. RP Jenkins, MA (reprint author), Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Level 3,207 Bouverie St, Parkville, Vic 3010, Australia. EM m.jenkins@unimelb.edu.au RI Gallinger, Steven/E-4575-2013; Jenkins, Mark/P-7803-2015; OI Jenkins, Mark/0000-0002-8964-6160; Potter, John/0000-0001-5439-1500; Dowty, James/0000-0003-2383-0886; Win, Aung Ko/0000-0002-2794-5261; English, Dallas/0000-0001-7828-8188; Buchanan, Daniel/0000-0003-2225-6675; Winship, Ingrid/0000-0001-8535-6003 FU National Cancer Institute, National Institutes of Health [CA-95-011]; NHMRC Australia [ID 400160] FX This work was supported by the National Cancer Institute, National Institutes of Health under RFA #CA-95-011 and through cooperative agreements with members of the Colon CFR and Principal Investigators. Collaborating centres include Australasian Colorectal Cancer Family Registry (U01 CA097735), the USC Familial Colorectal Neoplasia Collaborative Group (U01 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), Seattle Colorectal Cancer Family Registry (U01 CA074794) and University of Hawaii Colorectal Cancer Family Registry (U01 CA074806). This work was also supported by a grant from NHMRC Australia (ID 400160). The content of this manuscript neither necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFRs, nor does mention of trade names, commercial products or organisations implies endorsement by the US Government or the CFR. We had full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication and the writing of the manuscript. We thank Dr Elizabeth Williamson from Murdoch Childrens Research Institute, Melbourne, Australia for statistical advice. We thank all study participants of the Colon Cancer Family Registry and staff for their contributions to this project. NR 56 TC 15 Z9 16 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 28 PY 2011 VL 105 IS 1 BP 162 EP 169 DI 10.1038/bjc.2011.172 PG 8 WC Oncology SC Oncology GA 784TZ UT WOS:000292182400025 PM 21559014 ER PT J AU Ramsey, MR Ellisen, LW AF Ramsey, Matthew R. Ellisen, Leif W. TI Circadian function in cancer: Regulating the DNA damage response SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID OVARIAN-CANCER; CISPLATIN; CHEMOSENSITIVITY; CRYPTOCHROME; P73; CHEMOTHERAPY; CONNECTION; PATHWAY; PHASE; RISK C1 [Ellisen, Leif W.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Ellisen, LW (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM ellisen@helix.mgh.harvard.edu OI Ramsey, Matthew/0000-0003-2402-8502 NR 15 TC 4 Z9 5 U1 1 U2 3 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 JUN 28 PY 2011 VL 108 IS 26 BP 10379 EP 10380 DI 10.1073/pnas.1107319108 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 785SX UT WOS:000292251000009 PM 21673139 ER PT J AU Shazly, TA Farrag, AN Kamel, A Al-Hussaini, AK AF Shazly, Tarek A. Farrag, Abdelsattar N. Kamel, Asmaa Al-Hussaini, Ashraf K. TI Prevalence of Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma in Upper Egypt SO BMC OPHTHALMOLOGY LA English DT Article ID SENSORINEURAL HEARING-LOSS; POPULATION-BASED SURVEY; INTRAOCULAR-PRESSURE; FIBRILLOPATHIA EPITHELIOCAPSULARIS; PSEUDO-EXFOLIATION; LENS OPACITIES; SOUTHERN INDIA; EYE; CLASSIFICATION; CATARACT AB Background: Pseudoexfoliation (PXF) is a recognized risk factor for developing cataract, glaucoma and lens dislocation. PXF is also associated with increased risk of complications during cataract surgery due to poor mydriasis and zonular weakness. The aim of this study is to report the prevalence of pseudoexfoliation among Upper Egyptians attending the ophthalmology clinic of Assiut University Hospital. Methodology: A retrospective, chart review study conducted in the period from February 2002 to August 2009. A total of 7738 patients aged 40 years or older attending the general ophthalmic clinics were included in this study. A detailed evaluation including ophthalmic and general history, slit lamp biomicroscopy, intraocular pressure measurement, gonioscopy and dilated eye examination were performed. Patients with pseudoexfoliative material on the anterior lens surface and/or the pupillary margin in either or both eyes were labeled as having PXF. Results: Out of the 7738 patients included, three hundred twenty (4.14%) subjects had PXF. Mean age of PXF group was 68.15 years (SD 8.16, range 40-92 years). PXF was bilateral in 82.2% of cases. It was significantly associated with cataract, glaucoma and hearing loss. Of the PXF patients, 65% had cataract, 30.3% had glaucoma and 8.1% had hearing loss. Conclusion: Pseudoexfoliation appears to be a common disorder in older individuals in Upper Egypt. C1 [Shazly, Tarek A.; Al-Hussaini, Ashraf K.] Assiut Univ Hosp, Dept Ophthalmol, Assiut 71526, Egypt. [Shazly, Tarek A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Farrag, Abdelsattar N.; Kamel, Asmaa; Al-Hussaini, Ashraf K.] Al Hussaini Hosp, Dept Ophthalmol, Assiut 71111, Egypt. RP Shazly, TA (reprint author), Assiut Univ Hosp, Dept Ophthalmol, 1 Assiut Univ Campus, Assiut 71526, Egypt. EM shazlyt@gmail.com NR 32 TC 7 Z9 7 U1 0 U2 1 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 JUN 27 PY 2011 VL 11 AR 18 DI 10.1186/1471-2415-11-18 PG 5 WC Ophthalmology SC Ophthalmology GA 799LA UT WOS:000293287000001 PM 21707986 ER PT J AU Dudek, FE Staley, KJ AF Dudek, F. Edward Staley, Kevin J. TI The time course of acquired epilepsy: Implications for therapeutic intervention to suppress epileptogenesis SO NEUROSCIENCE LETTERS LA English DT Review DE Epilepsy ID TEMPORAL-LOBE EPILEPSY; SPONTANEOUS RECURRENT SEIZURES; SPONTANEOUS MOTOR SEIZURES; INDUCED STATUS EPILEPTICUS; RAT MODEL; ISCHEMIC ENCEPHALOPATHY; FEBRILE SEIZURES; HYPOXIA-ISCHEMIA; BRAIN-INJURY; KAINATE AB Relatively little is known about the time course of the development of spontaneous recurrent seizures (i.e., epileptogenesis) after brain injury in human patients, or even in animal models. This time course is determined, at least in part, by the underlying molecular and cellular mechanisms responsible for acquired epilepsy. An understanding of the critical mechanistic features of acquired epilepsy will be useful, if not essential, for developing strategies to block or suppress epileptogenesis. Here, data on the time course of the development of spontaneous recurrent seizures are summarized from experiments using nearly continuous electrographic (EEG) recordings in (1) kainate-treated rats, which are a model of temporal lobe epilepsy, and (2) rats subjected to unilateral carotid occlusion with superimposed hypoxia at postnatal day 7, which is a model of perinatal stroke. Although the classical view of the development of epileptogenesis is a step-function of time after the brain injury, with a latent period present between the brain injury and the first unprovoked seizure, the data described here show that seizure frequency was a sigmoid function of time after the insult in both animal models. Furthermore, the spontaneous recurrent seizures often occurred in clusters, even shortly after the first spontaneous seizure. These data suggest that (1) epileptogenesis is a continuous process that extends past the first spontaneous clinical seizure, (2) seizure clusters can obscure this continuous process, and (3) the potential time for administration of a therapy to suppress acquired epilepsy extends well past the first clinical seizure. (C) 2011 Published by Elsevier Ireland Ltd. C1 [Dudek, F. Edward] Univ Utah, Sch Med, Dept Physiol, Salt Lake City, UT 84108 USA. [Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Dudek, FE (reprint author), Univ Utah, Sch Med, Dept Physiol, 420 Chipeta Way,Suite 1700, Salt Lake City, UT 84108 USA. EM ed.dudek@hsc.utah.edu; kstaley@partners.org FU NINDS; American Heart Association FX Supported by the NINDS and the American Heart Association. These data were derived from collaborative experiments with Phil Williams, Shilpa Kadam, Andrew White, D.J. Ferraro, Suzanne Clark, and Walde Swiercz. NR 41 TC 33 Z9 33 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUN 27 PY 2011 VL 497 IS 3 SI SI BP 240 EP 246 DI 10.1016/j.neulet.2011.03.071 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 787YC UT WOS:000292411600013 PM 21458536 ER PT J AU Staley, KJ White, A Dudek, FE AF Staley, Kevin J. White, Andrew Dudek, F. Edward TI Interictal spikes: Harbingers or causes of epilepsy? SO NEUROSCIENCE LETTERS LA English DT Review DE Epilepsy ID TEMPORAL-LOBE EPILEPSY; RECURRENT COLLATERAL SYNAPSES; CA3 NETWORK ACTIVITY; EPILEPTIFORM ACTIVITY; DOUBLE-BLIND; SEIZURES; EPILEPTOGENESIS; EEG; DISCHARGES; ATROPHY AB Interictal spikes are brief paroxysmal electrographic discharges observed between spontaneous recurrent seizures in epileptic patients. The relationship between interictal spikes and the seizures that define acquired epilepsy has been debated for decades. Recent studies using long-term continuous electrographic recordings from the hippocampus and cortex in rats with kainate-induced epilepsy suggest that electrographic spikes, with waveforms similar to interictal spikes, precede the occurrence of the first spontaneous epileptic seizure. These data raise the possibility that spikes might serve as a surrogate marker of ongoing chronic epileptogenesis. Additionally, electrographic spikes might actually contribute to the development and maintenance of the epileptic state (i.e., the increased probability of spontaneous recurrent seizures). Correlational evidence for such a causal relationship has recently also been obtained in an in vitro model of epileptogenesis using organotypic hippocampal slices. Testing for a causal relationship will ultimately require selective anti-spike medications. Although no such agents currently exist, this new preparation is amenable to moderate-throughput screening, which should accelerate their discovery. Anti-spike agents may also be of benefit in ameliorating the cognitive dysfunctions associated with epilepsy, to which spike activity may contribute. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [White, Andrew] Univ Colorado, Sch Med, Dept Pediat, Denver, CO 80262 USA. [White, Andrew] Univ Colorado, Sch Med, Dept Neurol, Denver, CO 80262 USA. [Dudek, F. Edward] Univ Utah, Sch Med, Dept Physiol, Salt Lake City, UT 84108 USA. RP Staley, KJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St,WAC 708-D, Boston, MA 02114 USA. EM kstaley@partners.org; white.andrew@tchden.org; ed.dudek@hsc.utah.edu FU NINDS NIH HHS [K08 NS053610, K08 NS053610-04, R01 NS034360, R01 NS034360-13, R01 NS034700, R01 NS034700-19] NR 35 TC 30 Z9 30 U1 4 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUN 27 PY 2011 VL 497 IS 3 SI SI BP 247 EP 250 DI 10.1016/j.neulet.2011.03.070 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 787YC UT WOS:000292411600014 PM 21458535 ER PT J AU Gibson, R Grady, D AF Gibson, Rosemary Grady, Deborah TI Patient Experience of Overtreatment SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Gibson, Rosemary] Robert Wood Johnson Fdn, Princeton, NJ USA. [Grady, Deborah] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Grady, Deborah] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. RP Gibson, R (reprint author), Robert Wood Johnson Fdn, Princeton, NJ USA. EM rosemarygibson100@gmail.com NR 4 TC 0 Z9 0 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 JUN 27 PY 2011 VL 171 IS 12 BP 1054 EP 1054 DI 10.1001/archinternmed.2011.114 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 783WI UT WOS:000292114400001 PM 21444832 ER PT J AU Kullgren, JT Lieu, TA AF Kullgren, Jeffrey T. Lieu, Tracy A. TI More Health Care Is Not Necessarily Better Health Care Reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Kullgren, Jeffrey T.] Univ Penn, Robert Wood Johnson Fdn, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Lieu, Tracy A.] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Lieu, Tracy A.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. RP Kullgren, JT (reprint author), Univ Penn, Robert Wood Johnson Fdn, Philadelphia VA Med Ctr, 1303B Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM kullgren@mail.med.upenn.edu NR 3 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 JUN 27 PY 2011 VL 171 IS 12 BP 1124 EP 1124 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 783WI UT WOS:000292114400023 ER PT J AU Hwang, U Morrison, RS Richardson, LD Todd, KH AF Hwang, Ula Morrison, R. Sean Richardson, Lynne D. Todd, Knox H. TI A Painful Setback: Misinterpretation of Analgesic Safety in Older Adults May Inadvertently Worsen Pain Care SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Hwang, Ula; Richardson, Lynne D.] Mt Sinai Sch Med, Dept Emergency Med, New York, NY 10029 USA. [Hwang, Ula; Morrison, R. Sean] Mt Sinai Sch Med, Brookdale Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Richardson, Lynne D.] Mt Sinai Sch Med, Dept Hlth Evidence & Policy, New York, NY 10029 USA. [Morrison, R. Sean] James J PetersVA Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. [Todd, Knox H.] Univ Texas MD Anderson Canc Ctr, Dept Emergency Med, Houston, TX 77030 USA. RP Hwang, U (reprint author), Mt Sinai Sch Med, Dept Emergency Med, New York, NY 10029 USA. EM ula.hwang@mountsinai.org FU NIA NIH HHS [K23 AG31218, K23 AG031218, K24 AG22345, K24 AG022345] NR 10 TC 3 Z9 3 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 JUN 27 PY 2011 VL 171 IS 12 BP 1127 EP 1127 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 783WI UT WOS:000292114400028 PM 21709124 ER PT J AU Lenormand, G Millet, E Park, CY Hardin, CC Butler, JP Moldovan, NI Fredberg, JJ AF Lenormand, Guillaume Millet, Emil Park, Chan Young Hardin, C. Corey Butler, James P. Moldovan, Nicanor I. Fredberg, Jeffrey J. TI Dynamics of the cytoskeleton: How much does water matter? SO PHYSICAL REVIEW E LA English DT Article ID HYPER-MOBILE WATER; SMOOTH-MUSCLE-CELL; DEUTERIUM-OXIDE; LIVING CELL; ENERGY LANDSCAPE; PROTEIN DYNAMICS; ACTIN-FILAMENTS; HEAVY-WATER; BIOLOGY; SOLVENT AB The principal constituent of the living cell is water. The role of the hydration shell and bulk H2O solvent is well recognized in the dynamics of isolated proteins, but the role of water in the dynamics of the integrated living cytoskeleton (CSK) remains obscure. Here we report a direct connection of dynamics of water to dynamics of the integrated CSK. The latter are known to be scale-free and to hinge upon a frequency f(0) that is roughly invariant across cell types. Although f(0) is comparable in magnitude to the rotational relaxation frequency of water (gigahertz range), the physical basis of f(0) remains unknown. Using the human airway smooth muscle cell as a model system, we show here that replacing water acutely with deuterium oxide impacts CSK dynamics in major ways, slowing CSK remodeling dynamics appreciably, and lowering f(0) by up to four orders of magnitude. Although these observations do not distinguish contributions of bulk solvent versus hydration shell, they suggest a unifying hypothesis, namely, that dynamics of integrated CSK networks are slaved in a direct fashion to fluctuations arising in intracellular water. C1 [Lenormand, Guillaume; Millet, Emil; Park, Chan Young; Butler, James P.; Fredberg, Jeffrey J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hardin, C. Corey] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Moldovan, Nicanor I.] Ohio State Univ, Div Cardiovasc Med, Dept Internal Med, Columbus, OH 43210 USA. RP Lenormand, G (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM glenorma@hsph.harvard.edu FU National Institutes of Health; Parker B. Francis Foundation FX This work was supported by the National Institutes of Health and the Parker B. Francis Foundation. We are thankful to Professor Lester Kobzik and Amy Imrich for assistance in the toxicity assays. NR 57 TC 3 Z9 3 U1 1 U2 13 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 EI 1550-2376 J9 PHYS REV E JI Phys. Rev. E PD JUN 27 PY 2011 VL 83 IS 6 AR 061918 DI 10.1103/PhysRevE.83.061918 PN 1 PG 7 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 785VT UT WOS:000292260900009 PM 21797414 ER PT J AU Agrawal, N Leaman, DP Rowcliffe, E Kinkead, H Nohria, R Akagi, J Bauer, K Du, SX Whalen, RG Burton, DR Zwick, MB AF Agrawal, Nitish Leaman, Daniel P. Rowcliffe, Eric Kinkead, Heather Nohria, Raman Akagi, Junya Bauer, Katherine Du, Sean X. Whalen, Robert G. Burton, Dennis R. Zwick, Michael B. TI Functional Stability of Unliganded Envelope Glycoprotein Spikes among Isolates of Human Immunodeficiency Virus Type 1 (HIV-1) SO PLOS ONE LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; PROXIMAL EXTERNAL REGION; GP120 INNER DOMAIN; BROADLY NEUTRALIZING ANTIBODIES; GP41 TRANSMEMBRANE GLYCOPROTEIN; ENV-MEDIATED FUSION; SOLUBLE CD4; NONNEUTRALIZING ANTIBODIES; ECTODOMAIN REGION; CD4-BINDING SITE AB The HIV-1 envelope glycoprotein (Env) spike is challenging to study at the molecular level, due in part to its genetic variability, structural heterogeneity and lability. However, the extent of lability in Env function, particularly for primary isolates across clades, has not been explored. Here, we probe stability of function for variant Envs of a range of isolates from chronic and acute infection, and from clades A, B and C, all on a constant virus backbone. Stability is elucidated in terms of the sensitivity of isolate infectivity to destabilizing conditions. A heat-gradient assay was used to determine T(90) values, the temperature at which HIV-1 infectivity is decreased by 90% in 1 h, which ranged between similar to 40 to 49 degrees C (n = 34). For select Envs (n = 10), the half-lives of infectivity decay at 37 degrees C were also determined and these correlated significantly with the T90 (p = 0.029), though two 'outliers' were identified. Specificity in functional Env stability was also evident. For example, Env variant HIV-1(ADA) was found to be labile to heat, 37 degrees C decay, and guanidinium hydrochloride but not to urea or extremes of pH, when compared to its thermostable counterpart, HIV-1(JR-CSF). Blue native PAGE analyses revealed that Env-dependent viral inactivation preceded complete dissociation of Env trimers. The viral membrane and membrane-proximal external region (MPER) of gp41 were also shown to be important for maintaining trimer stability at physiological temperature. Overall, our results indicate that primary HIV-1 Envs can have diverse sensitivities to functional inactivation in vitro, including at physiological temperature, and suggest that parameters of functional Env stability may be helpful in the study and optimization of native Env mimetics and vaccines. C1 [Agrawal, Nitish; Leaman, Daniel P.; Rowcliffe, Eric; Kinkead, Heather; Nohria, Raman; Akagi, Junya; Bauer, Katherine; Burton, Dennis R.; Zwick, Michael B.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Du, Sean X.; Whalen, Robert G.] AltraVax Inc, Sunnyvale, CA USA. [Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA USA. RP Agrawal, N (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM zwick@scripps.edu RI AGRAWAL, NITISH/H-6186-2011; AGRAWAL, NITISH/E-3468-2013 OI AGRAWAL, NITISH/0000-0003-0823-7355; FU National Institutes of Health (NIH) [AI56375, AI77381, P01 AI056375, AI33292, T32 AI007606]; Summer Immunology and Virology Undergraduate Fellowship (SINAPSE); Neutralizing Antibody Consortium of the International AIDS Vaccine Initiative (IAVI NAC) FX This study was supported by the National Institutes of Health (NIH) grants AI56375 (MBZ and DRB), AI77381 (MBZ), P01 AI056375 (RGW), AI33292 (DRB), T32 AI007606 (DPL), Summer Immunology and Virology Undergraduate Fellowship (SINAPSE) (RN), and the Neutralizing Antibody Consortium of the International AIDS Vaccine Initiative (IAVI NAC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 112 TC 16 Z9 16 U1 1 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2011 VL 6 IS 6 AR e21339 DI 10.1371/journal.pone.0021339 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 783OD UT WOS:000292092600030 PM 21738637 ER PT J AU Schernhammer, ES Giovannucci, E Baba, Y Fuchs, CS Ogino, S AF Schernhammer, Eva S. Giovannucci, Edward Baba, Yoshifumi Fuchs, Charles S. Ogino, Shuji TI B Vitamins, Methionine and Alcohol Intake and Risk of Colon Cancer in Relation to BRAF Mutation and CpG Island Methylator Phenotype (CIMP) SO PLOS ONE LA English DT Article ID ONE-CARBON METABOLISM; POPULATION-BASED SAMPLE; METHYLENETETRAHYDROFOLATE REDUCTASE POLYMORPHISM; SPORADIC COLORECTAL-CANCER; MGMT PROMOTER METHYLATION; DNA METHYLATION; MICROSATELLITE INSTABILITY; MULTIVITAMIN USE; COMPETING RISKS; DIETARY-FOLATE AB Background: One-carbon metabolism appears to play an important role in DNA methylation reaction. Evidence suggests that a low intake of B vitamins or high alcohol consumption increases colorectal cancer risk. How one-carbon nutrients affect the CpG island methylator phenotype (CIMP) or BRAF mutation status in colon cancer remains uncertain. Methods: Utilizing incident colon cancers in a large prospective cohort of women (the Nurses' Health Study), we determined BRAF status (N = 386) and CIMP status (N = 375) by 8 CIMP-specific markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and 8 other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT-1, MINT-31, p14, and WRN). We examined the relationship between intake of one-carbon nutrients and alcohol and colon cancer risk, by BRAF mutation or CIMP status. Results: Higher folate intake was associated with a trend towards low risk of CIMP-low/0 tumors [ total folate intake >= 400 mg/day vs. <200 mu g/day; the multivariate relative risk = 0.73; 95% CI = 0.53-1.02], whereas total folate intake had no influence on CIMP-high tumor risks (P-heterogeneity = 0.73). Neither vitamin B-6, methionine or alcohol intake appeared to differentially influence risks for CIMP-high and CIMP-low/0 tumors. Using the 16-marker CIMP panel did not substantially alter our results. B vitamins, methionine or alcohol intake did not affect colon cancer risk differentially by BRAF status. Conclusions: This molecular pathological epidemiology study suggests that low level intake of folate may be associated with an increased risk of CIMP-low/0 colon tumors, but not that of CIMP-high tumors. However, the difference between CIMP-high and CIMP-low/0 cancer risks was not statistically significant, and additional studies are necessary to confirm these observations. C1 [Schernhammer, Eva S.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Schernhammer, Eva S.; Fuchs, Charles S.; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. [Schernhammer, Eva S.] KFJ Spital, Ludwig Boltzmann Inst Appl Canc Res, Vienna, Austria. [Schernhammer, Eva S.] Appl Canc Res Inst Translat Res Vienna ACR ITR VI, Vienna, Austria. [Schernhammer, Eva S.; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Baba, Yoshifumi; Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Schernhammer, ES (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. EM eva.schernhammer@channing.harvard.edu FU United States National Institutes of Health (NIH) [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826, R01 CA151993]; Bennett Family Fund for Targeted Therapies Research; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance FX This work was supported by the United States National Institutes of Health (NIH) [P01 CA87969 (to S. Hankinson), P01 CA55075 (to W. Willett), P50 CA127003 (to C.S.F.), K07 CA122826 (to S.O.), R01 CA151993 (to S.O.)], the Bennett Family Fund for Targeted Therapies Research; and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 26 Z9 26 U1 1 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 JUN 27 PY 2011 VL 6 IS 6 AR e21102 DI 10.1371/journal.pone.0021102 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 783OD UT WOS:000292092600012 PM 21738611 ER PT J AU Vaid, M Singh, T Katiyar, SK AF Vaid, Mudit Singh, Tripti Katiyar, Santosh K. TI Grape Seed Proanthocyanidins Inhibit Melanoma Cell Invasiveness by Reduction of PGE(2) Synthesis and Reversal of Epithelial-to-Mesenchymal Transition SO PLOS ONE LA English DT Article ID NF-KAPPA-B; LUNG-CANCER; MOUSE SKIN; INFLAMMATORY RESPONSES; GUANYLATE-CYCLASE; PROSTAGLANDIN E-2; CARCINOMA-CELLS; NITRIC-OXIDE; CYCLOOXYGENASE-2; MIGRATION AB Melanoma is the leading cause of death from skin disease due, in large part, to its propensity to metastasize. We have examined the effect of grape seed proanthocyanidins (GSPs) on melanoma cancer cell migration and the molecular mechanisms underlying these effects using highly metastasis-specific human melanoma cell lines, A375 and Hs294t. Using in vitro cell invasion assays, we observed that treatment of A375 and Hs294t cells with GSPs resulted in a concentration-dependent inhibition of invasion or cell migration of these cells, which was associated with a reduction in the levels of cyclooxygenase (COX)-2 expression and prostaglandin (PG) E-2 production. Treatment of cells with celecoxib, a COX-2 inhibitor, or transient transfection of melanoma cells with COX-2 small interfering RNA, also inhibited melanoma cell migration. Treatment of cells with 12-O-tetradecanoylphorbol-13-acetate, an inducer of COX-2, enhanced the phosphorylation of ERK1/2, a protein of mitogen-activated protein kinase family, and subsequently cell migration whereas both GSPs and celecoxib significantly inhibited 12-O-tetradecanoylphorbol-13-acetate - promoted cell migration as well as phosphorylation of ERK1/2. Treatment of cells with UO126, an inhibitor of MEK, also inhibited the migration of melanoma cells. Further, GSPs inhibited the activation of NF-kappa B/p65, an upstream regulator of COX-2, in melanoma cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-kappa B, also inhibited cell migration. Additionally, inhibition of melanoma cell migration by GSPs was associated with reversal of epithelial-mesenchymal transition process, which resulted in an increase in the levels of epithelial biomarkers (E-cadherin and cytokeratins) while loss of mesenchymal biomarkers (vimentin, fibronectin and N-cadherin) in melanoma cells. Together, these results indicate that GSPs have the ability to inhibit melanoma cell invasion/migration by targeting the endogenous expression of COX-2 and reversing the process of epithelial-to-mesenchymal transition. C1 [Vaid, Mudit; Singh, Tripti; Katiyar, Santosh K.] Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Vaid, M (reprint author), Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. EM skatiyar@uab.edu FU Veterans Administration FX This work was supported by funds from the Veterans Administration Merit Review Award (SKK). There is no grant number. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 29 Z9 30 U1 3 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2011 VL 6 IS 6 AR e21539 DI 10.1371/journal.pone.0021539 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 783OD UT WOS:000292092600051 PM 21738696 ER PT J AU Varthaman, A Clement, M Khallou-Laschet, J Fornasa, G Gaston, AT Dussiot, M Caligiuri, G Cantor, H Kaveri, S Nicoletti, A AF Varthaman, Aditi Clement, Marc Khallou-Laschet, Jamila Fornasa, Giulia Gaston, Anh-Thu Dussiot, Michael Caligiuri, Giuseppina Cantor, Harvey Kaveri, Srinivas Nicoletti, Antonino TI Physiological Induction of Regulatory Qa-1-Restricted CD8+T Cells Triggered by Endogenous CD4+T Cell Responses SO PLOS ONE LA English DT Article ID CD8-ALPHA-ALPHA+TCR-ALPHA-BETA(+) T-CELLS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; HLA-E; AUTOIMMUNE ENCEPHALOMYELITIS; DENDRITIC CELLS; VACCINATION; MOLECULE; RECEPTOR; MICE; SPECIFICITY AB T cell-dependent autoimmune diseases are characterized by the expansion of T cell clones that recognize immunodominant epitopes on the target antigen. As a consequence, for a given autoimmune disorder, pathogenic T cell clones express T cell receptors with a limited number of variable regions that define antigenic specificity. Qa-1, a MHC class I-like molecule, presents peptides from the variable region of TCRs to Qa-1-restricted CD8+ T cells. The induction of V beta-specific CD8+ T cells has been harnessed in an immunotherapeutic strategy known as the "T cell vaccination'' (TCV) that comprises the injection of activated and attenuated CD4+ T cell clones so as to induce protective CD8+ T cells. We hypothesized that Qa-1-restricted CD8+ regulatory T cells could also constitute a physiologic regulatory arm of lymphocyte responses upon expansion of endogenous CD4+ T cells, in the absence of deliberate exogenous T cell vaccination. We immunized mice with two types of antigenic challenges in order to sequentially expand antigen-specific endogenous CD4+ T cells with distinct antigenic specificities but characterized by a common V beta chain in their TCR. The first immunization was performed with a non-self antigen while the second challenge was performed with a myelin-derived peptide known to drive experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We show that regulatory V beta-specific Qa-1-restricted CD8+ T cells induced during the first endogenous CD4+ T cell responses are able to control the expansion of subsequently mobilized pathogenic autoreactive CD4+ T cells. In conclusion, apart from the immunotherapeutic TCV, Qa-1-restricted specialized CD8+ regulatory T cells can also be induced during endogenous CD4+ T cell responses. At variance with other regulatory T cell subsets, the action of these Qa-1-restricted T cells seems to be restricted to the immediate reactivation of CD4+ T cells. C1 [Varthaman, Aditi; Clement, Marc; Khallou-Laschet, Jamila; Fornasa, Giulia; Gaston, Anh-Thu; Dussiot, Michael; Caligiuri, Giuseppina; Nicoletti, Antonino] Univ Paris 07, INSERM, UMRS698, Paris, France. [Varthaman, Aditi; Clement, Marc; Khallou-Laschet, Jamila; Fornasa, Giulia; Gaston, Anh-Thu; Dussiot, Michael; Caligiuri, Giuseppina; Kaveri, Srinivas; Nicoletti, Antonino] Univ Paris 06, INSERM, UMRS872, Ctr Rech Cordeliers,Equipe 16, Paris, France. [Cantor, Harvey] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Cantor, Harvey] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Varthaman, A (reprint author), Univ Paris 07, INSERM, UMRS698, Paris, France. EM antonino.nicoletti@inserm.fr RI Caligiuri, Giuseppina/G-4810-2015; Nicoletti, Antonino/A-9460-2015 OI Caligiuri, Giuseppina/0000-0003-4973-2205; Nicoletti, Antonino/0000-0002-2623-0897 FU INSERM FX This study was funded by INSERM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 8 Z9 8 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 27 PY 2011 VL 6 IS 6 AR e21628 DI 10.1371/journal.pone.0021628 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 783OD UT WOS:000292092600063 PM 21738737 ER PT J AU Reese, PP Feldman, HI Bloom, RD Abt, PL Thomasson, A Shults, J Grossman, R Asch, DA AF Reese, Peter P. Feldman, Harold I. Bloom, Roy D. Abt, Peter L. Thomasson, Arwin Shults, Justine Grossman, Robert Asch, David A. TI Assessment of Variation in Live Donor Kidney Transplantation Across Transplant Centers in the United States SO TRANSPLANTATION LA English DT Article DE Live donor transplantation; Health services research; Center variation ID INTRAVENOUS IMMUNE GLOBULIN; RENAL-TRANSPLANTATION; RACIAL DISPARITIES; DONATION; RECIPIENTS; CANDIDATES; OUTCOMES; PROGRAM; BLACK; RISK AB Background. Transplant centers vary in the proportion of kidney transplants performed using live donors. Clinical innovations that facilitate live donation may drive this variation. Methods. We assembled a cohort of renal transplant candidates at 194 US centers using registry data from 1999 to 2005. We measured magnitude of live donor kidney transplantation (LDKTx) through development of a standardized live donor transplantation ratio (SLDTR) at each center that accounted for center population differences. We examined associations between center characteristics and the likelihood that individual transplant candidates underwent LDKTx. To identify practices through which centers increase LDKTx, we also examined center characteristics associated with consistently being in the upper three quartiles of SLDTR. Results. The cohort comprised 148,168 patients, among whom 34,593 (23.3%) underwent LDKTx. In multivariable logistic regression, candidates had an increased likelihood of undergoing LDKTx at centers with greater use of "unrelated donors" (defined as nonspouses and nonfirst-degree family members of the recipient; odds ratio [OR] 1.31 for highest vs. lowest use; P=0.02) and at centers with programs to overcome donor-recipient incompatibility (OR 1.33; P=0.01). Centers consistently in the upper three SLDTR quartiles were also more likely to use "unrelated" donors (OR 8.30 per tertile of higher use; P<0.01), to have incompatibility programs (OR 4.79, P<0.01), and to use laparoscopic nephrectomy (OR 2.53 per tertile of higher use; P=0.02). Conclusion. Differences in center population do not fully account for differences in the use of LDKTx. To maximize opportunities for LDKTx, centers may accept more unrelated donors and adopt programs to overcome biological incompatibility. C1 [Reese, Peter P.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Reese, Peter P.; Feldman, Harold I.; Bloom, Roy D.; Grossman, Robert] Univ Penn, Dept Med, Div Renal, Philadelphia, PA 19104 USA. [Reese, Peter P.; Feldman, Harold I.; Asch, David A.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Abt, Peter L.] Univ Penn, Transplant Inst, Dept Surg, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia VA Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. RP Reese, PP (reprint author), Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, 917 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM peter.reese@uphs.upenn.edu OI Asch, David/0000-0002-7970-286X FU Health Resources and Services Administration [234 2005 370011C]; NIH [K23 DK078688-01, K24-DK002651] FX This work was supported in part by Health Resources and Services Administration contract 234 2005 370011C, by NIH Career Development Award K23 DK078688-01 (P. P. R.), and by NIH grant K24-DK002651 (H.I.F.). NR 38 TC 7 Z9 7 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUN 27 PY 2011 VL 91 IS 12 BP 1357 EP 1363 DI 10.1097/TP.0b013e31821bf138 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 775BE UT WOS:000291430500011 PM 21562451 ER PT J AU Bogoch, II Andrews, JR Hohmann, EL Kotton, CN Marty, FM AF Bogoch, Isaac I. Andrews, Jason R. Hohmann, Elizabeth L. Kotton, Camille N. Marty, Francisco M. TI Pandemic H1N1 Influenza Infection in Adult Transplant Recipients SO TRANSPLANTATION LA English DT Letter C1 [Bogoch, Isaac I.; Andrews, Jason R.; Hohmann, Elizabeth L.; Kotton, Camille N.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Bogoch, Isaac I.; Andrews, Jason R.; Hohmann, Elizabeth L.; Kotton, Camille N.; Marty, Francisco M.] Harvard Univ, Sch Med, Boston, MA USA. [Marty, Francisco M.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. RP Bogoch, II (reprint author), Massachusetts Gen Hosp, Div Infect Dis, COX 5,55 Fruit St, Boston, MA 02114 USA. EM ibogoch@partners.org NR 4 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUN 27 PY 2011 VL 91 IS 12 BP E80 EP E81 DI 10.1097/TP.0b013e31821c1eac PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 775BE UT WOS:000291430500001 PM 21654492 ER PT J AU Pena, A AF Pena, Adolfo TI Philosophy, medicine and clinical reasoning. Part II SO MEDICINA CLINICA LA Spanish DT Editorial Material ID VISUAL WORKING-MEMORY; FLUID INTELLIGENCE; MODEL; CATEGORIZATION; MECHANISMS; WORKSPACE; EDUCATION; CAPACITY; SCRIPTS C1 Univ Alabama, Birmingham VA Med Ctr, UAB VAQS Qual Scholars Fellowship Program, Birmingham, AL 35294 USA. RP Pena, A (reprint author), Univ Alabama, Birmingham VA Med Ctr, UAB VAQS Qual Scholars Fellowship Program, Birmingham, AL 35294 USA. EM adolfope@uab.edu NR 44 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER DOYMA SL PI BARCELONA PA TRAVESERA DE GARCIA, 17-21, BARCELONA, 08021, SPAIN SN 0025-7753 J9 MED CLIN-BARCELONA JI Med. Clin. PD JUN 25 PY 2011 VL 137 IS 3 BP 131 EP 135 DI 10.1016/j.medcli.2009.10.049 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 779MR UT WOS:000291782500009 PM 20056259 ER PT J AU Yeh, RW Chandra, M McCulloch, CE Go, AS AF Yeh, Robert W. Chandra, Malini McCulloch, Charles E. Go, Alan S. TI Accounting for the mortality benefit of drug-eluting stents in percutaneous coronary intervention: a comparison of methods in a retrospective cohort study SO BMC MEDICINE LA English DT Article ID BARE-METAL STENTS; ACUTE MYOCARDIAL-INFARCTION; TERM CLINICAL-OUTCOMES; REAL-WORLD; CARDIOVASCULAR EVENTS; RANDOMIZED-TRIAL; REGISTRY; SAFETY; DISEASE; DEATH AB Background: Drug-eluting stents (DES) reduce rates of restenosis compared with bare metal stents (BMS). A number of observational studies have also found lower rates of mortality and non-fatal myocardial infarction with DES compared with BMS, findings not observed in randomized clinical trials. In order to explore reasons for this discrepancy, we compared outcomes after percutaneous coronary intervention (PCI) with DES or BMS by multiple statistical methods. Methods: We compared short-term rates of all-cause mortality and myocardial infarction for patients undergoing PCI with DES or BMS using propensity-score adjustment, propensity-score matching, and a stent-era comparison in a large, integrated health system between 1998 and 2007. For the propensity-score adjustment and stent era comparisons, we used multivariable logistic regression to assess the association of stent type with outcomes. We used McNemar's Chi-square test to compare outcomes for propensity-score matching. Results: Between 1998 and 2007, 35,438 PCIs with stenting were performed among health plan members (53.9% DES and 46.1% BMS). After propensity-score adjustment, DES was associated with significantly lower rates of death at 30 days (OR 0.49, 95% CI 0.39-0.63, P < 0.001) and one year (OR 0.58, 95% CI 0.49 - 0.68, P < 0.001), and a lower rate of myocardial infarction at one year (OR 0.72, 95% CI 0.59 - 0.87, P < 0.001). Thirty day and one year mortality were also lower with DES after propensity-score matching. However, a stent era comparison, which eliminates potential confounding by indication, showed no difference in death or myocardial infarction for DES and BMS, similar to results from randomized trials. Conclusions: Although propensity-score methods suggested a mortality benefit with DES, consistent with prior observational studies, a stent era comparison failed to support this conclusion. Unobserved factors influencing stent selection in observational studies likely account for the observed mortality benefit of DES not seen in randomized clinical trials. C1 [Yeh, Robert W.] Harvard Univ, Div Cardiol, Dept Med, Sch Med,Massachusetts Gen Hosp,GRB800, Boston, MA 02114 USA. [Chandra, Malini; Go, Alan S.] Kaiser Permanente No Calif, Div Res, Oakland, CA 94612 USA. [McCulloch, Charles E.] Univ Calif San Francisco, Div Biostat, Dept Epidemiol & Biostat, San Francisco, CA 94107 USA. RP Yeh, RW (reprint author), Harvard Univ, Div Cardiol, Dept Med, Sch Med,Massachusetts Gen Hosp,GRB800, Boston, MA 02114 USA. EM ryeh@partners.org NR 45 TC 9 Z9 9 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD JUN 24 PY 2011 VL 9 AR 78 DI 10.1186/1741-7015-9-78 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 795XH UT WOS:000293011500001 PM 21702899 ER PT J AU Abdel-Bakky, MS Hammad, MA Walker, LA Ashfaq, MK AF Abdel-Bakky, Mohamed Sadek Hammad, Mohamed A. Walker, Larry A. Ashfaq, Mohammad K. TI Tissue factor dependent liver injury causes release of retinoid receptors (RXR-alpha and RAR-alpha) as lipid droplets SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Tissue factor; Retinoic acid receptor alpha; Retinoid X receptor alpha; Tissue factor antisense oligodeoxynucleotides ID FAT-STORING CELLS; HEPATIC LIPOCYTES; STELLATE CELLS; VITAMIN-A; THROMBOMODULIN; PROLIFERATION; FIBROSIS; DISEASE; BETA AB Hepatic stellate cells (HSC) store retinoids and upon activation differentiate into myofibroblast-like cells, a process whereby they lose their retinoid-containing lipid droplets. We reported earlier, activation of tissue factor (TF) in our MCT/LPS hepatotoxicity model. We now report the involvement of TF in the release of retinoid receptors RAR-alpha and RXR-alpha as accumulated lipid droplet during monocrotaline/lipopolysaccharide (MCT/LPS)-liver injury. Constitutive expression of RAR-alpha was observed in HSCs and endothelial cells of bile duct and portal vein, while expression of RXR-alpha was observed in certain pericentral hepatocytes and HSCs. Administration of sub-toxic doses of MCT or LPS strongly increased TF and RXR-alpha but not RAR-alpha expressions in HSCs and hepatocytes. However MCT/LPS co-treatment showed insoluble droplets containing RAR-alpha and RXR-alpha in the vicinity of the necrotic areas. Blocking TF with TF antisense oligonucleotides (TF-AS ODN) led to normal hepatocyte expression of RXR-alpha and upregulated the expression of RAR-alpha in HSCs. This study shows clear evidence of in vivo release of RAR-alpha and RXR-alpha as insoluble lipid droplets in liver injury. It is possible that these insoluble droplets of RAR-alpha and RXR-alpha could be used as markers for liver injury in general and activation of HSCs in particular. RXR-alpha appears to be a more sensitive than RAR-alpha as it was affected by even the subtoxic doses of MCT or LPS. The fact that IF-AS treatment not only down-regulated TF but also obliterated the release of RAR-alpha and RXR-alpha as insoluble lipid droplets in hepatocytes points towards TF being an important regulatory molecule for RAR-alpha and RXR-alpha. (C) 2011 Elsevier Inc. All rights reserved. C1 [Abdel-Bakky, Mohamed Sadek; Hammad, Mohamed A.; Walker, Larry A.; Ashfaq, Mohammad K.] Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA. [Hammad, Mohamed A.; Walker, Larry A.] Univ Mississippi, Sch Pharm, Dept Pharmacol, University, MS 38677 USA. [Abdel-Bakky, Mohamed Sadek] Al Azhar Univ, Fac Pharm, Cairo, Egypt. [Hammad, Mohamed A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. RP Ashfaq, MK (reprint author), Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA. EM mkashfaq@olemiss.edu NR 20 TC 4 Z9 5 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 24 PY 2011 VL 410 IS 1 BP 146 EP 151 DI 10.1016/j.bbrc.2011.05.127 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 788HG UT WOS:000292435400026 PM 21658367 ER PT J AU Patricelli, MP Nomanbhoy, TK Wu, JY Brown, H Zhou, D Zhang, JM Jagannathan, S Aban, A Okerberg, E Herring, C Nordin, B Weissig, H Yang, QK Lee, JD Gray, NS Kozarich, JW AF Patricelli, Matthew P. Nomanbhoy, Tyzoon K. Wu, Jiangyue Brown, Heidi Zhou, David Zhang, Jianming Jagannathan, Subadhra Aban, Arwin Okerberg, Eric Herring, Chris Nordin, Brian Weissig, Helge Yang, Qingkai Lee, Jiing-Dwan Gray, Nathanael S. Kozarich, John W. TI In Situ Kinase Profiling Reveals Functionally Relevant Properties of Native Kinases SO CHEMISTRY & BIOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; P38 MAP KINASE; B-RAF KINASE; TYROSINE KINASE; PROTEOMICS STRATEGY; TUMOR PROGRESSION; PROTEIN-KINASES; INHIBITORS; POTENT; BRAF AB Protein kinases are intensely studied mediators of cellular signaling, yet important questions remain regarding their regulation and in vivo properties. Here, we use a probe-based chemoprotemics platform to profile several well studied kinase inhibitors against >200 kinases in native cell proteomes and reveal biological targets for some of these inhibitors. Several striking differences were identified between native and recombinant kinase inhibitory profiles, in particular, for the Raf kinases. The native kinase binding profiles presented here closely mirror the cellular activity of these inhibitors, even when the inhibition profiles differ dramatically from recombinant assay results. Additionally, Raf activation events could be detected on live cell treatment with inhibitors. These studies highlight the complexities of protein kinase behavior in the cellular context and demonstrate that profiling with only recombinant/purified enzymes can be misleading. C1 [Patricelli, Matthew P.; Nomanbhoy, Tyzoon K.; Wu, Jiangyue; Brown, Heidi; Zhou, David; Jagannathan, Subadhra; Aban, Arwin; Okerberg, Eric; Herring, Chris; Nordin, Brian; Weissig, Helge; Kozarich, John W.] ActivX Biosci, La Jolla, CA 92037 USA. [Zhang, Jianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zhang, Jianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Yang, Qingkai; Lee, Jiing-Dwan] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. RP Patricelli, MP (reprint author), ActivX Biosci, La Jolla, CA 92037 USA. EM mattp@activx.com OI Yang, Qingkai/0000-0001-6628-5393 FU NCI NIH HHS [R01 CA130876, R01 CA130876-01A1, R01 CA130876-02, R01 CA130876-03, R01 CA130876-04]; NIGMS NIH HHS [P41 GM079575, P41 GM079575-01, P41 GM079575-02, P41 GM079575-03, P41 GM079575-03S1] NR 43 TC 128 Z9 128 U1 1 U2 25 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 JUN 24 PY 2011 VL 18 IS 6 BP 699 EP 710 DI 10.1016/j.chembiol.2011.04.011 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 790JH UT WOS:000292583800005 PM 21700206 ER PT J AU Zuo, XF Fogelgren, B Lipschutz, JH AF Zuo, Xiaofeng Fogelgren, Ben Lipschutz, Joshua H. TI The Small GTPase Cdc42 Is Necessary for Primary Ciliogenesis in Renal Tubular Epithelial Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLYCYSTIC KIDNEY-DISEASE; REGULATED KINASE PATHWAY; RAC1 SMALL GTPASES; RHO-GTPASES; SPINDLE ORIENTATION; AUTOSOMAL-DOMINANT; CYST FORMATION; PRIMARY CILIUM; IN-VITRO; EXOCYST AB Primary cilia are found on many epithelial cell types, including renal tubular epithelial cells, where they participate in flow sensing. Disruption of cilia function has been linked to the pathogenesis of polycystic kidney disease. We demonstrated previously that the exocyst, a highly conserved eight-protein membrane trafficking complex, localizes to primary cilia of renal tubular epithelial cells, is required for ciliogenesis, biochemically and genetically interacts with polycystin-2 (the protein product of the polycystic kidney disease 2 gene), and, when disrupted, results in MAPK pathway activation both in vitro and in vivo. The small GTPase Cdc42 is a candidate for regulation of the exocyst at the primary cilium. Here, we demonstrate that Cdc42 biochemically interacts with Sec10, a crucial component of the exocyst complex, and that Cdc42 colocalizes with Sec10 at the primary cilium. Expression of dominant negative Cdc42 and shRNA-mediated knockdown of both Cdc42 and Tuba, a Cdc42 guanine nucleotide exchange factor, inhibit ciliogenesis in Madin-Darby canine kidney cells. Furthermore, exocyst Sec8 and polycystin-2 no longer localize to primary cilia or the ciliary region following Cdc42 and Tuba knockdown. We also show that Sec10 directly interacts with Par6, a member of the Par complex that itself directly interacts with Cdc42. Finally, we show that Cdc42 knockdown results in activation of the MAPK pathway, something observed in cells with dysfunctional primary cilia. These data support a model in which Cdc42 localizes the exocyst to the primary cilium, whereupon the exocyst then targets and docks vesicles carrying proteins necessary for ciliogenesis. C1 [Zuo, Xiaofeng; Fogelgren, Ben; Lipschutz, Joshua H.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Lipschutz, Joshua H.] Philadelphia Vet Affairs Med Ctr, Dept Med, Philadelphia, PA 19104 USA. RP Lipschutz, JH (reprint author), 413 Hill Pavil,380 S Univ Ave, Philadelphia, PA 19104 USA. EM jhlipsch@mail.med.upenn.edu FU National Institutes of Health [DK069909, K01DK087852]; Veterans Affairs; Satellite Healthcare; University of Pennsylvania Translational Medicine Institute FX This work was supported, in whole or in part, by National Institutes of Health Grants DK069909 (to J. H. L.) and K01DK087852 (to B. F.). This work was also supported by a Veterans Affairs Merit Award (to J. H. L.), a Satellite Healthcare Norman S. Coplon extramural research grant (to J. H. L.), and a University of Pennsylvania Translational Medicine Institute pilot grant (to J. H. L). NR 41 TC 25 Z9 25 U1 0 U2 1 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 JUN 24 PY 2011 VL 286 IS 25 BP 22469 EP 22477 DI 10.1074/jbc.M111.238469 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 778QP UT WOS:000291719900055 PM 21543338 ER PT J AU Lefort, K Dotto, GP AF Lefort, Karine Dotto, G. Paolo TI p63 and Epithelial Metaplasia: A Gutsy Choice SO CELL LA English DT Editorial Material ID LIMB AB Barrett's esophagus is an epithelial metaplasia associated with an increased risk for cancer, but its underlying mechanisms have been debated. Now Wang et al. (2011) suggest an intriguing explanation for this puzzle: a population of residual embryonic cells, lacking the transcription factor p63, migrates and repopulates a normal tissue damaged by inflammation or gastroesophageal reflux. C1 [Lefort, Karine; Dotto, G. Paolo] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Dotto, G. Paolo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP Dotto, GP (reprint author), Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. EM paolo.dotto@unil.ch NR 9 TC 3 Z9 4 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUN 24 PY 2011 VL 145 IS 7 BP 1003 EP 1005 DI 10.1016/j.cell.2011.06.008 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 782QV UT WOS:000292025700005 PM 21703442 ER PT J AU Desmonde, S Coffie, P Aka, E Amani-Bosse, C Messou, E Dabis, F Alioum, A Ciaranello, A Leroy, V AF Desmonde, Sophie Coffie, Patrick Aka, Edmond Amani-Bosse, Clarisse Messou, Eugene Dabis, Francois Alioum, Ahmadou Ciaranello, Andrea Leroy, Valeriane TI Severe morbidity and mortality in untreated HIV-infected children in a paediatric care programme in Abidjan, Cote d'Ivoire, 2004-2009 SO BMC INFECTIOUS DISEASES LA English DT Article ID RESOURCE-LIMITED SETTINGS; 1ST 2 YEARS; ANTIRETROVIRAL THERAPY; HIV-1-INFECTED CHILDREN; NATURAL-HISTORY; COST-EFFECTIVENESS; INFANTS BORN; SCALING-UP; AFRICA; IMMUNODEFICIENCY AB Background: Clinical evolution of HIV-infected children who have not yet initiated antiretroviral treatment (ART) is poorly understood in Africa. We describe severe morbidity and mortality of untreated HIV-infected children. Methods: All HIV-infected children enrolled from 2004-2009 in a prospective HIV programme in two health facilities in Abidjan, Cote d'Ivoire, were eligible from their time of inclusion. Risks of severe morbidity (the first clinical event leading to death or hospitalisation) and mortality were documented retrospectively and estimated using cumulative incidence functions. Associations with baseline characteristics were assessed by competing risk regression models between outcomes and antiretroviral initiation. Results: 405 children were included at a median age of 4.5 years; at baseline, 66.9% were receiving cotrimoxazole prophylaxis, and 27.7% met the 2006 WHO criteria for immunodeficiency by age. The risk of developing a severe morbid event was 14% (95% CI: 10.7 - 17.8) at 18 months; this risk was lower in children previously exposed to any prevention of mother-to-child-transmission (PMTCT) intervention (adjusted subdistribution hazard ratio [sHR]: 0.16, 95% CI: 0.04 - 0.71) versus those without known exposure. Cumulative mortality reached 5.5% (95% CI: 3.5 - 8.1) at 18 months. Mortality was associated with immunodeficiency (sHR: 6.02, 95% CI: 1.28-28.42). Conclusions: Having benefited from early access to care minimizes the severe morbidity risk for children who acquire HIV. Despite the receipt of cotrimoxazole prophylaxis, the risk of severe morbidity and mortality remains high in untreated HIV-infected children. Such evidence adds arguments to promote earlier access to ART in HIV-infected children in Africa and improve care interventions in a context where treatment is still not available to all. C1 [Desmonde, Sophie; Dabis, Francois; Alioum, Ahmadou; Leroy, Valeriane] Univ Bordeaux 2, INSERM, U897, F-33076 Bordeaux, France. [Desmonde, Sophie; Dabis, Francois; Alioum, Ahmadou; Leroy, Valeriane] Univ Bordeaux 2, ISPED, F-33076 Bordeaux, France. [Coffie, Patrick] CHU Treichville, Programme PAC CI, Abidjan, Cote Ivoire. [Aka, Edmond; Messou, Eugene] ACONDA, CePReF, Abidjan, Cote Ivoire. [Amani-Bosse, Clarisse] ACONDA, MTCT Plus Initiat, Abidjan, Cote Ivoire. [Ciaranello, Andrea] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Leroy, V (reprint author), Univ Bordeaux 2, INSERM, U897, F-33076 Bordeaux, France. EM Valeriane.Leroy@isped.u-bordeaux2.fr RI Leroy, Valeriane/F-8129-2013 OI Leroy, Valeriane/0000-0003-3542-8616 FU US National Institutes of Health: NIAID [R0I AI058736, 5U01AI09919-01 to 05, K01 AI078754, R01AI058736] FX This study was supported in part by grants from the US National Institutes of Health: NIAID R0I AI058736 and 5U01AI09919-01 to 05 (IeDEA West Africa) and K01 AI078754 (AC) and R01AI058736 (SD). The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned above. NR 41 TC 13 Z9 13 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JUN 23 PY 2011 VL 11 AR 182 DI 10.1186/1471-2334-11-182 PG 12 WC Infectious Diseases SC Infectious Diseases GA 790TW UT WOS:000292613100001 PM 21699728 ER PT J AU Goss, PE Ingle, JN Ales-Martinez, JE Cheung, AM Chlebowski, RT Wactawski-Wende, J McTiernan, A Robbins, J Johnson, KC Martin, LW Winquist, E Sarto, GE Garber, JE Fabian, CJ Pujol, P Maunsell, E Farmer, P Gelmon, KA Tu, D Richardson, H AF Goss, Paul E. Ingle, James N. Ales-Martinez, Jose E. Cheung, Angela M. Chlebowski, Rowan T. Wactawski-Wende, Jean McTiernan, Anne Robbins, John Johnson, Karen C. Martin, Lisa W. Winquist, Eric Sarto, Gloria E. Garber, Judy E. Fabian, Carol J. Pujol, Pascal Maunsell, Elizabeth Farmer, Patricia Gelmon, Karen A. Tu, Dongsheng Richardson, Harriet CA NCIC CTG MAP 3 Study Investigators TI Exemestane for Breast-Cancer Prevention in Postmenopausal Women SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID QUALITY-OF-LIFE; BONE-MINERAL DENSITY; NONSTEROIDAL AROMATASE INHIBITORS; RANDOMIZED-TRIAL; PHARMACOLOGICAL INTERVENTIONS; INCLUDING TAMOXIFEN; AMERICAN-SOCIETY; RISK REDUCTION; MAMMARY-TUMORS; ATAC TRIAL AB Background Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer. Methods In a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, eligible postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy. Toxic effects and health-related and menopause-specific qualities of life were measured. Results A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P = 0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P = 0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P = 0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed. Conclusions Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life. C1 [Goss, Paul E.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ingle, James N.] Mayo Clin, Rochester, MN USA. [Ales-Martinez, Jose E.] Hosp Nuestra Senora Sonsoles, Avila, Spain. [Chlebowski, Rowan T.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Buffalo, NY 14260 USA. [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Robbins, John] Univ Calif Davis, Sacramento, CA 95817 USA. [Johnson, Karen C.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Martin, Lisa W.] George Washington Univ, Sch Med, Washington, DC USA. [Sarto, Gloria E.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Fabian, Carol J.] Univ Kansas, Med Ctr, Kansas City, KS USA. [Pujol, Pascal] Univ Arnaud Villeneuve, Ctr Hosp, Montpellier, France. [Cheung, Angela M.] Univ Hlth Network, Toronto, ON, Canada. [Winquist, Eric] London Hlth Sci Ctr, London, ON, Canada. [Maunsell, Elizabeth] Univ Laval, Unit Rech Sante Populat, Quebec City, PQ, Canada. [Farmer, Patricia] Univ Pathol & Mol Med, Kingston, ON, Canada. [Gelmon, Karen A.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Tu, Dongsheng; Richardson, Harriet] NCIC Clin Trials Grp, Kingston, ON, Canada. RP Goss, PE (reprint author), Massachusetts Gen Hosp, Ctr Canc, Lawrence House,LRH 302, Boston, MA 02114 USA. EM pgoss@partners.org RI Avisar, Eli/D-3008-2013; Calvo, Lourdes/M-2352-2014; OI Blanco, Ignacio/0000-0002-7414-7481; Martin, Lisa Warsinger/0000-0003-4352-0914; Brunet, Joan/0000-0003-1945-3512 FU Canadian Cancer Society Research Institute; Canadian Institutes for Health Research; Pfizer; Avon Foundation; Pfizer Pharmaceuticals FX Supported by the Canadian Cancer Society Research Institute, the Canadian Institutes for Health Research, Pfizer, and the Avon Foundation.; We thank the 4560 women (2824 from the United States, 1285 from Canada, 432 from Spain, and 19 from France) who agreed to participate in this study; the trial committee; the many investigators, pharmacists, and clinical research associates involved in the trial; Drs. Joe Pater and Lois Shepherd, Dianne Johnston, and Andrea Hiltz for their enthusiastic and unwavering support; the members of the NCIC CTG Data Safety Monitoring Committee; the Central Office staff of the NCIC CTG who contributed to the conduct of the trial; and Pfizer Pharmaceuticals for support and for providing exemestane and placebo. NR 53 TC 339 Z9 346 U1 4 U2 27 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 JUN 23 PY 2011 VL 364 IS 25 BP 2381 EP 2391 DI 10.1056/NEJMoa1103507 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 781MG UT WOS:000291936100004 PM 21639806 ER PT J AU Harris, JB Ivers, LC Ferraro, MJ AF Harris, Jason B. Ivers, Louise C. Ferraro, Mary Jane TI A Boy with Vomiting and Diarrhea Vibrio cholerae O1 (toxigenic), serotype Ogawa (testing performed at the CDC). SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DEVELOPING-COUNTRIES; GLOBAL BURDEN; BANGLADESH; MORTALITY; CHILDREN C1 [Harris, Jason B.] Massachusetts Gen Hosp, Dept Infect Dis, Boston, MA 02114 USA. [Ferraro, Mary Jane] Massachusetts Gen Hosp, Dept Pathol & Microbiol, Boston, MA 02114 USA. [Ivers, Louise C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Harris, Jason B.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Ivers, Louise C.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Ferraro, Mary Jane] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Harris, JB (reprint author), Massachusetts Gen Hosp, Dept Infect Dis, Boston, MA 02114 USA. NR 21 TC 2 Z9 2 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 JUN 23 PY 2011 VL 364 IS 25 BP 2452 EP 2461 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 781MG UT WOS:000291936100013 PM 21696312 ER PT J AU Renella, R Roberts, NA Brown, JM De Gobbi, M Bird, LE Hassanali, T Sharpe, JA Sloane-Stanley, J Ferguson, DJP Cordell, J Buckle, VJ Higgs, DR Wood, WG AF Renella, Raffaele Roberts, Nigel A. Brown, Jill M. De Gobbi, Marco Bird, Louise E. Hassanali, Tasneem Sharpe, Jacqueline A. Sloane-Stanley, Jacqueline Ferguson, David J. P. Cordell, Jacqueline Buckle, Veronica J. Higgs, Douglas R. Wood, William G. TI Codanin-1 mutations in congenital dyserythropoietic anemia type 1 affect HP1 alpha localization in erythroblasts SO BLOOD LA English DT Article ID BLACKFAN ANEMIA; ES CELLS; GENE; HP1; IDENTIFICATION; EXPRESSION; PROTEINS; CULTURE; BINDING; CLONING AB Congenital dyserythropoietic anemia type 1 (CDA-1), a rare inborn anemia characterized by abnormal chromatin ultrastructure in erythroblasts, is caused by abnormalities in codanin-1, a highly conserved protein of unknown function. We have produced 3 monoclonal antibodies to codanin-1 that demonstrate its distribution in both nucleus and cytoplasm by immunofluorescence and allow quantitative measurements of patient and normal material by Western blot. A detailed analysis of chromatin structure in CDA-1 erythroblasts shows no abnormalities in overall histone composition, and the genome-wide epigenetic landscape of several histone modifications is maintained. However, immunofluorescence analysis of intermediate erythroblasts from patients with CDA-1 reveals abnormal accumulation of HP1 alpha in the Golgi apparatus. A link between mutant codanin-1 and the aberrant localization of HP1 alpha is supported by the finding that codanin-1 can be coimmunoprecipitated by anti-HP1 alpha antibodies. Furthermore, we show colocalization of codanin-1 with Sec23B, the protein defective in CDA-2 suggesting that the CDAs might be linked at the molecular level. Mice containing a gene-trapped Cdan1 locus demonstrate its widespread expression during development. Cdan1(gt/gt) homozygotes die in utero before the onset of primitive erythropoiesis, suggesting that Cdan1 has other critical roles during embryogenesis. (Blood. 2011;117(25):6928-6938) C1 [Renella, Raffaele; Roberts, Nigel A.; Brown, Jill M.; De Gobbi, Marco; Sharpe, Jacqueline A.; Sloane-Stanley, Jacqueline; Buckle, Veronica J.; Higgs, Douglas R.; Wood, William G.] Univ Oxford, John Radcliffe Hosp, Med Res Council Mol Haematol Unit, Weatherall Inst Mol Med, Oxford OX3 9DU, England. [Bird, Louise E.] Univ Oxford, Oxford Prot Prod Facil, Wellcome Trust Ctr Human Genet, Oxford OX3 9DU, England. [Hassanali, Tasneem; Cordell, Jacqueline] Univ Oxford, Leukemia & Lymphoma Res Monoclonal Antibody Facil, Nuffield Dept Clin Lab Sci, Oxford OX3 9DU, England. RP Renella, R (reprint author), Dana Farber Canc Inst, Jimmy Fund Clin, Dept Pediat Oncol, Dana 3,44 Binney St, Boston, MA 02115 USA. EM raffaele.renella@childrens.harvard.edu RI De Gobbi, Marco/E-8136-2013; OI Renella, Raffaele/0000-0002-5041-2308; Roberts, Nigel/0000-0002-5091-3604; Ferguson, David/0000-0001-5045-819X; Bird, Louise/0000-0002-9846-5716 FU Berrow Foundation & Oxford University, United Kingdom; Valeria Rossi di Montelera Foundation, Switzerland; Wellcome Trust FX The authors thank the Medical Research Council for continuing support. R. R. was supported by the Berrow Foundation & Oxford University, United Kingdom (Lord Florey Scholarship) and the Valeria Rossi di Montelera Foundation, Switzerland (Eugenio Litta Scholarship). D.J.P.F. is supported by an equipment grant from the Wellcome Trust. Sue Butler, Pik-Shan Li and Joanne Green provided core technical support in this study. NR 34 TC 17 Z9 20 U1 0 U2 6 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 JUN 23 PY 2011 VL 117 IS 25 BP 6928 EP 6938 DI 10.1182/blood-2010-09-308478 PG 11 WC Hematology SC Hematology GA 782AM UT WOS:000291979800025 PM 21364188 ER PT J AU Soiffer, RJ LeRademacher, J Ho, V Kan, FY Artz, A Champlin, RE Devine, S Isola, L Lazarus, HM Marks, DI Porter, DL Waller, EK Horowitz, MM Eapen, M AF Soiffer, Robert J. LeRademacher, Jennifer Ho, Vincent Kan, Fangyu Artz, Andrew Champlin, Richard E. Devine, Steven Isola, Luis Lazarus, Hillard M. Marks, David I. Porter, David L. Waller, Edmund K. Horowitz, Mary M. Eapen, Mary TI Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; CONDITIONING REGIMEN; UNRELATED DONORS; ALEMTUZUMAB; GLOBULIN; SURVIVAL; GVHD; PHARMACOKINETICS; PROPHYLAXIS; RISK AB The success of reduced intensity conditioning (RIC) transplantation is largely dependent on alloimmune effects. It is critical to determine whether immune modulation with anti-T-cell antibody infusion abrogates the therapeutic benefits of transplantation. We examined 1676 adults undergoing RIC transplantation for hematologic malignancies. All patients received alkylating agent plus fludarabine; 792 received allografts from a human leukocyte antigen-matched sibling, 884 from a 7 or 8 of 8 HLA-matched unrelated donor. Using Cox regression, outcomes after in vivo T-cell depletion (n = 584 anti-thymocyte globulin [ATG]; n = 213 alemtuzumab) were compared with T cell-replete (n = 879) transplantation. Grade 2 to 4 acute GVHD was lower with alemtuzumab compared with ATG or T cell-replete regimens (19% vs 38% vs 40%, P < .0001) and chronic GVHD, lower with alemtuzumab, and ATG regimens compared with T-replete approaches (24% vs 40% vs 52%, P < .0001). However, relapse was more frequent with alemtuzumab and ATG compared with T cell-replete regimens (49%, 51%, and 38%, respectively, P < .001). Disease-free survival was lower with alemtuzumab and ATG compared with T cell-replete regimens (30%, 25%, and 39%, respectively, P < .001). Corresponding probabilities of overall survival were 50%, 38%, and 46% (P = .008). These data suggest adopting a cautious approach to routine use of in vivo T-cell depletion with RIC regimens. (Blood. 2011;117(25):6963-6970) C1 [Soiffer, Robert J.; Ho, Vincent] Dana Farber Canc Inst, Boston, MA 02115 USA. [LeRademacher, Jennifer; Horowitz, Mary M.; Eapen, Mary] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI USA. [Kan, Fangyu] Natl Marrow Donor Program, Minneapolis, MN USA. [Artz, Andrew] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Champlin, Richard E.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Devine, Steven] Ohio State Univ, Columbus, OH 43210 USA. [Isola, Luis] Mt Sinai Hosp, New York, NY 10029 USA. [Lazarus, Hillard M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Marks, David I.] United Bristol Hlth Care Trust, Bristol, Avon, England. [Porter, David L.] Univ Penn, Philadelphia, PA 19104 USA. [Waller, Edmund K.] Emory Univ, Atlanta, GA 30322 USA. RP Soiffer, RJ (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM Robert_Soiffer@dfci.harvard.edu FU National Cancer Institute, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases [U24-CA76518]; Health Resources and Services Administration [HHSH234200637015C]; Office of Naval Research; Department of Navy [N00014-08-1-1207] FX This work was supported by the National Cancer Institute, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases (U24-CA76518), Health Resources and Services Administration (HHSH234200637015C), Office of Naval Research, and Department of Navy (N00014-08-1-1207). Clinical trials at M. D. Anderson Cancer Center (R. E. C.) for plerixafor and clofarabine are supported by Genzyme and for busulfan by Otsuka. NR 21 TC 163 Z9 165 U1 0 U2 6 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 JUN 23 PY 2011 VL 117 IS 25 BP 6963 EP 6970 DI 10.1182/blood-2011-01-332007 PG 8 WC Hematology SC Hematology GA 782AM UT WOS:000291979800029 PM 21464372 ER PT J AU Rietman, EA Karp, RL Tuszynski, JA AF Rietman, Edward A. Karp, Robert L. Tuszynski, Jack A. TI Review and application of group theory to molecular systems biology SO THEORETICAL BIOLOGY AND MEDICAL MODELLING LA English DT Review ID MAMMALIAN-CELL FUSION; GENETIC-CODE; REGULATORY NETWORKS; LIVING MACHINES; TRANSCRIPTION; YEAST; CYCLE; UNDECIDABILITY; MODULARITY; GRAPH AB In this paper we provide a review of selected mathematical ideas that can help us better understand the boundary between living and non-living systems. We focus on group theory and abstract algebra applied to molecular systems biology. Throughout this paper we briefly describe possible open problems. In connection with the genetic code we propose that it may be possible to use perturbation theory to explore the adjacent possibilities in the 64-dimensional space-time manifold of the evolving genome. With regards to algebraic graph theory, there are several minor open problems we discuss. In relation to network dynamics and groupoid formalism we suggest that the network graph might not be the main focus for understanding the phenotype but rather the phase space of the network dynamics. We show a simple case of a C-6 network and its phase space network. We envision that the molecular network of a cell is actually a complex network of hypercycles and feedback circuits that could be better represented in a higher-dimensional space. We conjecture that targeting nodes in the molecular network that have key roles in the phase space, as revealed by analysis of the automorphism decomposition, might be a better way to drug discovery and treatment of cancer. C1 [Tuszynski, Jack A.] Cross Canc Inst, Dept Expt Oncol, Edmonton, AB T6G 1Z2, Canada. [Rietman, Edward A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Rietman, Edward A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Karp, Robert L.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Tuszynski, Jack A.] Univ Alberta, Dept Phys, Edmonton, AB T6G 2G7, Canada. [Rietman, Edward A.] Tufts Univ, Sch Med, St Elizabeths Med Ctr, Ctr Canc Syst Biol, Brighton, MA 02135 USA. RP Tuszynski, JA (reprint author), Cross Canc Inst, Dept Expt Oncol, 11560 Univ Ave, Edmonton, AB T6G 1Z2, Canada. EM jackt@ualberta.ca NR 81 TC 6 Z9 7 U1 2 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4682 J9 THEOR BIOL MED MODEL JI Theor. Biol. Med. Model. PD JUN 22 PY 2011 VL 8 AR 21 DI 10.1186/1742-4682-8-21 PG 29 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 804DK UT WOS:000293634200001 PM 21696623 ER PT J AU Preiss, D Seshasai, SRK Welsh, P Murphy, SA Ho, JE Waters, DD DeMicco, DA Barter, P Cannon, CP Sabatine, MS Braunwald, E Kastelein, JJP de Lemos, JA Blazing, MA Pedersen, TR Tikkanen, MJ Sattar, N Ray, KK AF Preiss, David Seshasai, Sreenivasa Rao Kondapally Welsh, Paul Murphy, Sabina A. Ho, Jennifer E. Waters, David D. DeMicco, David A. Barter, Philip Cannon, Christopher P. Sabatine, Marc S. Braunwald, Eugene Kastelein, John J. P. de Lemos, James A. Blazing, Michael A. Pedersen, Terje R. Tikkanen, Matti J. Sattar, Naveed Ray, Kausik K. TI Risk of Incident Diabetes With Intensive-Dose Compared With Moderate-Dose Statin Therapy A Meta-analysis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; ACUTE CORONARY SYNDROMES; LIPID-LOWERING THERAPY; MYOCARDIAL-INFARCTION; SYSTEMATIC REVIEWS; LDL CHOLESTEROL; CLINICAL-TRIALS; HEART-DISEASE; ATORVASTATIN; EFFICACY AB Context A recent meta-analysis demonstrated that statin therapy is associated with excess risk of developing diabetes mellitus. Objective To investigate whether intensive-dose statin therapy is associated with increased risk of new-onset diabetes compared with moderate-dose statin therapy. Data Sources We identified relevant trials in a literature search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (January 1, 1996, through March 31, 2011). Unpublished data were obtained from investigators. Study Selection We included randomized controlled end-point trials that compared intensive-dose statin therapy with moderate-dose statin therapy and included more than 1000 participants who were followed up for more than 1 year. Data Extraction Tabular data provided for each trial described baseline characteristics and numbers of participants developing diabetes and experiencing major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization). We calculated trial-specific odds ratios (ORs) for new-onset diabetes and major cardiovascular events and combined these using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I-2 statistic. Results In 5 statin trials with 32 752 participants without diabetes at baseline, 2749 developed diabetes (1449 assigned intensive-dose therapy, 1300 assigned moderate-dose therapy, representing 2.0 additional cases in the intensive-dose group per 1000 patient years) and 6684 experienced cardiovascular events(3134 and 3550, respectively, representing 6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 (95% confidence interval [CI], 1.04-1.22; I-2 = 0%) for new-onset diabetes and 0.84(95% CI, 0.75-0.94; I-2 = 74%) for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events. Conclusion In a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate dose statin therapy. JAMA. 2011;305(24):2556-2564 C1 [Preiss, David; Welsh, Paul; Sattar, Naveed] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [Seshasai, Sreenivasa Rao Kondapally] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Murphy, Sabina A.; Cannon, Christopher P.; Sabatine, Marc S.; Braunwald, Eugene] Harvard Univ, Sch Med, Div Cardiovasc, TIMI Study Grp, Boston, MA USA. [Ho, Jennifer E.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Waters, David D.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [DeMicco, David A.] Pfizer, Global Pharmaceut, New York, NY USA. [Barter, Philip] Heart Res Inst, Sydney, NSW, Australia. [Kastelein, John J. P.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [de Lemos, James A.] Univ Texas SW Med Ctr Dallas, Div Cardiol, Dallas, TX 75390 USA. [Blazing, Michael A.] Duke Clin Res Inst, Durham, NC USA. [Pedersen, Terje R.] Univ Oslo, Oslo, Norway. [Pedersen, Terje R.] Oslo Univ Hosp, Ctr Preventat Med, Oslo, Norway. [Tikkanen, Matti J.] Univ Helsinki, Helsinki, Finland. [Tikkanen, Matti J.] Helsinki Univ Hosp, Div Cardiol, Helsinki, Finland. [Tikkanen, Matti J.] Folkhalsan Res Ctr, Helsinki, Finland. [Ray, Kausik K.] St Georges Univ London, Div Cardiac & Vasc Sci, London, England. RP Preiss, D (reprint author), Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, 126 Univ Pl, Glasgow G12 8TA, Lanark, Scotland. EM david.preiss@glasgow.ac.uk; kray@sgul.ac.uk OI Ho, Jennifer/0000-0002-7987-4768; Welsh, Paul/0000-0002-7970-3643; Preiss, David/0000-0003-3139-1836 FU Bristol-Myers Squibb through the TIMI Study Group; Merck; Pfizer; Bristol-Myers Squibb; AstraZeneca; Roche; Accumetrics; GlaxoSmithKline; Intekrin Therapeutics; Takeda; AstraZeneca through Brigham and Women's Hospital; Bristol-Myers Squibb/sanofi-aventis; Schering Plough; Amgen; Eli Lilly; sanofi-aventis; Novartis; Boehringer Ingelheim; Isis; Genzyme; Kowa; Schering-Plough; Novo Nordisk FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Ms Murphy reported receiving research grant support through the TIMI Study Group from Bristol-Myers Squibb and Merck. Dr Ho reported receiving consulting fees from Pfizer. Dr Waters reported receiving honoraria for lectures from Bristol-Myers Squibb and Pfizer and consulting for Merck Schering Plough and Pfizer for participation in clinical trial committees. Dr DeMicco reported being an employee of Pfizer. Dr Barter reported acting as member on advisory boards for AstraZeneca, CSL, Merck, Novartis, Pfizer, and Roche; receiving honoraria from Abbott, AstraZeneca, Merck, Novartis, Pfizer, and Roche; and participating in clinical trials sponsored by AstraZeneca, Merck, Pfizer, and Roche. Dr Cannon reported receiving research grants or support from Accumetrics, AstraZeneca, GlaxoSmithKline, Intekrin Therapeutics, Merck, and Takeda; acting on advisory boards (funds donated to charity) for Alnylam, Bristol-Myers Squibb/sanofi, and Novartis; receiving honoraria for independent educational symposia from AstraZeneca and Pfizer; and acting as a clinical advisor with equity for Automedics Medical Systems. Dr Sabatine reported receiving research grant support through Brigham and Women's Hospital from AstraZeneca, Bristol-Myers Squibb/sanofi-aventis, Schering Plough, and Amgen; consulting for AstraZeneca and Bristol-Myers Squibb/sanofi-aventis; and lecturing for Bristol-Myers Squibb/sanofi-aventis. Dr Braunwald reported receiving research support for the TIMI Study Group from Merck, AstraZeneca, and Pfizer. Dr Kastelein reported having participated in clinical trials sponsored by Pfizer, AstraZeneca, Merck, Eli Lilly, sanofi-aventis, Roche, Novartis, Boehringer Ingelheim, Isis, and Genzyme and receiving lecturing and consulting fees from Pfizer, AstraZeneca, Merck, Eli Lilly, sanofi-aventis, Roche, Novartis, Isis, Genzyme, and Kowa. Dr de Lemos reported consulting for AstraZeneca and receiving honoraria from Merck/Schering and Pfizer for lectures (>2 years ago). Dr Blazing reported receiving speaking or consulting fees from Merck and being the principal investigator on a research grant from Schering-Plough administered through the Duke Clinical Research Institute. Dr Pedersen reported receiving speakers' honoraria from and consulting for Pfizer and Merck-Schering Plough and receiving speakers' honoraria from AstraZeneca. Dr Tikkanen reported participating in clinical trials sponsored by Pfizer and Takeda, acting as member of a steering committee for a trial sponsored by Pfizer, and being a member of an advisory board of MSD Finland. Dr Sattar reported consulting for and receiving lecture fees from Merck, Pfizer, and AstraZeneca and having received research grant support from Pfizer. Dr Ray reported consulting/lecturing at symposia funded by Novo Nordisk, Roche, Pfizer, Merck, sanofi-aventis, and AstraZeneca. No other disclosures were reported. NR 31 TC 518 Z9 550 U1 4 U2 32 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 22 PY 2011 VL 305 IS 24 BP 2556 EP 2564 DI 10.1001/jama.2011.860 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 780MF UT WOS:000291860400023 PM 21693744 ER PT J AU Katiyar, SK Mantena, SK Meeran, SM AF Katiyar, Santosh K. Mantena, Sudheer K. Meeran, Syed M. TI Silymarin Protects Epidermal Keratinocytes from Ultraviolet Radiation-Induced Apoptosis and DNA Damage by Nucleotide Excision Repair Mechanism SO PLOS ONE LA English DT Article ID GREEN TEA POLYPHENOLS; A-DEPENDENT MECHANISM; INDUCED IMMUNOSUPPRESSION; SKIN-CANCER; ACTIVATION; PHOTOCARCINOGENESIS; INTERLEUKIN-12; ENHANCEMENT; CONTRIBUTE; CELLS AB Solar ultraviolet (UV) radiation is a well recognized epidemiologic risk factor for melanoma and non-melanoma skin cancers. This observation has been linked to the accumulation of UVB radiation-induced DNA lesions in cells, and that finally lead to the development of skin cancers. Earlier, we have shown that topical treatment of skin with silymarin, a plant flavanoid from milk thistle (Silybum marianum), inhibits photocarcinogenesis in mice; however it is less understood whether chemopreventive effect of silymarin is mediated through the repair of DNA lesions in skin cells and that protect the cells from apoptosis. Here, we show that treatment of normal human epidermal keratinocytes (NHEK) with silymarin blocks UVB-induced apoptosis of NHEK in vitro. Silymarin reduces the amount of UVB radiation-induced DNA damage as demonstrated by reduced amounts of cyclobutane pyrimidine dimers (CPDs) and as measured by comet assay, and that ultimately may lead to reduced apoptosis of NHEK. The reduction of UV radiation-induced DNA damage by silymarin appears to be related with induction of nucleotide excision repair (NER) genes, because UV radiation-induced apoptosis was not blocked by silymarin in NER-deficient human fibroblasts. Cytostaining and dot-blot analysis revealed that silymarin repaired UV-induced CPDs in NER-proficient fibroblasts from a healthy individual but did not repair UV-induced CPD-positive cells in NER-deficient fibroblasts from patients suffering from xeroderma pigmentosum complementation-A disease. Similarly, immunohistochemical analysis revealed that silymarin did not reduce the number of UVB-induced sunburn/apoptotic cells in the skin of NER-deficient mice, but reduced the number of sunburn cells in their wild-type counterparts. Together, these results suggest that silymarin exert the capacity to reduce UV radiation-induced DNA damage and, thus, prevent the harmful effects of UV radiation on the genomic stability of epidermal cells. C1 [Katiyar, Santosh K.; Mantena, Sudheer K.; Meeran, Syed M.] Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama, Nutr Obes Res Ctr, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama, Ctr Aging, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Katiyar, SK (reprint author), Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. EM skatiyar@uab.edu FU National Cancer Institute [RO1 CA140197]; Veterans Administration Merit Review Award FX RO1 CA140197 by National Cancer Institute (http//www.cancer.gov) and the Veterans Administration Merit Review Award *SKK). The human keratinocytes were obtained from the UAB Skin Diseases Research Center (AR050948). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 32 Z9 33 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 22 PY 2011 VL 6 IS 6 AR e21410 DI 10.1371/journal.pone.0021410 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 782TF UT WOS:000292033700079 PM 21731736 ER PT J AU Macotela, Y Emanuelli, B Bang, AM Espinoza, DO Boucher, J Beebe, K Gall, W Kahn, CR AF Macotela, Yazmin Emanuelli, Brice Bang, Anneli M. Espinoza, Daniel O. Boucher, Jeremie Beebe, Kirk Gall, Walter Kahn, C. Ronald TI Dietary Leucine - An Environmental Modifier of Insulin Resistance Acting on Multiple Levels of Metabolism SO PLOS ONE LA English DT Article ID AMINO-ACIDS; GLUCOSE-METABOLISM; SKELETAL-MUSCLE; INDUCED OBESITY; RECEPTOR SUBSTRATE-1; MAMMALIAN TARGET; PROTEIN INTAKE; BLOOD-GLUCOSE; WEIGHT-LOSS; PHOSPHORYLATION AB Environmental factors, such as the macronutrient composition of the diet, can have a profound impact on risk of diabetes and metabolic syndrome. In the present study we demonstrate how a single, simple dietary factor-leucine-can modify insulin resistance by acting on multiple tissues and at multiple levels of metabolism. Mice were placed on a normal or high fat diet (HFD). Dietary leucine was doubled by addition to the drinking water. mRNA, protein and complete metabolomic profiles were assessed in the major insulin sensitive tissues and serum, and correlated with changes in glucose homeostasis and insulin signaling. After 8 weeks on HFD, mice developed obesity, fatty liver, inflammatory changes in adipose tissue and insulin resistance at the level of IRS-1 phosphorylation, as well as alterations in metabolomic profile of amino acid metabolites, TCA cycle intermediates, glucose and cholesterol metabolites, and fatty acids in liver, muscle, fat and serum. Doubling dietary leucine reversed many of the metabolite abnormalities and caused a marked improvement in glucose tolerance and insulin signaling without altering food intake or weight gain. Increased dietary leucine was also associated with a decrease in hepatic steatosis and a decrease in inflammation in adipose tissue. These changes occurred despite an increase in insulin-stimulated phosphorylation of p70S6 kinase indicating enhanced activation of mTOR, a phenomenon normally associated with insulin resistance. These data indicate that modest changes in a single environmental/nutrient factor can modify multiple metabolic and signaling pathways and modify HFD induced metabolic syndrome by acting at a systemic level on multiple tissues. These data also suggest that increasing dietary leucine may provide an adjunct in the management of obesity-related insulin resistance. C1 [Macotela, Yazmin; Emanuelli, Brice; Bang, Anneli M.; Espinoza, Daniel O.; Boucher, Jeremie; Kahn, C. Ronald] Joslin Diabet Ctr, Boston, MA 02215 USA. [Macotela, Yazmin; Emanuelli, Brice; Bang, Anneli M.; Espinoza, Daniel O.; Boucher, Jeremie; Kahn, C. Ronald] Harvard Univ, Sch Med, Boston, MA USA. [Beebe, Kirk; Gall, Walter] Metabolon Inc, Durham, NC USA. RP Macotela, Y (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu RI Emanuelli, Brice/M-2097-2016; OI Emanuelli, Brice/0000-0001-5795-5666 FU Pew Latin American Fellows program; NIH [DK33201]; Loveman Foundation; Mary K. Iacocca Professorship FX This work was supported by the Pew Latin American Fellows program fellowship an ADA grant to YM, NIH grant DK33201 to CRK, the Loveman Foundation and the Mary K. Iacocca Professorship. Metabolon, Inc, acted as a funder only through employment of KB and WG. The role of Metabolon was performance of the metabolomic analysis reported in this study. Other than that, Metabolon had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 96 Z9 104 U1 2 U2 23 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 JUN 22 PY 2011 VL 6 IS 6 AR e21187 DI 10.1371/journal.pone.0021187 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 782TF UT WOS:000292033700045 PM 21731668 ER PT J AU Yan, JQ Xu, YQ Zhu, CS Zhang, LM Wu, AM Yang, Y Xiong, ZJ Deng, C Huang, XF Yenari, MA Yang, YG Ying, WH Wang, Q AF Yan, Junqiang Xu, Yunqi Zhu, Cansheng Zhang, Limin Wu, Aimin Yang, Yu Xiong, Zhaojun Deng, Chao Huang, Xu-Feng Yenari, Midori A. Yang, Yuan-Guo Ying, Weihai Wang, Qing TI Simvastatin Prevents Dopaminergic Neurodegeneration in Experimental Parkinsonian Models: The Association with Anti-Inflammatory Responses SO PLOS ONE LA English DT Article ID NMDA RECEPTOR ANTAGONISTS; D-ASPARTATE RECEPTORS; ALZHEIMERS-DISEASE; GLUTAMATE RECEPTORS; PREFRONTAL CORTEX; CORTICAL-NEURONS; RAT-BRAIN; SYNAPTIC PLASTICITY; MESSENGER-RNA; BASAL GANGLIA AB Background: In addition to their original applications to lowering cholesterol, statins display multiple neuroprotective effects. N-methyl-D-aspartate (NMDA) receptors interact closely with the dopaminergic system and are strongly implicated in therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate how simvastatin impacts on experimental parkinsonian models via regulating NMDA receptors. Methodology/Principal Findings: Regional changes in NMDA receptors in the rat brain and anxiolytic-like activity were examined after unilateral medial forebrain bundle lesion by 6-hydroxydopamine via a 3-week administration of simvastatin. NMDA receptor alterations in the post-mortem rat brain were detected by [(3)H]MK-801(Dizocilpine) binding autoradiography. 6-hydroxydopamine treated PC12 was applied to investigate the neuroprotection of simvastatin, the association with NMDA receptors, and the anti-inflammation. 6-hydroxydopamine induced anxiety and the downregulation of NMDA receptors in the hippocampus, CA1(Cornu Ammonis 1 Area), amygdala and caudate putamen was observed in 6-OHDA(6-hydroxydopamine) lesioned rats whereas simvastatin significantly ameliorated the anxiety-like activity and restored the expression of NMDA receptors in examined brain regions. Significant positive correlations were identified between anxiolytic-like activity and the restoration of expression of NMDA receptors in the hippocampus, amygdala and CA1 following simvastatin administration. Simvastatin exerted neuroprotection in 6-hydroxydopamine-lesioned rat brain and 6-hydroxydopamine treated PC12, partially by regulating NMDA receptors, MMP9 (matrix metalloproteinase-9), and TNF-a (tumour necrosis factor-alpha). Conclusions/Significance: Our results provide strong evidence that NMDA receptor modulation after simvastatin treatment could partially explain its anxiolytic-like activity and anti-inflammatory mechanisms in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD via NMDA receptors. C1 [Yan, Junqiang; Xu, Yunqi; Zhu, Cansheng; Zhang, Limin; Wu, Aimin; Yang, Yu; Wang, Qing] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Neurol, Guangzhou 510275, Guangdong, Peoples R China. [Deng, Chao; Huang, Xu-Feng; Wang, Qing] Univ Wollongong, Sch Hlth Sci, Ctr Translat Neurosci, Wollongong, NSW 2522, Australia. [Xiong, Zhaojun] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Cardiol, Guangzhou 510275, Guangdong, Peoples R China. [Yenari, Midori A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yenari, Midori A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Yang, Yuan-Guo; Ying, Weihai] Shanghai Jiao Tong Univ, Med X Res Inst, Shanghai 200030, Peoples R China. RP Yan, JQ (reprint author), Sun Yat Sen Univ, Affiliated Hosp 3, Dept Neurol, Guangzhou 510275, Guangdong, Peoples R China. EM denniswq@yahoo.com RI Huang, Xu-Feng/D-6053-2013; Huang, Xu-Feng/H-7408-2015; Deng, Chao/F-4417-2016 OI Huang, Xu-Feng/0000-0002-5895-2253; Deng, Chao/0000-0003-1147-5741 FU Third Affiliated Hospital of Sun Yat-Sen University; Fundamental Research Funds for the Central Universities [A77, 10ykzd08]; Program for New Century Excellent Talents in University (NCET2010, P.R. China); National Natural Science Foundation of China [81071031]; Australia National Health and Medical Research Council [NHMRC 514640] FX This work was supported by the Grant-In-Aid from the Third Affiliated Hospital of Sun Yat-Sen University, Fundamental Research Funds for the Central Universities (Grant No. A77 and 10ykzd08), Program for New Century Excellent Talents in University (NCET2010, P.R. China), National Natural Science Foundation of China (81071031), and Australia National Health and Medical Research Council Grant (NHMRC 514640) to Q.W. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 38 Z9 40 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 22 PY 2011 VL 6 IS 6 AR e20945 DI 10.1371/journal.pone.0020945 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 782TF UT WOS:000292033700020 PM 21731633 ER PT J AU Wang, YL Wu, WJ Negre, NN White, KP Li, C Shah, PK AF Wang, Yulong Wu, Wenjun Negre, Nicolas N. White, Kevin P. Li, Cheng Shah, Parantu K. TI Determinants of antigenicity and specificity in immune response for protein sequences SO BMC BIOINFORMATICS LA English DT Article ID B-CELL EPITOPES; SECONDARY STRUCTURE PREDICTION; DATABASE; PEPTIDE; RESIDUES; SCALE; INFORMATION; GENERATION; SELECTION; ALIGNMENT AB Background: Target specific antibodies are pivotal for the design of vaccines, immunodiagnostic tests, studies on proteomics for cancer biomarker discovery, identification of protein-DNA and other interactions, and small and large biochemical assays. Therefore, it is important to understand the properties of protein sequences that are important for antigenicity and to identify small peptide epitopes and large regions in the linear sequence of the proteins whose utilization result in specific antibodies. Results: Our analysis using protein properties suggested that sequence composition combined with evolutionary information and predicted secondary structure, as well as solvent accessibility is sufficient to predict successful peptide epitopes. The antigenicity and the specificity in immune response were also found to depend on the epitope length. We trained the B-Cell Epitope Oracle (BEOracle), a support vector machine (SVM) classifier, for the identification of continuous B-Cell epitopes with these protein properties as learning features. The BEOracle achieved an F1-measure of 81.37% on a large validation set. The BEOracle classifier outperformed the classical methods based on propensity and sophisticated methods like BCPred and Bepipred for B-Cell epitope prediction. The BEOracle classifier also identified peptides for the ChIP-grade antibodies from the modENCODE/ ENCODE projects with 96.88% accuracy. High BEOracle score for peptides showed some correlation with the antibody intensity on Immunofluorescence studies done on fly embryos. Finally, a second SVM classifier, the B-Cell Region Oracle (BROracle) was trained with the BEOracle scores as features to predict the performance of antibodies generated with large protein regions with high accuracy. The BROracle classifier achieved accuracies of 75.2663.88% on a validation set with immunofluorescence, immunohistochemistry, protein arrays and western blot results from Protein Atlas database. Conclusions: Together our results suggest that antigenicity is a local property of the protein sequences and that protein sequence properties of composition, secondary structure, solvent accessibility and evolutionary conservation are the determinants of antigenicity and specificity in immune response. Moreover, specificity in immune response could also be accurately predicted for large protein regions without the knowledge of the protein tertiary structure or the presence of discontinuous epitopes. The dataset prepared in this work and the classifier models are available for download at https:// sites. google. com/ site/ oracleclassifiers/. C1 [Wang, Yulong; Li, Cheng; Shah, Parantu K.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Wang, Yulong; Li, Cheng; Shah, Parantu K.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Wu, Wenjun] Beihang Univ, State Key Lab Software Dev Environm, Beijing 100191, Peoples R China. [Negre, Nicolas N.; White, Kevin P.] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA. RP Shah, PK (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM parantu.shah@gmail.com OI Negre, Nicolas/0000-0001-9727-3416 FU modENCODE [U01 HG004264-04]; NIH [R01 GM077122]; State Key Laboratory of Software Development Environment [SKLSDE-2009ZX-12] FX Part of the work was supported by the modENCODE grant U01 HG004264-04 awarded to Kevin P White, NIH grant R01 GM077122 awarded to Cheng Li, State Key Laboratory of Software Development Environment Funding No. SKLSDE-2009ZX-12 to Wenjun Wu and the Claudia Adams Barr award to Parantu K Shah. NR 46 TC 11 Z9 14 U1 2 U2 9 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 JUN 21 PY 2011 VL 12 AR 251 DI 10.1186/1471-2105-12-251 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 790RE UT WOS:000292606100001 PM 21693021 ER PT J AU Kansagara, D Shekelle, P Qaseem, A AF Kansagara, Devan Shekelle, Paul Qaseem, Amir TI Intensive Insulin Therapy in Hospitalized Patients RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID CRITICALLY-ILL PATIENTS C1 [Kansagara, Devan] Portland VA Med Ctr, Portland, OR 97239 USA. [Shekelle, Paul] W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. [Qaseem, Amir] Amer Coll Physicians, Philadelphia, PA 19106 USA. RP Kansagara, D (reprint author), Portland VA Med Ctr, Portland, OR 97239 USA. NR 8 TC 0 Z9 0 U1 0 U2 3 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 JUN 21 PY 2011 VL 154 IS 12 BP 847 EP 848 DI 10.7326/0003-4819-154-12-201106210-00022 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 779SA UT WOS:000291800500028 ER PT J AU Marincheva-Savcheva, G Subramanian, S Qadir, S Figueroa, A Truong, Q Vijayakumar, J Brady, TJ Hoffmann, U Tawakol, A AF Marincheva-Savcheva, Gergana Subramanian, Sharath Qadir, Sadia Figueroa, Amparo Truong, Quynh Vijayakumar, Jayanthi Brady, Thomas J. Hoffmann, Udo Tawakol, Ahmed TI Imaging of the Aortic Valve Using Fluorodeoxyglucose Positron Emission Tomography Increased Valvular Fluorodeoxyglucose Uptake in Aortic Stenosis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material C1 [Marincheva-Savcheva, Gergana; Truong, Quynh; Tawakol, Ahmed] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Marincheva-Savcheva, Gergana; Subramanian, Sharath; Qadir, Sadia; Figueroa, Amparo; Truong, Quynh; Vijayakumar, Jayanthi; Brady, Thomas J.; Hoffmann, Udo; Tawakol, Ahmed] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Subramanian, Sharath; Qadir, Sadia; Figueroa, Amparo; Truong, Quynh; Vijayakumar, Jayanthi; Brady, Thomas J.; Hoffmann, Udo; Tawakol, Ahmed] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Marincheva-Savcheva, G (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. FU NHLBI NIH HHS [R01 HL095123-01] NR 0 TC 30 Z9 30 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 21 PY 2011 VL 57 IS 25 BP 2507 EP 2507 DI 10.1016/j.jacc.2010.12.046 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 777RI UT WOS:000291641800008 PM 21679852 ER PT J AU Marincheva-Savcheva, G Subramanian, S Figueroa, SQ Figueroa, A Truong, Q Vijayakumar, J Brady, TJ Hoffmann, U Tawakol, A AF Marincheva-Savcheva, Gergana Subramanian, Sharath Figueroa, Sadia QadirAmparo Figueroa, Amparo Truong, Quynh Vijayakumar, Jayanthi Brady, Thomas J. Hoffmann, Udo Tawakol, Ahmed TI Imaging of the Aortic Valve Using Fluorodeoxyglucose Positron Emission Tomography Increased Valvular Fluorodeoxyglucose Uptake in Aortic Stenosis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE aortic stenosis; cardiac imaging; FDG-PET; inflammation ID ATHEROSCLEROTIC PLAQUE INFLAMMATION; C-REACTIVE PROTEIN; RISK-FACTORS; IN-VIVO; PROGRESSION; DISEASE; CALCIFICATION; FDG; ASSOCIATION; SIMVASTATIN AB Objectives Because fluorodeoxyglucose positron emission tomography (FDG-PET) imaging provides a noninvasive index of inflammation, we sought to assess whether FDG uptake in the aortic valve (AV) is increased in aortic stenosis (AS). Background AS is associated with valvular inflammation. Methods FDG-PET/computed tomography data were retrospectively evaluated in 84 patients (age 73 +/- 9 years, 45% female), 42 patients with AS, and 42 age-matched controls. FDG uptake was determined within the AV while blinded to AS severity. Target-to-background ratio (TBR) was calculated as valvular/blood activity. Stenosis severity was established on echocardiography, and presence of AV calcification was independently assessed on computed tomography. Results The aortic valve PET signal (TBR) was increased in AS compared with controls (median 1.53 [interquartile range (IQR): 1.42 to 1.76] vs. 1.34 [IQR: 1.20 to 1.55]; p < 0.001). Further, compared with controls, TBR was increased in mild (median 1.50 [IQR: 1.36 to 1.75]; p = 0.01) and moderate (median 1.70 [IQR: 1.52 to 1.94]; p < 0.001), but not in severe AS (median 1.49 [IQR: 1.40 to 1.54]; p = 0.08). When subjects were categorized according to AV calcification, valvular FDG uptake was increased in mildly (median 1.50 [IQR: 1.36 to 1.79]; p < 0.01) and moderately (median 1.67 [IQR: 1.50 to 1.85]; p < 0.001), but not severely calcified valves (median 1.51 [IQR: 1.38 to 1.54]; p = 0.15), compared with noncalcified valves (median 1.35 [IQR: 1.20 to 1.52]). Conclusions This study supports the hypothesis that AS is an inflammatory condition and suggests that inflammation may be reduced in late-stage disease. This may have important implications in the design of studies assessing the effect of therapeutic agents in modifying progression of AS. (J Am Coll Cardiol 2011;57:2507-15) (C) 2011 by the American College of Cardiology Foundation C1 [Marincheva-Savcheva, Gergana; Subramanian, Sharath; Figueroa, Sadia QadirAmparo; Figueroa, Amparo; Truong, Quynh; Vijayakumar, Jayanthi; Brady, Thomas J.; Hoffmann, Udo; Tawakol, Ahmed] Massachusetts Gen Hosp, Div Cardiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. RP Tawakol, A (reprint author), Massachusetts Gen Hosp, Div Cardiol, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM atawakol@partners.org NR 34 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 21 PY 2011 VL 57 IS 25 BP 2508 EP 2515 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 777RI UT WOS:000291641800009 ER PT J AU Jaffer, FA Calfon, MA Rosenthal, A Mallas, G Razansky, RN Mauskapf, A Weissleder, R Libby, P Ntziachristos, V AF Jaffer, Farouc A. Calfon, Marcella A. Rosenthal, Amir Mallas, Georgios Razansky, R. Nika Mauskapf, Adam Weissleder, Ralph Libby, Peter Ntziachristos, Vasilis TI Two-Dimensional Intravascular Near-Infrared Fluorescence Molecular Imaging of Inflammation in Atherosclerosis and Stent-Induced Vascular Injury SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE atherosclerosis; inflammation; intravascular imaging; molecular imaging; stent ID DRUG-ELUTING STENT; IN-VIVO; CARDIOVASCULAR-DISEASE; CYSTEINE PROTEASES; THROMBOSIS; DESIGN; SYSTEM AB Objectives This study sought to develop a 2-dimensional (2D) intravascular near-infrared fluorescence (NIRF) imaging strategy for investigation of arterial inflammation in coronary-sized vessels. Background Molecular imaging of arterial inflammation could provide new insights into the pathogenesis of acute myocardial infarction stemming from coronary atheromata and implanted stents. Presently, few high-resolution approaches can image inflammation in coronary-sized arteries in vivo. Methods A new 2.9-F rotational, automated pullback 2D imaging catheter was engineered and optimized for 360 degrees viewing intravascular NIRF imaging. In conjunction with the cysteine protease-activatable imaging reporter Prosense VM110 (VisEn Medical, Woburn, Massachusetts), intra-arterial 2D NIRF imaging was performed in rabbit aortas with atherosclerosis (n = 10) or implanted coronary bare-metal stents (n = 10, 3.5-mm diameter, day 7 post-implantation). Intravascular ultrasound provided coregistered anatomical images of arteries. After sacrifice, specimens underwent ex vivo NIRF imaging, fluorescence microscopy, and histological and immunohistochemical analyses. Results Imaging of coronary artery-scaled phantoms demonstrated 8-sector angular resolution and submillimeter axial resolution, nanomolar sensitivity to NIR fluorochromes, and modest NIRF light attenuation through blood. High-resolution NIRF images of vessel wall inflammation with signal-to-noise ratios > 10 were obtained in real-time through blood, without flushing or occlusion. In atherosclerosis, 2D NIRF, intravascular ultrasound-NIRF fusion, microscopy, and immunoblotting studies provided insight into the spatial distribution of plaque protease activity. In stent-implanted vessels, real-time imaging illuminated an edge-based pattern of stent-induced arterial inflammation. Conclusions A new 2D intravascular NIRF imaging strategy provides high-resolution in vivo spatial mapping of arterial inflammation in coronary-sized arteries and reveals increased inflammation-regulated cysteine protease activity in atheromata and stent-induced arterial injury. (J Am Coll Cardiol 2011;57:2516-26) (C) 2011 by the American College of Cardiology Foundation C1 [Jaffer, Farouc A.; Calfon, Marcella A.; Rosenthal, Amir; Mallas, Georgios; Mauskapf, Adam] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Jaffer, Farouc A.; Calfon, Marcella A.; Rosenthal, Amir; Mallas, Georgios; Mauskapf, Adam] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Jaffer, Farouc A.; Weissleder, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA 02114 USA. [Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Libby, Peter] Harvard Univ, Brigham & Womens Hosp, Sch Med, Cardiovasc Div, Boston, MA 02114 USA. [Rosenthal, Amir; Razansky, R. Nika; Ntziachristos, Vasilis] Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Munich, Germany. [Rosenthal, Amir; Razansky, R. Nika; Ntziachristos, Vasilis] Tech Univ Munich, Munich, Germany. [Mallas, Georgios] Northeastern Univ, Dept Elect & Comp Engn, Boston, MA 02115 USA. RP Jaffer, FA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Simches Res Bldg,Room 3206,185 Cambridge St, Boston, MA 02114 USA. EM fjaffer@mgh.harvard.edu; v.ntziachristos@tum.de RI Rosenthal, Amir/C-8650-2014; OI Jaffer, Farouc/0000-0001-7980-384X FU National Institutes of Health [R01 HL 108229, R01 HL 80472]; American Heart Association [0830352N]; Howard Hughes Medical Institute; Broadview Ventures; Donald W. Reynolds Foundation; European Community [FP7/2007-2013, 235689]; MGH; Abbott Vascular FX This work was supported by National Institutes of Health grants #R01 HL 108229 (to Dr. Jaffer) and #R01 HL 80472 (to Dr. Libby), American Heart Association Scientist Development Grant #0830352N (to Dr. Jaffer), Howard Hughes Medical Institute Career Development Award (to Dr. Jaffer), Broadview Ventures (to Drs. Jaffer and Ntziachristos), Donald W. Reynolds Foundation (to Drs. Jaffer, Weissleder, and Libby), European Community's Seventh Framework Programme (FP7/2007-2013 under grant agreement #235689 [to Dr. Rosenthal]), and MGH William Schreyer Fellowship (to Dr. Calfon). Dr. Jaffer has been a consultant to VisEn Medical; and received a research grant from Abbott Vascular. Dr. Weissleder has been a consultant to and has an equity interest in VisEn Medical. All other authors have reported that they have no relationships to disclose. Drs. Jaffer and Calfon contributed equally to this work. NR 20 TC 65 Z9 68 U1 1 U2 30 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 JUN 21 PY 2011 VL 57 IS 25 BP 2516 EP 2526 DI 10.1016/j.jacc.2011.02.036 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 777RI UT WOS:000291641800010 PM 21679853 ER PT J AU Rienstra, M Lubitz, SA Zhang, ML Cooper, RR Ellinor, PT AF Rienstra, Michiel Lubitz, Steven A. Zhang, Michael L. Cooper, Rebecca R. Ellinor, Patrick T. TI Elevation of Parathyroid Hormone Levels in Atrial Fibrillation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter ID PROTEIN C1 [Rienstra, Michiel; Lubitz, Steven A.; Zhang, Michael L.; Cooper, Rebecca R.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. RP Rienstra, M (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St,GRB 109, Boston, MA 02114 USA. EM pellinor@partners.org OI Rienstra, Michiel/0000-0002-2581-070X FU NHLBI NIH HHS [K24 HL105780, R01 HL092577, R01 HL104156, R01HL092577]; NIDA NIH HHS [R21 DA027021, R21DA027021] NR 3 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 21 PY 2011 VL 57 IS 25 BP 2542 EP 2543 DI 10.1016/j.jacc.2011.01.041 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 777RI UT WOS:000291641800014 PM 21679857 ER PT J AU Cambria, RP AF Cambria, Richard P. TI Endovascular Repair of Abdominal Aortic Aneurysm No Cause for Alarm SO CIRCULATION LA English DT Editorial Material DE Editorials; aortic aneurysm, abdominal; endovascular procedures ID OUTCOMES; EVAR; EUROSTAR; DEVICE; TRIAL; GRAFT C1 Massachusetts Gen Hosp, Vasc Ctr, Thorac Aort Ctr, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. RP Cambria, RP (reprint author), Massachusetts Gen Hosp, Vasc Ctr, Thorac Aort Ctr, Div Vasc & Endovasc Surg, 15 Parkman St, Boston, MA 02114 USA. EM rcambria@partners.org NR 15 TC 3 Z9 3 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 JUN 21 PY 2011 VL 123 IS 24 BP 2782 EP 2783 DI 10.1161/CIRCULATIONAHA.111.033134 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 779QM UT WOS:000291795200010 PM 21690501 ER PT J AU Rietman, EA Colt, JZ Tuszynski, JA AF Rietman, Edward A. Colt, John Z. Tuszynski, Jack A. TI Interactomes, manufacturomes and relational biology: analogies between systems biology and manufacturing systems SO THEORETICAL BIOLOGY AND MEDICAL MODELLING LA English DT Article ID INTERACTION MAP; NETWORK; YEAST; CLOSURE; GENES; LIFE AB Background: We review and extend the work of Rosen and Casti who discuss category theory with regards to systems biology and manufacturing systems, respectively. Results: We describe anticipatory systems, or long-range feed-forward chemical reaction chains, and compare them to open-loop manufacturing processes. We then close the loop by discussing metabolism-repair systems and describe the rationality of the self-referential equation f = f (f). This relationship is derived from some boundary conditions that, in molecular systems biology, can be stated as the cardinality of the following molecular sets must be about equal: metabolome, genome, proteome. We show that this conjecture is not likely correct so the problem of self-referential mappings for describing the boundary between living and nonliving systems remains an open question. We calculate a lower and upper bound for the number of edges in the molecular interaction network (the interactome) for two cellular organisms and for two manufacturomes for CMOS integrated circuit manufacturing. Conclusions: We show that the relevant mapping relations may not be Abelian, and that these problems cannot yet be resolved because the interactomes and manufacturomes are incomplete. C1 [Tuszynski, Jack A.] Cross Canc Inst, Dept Expt Oncol, Edmonton, AB T6G 1Z2, Canada. [Rietman, Edward A.] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Rietman, Edward A.] Harvard Univ, Dept Genet, Sch Med, Boston, MA 02115 USA. [Colt, John Z.] IBM Corp, Essex Jct, VT 05452 USA. [Tuszynski, Jack A.] Univ Alberta, Dept Phys, Edmonton, AB T6G 2G7, Canada. [Rietman, Edward A.] Tufts Univ, Ctr Canc Syst Biol, St Elizabeths Med Ctr, Sch Med, Boston, MA 02135 USA. RP Tuszynski, JA (reprint author), Cross Canc Inst, Dept Expt Oncol, 11560 Univ Av, Edmonton, AB T6G 1Z2, Canada. EM jackt@ualberta.ca NR 48 TC 2 Z9 2 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4682 J9 THEOR BIOL MED MODEL JI Theor. Biol. Med. Model. PD JUN 20 PY 2011 VL 8 AR 19 DI 10.1186/1742-4682-8-19 PG 16 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 798NH UT WOS:000293214800001 PM 21689427 ER PT J AU Elkin, EB Klem, ML Gonzales, AM Ishill, NM Hodgson, D Ng, AK Marks, LB Weidhaas, J Freedman, GM Miller, RC Constine, LS Myrehaug, S Yahalom, J AF Elkin, Elena B. Klem, Michelle L. Gonzales, Anne Marie Ishill, Nicole M. Hodgson, David Ng, Andrea K. Marks, Lawrence B. Weidhaas, Joanne Freedman, Gary M. Miller, Robert C. Constine, Louis S. Myrehaug, Sten Yahalom, Joachim TI Characteristics and Outcomes of Breast Cancer in Women With and Without a History of Radiation for Hodgkin's Lymphoma: A Multi-Institutional, Matched Cohort Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LONG-TERM SURVIVAL; FEMALE SURVIVORS; RISK-FACTORS; 2ND CANCER; DISEASE; CHILDHOOD; MORTALITY; AGE; CHEMOTHERAPY; RADIOTHERAPY AB Purpose To compare characteristics and outcomes of breast cancer in women with and without a history of radiation therapy (RT) for Hodgkin's lymphoma (HL). Patients and Methods Women with breast cancer diagnosed from 1980 to 2006 after RT for HL were identified from eight North American hospitals and were matched three-to-one with patients with sporadic breast cancer by age, race, and year of breast cancer diagnosis. Information on patient, tumor and treatment characteristics, and clinical outcomes was abstracted from medical records. Results A total of 253 patients with breast cancer with a history of RT for HL were matched with 741 patients with sporadic breast cancer. Median time from HL to breast cancer diagnosis was 18 years. Median age at breast cancer diagnosis was 42 years. Breast cancer after RT for HL was more likely to be detected by screening, was more likely to be diagnosed at an earlier stage, and was more likely to be bilateral at diagnosis. HL survivors had an increased risk of metachronous contralateral breast cancer (adjusted hazard ratio [HR], 4.3; 95% CI, 1.7 to 11.0) and death as a result of any cause (adjusted HR, 1.9; 95% CI, 1.1 to 3.3). Breast cancer-specific mortality was also elevated, but this difference was not statistically significant (adjusted HR, 1.6; 95% CI, 0.7 to 3.4). Conclusion In women with a history of RT for HL, breast cancer is diagnosed at an earlier stage, but these women are at greater risk for bilateral disease and are more likely to die as a result of causes other than breast cancer. Our findings support close follow-up for contralateral tumors in these patients and ongoing primary care to manage comorbid conditions. C1 [Elkin, Elena B.; Gonzales, Anne Marie; Ishill, Nicole M.; Yahalom, Joachim] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Klem, Michelle L.] Exempla St Joseph Hosp, Denver, CO USA. [Hodgson, David] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Ng, Andrea K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Marks, Lawrence B.] Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Durham, NC 27710 USA. [Weidhaas, Joanne] Yale Univ, New Haven, CT USA. [Freedman, Gary M.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Miller, Robert C.] Mayo Clin, Rochester, MN USA. [Constine, Louis S.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Myrehaug, Sten] NIH, Bethesda, MD 20892 USA. RP Yahalom, J (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. EM yahalomj@mskcc.org OI Weidhaas, Joanne/0000-0002-5096-3281 FU Lymphoma Foundation; Sports Foundation Against Cancer; National Cancer Institute [1 K07 CA118189-01A2]; Memorial Sloan-Kettering Cancer Center FX Supported by the Lymphoma Foundation and the Sports Foundation Against Cancer (J.Y.); by mentored career development award No. 1 K07 CA118189-01A2 from the National Cancer Institute (E. B. E.); and by the Dr. Mortimer J. Lacher, MD, fellowship at Memorial Sloan-Kettering Cancer Center (M.L.K.). NR 40 TC 26 Z9 26 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 JUN 20 PY 2011 VL 29 IS 18 BP 2466 EP 2473 DI 10.1200/JCO.2010.32.4079 PG 8 WC Oncology SC Oncology GA 778EQ UT WOS:000291684600020 PM 21576642 ER PT J AU Yang, M Xie, WL Mostaghel, E Nakabayashi, M Werner, L Sun, T Pomerantz, M Freedman, M Ross, R Regan, M Sharifi, N Figg, WD Balk, S Brown, M Taplin, ME Oh, WK Lee, GSM Kantoff, PW AF Yang, Ming Xie, Wanling Mostaghel, Elahe Nakabayashi, Mari Werner, Lillian Sun, Tong Pomerantz, Mark Freedman, Matthew Ross, Robert Regan, Meredith Sharifi, Nima Figg, William Douglas Balk, Steven Brown, Myles Taplin, Mary-Ellen Oh, William K. Lee, Gwo-Shu Mary Kantoff, Philip W. TI SLCO2B1 and SLCO1B3 May Determine Time to Progression for Patients Receiving Androgen Deprivation Therapy for Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DIHYDROTESTOSTERONE LEVELS; ADRENAL ANDROGENS; TESTOSTERONE; TRANSPORTER; RECEPTOR; TISSUE; IDENTIFICATION; MECHANISMS; EFFICACY; BIOLOGY AB Purpose Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT. Patients and Methods A cohort of 538 patients with prostate cancer treated with ADT was genotyped for SLCO2B1 and SLCO1B3 single nucleotide polymorphisms (SNP). The biologic function of a SLCO2B1 coding SNP in transporting androgen was examined through biochemical assays. Results Three SNPs in SLCO2B1 were associated with time to progression (TTP) on ADT (P < .05). The differences in median TTP for each of these polymorphisms were about 10 months. The SLCO2B1 genotype, which allows more efficient import of androgen, enhances cell growth and is associated with a shorter TTP on ADT. Patients carrying both SLCO2B1 and SLCO1B3 genotypes, which import androgens more efficiently, exhibited a median 2-year shorter TTP on ADT, demonstrating a gene-gene interaction (P-interaction = .041). Conclusion Genetic variants of SLCO2B1 and SLCO1B3 may function as pharmacogenomic determinants of resistance to ADT in prostate cancer. J Clin Oncol 29:2565-2573. (C) 2011 by American Society of Clinical Oncology C1 [Yang, Ming; Xie, Wanling; Nakabayashi, Mari; Werner, Lillian; Sun, Tong; Pomerantz, Mark; Freedman, Matthew; Ross, Robert; Regan, Meredith; Brown, Myles; Taplin, Mary-Ellen; Lee, Gwo-Shu Mary; Kantoff, Philip W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Balk, Steven] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Mostaghel, Elahe] Univ Washington, Seattle, WA 98195 USA. [Sharifi, Nima] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Figg, William Douglas] NCI, NIH, Bethesda, MD 20892 USA. [Oh, William K.] Mt Sinai Sch Med, New York, NY USA. RP Lee, GSM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dana 710B,44 Binney St, Boston, MA 02115 USA. EM gwo-shu_lee@dfci.harvard.edu RI Oh, William/B-9163-2012; Yang, Ming/G-4705-2012; Figg Sr, William/M-2411-2016; OI Oh, William/0000-0001-5113-8147; Yang, Ming/0000-0002-7722-7487; Brown, Myles/0000-0002-8213-1658 FU Dana-Farber/Harvard Cancer Center [2 P50 CA090381-11]; Prostate Cancer Foundation FX Supported by the Dana-Farber/Harvard Cancer Center Prostate Cancer Specialized Program of Research Excellence Grant No. 2 P50 CA090381-11 and a Prostate Cancer Foundation Challenge Grant. NR 34 TC 77 Z9 79 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2011 VL 29 IS 18 BP 2565 EP 2573 DI 10.1200/JCO.2010.31.2405 PG 9 WC Oncology SC Oncology GA 778EQ UT WOS:000291684600034 PM 21606417 ER PT J AU Chapman, PB Hauschild, A Robert, C Larkin, JMG Haanen, JBAG Ribas, A Hogg, D O'Day, S Ascierto, PA Testori, A Lorigan, P Dummer, R Sosman, JA Garbe, C Lee, RJ Nolop, KB Nelson, B Hou, J Flaherty, KT McArthur, GA AF Chapman, P. B. Hauschild, A. Robert, C. Larkin, J. M. G. Haanen, J. B. A. G. Ribas, A. Hogg, D. O'Day, S. Ascierto, P. A. Testori, A. Lorigan, P. Dummer, R. Sosman, J. A. Garbe, C. Lee, R. J. Nolop, K. B. Nelson, B. Hou, J. Flaherty, K. T. McArthur, G. A. TI Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with (V600E)BRAF-mutated melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Klinikum Schleswig Holstein, Kiel Schleswig Holstein, Germany. Canc Inst Gustave Roussy, Villejuif, France. Royal Marsden Hosp, Urol Unit, London SW3 6JJ, England. Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. Princess Margaret Hosp, Dept Med Oncol, Toronto, ON M4X 1K9, Canada. Univ Toronto, Toronto, ON, Canada. Angeles Clin & Res Inst, Los Angeles, CA USA. Ist Nazl Tumori, Naples, Italy. European Inst Oncol, Milan, Italy. Christie Hosp, Manchester, Lancs, England. Univ Zurich Hosp, CH-8091 Zurich, Switzerland. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Univ Tubingen, Tubingen, Germany. Hoffmann La Roche Inc, Pharma Res & Early Dev, Nutley, NJ 07110 USA. Plexxikon Inc, Berkeley, CA USA. Genentech Inc, San Francisco, CA 94080 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Peter MacCallum Canc Ctr, Dept Med Oncol, Melbourne, Australia. RI Lorigan, Paul/J-6898-2015 OI Lorigan, Paul/0000-0002-8875-2164 NR 0 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 EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2011 VL 29 IS 18 SU S MA LBA4 PG 1 WC Oncology SC Oncology GA V31EB UT WOS:000208865800016 ER PT J AU Goss, PE Ingle, JN Ales-Martinez, J Cheung, A Chlebowski, RT Wactawski-Wende, J McTiernan, A Robbins, J Johnson, K Martin, L Winquist, E Sarto, G Garber, JE Fabian, CJ Pujol, P Maunsell, E Farmer, P Gelmon, KA Tu, D Richardson, H AF Goss, P. E. Ingle, J. N. Ales-Martinez, J. Cheung, A. Chlebowski, R. T. Wactawski-Wende, J. McTiernan, A. Robbins, J. Johnson, K. Martin, L. Winquist, E. Sarto, G. Garber, J. E. Fabian, C. J. Pujol, P. Maunsell, E. Farmer, P. Gelmon, K. A. Tu, D. Richardson, H. TI Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3-A randomized, placebo-controlled clinical trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Mayo Clin, Rochester, MN USA. Hosp Ruber Int, Madrid, Spain. Univ Hlth Network, Toronto, ON, Canada. Harbor UCLA Med Ctr, Torrance, CA 90509 USA. SUNY Buffalo, Buffalo, NY 14260 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Calif Davis, Sacramento, CA 95817 USA. Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. George Washington Univ, Sch Med, Washington, DC USA. London Hlth Sci Ctr, London, ON, Canada. Ctr Womens Hlth & Hlth Res, Madison, WI USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. CHU Hop Arnaud de Villeneuve, Montpellier, France. Univ Laval, Quebec City, PQ, Canada. Queens Univ Pathol & Mol Med, Kingston, ON, Canada. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. NCIC Clin Trials Grp, Kingston, ON, Canada. NR 0 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 EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2011 VL 29 IS 18 SU S MA LBA504 PG 2 WC Oncology SC Oncology GA V31EB UT WOS:000208865800025 ER PT J AU Infante, JR Falchook, GS Lawrence, DP Weber, JS Kefford, RF Bendell, JC Kurzrock, R Shapiro, G Kudchadkar, RR Long, GV Burris, HA Kim, KB Clements, A Peng, S Yi, B Allred, AJ Ouellet, D Patel, K Lebowitz, PF Flaherty, KT AF Infante, J. R. Falchook, G. S. Lawrence, D. P. Weber, J. S. Kefford, R. F. Bendell, J. C. Kurzrock, R. Shapiro, G. Kudchadkar, R. R. Long, G. V. Burris, H. A. Kim, K. B. Clements, A. Peng, S. Yi, B. Allred, A. J. Ouellet, D. Patel, K. Lebowitz, P. F. Flaherty, K. T. TI Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Sarah Cannon Canc Ctr, Nashville, TN USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Univ Sydney, Westmead Hosp, Melanoma Inst Australia, Westmead Inst Canc Res, Sydney, NSW 2006, Australia. Sarah Cannon Res Inst, Nashville, TN USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. Royal Prince Alfred Hosp, Sydney, NSW, Australia. Westmead Hosp, Sydney, NSW, Australia. GlaxoSmithKline, Collegeville, PA USA. GlaxoSmithKline, Res Triangle Pk, NC USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 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 EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2011 VL 29 IS 18 SU S MA CRA8503 PG 1 WC Oncology SC Oncology GA V31EB UT WOS:000208865800007 ER PT J AU Kris, MG Johnson, BE Kwiatkowski, DJ Iafrate, AJ Wistuba, II Aronson, SL Engelman, JA Shyr, Y Khuri, FR Rudin, CM Garon, EB Pao, W Schiller, JH Haura, EB Shirai, K Giaccone, G Berry, LD Kugler, K Minna, JD Bunn, PA AF Kris, M. G. Johnson, B. E. Kwiatkowski, D. J. Iafrate, A. J. Wistuba, I. I. Aronson, S. L. Engelman, J. A. Shyr, Y. Khuri, F. R. Rudin, C. M. Garon, E. B. Pao, W. Schiller, J. H. Haura, E. B. Shirai, K. Giaccone, G. Berry, L. D. Kugler, K. Minna, J. D. Bunn, P. A. TI Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI's Lung Cancer Mutation Consortium (LCMC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Partners Hlth Canc Ctr, Boston, MA USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. Med Univ S Carolina, Charleston, SC 29425 USA. NCI, Bethesda, MD 20892 USA. Vanderbilt Univ, Nashville, TN 37235 USA. Univ Colorado, Canc Ctr Denver, Aurora, CO USA. Univ Colorado Denver, Ctr Canc, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 2 U2 7 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 JUN 20 PY 2011 VL 29 IS 18 SU S MA CRA7506 PG 1 WC Oncology SC Oncology GA V31EB UT WOS:000208865800005 ER PT J AU Stanley, TL Falutz, J Mamputu, JC Soulban, G Potvin, D Grinspoon, SK AF Stanley, Takara L. Falutz, Julian Mamputu, Jean-Claude Soulban, Graziella Potvin, Diane Grinspoon, Steven K. TI Effects of tesamorelin on inflammatory markers in HIV patients with excess abdominal fat: relationship with visceral adipose reduction SO AIDS LA English DT Article DE adiponectin; growth hormone releasing hormone; HIV; intra-abdominal fat; plasminogen activator inhibitor 1; tesamorelin; tissue plasminogen activator ID CORONARY-HEART-DISEASE; TISSUE-PLASMINOGEN ACTIVATOR; ACUTE MYOCARDIAL-INFARCTION; HORMONE-RELEASING FACTOR; VIRUS-INFECTED PATIENTS; C-REACTIVE PROTEIN; CARDIOVASCULAR RISK; INSULIN-RESISTANCE; BODY-COMPOSITION; ANTIRETROVIRAL THERAPY AB Objective: To report the effects of tesamorelin, a growth hormone-releasing hormone analogue, on inflammatory and fibrinolytic markers and to relate these effects to changes in visceral adipose tissue (VAT). Design and methods: Four hundred and ten HIV-infected patients with abdominal adiposity were randomized to 2mg tesamorelin (n = 273) or placebo (n = 137) subcutaneously daily for 26 weeks. Circulating plasminogen activator inhibitor-1 (PAI-1) antigen, tissue plasminogen activator (tPA) antigen, C-reactive protein (CRP), and adiponectin were assessed. Results: At baseline, VAT was significantly associated with PAI-1 antigen (rho = 0.36, P<0.001), tPA antigen (rho = 0.29, P<0.001), CRP (rho = 0.18, P<0.001), and adiponectin (rho = -0.22, P<0.001). Treatment with tesamorelin resulted in a significant decrease from baseline in tPA antigen (-2.2 +/- 2.5 vs. -1.6 +/- 2.9 ng/ml, tesamorelin vs. placebo, P<0.05). Changes in PAI-1 antigen were not significant in the tesamorelin group compared to placebo. Among patients receiving tesamorelin, changes in inflammatory markers were associated with change in VAT (PAI-1 antigen: rho = 0.16, P = 0.02; tPA antigen: rho = 0.16, P = 0.02; adiponectin: rho = -0.27, P<0.001), and these associations remained significant when controlling for changes in insulin-like growth factor-1. Conclusion: In HIV patients with abdominal adiposity, tesamorelin may have a modest beneficial effect on adiponectin and fibrinolytic markers in association with changes in VAT. Further studies are needed to determine the clinical significance of these changes. These data further highlight the deleterious role of excessive VAT and the utility of strategies to improve VAT in this population. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Stanley, Takara L.; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Stanley, Takara L.; Grinspoon, Steven K.] Harvard Univ, Sch Med, Boston, MA USA. [Falutz, Julian] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Mamputu, Jean-Claude; Soulban, Graziella; Potvin, Diane] Theratechnologies Inc, Montreal, PQ, Canada. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 5 Longfellow Pl,Suite 207, Boston, MA 02114 USA. EM sgrinspoon@partners.org OI Mamputu, Jean-Claude/0000-0001-8493-959X FU Theratechnologies Inc., Montreal, Canada; NIH [K23 DK089910, K24 DK064545]; Theratechnologies, Inc.; EMD Serono, Inc. FX This work was supported by Theratechnologies Inc., Montreal, Canada. NIH funding through K23 DK089910 to T. L. S, and K24 DK064545 to S. K. G. T. L. S. has nothing to disclose. J.F. reports having received research support from Theratechnologies, Inc. and serving as a consultant to Theratechnologies Inc. J.C.M, G. S., and D. P. are employees of Theratechnologies, Inc. S. K. G. reports having received research support from Theratechnologies, Inc. and EMD Serono, Inc., and serving as a consultant to Theratechnologies, Inc. and EMD Serono, Inc. NR 42 TC 9 Z9 9 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 19 PY 2011 VL 25 IS 10 BP 1281 EP 1288 DI 10.1097/QAD.0b013e328347f3f1 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 775MI UT WOS:000291463200005 PM 21516030 ER PT J AU Choi, AI Vittinghoff, E Deeks, SG Weekley, CC Li, YM Shlipak, MG AF Choi, Andy I. Vittinghoff, Eric Deeks, Steven G. Weekley, Cristin C. Li, Yongmei Shlipak, Michael G. TI Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons SO AIDS LA English DT Article DE antiretroviral therapy; cardiovascular disease; heart failure; HIV ID CHRONIC KIDNEY-DISEASE; COMBINATION ANTIRETROVIRAL THERAPY; REVERSE-TRANSCRIPTASE INHIBITORS; OF-VETERANS-AFFAIRS; MYOCARDIAL-INFARCTION; RENAL-FUNCTION; NAIVE PATIENTS; YOUNG-ADULTS; COHORT; RATES AB Objective: Abacavir use has been associated with cardiovascular risk, but it is unknown whether this association may be partly explained by patients with kidney disease being preferentially treated with abacavir to avoid tenofovir. Our objective was to compare associations of abacavir and tenofovir with cardiovascular risks in HIV-infected veterans. Design: Cohort study of 10 931 HIV-infected patients initiating antiretroviral therapy in the Veterans Health Administration from 1997 to 2007, using proportional hazards survival regression. Methods: Primary predictors were exposure to abacavir or tenofovir within the past 6 months, compared with no exposure to these drugs, respectively. Outcomes were time to first atherosclerotic cardiovascular event, defined as coronary, cerebrovascular, or peripheral arterial disease; and time to incident heart failure. Results: Over 60 588 person-years of observation, there were 501 cardiovascular and 194 heart failure events. Age-standardized event rates among abacavir and tenofovir users were 12.5 versus 8.2 per 1000 person-years for cardiovascular disease, and 3.9 and 3.7 per 1000 person-years for heart failure, respectively. In multivariate-adjusted models, including time-updated measurements of kidney function, recent abacavir use was significantly associated with incident cardiovascular disease [hazard ratio 1.48, 95% confidence interval (CI) 1.08-2.04]; the association was similar but nonsignificant for heart failure (1.45, 0.85-2.47). In contrast, recent tenofovir use was significantly associated with heart failure (1.82, 1.02-3.24), but not with cardiovascular events (0.78, 0.52-1.16). Conclusion: Recent abacavir exposure was independently associated with increased risk for cardiovascular events. We also observed an association between recent tenofovir exposure and heart failure, which needs to be confirmed in future studies. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Choi, Andy I.; Weekley, Cristin C.; Li, Yongmei; Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94121 USA. [Choi, Andy I.; Vittinghoff, Eric; Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Deeks, Steven G.] San Francisco Gen Hosp, Posit Hlth Program, San Francisco, CA 94110 USA. RP Shlipak, MG (reprint author), San Francisco VA Med Ctr, Dept Med, Box 111A1,4150 Clement St, San Francisco, CA 94121 USA. EM michael.shlipak@ucsf.edu FU National Institutes of Health [K23DK080645-01A1, 1R03AG034871-01, K24AI069994, R01 DK066488-01]; National Center for Research Resources [KL2 RR024130]; American Heart Association; VA Public Health Strategic Healthcare Group; Merck; Bristol-Myers Squibb; Gilead; Roche Molecular Sciences FX This study was supported by the National Institutes of Health [K23DK080645-01A1 (AIC), 1R03AG034871-01 (AIC/MGS), K24AI069994, R01 DK066488-01 (MGS/AIC)], the National Center for Research Resources (KL2 RR024130), the American Heart Association Established Investigator Award (MGS), and the VA Public Health Strategic Healthcare Group. These funding sources had no involvement in the design or execution of this study.; S.G.D. receives research support from Merck, Bristol-Myers Squibb, Gilead, and Roche Molecular Sciences. NR 52 TC 76 Z9 76 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 19 PY 2011 VL 25 IS 10 BP 1289 EP 1298 DI 10.1097/QAD.0b013e328347fa16 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 775MI UT WOS:000291463200006 PM 21516027 ER PT J AU Feehan, M Hartman, J Durante, R Morrison, MA Miller, JW Kim, IK DeAngelis, MM AF Feehan, Michael Hartman, John Durante, Richard Morrison, Margaux A. Miller, Joan W. Kim, Ivana K. DeAngelis, Margaret M. TI Identifying subtypes of patients with neovascular age-related macular degeneration by genotypic and cardiovascular risk characteristics SO BMC MEDICAL GENETICS LA English DT Article ID COMPLEMENT FACTOR-H; BEAVER DAM EYE; LOW-DENSITY LIPOPROTEINS; BLUE-MOUNTAINS-EYE; CHOROIDAL NEOVASCULARIZATION; PERSONALIZED MEDICINE; ALCOHOL-CONSUMPTION; CIGARETTE-SMOKING; 10-YEAR INCIDENCE; EPITHELIAL-CELLS AB Background: One of the challenges in the interpretation of studies showing associations between environmental and genotypic data with disease outcomes such as neovascular age-related macular degeneration (AMD) is understanding the phenotypic heterogeneity within a patient population with regard to any risk factor associated with the condition. This is critical when considering the potential therapeutic response of patients to any drug developed to treat the condition. In the present study, we identify patient subtypes or clusters which could represent several different targets for treatment development, based on genetic pathways in AMD and cardiovascular pathology. Methods: We identified a sample of patients with neovascular AMD, that in previous studies had been shown to be at elevated risk for the disease through environmental factors such as cigarette smoking and genetic variants including the complement factor H gene (CFH) on chromosome 1q25 and variants in the ARMS2/HtrA serine peptidase 1 (HTRA1) gene(s) on chromosome 10q26. We conducted a multivariate segmentation analysis of 253 of these patients utilizing available epidemiologic and genetic data. Results: In a multivariate model, cigarette smoking failed to differentiate subtypes of patients. However, four meaningfully distinct clusters of patients were identified that were most strongly differentiated by their cardiovascular health status (histories of hypercholesterolemia and hypertension), and the alleles of ARMS2/HTRA1 rs1049331. Conclusions: These results have significant personalized medicine implications for drug developers attempting to determine the effective size of the treatable neovascular AMD population. Patient subtypes or clusters may represent different targets for therapeutic development based on genetic pathways in AMD and cardiovascular pathology, and treatments developed that may elevate CV risk, may be ill advised for certain of the clusters identified. C1 [Morrison, Margaux A.; Miller, Joan W.; Kim, Ivana K.; DeAngelis, Margaret M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Mol Genet Inst, Boston, MA 02114 USA. [Morrison, Margaux A.; Miller, Joan W.; Kim, Ivana K.; DeAngelis, Margaret M.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Retina Serv, Boston, MA 02114 USA. [Feehan, Michael; Hartman, John; Durante, Richard] Observant LLC, Waltham, MA 02451 USA. [Morrison, Margaux A.; DeAngelis, Margaret M.] Univ Utah, Moran Eye Ctr, Salt Lake City, UT 84132 USA. RP DeAngelis, MM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Mol Genet Inst, 243 Charles St, Boston, MA 02114 USA. EM Margaret.deangelis@utah.edu RI DeAngelis, e/J-7863-2015 FU Lincy Foundation; Marion W. and Edward F. Knight Age-Related Macular Degeneration Fund; Genetics of Age-Related Macular Degeneration Fund; MEEI; Research to Prevent Blindness (University of Utah); Edward N. and Della L. Thome Award; NIH [EY014458] FX Supported by grants from the Lincy Foundation, the Marion W. and Edward F. Knight Age-Related Macular Degeneration Fund, Genetics of Age-Related Macular Degeneration Fund, MEEI, Unrestricted grant from the Research to Prevent Blindness (University of Utah), The Edward N. and Della L. Thome Award, and NIH grant EY014458. We thank Liza Pliss and Michael Walsh from Observant LLC for support in these analyses, and we are especially grateful to the patients for their participation in this study. NR 73 TC 5 Z9 5 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JUN 17 PY 2011 VL 12 AR 83 DI 10.1186/1471-2350-12-83 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 793OA UT WOS:000292831800001 PM 21682878 ER PT J AU Woods, DC White, YAR Dau, C Johnson, AL AF Woods, Dori C. White, Yvonne A. R. Dau, Caroline Johnson, A. L. TI TLR4 activates NF-kappa B in human ovarian granulosa tumor cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Granulosa cell tumor; Toll-like receptor; TLR; Ovary; LPS; Lipopolysaccharide; Ovarian cancer ID TRAIL-INDUCED APOPTOSIS; TNF-ALPHA; CANCER; INHIBITION; LIPOPOLYSACCHARIDE; EXPRESSION; LINES; CHEMORESISTANCE; SENSITIVITY; RECEPTORS AB Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (USE) and in epithelial ovarian tumors. Most notably, USE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-kappa B) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to I kappa B degradation and activation of NF-kappa B. NF-kappa B activation was confirmed by nuclear localization of NF-kappa B p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-kappa B signaling attenuated LPS-induced TNF alpha plus increased doubling time in both cell lines. Contradictory to reports using human USE cell lines, inhibition of NF-kappa B signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to USE-derived cancers, inhibition of NF-kappa B does not sensitize GCTs to TRAIL or cisplatin. (C) 2011 Elsevier Inc. All rights reserved. C1 [Woods, Dori C.; White, Yvonne A. R.] Harvard Univ, Vincent Obstet & Gynecol Serv, Massachusetts Gen Hosp, Vincent Ctr Reprod Biol,Sch Med, Boston, MA 02114 USA. [Johnson, A. L.] Penn State Univ, Ctr Reprod Biol & Hlth, University Pk, PA 16802 USA. [Dau, Caroline] Univ Calif San Francisco, Sch Dent, San Francisco, CA 94143 USA. RP Woods, DC (reprint author), Harvard Univ, Vincent Obstet & Gynecol Serv, Massachusetts Gen Hosp, Vincent Ctr Reprod Biol,Sch Med, Boston, MA 02114 USA. EM dwoods2@partners.org FU USDA Cooperative State Research, Education, and Extension Service [2007-35203-18085]; [F32AG034809-02] FX This work was supported by National Research Initiative Competitive Grant No. 2007-35203-18085 from the USDA Cooperative State Research, Education, and Extension Service and F32AG034809-02 (to D.C.W.). NR 28 TC 17 Z9 21 U1 0 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 17 PY 2011 VL 409 IS 4 BP 675 EP 680 DI 10.1016/j.bbrc.2011.05.063 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 787ED UT WOS:000292358500015 PM 21616060 ER PT J AU Goebel-Stengel, M Wang, LX Stengel, A Tache, Y AF Goebel-Stengel, Miriam Wang, Lixin Stengel, Andreas Tache, Yvette TI Localization of nesfatin-1 neurons in the mouse brain and functional implication SO BRAIN RESEARCH LA English DT Article DE Fos; Hypothalamus; Medulla; NUCB2; Gastric emptying; Water avoidance stress ID CORTICOTROPIN-RELEASING-FACTOR; MELANIN-CONCENTRATING HORMONE; EDINGER-WESTPHAL-NUCLEUS; PITUITARY-ADRENAL AXIS; WATER-AVOIDANCE STRESS; DORSAL MOTOR NUCLEUS; FOS EXPRESSION; RAT-BRAIN; PARAVENTRICULAR NUCLEUS; FOOD-INTAKE AB Nesfatin-1 reduces food intake when injected centrally in rodents. We recently described wide distribution of nucleobindin2 (NUCB2)/nesfatin-1 immunoreactivity in rat brain autonomic nuclei activated by various stressors. We used C57BL/6 mice to localize brain NUCB2/nesfatin-1 immunoreactivity and assessed activation of NUCB2/nesfatin 1 neurons after water avoidance stress (WAS). Gastric emptying of a non-nutrient liquid was also determined. NUCB2/nesfatin-1 immunoreactivity was detected in cortical areas including piriform, insular, cingulate and somatomotor cortices, the limbic system including amygdaloid nuclei, hippocampus and septum, the basal ganglia, bed nucleus of the stria terminalis, the thalamus including paraventricular and parafascicular nuclei, the hypothalamus including supraoptic, periventricular, paraventricular (PVN), arcuate nuclei and ventromedial and lateral hypothalamic areas. Intensely labeled NUCB2/nesfatin-1 neurons were detected in a previously undefined region which we named intermediate dorsomedial hypothalamus. In the brainstem, NUCB2/nesfatin-1 immunoreactivity was detected in the raphe nuclei, Edinger-Westphal nucleus, locus coeruleus (LC), lateral parabrachial nucleus, ventrolateral medulla (VLM) and dorsal vagal complex. WAS induced Fos expression in 35% of NUCB2/nesfatin-1-immunoreactive neurons in the PVN, 50% in the LC, 54% in the rostral raphe pallidus, 58% in the VLM, 39% in the middle part of the nucleus of the solitary tract (NTS) and 33% in the caudal NTS. Nesfatin-1 injected intracerebroventricularly significantly decreased gastric emptying. These data showed that NUCB2/nesfatin-1 immunoreactivity is distributed in mouse brain areas involved in the regulation of stress response and visceral functions activated by an acute psychological stressor suggesting that nesfatin-1 might play a role in the efferent component of the stress response. Published by Elsevier B.V. C1 [Tache, Yvette] VA Greater Los Angeles Healthcare Syst, Ctr Neurovisceral Sci & Womens Hlth, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, CURE Digest Dis Res Ctr, Ctr Neurobiol Stress,Digest Dis Div,Dept Med, Los Angeles, CA 90095 USA. RP Tache, Y (reprint author), VA Greater Los Angeles Healthcare Syst, Ctr Neurovisceral Sci & Womens Hlth, CURE Bldg 115,Room 117,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM ytache@mednet.ucla.edu FU Department of Veterans Affairs, NIHDK [33061]; [DK-41301] FX This work was supported by the VA Research Career Scientist Award, Department of Veterans Affairs, NIHDK 33061 (Y.T.) and Center grant DK-41301 (Animal Core, Y.T.). We are grateful to Ms. Honghui Liang for her excellent technical support and Ms. Eugenia Hu for reviewing the manuscript. NR 57 TC 55 Z9 60 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 17 PY 2011 VL 1396 BP 20 EP 34 DI 10.1016/j.brainres.2011.04.031 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 788AD UT WOS:000292416900003 PM 21555116 ER PT J AU James, SK Roe, MT Cannon, CP Cornel, JH Horrow, J Husted, S Katus, H Morais, J Steg, PG Storey, RF Stevens, S Wallentin, L Harrington, RA AF James, Stefan K. Roe, Matthew T. Cannon, Christopher P. Cornel, Jan H. Horrow, Jay Husted, Steen Katus, Hugo Morais, Joao Steg, Ph Gabriel Storey, Robert F. Stevens, Susanna Wallentin, Lars Harrington, Robert A. TI Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial SO BRITISH MEDICAL JOURNAL LA English DT Article ID ST-SEGMENT ELEVATION; GUSTO IV-ACS; MEDICAL-MANAGEMENT; INVASIVE STRATEGY; REVASCULARIZATION; ABCIXIMAB AB Objective To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy. Design Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial. Setting 862 centres in 43 countries. Participants 5216 (28%) of 18 624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management. Interventions Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615). Main outcome measurements Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year. Results 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel. Conclusions In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy. C1 [James, Stefan K.; Wallentin, Lars] Uppsala Univ, Uppsala Clin Res Ctr, S-75185 Uppsala, Sweden. [Roe, Matthew T.; Stevens, Susanna; Harrington, Robert A.] Duke Clin Res Inst, Durham, NC USA. [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Cornel, Jan H.] Med Ctr Alkmaar, Alkmaar, Netherlands. [Horrow, Jay] AstraZeneca R&D, Global Med Dev, Wilmington, DE USA. [Husted, Steen] Arhus Univ Hosp, Dept Cardiol, Thrombosis Unit, Aarhus, Denmark. [Katus, Hugo] Univ Klinikum Heidelberg, Med Klin, Dept Internal Med, Heidelberg, Germany. [Morais, Joao] Santo Andres Hosp, Leiria, Portugal. [Steg, Ph Gabriel] INSERM, U698, Paris, France. [Steg, Ph Gabriel] Univ Paris 07, Paris, France. [Steg, Ph Gabriel] Hop Bichat Claude Bernard, AP HP, F-75877 Paris, France. [Storey, Robert F.] Univ Sheffield, Dept Cardiovasc Sci, Sheffield, S Yorkshire, England. RP James, SK (reprint author), Uppsala Univ, Uppsala Clin Res Ctr, Dag Hammarskjolds Vag 50A,MTC Huset,Sci Pk,Box 63, S-75185 Uppsala, Sweden. EM Stefan.James@ucr.uu.se RI Katus, Hugo/P-1712-2016 FU AstraZeneca; Eli Lilly; Bristol-Myers Squibb; Sanofi-Aventis; Merck/Schering-Plough; GlaxoSmithKline; Novartis; Accumetrics; Intekrin Therapeutics; Merck; Takeda; Pfizer; Bayer; Daiichi; Sankoy; Roche; Daiichi Sankyo; MSD/Schering-Plough; Servier; Astellas; Daiichi/Sankyo/Eli Lilly alliance; Medtronic; Otsuka Pharmaceutical; Medicines Company; Dynabyte; Eli Lilly/Daiichi Sankyo alliance; Sanofi-Aventis/Bristol-Myers Squibb; Regado Biotechnologies; Athera Biotechnologies; Portola Pharmaceutical; Portola FX This work was supported by AstraZeneca, who funded the PLATO trial. Representatives of the sponsor were involved in study design; data gathering, analysis, and interpretation; and revision of the report. Support for the analysis and interpretation of results and preparation of the manuscript was provided through funds to the Uppsala Clinical Research Center and Duke Clinical Research Institute as part of the clinical study agreement.; All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available upon request from the corresponding author). SKJ declares research grants and advisory board fees from AstraZeneca and honorariums from AstraZeneca, Bristol-Myers Squibb, Schering-Plough, Merck, and Eli-Lilly. MTR declares research grants from Eli Lilly, Bristol-Myers Squibb, Sanofi-Aventis, and Merck/Schering-Plough; consulting fees or honorariums from GlaxoSmithKline, Novartis, Eli Lilly, Bristol-Myers Squibb, Sanofi-Aventis, Merck/Schering-Plough, and AstraZeneca. CPC receives research grants/support from Accumetrics, AstraZeneca, Glaxo-SmithKline, Intekrin Therapeutics, Merck, and Takeda; has served on advisory boards for Bristol-Myers Squibb/Sanofi-Aventis, Novartis, and Alnyam (but donates funds to charity); receives honorariums for development of independent educational symposiums from Pfizer and AstraZeneca; and is a clinical adviser for and holds equity in Automedics Medical Systems. JHC declares consulting fees from Eli Lilly and Pfizer. JH is an employee of AstraZeneca and has equity ownership in AstraZeneca. SH declares research grants from AstraZeneca, Bristol-Myers Squibb, Pfizer, and Bayer and consultant fees from Sanofi-Aventis, Pfizer, and AstraZeneca. HK declares consulting and lecture fees from AstraZeneca., Bayer, Daiichi, Sankoy, and Roche. JM declares research grants from AstraZeneca, Bayer, Daiichi Sankyo, MSD/Schering-Plough, and Eli Lilly. PGS declares research grants from Servier; consultant fees from/advisory board membership for Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi/Sankyo/Eli Lilly alliance, GlaxoSmithKline, Medtronic, Merck, Otsuka Pharmaceutical, Roche, Sanofi-Aventis, Servier, and the Medicines Company; and having equity ownership in Aterovax. RFS declares institutional grants from AstraZeneca, Dynabyte, Eli Lilly/Daiichi Sankyo alliance, Merck/Schering-Plough, and Accumetrics; honorariums from AstraZeneca, Eli Lilly/Daiichi Sankyo alliance, Novartis, Medscape, GlaxoSmithKline, and Merck/Schering-Plough; consultant fees from AstraZeneca, Eli Lilly/Daiichi Sankyo alliance, Merck/Schering-Plough, Novartis, Sanofi-Aventis/Bristol-Myers Squibb, the Medicines Company, and Accumetrics; travel support from AstraZeneca, Eli Lilly/Daiichi Sankyo alliance, and Merck/Schering-Plough. LW reports research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, and Schering-Plough; honorariums from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Schering-Plough, and Eli Lilly; consultant fees from Regado Biotechnologies, Athera Biotechnologies, Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, and Eli Lilly; and lecture fees from AstraZeneca, Boehringer Ingelheim, and Eli Lilly. RAH reports advisory board fees from Novartis, Portola Pharmaceutical, and Merck; consulting fees from AstraZeneca, Bristol-Myers Squibb, Merck, Novartis, Portola, and Sanofi-Aventis; honorariums/lecture fees from Eli Lilly, Merck, and AstraZeneca; grant support from AstraZeneca, Bristol-Myers Squibb, Portola Pharmaceutical, and Merck; travel support from AstraZeneca, Novartis, and Merck; and potential grant support from the Medicines Company. NR 17 TC 113 Z9 118 U1 0 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JUN 17 PY 2011 VL 342 AR d3527 DI 10.1136/bmj.d3527 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 781LH UT WOS:000291933200003 PM 21685437 ER PT J AU Helfand, M AF Helfand, Mark TI Medical Research for Hire The Political Economy of Pharmaceutical Clinical Trials SO SCIENCE LA English DT Book Review C1 [Helfand, Mark] Portland VA Med Ctr, Portland, OR 97239 USA. [Helfand, Mark] Oregon Hlth & Sci Univ, Ctr Biomed Informat Commun, Dept Med Informat & Clin Epidemiol, Portland, OR 97239 USA. RP Helfand, M (reprint author), Portland VA Med Ctr, Portland, OR 97239 USA. EM helfand@ohsu.edu NR 2 TC 0 Z9 0 U1 1 U2 1 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 JUN 17 PY 2011 VL 332 IS 6036 BP 1383 EP 1383 DI 10.1126/science.1198268 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 778FT UT WOS:000291689000023 ER PT J AU Anderson, E Siegel, EH Bliss-Moreau, E Barrett, LF AF Anderson, Eric Siegel, Erika H. Bliss-Moreau, Eliza Barrett, Lisa Feldman TI The Visual Impact of Gossip SO SCIENCE LA English DT Article ID BINOCULAR-RIVALRY; DOMINANCE DURATIONS; FACIAL EXPRESSIONS; PERCEPTION; ATTENTION; CONTRAST; EMOTION; FACES; RECOGNITION; PREDOMINATE AB Gossip is a form of affective information about who is friend and who is foe. We show that gossip does not influence only how a face is evaluated-it affects whether a face is seen in the first place. In two experiments, neutral faces were paired with negative, positive, or neutral gossip and were then presented alone in a binocular rivalry paradigm (faces were presented to one eye, houses to the other). In both studies, faces previously paired with negative (but not positive or neutral) gossip dominated longer in visual consciousness. These findings demonstrate that gossip, as a potent form of social affective learning, can influence vision in a completely top-down manner, independent of the basic structural features of a face. C1 [Anderson, Eric; Siegel, Erika H.; Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Bliss-Moreau, Eliza] Univ Calif Davis, Dept Psychiat & Behav Sci, Davis, CA 95616 USA. [Barrett, Lisa Feldman] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Barrett, Lisa Feldman] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Barrett, LF (reprint author), Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. EM l.barrett@neu.edu OI Anderson, Eric/0000-0002-4215-6308 FU NIH [DP1OD003312]; U.S. Army Research Institute for the Behavioral and Social Sciences [W91WAW-08-C-0018] FX Preparation of this manuscript was supported by the NIH Director's Pioneer Award (DP1OD003312) and by the U.S. Army Research Institute for the Behavioral and Social Sciences (contract W91WAW-08-C-0018) to L.F.B. The views, opinions, and/or findings contained in this article are solely those of the author(s) and should not be construed as an official Department of the Army or Department of Defense position, policy, or decision. We thank J. Shang and M. Norton for their help with data collection. NR 34 TC 53 Z9 54 U1 0 U2 40 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 JUN 17 PY 2011 VL 332 IS 6036 BP 1446 EP 1448 DI 10.1126/science.1201574 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 778FT UT WOS:000291689000046 PM 21596956 ER PT J AU Gradmark, A Pomeroy, J Renstrom, F Steiginga, S Persson, M Wright, A Bluck, L Domellof, M Kahn, SE Mogren, I Franks, PW AF Gradmark, Anna Pomeroy, Jeremy Renstrom, Frida Steiginga, Susanne Persson, Margareta Wright, Antony Bluck, Les Domellof, Magnus Kahn, Steven E. Mogren, Ingrid Franks, Paul W. TI Physical activity, sedentary behaviors, and estimated insulin sensitivity and secretion in pregnant and non-pregnant women SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE pregnancy; physical activity; sedentary time; beta?beta?-cell response; insulin sensitivity ID ENERGY-EXPENDITURE; LONGITUDINAL CHANGES; GLUCOSE-TOLERANCE; LABELED WATER; RESISTANCE; INTERVENTION; PREVENTION; HUMANS AB Background: Overweight and obesity during pregnancy raise the risk of gestational diabetes and birth complications. Lifestyle factors like physical activity may decrease these risks through beneficial effects on glucose homeostasis. Here we examined physical activity patterns and their relationships with measures of glucose homeostasis in late pregnancy compared to non-pregnant women. Methods: Normal weight and overweight women without diabetes (N = 108; aged 25-35 years) were studied; 35 were pregnant (in gestational weeks 28-32) and 73 were non-pregnant. Insulin sensitivity and beta-cell response were estimated from an oral glucose tolerance test. Physical activity was measured during 10-days of free-living using a combined heart rate sensor and accelerometer. Total (TEE), resting (REE), and physical activity (PAEE) energy expenditure were measured using doubly-labeled water and expired gas indirect calorimetry. Results: Total activity was associated with reduced first-phase insulin response in both pregnant (Regression r(2) = 0.11; Spearman r = -0.47; p = 0.007) and non-pregnant women (Regression r2 = 0.11 Spearman; r = -0.36; p = 0.002). Relative to non-pregnant women, pregnant women were estimated to have secreted 67% more insulin and had 10% lower fasting glucose than non-pregnant women. Pregnant women spent 13% more time sedentary, 71% less time in moderate-to-vigorous intensity activity, had 44% lower objectively measured total activity, and 12% lower PAEE than non-pregnant women. Correlations did not differ significantly for any comparison between physical activity subcomponents and measures of insulin sensitivity or secretion. Conclusions: Our findings suggest that physical activity conveys similar benefits on glucose homeostasis in pregnant and non-pregnant women, despite differences in subcomponents of physical activity. C1 [Gradmark, Anna; Pomeroy, Jeremy; Renstrom, Frida; Steiginga, Susanne; Franks, Paul W.] Umea Univ Hosp, Med Sect, Dept Publ Hlth & Clin Med, Genet Epidemiol & Clin Res Grp, S-90185 Umea, Sweden. [Pomeroy, Jeremy] NIDDK, NIH, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Pomeroy, Jeremy; Renstrom, Frida; Franks, Paul W.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Renstrom, Frida; Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Steiginga, Susanne] Free Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Persson, Margareta] Umea Univ Hosp, Dept Clin Sci, S-90185 Umea, Sweden. [Persson, Margareta] Umea Univ Hosp, Dept Nursing, S-90185 Umea, Sweden. [Wright, Antony; Bluck, Les] MRC Human Nutr Res, Cambridge, England. [Domellof, Magnus] Umea Univ Hosp, Dept Pediat, S-90185 Umea, Sweden. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. [Mogren, Ingrid] Umea Univ Hosp, Dept Clin Sci Obstet & Gynecol, S-90185 Umea, Sweden. RP Franks, PW (reprint author), Umea Univ Hosp, Med Sect, Dept Publ Hlth & Clin Med, Genet Epidemiol & Clin Res Grp, S-90185 Umea, Sweden. EM paul.franks@med.lu.se RI Domellof, Magnus/E-5307-2011; OI Domellof, Magnus/0000-0002-0726-7029; Steiginga, Susanne/0000-0002-7015-2259; Mogren, Ingrid/0000-0003-2985-1135; Franks, Paul/0000-0002-0520-7604; Kahn, Steven/0000-0001-7307-9002 FU Torsten & Ragnar Soderbergs Foundation (via LifeGene); Fredrik; Ingrid Thurings Foundation, Visare Norr; Vasterbotten regional health authority; United States Department of Veterans Affairs; Heart-Lung Foundation; Swedish Diabetes Association; Swedish Heart-Lung Foundation; Swedish Research Council; Novo Nordisk FX We thank the participants in this study and M. Holmgren for assistance in collecting data. The study was a preparatory project for the LifeGene Study http://www.lifegene.se and was funded by Torsten & Ragnar Soderbergs Foundation (via LifeGene), Fredrik and Ingrid Thurings Foundation, Visare Norr, and Vasterbotten regional health authority (all grants to PWF). SEK was supported by the United States Department of Veterans Affairs. FR was support by a post-doctoral stipend from the Heart-Lung Foundation. PWF was supported by grants from the Swedish Diabetes Association, the Swedish Heart-Lung Foundation, the Swedish Research Council, and Novo Nordisk. NR 24 TC 21 Z9 21 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD JUN 16 PY 2011 VL 11 AR 44 DI 10.1186/1471-2393-11-44 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 840VP UT WOS:000296469800001 PM 21679399 ER PT J AU Sand-Dejmek, J Adelmant, G Sobhian, B Calkins, AS Marto, J Iglehart, DJ Lazaro, JB AF Sand-Dejmek, Janna Adelmant, Guillaume Sobhian, Bijan Calkins, Anne S. Marto, Jarrod Iglehart, Dirk J. Lazaro, Jean-Bernard TI Concordant and opposite roles of DNA-PK and the "facilitator of chromatin transcription" (FACT) in DNA repair, apoptosis and necrosis after cisplatin SO MOLECULAR CANCER LA English DT Article ID DEPENDENT PROTEIN-KINASE; DOUBLE-STRAND BREAKS; OVARIAN-CANCER; PLATINUM RESISTANCE; CATALYTIC SUBUNIT; CELL; DAMAGE; H2AX; PHOSPHORYLATION; CHEMOTHERAPY AB Background: Platinum-containing chemotherapy produces specific DNA damage and is used to treat several human solid tumors. Tumors initially sensitive to platinum-based drugs frequently become resistant. Inhibition of DNA repair is a potential strategy to enhance cisplatin effectiveness. After cisplatin treatment, a balance between repair and apoptosis determines whether cancer cells proliferate or die. DNA-dependent protein kinase (DNA-PK) binds to DNA double strand breaks (DSBs) through its Ku subunits and initiates non-homologous end joining. Inhibition of DNA-PK sensitizes cancer cells to cisplatin killing. The goal of this study is to elucidate the mechanism underlying the effects of DNA-PK on cisplatin sensitivity. Results: Silencing the expression of the catalytic subunit of DNA-PK (DNA-PKcs) increased sensitivity to cisplatin and decreased the appearance of gamma H2AX after cisplatin treatment. We purified DNA-PK by its Ku86 subunit and identified interactors by tandem mass spectrometry before and after cisplatin treatment. The structure specific recognition protein 1 (SSRP1), Spt16 and gamma H2AX appeared in the Ku86 complex 5 hours after cisplatin treatment. SSRP1 and Spt16 form the facilitator of chromatin transcription (FACT). The cisplatin-induced association of FACT with Ku86 and gamma H2AX was abrogated by DNase treatment. In living cells, SSRP1 and Ku86 were recruited at sites of DSBs induced by laser beams. Silencing SSRP1 expression increased sensitivity to cisplatin and decreased gamma H2AX appearance. However, while silencing SSRP1 in cisplatin-treated cells increased both apoptosis and necrosis, DNA-PKcs silencing, in contrast, favored necrosis over apoptosis. Conclusions: DNA-PK and FACT both play roles in DNA repair. Therefore both are putative targets for therapeutic inhibition. Since DNA-PK regulates apoptosis, silencing DNA-PKcs redirects cells treated with cisplatin toward necrosis. Silencing FACT however, allows both apoptosis and necrosis. Targeting DNA repair in cancer patients may have different therapeutic effects depending upon the roles played by factors targeted. C1 [Sand-Dejmek, Janna; Adelmant, Guillaume; Sobhian, Bijan; Calkins, Anne S.; Marto, Jarrod; Iglehart, Dirk J.; Lazaro, Jean-Bernard] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Sand-Dejmek, Janna; Iglehart, Dirk J.; Lazaro, Jean-Bernard] Brigham & Womens Hosp, Dept Surg, Boston, MA 02215 USA. [Adelmant, Guillaume; Marto, Jarrod] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA. RP Iglehart, DJ (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 450 Brookline Ave, Boston, MA 02215 USA. EM JIGLEHART@PARTNERS.ORG; jlazaro@partners.org FU Susan F. Smith Center for Women's Cancers (SCWC) at Dana-Farber Cancer Institute (DFCI); Catt Family Foundation; Marsha Rivkin Center for Ovarian Cancer Research; Lund University, Sweden; Swedish Society for Medical Research (SSMF); NCI SPORE in breast cancer at Harvard; Breast Cancer Research Foundation of New York FX This work was funded by awards from the Susan F. Smith Center for Women's Cancers (SCWC) at Dana-Farber Cancer Institute (DFCI), the Catt Family Foundation, and the Marsha Rivkin Center for Ovarian Cancer Research (to JBL). JBL is a SCWC Pallotta Investigator at DFCI. JSD was a recipient of fellowships from Lund University, Sweden, and the Swedish Society for Medical Research (SSMF). JDI is supported by the NCI SPORE in breast cancer at Harvard and the Breast Cancer Research Foundation of New York. NR 51 TC 12 Z9 12 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD JUN 16 PY 2011 VL 10 AR 74 DI 10.1186/1476-4598-10-74 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 791YF UT WOS:000292705200001 PM 21679440 ER PT J AU Li, YT Prasad, A Jia, YH Roy, SG Loison, F Mondal, S Kocjan, P Silberstein, LE Ding, S Luo, HR AF Li, Yitang Prasad, Amit Jia, Yonghui Roy, Saurabh Ghosh Loison, Fabien Mondal, Subhanjan Kocjan, Paulina Silberstein, Leslie E. Ding, Sheng Luo, Hongbo R. TI Pretreatment with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670 augments the efficacy of granulocyte transfusion in a clinically relevant mouse model SO BLOOD LA English DT Article ID TUMOR-SUPPRESSOR PTEN; NEUTROPHIL CHEMOTAXIS; HOST-DEFENSE; THERAPY; INFECTIONS; TRANSPLANTATION; ACTIVATION; GROWTH; MACROPHAGES; SEPTICEMIA AB The clinical outcome of granulocyte transfusion therapy is often hampered by short ex vivo shelf life, inefficiency of recruitment to sites of inflammation, and poor pathogen-killing capability of transplanted neutrophils. Here, using a recently developed mouse granulocyte transfusion model, we revealed that the efficacy of granulocyte transfusion can be significantly increased by elevating intracellular phosphatidylinositol (3,4,5)trisphosphate signaling with a specific phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670. Neutrophils treated with SF1670 were much sensitive to chemoattractant stimulation. Neutrophil functions, such as phagocytosis, oxidative burst, polarization, and chemotaxis, were augmented after SF1670 treatment. The recruitment of SF1670-pretreated transfused neutrophils to the inflamed peritoneal cavity and lungs was significantly elevated. In addition, transfusion with SF1670-treated neutrophils led to augmented bacteria-killing capability (decreased bacterial burden) in neutropenic recipient mice in both peritonitis and bacterial pneumonia. Consequently, this alleviated the severity of and decreased the mortality of neutropenia-related pneumonia. Together, these observations demonstrate that the innate immune responses can be enhanced and the severity of neutropenia-related infection can be alleviated by augmenting phosphatidylinositol (3,4,5)-trisphosphate in transfused neutrophils with PTEN inhibitor SF1670, providing a therapeutic strategy for improving the efficacy of granulocyte transfusion. (Blood. 2011;117(24):6702-6713) C1 [Li, Yitang; Prasad, Amit; Jia, Yonghui; Roy, Saurabh Ghosh; Loison, Fabien; Mondal, Subhanjan; Kocjan, Paulina; Silberstein, Leslie E.; Luo, Hongbo R.] Harvard Univ, Sch Med,Joint Program Transfus Med, Childrens Hosp Boston,Div Blood Bank, Dana Farber Harvard Canc Ctr,Dept Lab Med, Boston, MA USA. [Li, Yitang; Prasad, Amit; Jia, Yonghui; Roy, Saurabh Ghosh; Loison, Fabien; Mondal, Subhanjan; Kocjan, Paulina; Silberstein, Leslie E.; Luo, Hongbo R.] Harvard Univ, Sch Med, Childrens Hosp Boston,Div Blood Bank,Dept Pathol, Dana Farber Harvard Canc Ctr,Dept Lab Med, Boston, MA USA. [Ding, Sheng] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. RP Luo, HR (reprint author), Karp Family Res Bldg,Rm 10214, Boston, MA 02115 USA. EM hongbo.luo@childrens.harvard.edu RI Loison, Fabien/G-3385-2014 OI Loison, Fabien/0000-0002-6678-1730 FU National Institutes of Health [HL085100, AI076471, HL092020, GM076084] FX H.R.L. is supported by National Institutes of Health grants HL085100, AI076471, HL092020, and GM076084. NR 49 TC 23 Z9 23 U1 0 U2 5 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 JUN 16 PY 2011 VL 117 IS 24 BP 6702 EP 6713 DI 10.1182/blood-2010-09-309864 PG 12 WC Hematology SC Hematology GA 778EP UT WOS:000291684300038 PM 21521784 ER PT J AU Arora, M Klein, JP Weisdorf, DJ Hassebroek, A Flowers, MED Cutler, CS Urbano-Ispizua, A Antin, JH Bolwell, BJ Boyiadzis, M Cahn, JY Cairo, MS Isola, L Jacobsohn, DA Jagasia, M Klumpp, TR Lee, SJ Petersdorf, EW Santarone, S Gale, RP Schouten, HC Spellman, S Wingard, JR Horowitz, MM Pavletic, SZ AF Arora, Mukta Klein, John P. Weisdorf, Daniel J. Hassebroek, Anna Flowers, Mary E. D. Cutler, Corey S. Urbano-Ispizua, Alvaro Antin, Joseph H. Bolwell, Brian J. Boyiadzis, Michael Cahn, Jean-Yves Cairo, Mitchell S. Isola, Luis Jacobsohn, David A. Jagasia, Madan Klumpp, Thomas R. Lee, Stephanie J. Petersdorf, Effie W. Santarone, Stella Gale, Robert Peter Schouten, Harry C. Spellman, Stephen Wingard, John R. Horowitz, Mary M. Pavletic, Steven Z. TI Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; CHRONIC GRAFT; SURVIVAL; CLASSIFICATION; SEVERITY; CRITERIA AB Several risk factors are associated with increased mortality in patients with chronic graft-versus-host disease (cGVHD), but there is considerable variability in the reported factors. Therefore, we evaluated patient, transplantation, and cGVHD characteristics to develop a risk score in 5343 patients with cGVHD. Ten variables were identified as being significant in multivariate analysis of overall survival and nonrelapse mortality (NRM): age, prior acute GVHD, time from trans-plantation to cGVHD, donor type, disease status at transplantation, GVHD prophylaxis, gender mismatch, serum bilirubin, Karnofsky score, and platelet count. These 10 variables were used to build a cGVHD risk score, and 6 risk groups (RGs) were identified. The 5-year NRM was 5% (1%-9%) in RG1, 20% (19%-23%) in RG2, 33% (29%-37%) in RG3, 43% (40%-46%) in RG4, 63% (53%-74%) in RG5, and 72% (59%-85%) in RG6. The 5-year overall survival was highest at 91% (95% confidence interval [CI]: 85%-97%) in RG1, followed by 67% (65%-69%) in RG2, 51% (46%-55%) in RG3, 40% (37%-43%) in RG4, 21% (12%-30%) in RG5, and 4% (0%-9%) in RG6 (all P < .01). This analysis demonstrates the usefulness of data from a large registry to develop risk-score categories for major transplantation outcomes. Validation of this cGVHD risk score is needed in a different population to ensure its broad applicability. (Blood. 2011;117(24):6714-6720) C1 [Arora, Mukta; Weisdorf, Daniel J.] Univ Minnesota, Dept Hematol Oncol & Transplant, Minneapolis, MN USA. [Klein, John P.] Med Coll Wisconsin, Dept Biostat, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Hassebroek, Anna] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Flowers, Mary E. D.; Lee, Stephanie J.; Petersdorf, Effie W.; Spellman, Stephen] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Flowers, Mary E. D.; Lee, Stephanie J.; Petersdorf, Effie W.; Spellman, Stephen] Univ Washington, Seattle, WA 98195 USA. [Cutler, Corey S.; Antin, Joseph H.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Urbano-Ispizua, Alvaro] Hosp Clin Barcelona, Dept Hematol, Barcelona, Spain. [Bolwell, Brian J.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Boyiadzis, Michael] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Cahn, Jean-Yves] CHU Grenoble, F-38043 Grenoble, France. [Cairo, Mitchell S.] Columbia Univ, Dept Pediat Med Pathol & Cell Biol, New York, NY USA. [Cairo, Mitchell S.] New York Presbyterian Morgan Stanley Childrens Ho, New York, NY USA. [Isola, Luis] Mt Sinai Med Ctr, Dept Bone Marrow Transplantat, New York, NY 10029 USA. [Jacobsohn, David A.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Dept Hematol Stem Cell Transplant, Nashville, TN USA. [Klumpp, Thomas R.] Temple Univ, Wynnewood, PA USA. [Santarone, Stella] Osped Civile, Bone Marrow Transplantat Ctr, Pescara, Italy. [Gale, Robert Peter] Celgene Corp, Summit, NJ USA. [Schouten, Harry C.] Acad Ziekenhuis, Maastricht, Netherlands. [Wingard, John R.] Univ Florida, Shands Canc Ctr, Gainesville, FL USA. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Arora, M (reprint author), MMC 480,420 Delaware St SE, Minneapolis, MN 55455 USA. EM arora005@umn.edu FU National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung and Blood Institute (NHLBI) [5U01HL069294]; National Institute of Allergy and Infectious Diseases (NIAID); Health Resources and Services Administration (HRSA/DHHS) [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; AABB; Allos Inc; Amgen Inc FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Allos Inc; Amgen Inc; an anonymous donation to the Medical College of Wisconsin; Astellas Pharma US Inc; Be the Match Foundation; Biogen Idec Inc; BioMarin Pharmaceutical Inc; Biovitrum AB; Blood Center of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix GmbH; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Eisai Inc; Genentech Inc; Genzyme Corporation; Histogenetics Inc; HKS Medical Information Systems; Hospira Inc; Kirin Brewery Co Ltd; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; Millennium Pharmaceuticals Inc; Miller Pharmacal Group; Milliman USA Inc; Miltenyi Biotec Inc; National Marrow Donor Program; Nature Publishing Group; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics Inc; Otsuka America Pharmaceutical Inc; Pall Life Sciences; Pfizer Inc; Schering Corporation; Sigma-Tau Pharmaceuticals; Soligenix Inc; StemCyte Inc; StemSoft Software Inc; Sysmex America Inc; Therakos Inc; Vidacare Corporation; ViraCor Laboratories; ViroPharma Inc; and Wellpoint Inc. NR 20 TC 53 Z9 56 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 JUN 16 PY 2011 VL 117 IS 24 BP 6714 EP 6720 DI 10.1182/blood-2010-12-323824 PG 7 WC Hematology SC Hematology GA 778EP UT WOS:000291684300039 PM 21493797 ER PT J AU Leventhal, JS Alsauskas, Z Snyder, A Gong, PF Wang, B D'Agati, V Ross, MJ AF Leventhal, Jeremy S. Alsauskas, Zygimantas Snyder, Alexandra Gong, Pengfei Wang, Bin D'Agati, Vivette Ross, Michael J. TI Renal HIV Expression Is Unaffected by Serum LPS Levels in an HIV Transgenic Mouse Model of LPS Induced Kidney Injury SO PLOS ONE LA English DT Article ID FACTOR-KAPPA-B; TUBULAR EPITHELIAL-CELLS; HOSPITALIZED-PATIENTS; INFECTED PATIENTS; GENE-EXPRESSION; VIRAL LOAD; FAILURE; ACTIVATION; NEPHROPATHY; TAT AB Acute kidney injury (AKI) is associated with increased rates of mortality. For unknown reasons, HIV infected individuals have a higher risk of AKI than uninfected persons. We tested our hypothesis that increased circulating LPS increases renal expression of HIV and that HIV transgenic (Tg26) mice have increased susceptibility to AKI. Tg26 mice harbor an HIV transgene encoding all HIV genes except gag and pol, and develop a phenotype analogous to HIVAN. Mice were used at 4-6 weeks of age before the onset of gross renal disease. Mice were injected i.p. with LPS or sterile saline. Renal function, tubular injury, cytokine expression, and HIV transcription were evaluated in Tg26 and wild type (WT) mice. LPS injection induced a median 60.1-fold increase in HIV expression in spleen but no change in kidney. There was no significant difference in renal function, cytokine expression, or tubular injury scores at baseline or 24 hours after LPS injection. HIV transcription was also analyzed in vitro using a human renal tubular epithelial cell (RTEC) line. HIV transcription increased minimally in human RTEC, by 1.47 fold, 48 hours after LPS exposure. We conclude that Tg26 mice do not increase HIV expression or have increased susceptibility to LPS induced AKI. The increased risk of AKI in HIV infected patients is not mediated via increased renal expression of HIV in the setting of sepsis. Moreover, renal regulation of HIV transcription is different to that in the spleen. C1 [Leventhal, Jeremy S.; Gong, Pengfei; Wang, Bin; Ross, Michael J.] Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY 10029 USA. [Leventhal, Jeremy S.] James J Peters Bronx VA Med Ctr, Div Nephrol, Bronx, NY USA. [Alsauskas, Zygimantas] Univ Louisville, Div Nephrol, Louisville, KY 40292 USA. [D'Agati, Vivette] Columbia Univ, Dept Pathol, Med Ctr, New York, NY USA. RP Leventhal, JS (reprint author), Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY 10029 USA. EM jeremy.leventhal@mssm.edu FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK078510]; National Kidney Foundation FX This work was supported by a National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant R01 DK078510 (to PI MR) and by a National Kidney Foundation Fellowship Grant (to JL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 2 Z9 2 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 16 PY 2011 VL 6 IS 6 AR e20688 DI 10.1371/journal.pone.0020688 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 778UW UT WOS:000291734100014 PM 21698182 ER PT J AU Marsili, A Aguayo-Mazzucato, C Chen, T Kumar, A Chung, M Lunsford, EP Harney, JW Thuy, VT Gianetti, E Ramadan, W Chou, C Bonner-Weir, S Larsen, PR Silva, JE Zavacki, AM AF Marsili, Alessandro Aguayo-Mazzucato, Cristina Chen, Ting Kumar, Aditi Chung, Mirra Lunsford, Elaine P. Harney, John W. Thuy Van-Tran Gianetti, Elena Ramadan, Waile Chou, Cyril Bonner-Weir, Susan Larsen, Philip Reed Silva, Jorge Enrique Zavacki, Ann Marie TI Mice with a Targeted Deletion of the Type 2 Deiodinase Are Insulin Resistant and Susceptible to Diet Induced Obesity SO PLOS ONE LA English DT Article ID BROWN ADIPOSE-TISSUE; THYROID-HORMONE ACTIVATION; LIFE-STYLE INTERVENTION; IODOTHYRONINE DEIODINASE; ADAPTIVE THERMOGENESIS; ENERGY-EXPENDITURE; NUCLEAR 3,5,3'-TRIIODOTHYRONINE; THR92ALA POLYMORPHISM; DIABETES-MELLITUS; SKELETAL-MUSCLE AB Background: The type 2 iodothyronine deiodinase (D2) converts the pro-hormone thyroxine into T3 within target tissues. D2 is essential for a full thermogenic response of brown adipose tissue (BAT), and mice with a disrupted Dio2 gene (D2KO) have an impaired response to cold. BAT is also activated by overfeeding. Methodology/Principal Findings: After 6-weeks of HFD feeding D2KO mice gained 5.6% more body weight and had 28% more adipose tissue. Oxygen consumption (V0(2)) was not different between genotypes, but D2KO mice had an increased respiratory exchange ratio (RER), suggesting preferential use of carbohydrates. Consistent with this, serum free fatty acids and b-hydroxybutyrate were lower in D2KO mice on a HFD, while hepatic triglycerides were increased and glycogen content decreased. Neither genotype showed glucose intolerance, but D2KO mice had significantly higher insulin levels during GTT independent of diet. Accordingly, during ITT testing D2KO mice had a significantly reduced glucose uptake, consistent with insulin resistance. Gene expression levels in liver, muscle, and brown and white adipose tissue showed no differences that could account for the increased weight gain in D2KO mice. However, D2KO mice have higher PEPCK mRNA in liver suggesting increased gluconeogenesis, which could also contribute to their apparent insulin resistance. Conclusions/Significance: We conclude that the loss of the Dio2 gene has significant metabolic consequences. D2KO mice gain more weight on a HFD, suggesting a role for D2 in protection from diet-induced obesity. Further, D2KO mice appear to have a greater reliance on carbohydrates as a fuel source, and limited ability to mobilize and to burn fat. This results in increased fat storage in adipose tissue, hepatic steatosis, and depletion of liver glycogen in spite of increased gluconeogenesis. D2KO mice are also less responsive to insulin, independent of diet-induced obesity. C1 [Marsili, Alessandro; Chen, Ting; Kumar, Aditi; Chung, Mirra; Harney, John W.; Thuy Van-Tran; Gianetti, Elena; Larsen, Philip Reed; Zavacki, Ann Marie] Brigham & Womens Hosp, Thyroid Sect, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Aguayo-Mazzucato, Cristina; Bonner-Weir, Susan] Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. [Lunsford, Elaine P.] Beth Israel Deaconess Med Ctr, Longwood Small Anim Imaging Facil, Boston, MA 02215 USA. [Ramadan, Waile; Chou, Cyril; Silva, Jorge Enrique] Baystate Med Ctr, Div Endocrinol Diabet & Metab, Springfield, MA USA. RP Marsili, A (reprint author), Brigham & Womens Hosp, Thyroid Sect, Div Endocrinol Diabet & Hypertens, 75 Francis St, Boston, MA 02115 USA. EM azavacki@rics.bwh.harvard.edu FU National Institutes of Health (NIH)/NIDDK [DK076117, DK036256]; Harvard Medical School; Department of Endocrinology; Kidney of the University Hospital of Pisa; internal Baystate; University of Massachusetts; Department of Medicine of Baystate Medical Center; Academic Affairs Office of Baystate Health Inc.; Graetz Fund; Sheenan Family Fund; NIH/NCRR [S10-RR-023010]; [5P30 DK36836] FX This work was supported by National Institutes of Health (NIH)/NIDDK grants DK076117 to AMZ and DK036256 to PRL, and the Dr. Lynn Reid/Drs. Eleanor and Miles Shore Fellowship from the Drs. Eleanor and Miles Shore 50th Anniversary Program for Scholars in Medicine Program of Harvard Medical School to AMZ. AM was supported in part by a fellowship from the Department of Endocrinology and Kidney of the University Hospital of Pisa. JES is supported by internal Baystate and University of Massachusetts joint grants. His research time is funded by the Department of Medicine of Baystate Medical Center, and the Academic Affairs Office of Baystate Health Inc. WR and CC are supported by the Academic Affairs Office of Baystate Health Inc. SBW and CAM are supported by the Graetz Fund and Sheenan Family Fund. The Joslin Diabetes Center Specialized Assay Core is supported by 5P30 DK36836 and the Longwood Small Animal Imaging Facility is supported by NIH/NCRR shared instrumentation grant S10-RR-023010. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 34 Z9 34 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 16 PY 2011 VL 6 IS 6 AR e20832 DI 10.1371/journal.pone.0020832 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 778UW UT WOS:000291734100022 PM 21698184 ER PT J AU Khor, B Gardet, A Xavier, RJ AF Khor, Bernard Gardet, Agnes Xavier, Ramnik J. TI Genetics and pathogenesis of inflammatory bowel disease SO NATURE LA English DT Review ID REGULATORY T-CELLS; GENOME-WIDE ASSOCIATION; CROHNS-DISEASE; TGF-BETA; SUSCEPTIBILITY LOCI; DENDRITIC CELLS; INTESTINAL HOMEOSTASIS; TRANSCRIPTION FACTOR; IMMUNE-RESPONSES; INDUCED COLITIS AB Recent advances have provided substantial insight into the maintenance of mucosal immunity and the pathogenesis of inflammatory bowel disease. Cellular programs responsible for intestinal homeostasis use diverse intracellular and intercellular networks to promote immune tolerance, inflammation or epithelial restitution. Complex interfaces integrate local host and microbial signals to activate appropriate effector programs selectively and even drive plasticity between these programs. In addition, genetic studies and mouse models have emphasized the role of genetic predispositions and how they affect interactions with microbial and environmental factors, leading to pro-colitogenic perturbations of the host-commensal relationship. C1 [Khor, Bernard; Gardet, Agnes; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Khor, Bernard; Gardet, Agnes; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Khor, Bernard; Gardet, Agnes; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Khor, Bernard] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge Ctr 7, Cambridge, MA 02142 USA. RP Xavier, RJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. EM xavier@molbio.mgh.harvard.edu OI Khor, Bernard/0000-0003-4689-5092 FU National Institutes of Health; Crohn's and Colitis Foundation of America FX R.J.X., A.G. and B.K. are supported by grants from the National Institutes of Health and the Crohn's and Colitis Foundation of America. We apologize to those whose work is not cited owing to space constraints. NR 100 TC 655 Z9 669 U1 16 U2 138 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 JUN 16 PY 2011 VL 474 IS 7351 BP 307 EP 317 DI 10.1038/nature10209 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 777TD UT WOS:000291647100034 PM 21677747 ER PT J AU Shi, ML Zhu, JH Wang, R Chen, X Mi, LZ Walz, T Springer, TA AF Shi, Minlong Zhu, Jianghai Wang, Rui Chen, Xing Mi, Lizhi Walz, Thomas Springer, Timothy A. TI Latent TGF-beta structure and activation SO NATURE LA English DT Article ID GROWTH-FACTOR-BETA; BINDING-PROTEIN; TRANSFORMING GROWTH-FACTOR-BETA-2; CRYSTAL-STRUCTURE; SUPERFAMILY; SECRETION; MATURE; FACTOR-BETA-1; TGF-BETA-1; COMPLEXES AB Transforming growth factor (TGF)-beta is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-beta 1 requires the binding of alpha(v) integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-beta binding proteins. Crystals of dimeric porcine proTGF-beta 1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between alpha(v)beta(6) integrin and the prodomain is insufficient for TGF-beta 1 release. Force-dependent activation requires unfastening of a 'straitjacket' that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-beta family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis. C1 [Shi, Minlong; Zhu, Jianghai; Wang, Rui; Chen, Xing; Mi, Lizhi; Springer, Timothy A.] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Shi, Minlong; Zhu, Jianghai; Wang, Rui; Chen, Xing; Mi, Lizhi; Springer, Timothy A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Walz, Thomas] Howard Hughes Med Inst, Boston, MA 02115 USA. [Walz, Thomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. EM springer@idi.harvard.edu RI shi, minlong/G-8734-2013; Zhu, Jianghai/B-7339-2014; Mi, Li-Zhi/B-1371-2016 OI Mi, Li-Zhi/0000-0001-9907-5245 FU Howard Hughes Medical Institute; NHLBI NIH HHS [P01 HL103526] NR 46 TC 257 Z9 265 U1 3 U2 31 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 16 PY 2011 VL 474 IS 7351 BP 343 EP U370 DI 10.1038/nature10152 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 777TD UT WOS:000291647100038 PM 21677751 ER PT J AU Costello, DJ Gonzalez, RG Frosch, MP AF Costello, Daniel J. Gonzalez, R. Gilberto Frosch, Matthew P. TI Case 18-2011: A 35-Year-Old HIV-Positive Woman with Headache and Altered Mental Status SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RECONSTITUTION INFLAMMATORY SYNDROME; IMMUNODEFICIENCY-VIRUS-INFECTION; IMMUNE RECONSTITUTION; ANTIRETROVIRAL TREATMENT; LEUKOENCEPHALOPATHY; TOXOPLASMOSIS; RESTORATION; DISORDERS; HIV/AIDS; STEROIDS C1 [Costello, Daniel J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Gonzalez, R. Gilberto] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Costello, Daniel J.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Gonzalez, R. Gilberto] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Frosch, Matthew P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Costello, DJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. FU Penumbra FX Dr. Gonzalez reports receiving grant support from Penumbra. No other potential conflict of interest relevant to this article was reported. Dr. Costello's current affiliation is the Department of Neurology, Cork University Hospital, and University College Cork, Cork, Ireland. NR 25 TC 5 Z9 5 U1 1 U2 2 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 JUN 16 PY 2011 VL 364 IS 24 BP 2343 EP 2352 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 777RZ UT WOS:000291643800014 PM 21675893 ER PT J AU Palumbo, A Anderson, K AF Palumbo, Antonio Anderson, Kenneth TI Multiple Myeloma REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID STEM-CELL TRANSPLANTATION C1 [Palumbo, Antonio] Univ Turin, Turin, Italy. [Anderson, Kenneth] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Palumbo, A (reprint author), Univ Turin, Turin, Italy. EM appalumbo@yahoo.com NR 2 TC 1 Z9 1 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 JUN 16 PY 2011 VL 364 IS 24 BP 2364 EP 2364 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 777RZ UT WOS:000291643800027 ER PT J AU Spitzer, TR Sachs, DH Cosimi, B AF Spitzer, Thomas R. Sachs, David H. Cosimi, Benedict TI Multiple Myeloma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID TRANSPLANTATION TOLERANCE C1 [Spitzer, Thomas R.; Sachs, David H.; Cosimi, Benedict] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Spitzer, TR (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM tspitzer@partners.org NR 5 TC 2 Z9 3 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 16 PY 2011 VL 364 IS 24 BP 2364 EP 2364 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 777RZ UT WOS:000291643800026 PM 21675904 ER PT J AU Ghamsari, L Balaji, S Shen, Y Yang, XP Balcha, D Fan, CY Hao, T Yu, HY Papin, JA Salehi-Ashtiani, K AF Ghamsari, Lila Balaji, Santhanam Shen, Yun Yang, Xinping Balcha, Dawit Fan, Changyu Hao, Tong Yu, Haiyuan Papin, Jason A. Salehi-Ashtiani, Kourosh TI Genome-wide functional annotation and structural verification of metabolic ORFeome of Chlamydomonas reinhardtii SO BMC GENOMICS LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; GENE-EXPRESSION; SUBCELLULAR-LOCALIZATION; SORTING SIGNALS; HIGH-THROUGHPUT; RNA-SEQ; PREDICTION; REVEALS; NETWORK; CELLS AB Background: Recent advances in the field of metabolic engineering have been expedited by the availability of genome sequences and metabolic modelling approaches. The complete sequencing of the C. reinhardtii genome has made this unicellular alga a good candidate for metabolic engineering studies; however, the annotation of the relevant genes has not been validated and the much-needed metabolic ORFeome is currently unavailable. We describe our efforts on the functional annotation of the ORF models released by the Joint Genome Institute (JGI), prediction of their subcellular localizations, and experimental verification of their structural annotation at the genome scale. Results: We assigned enzymatic functions to the translated JGI ORF models of C. reinhardtii by reciprocal BLAST searches of the putative proteome against the UniProt and AraCyc enzyme databases. The best match for each translated ORF was identified and the EC numbers were transferred onto the ORF models. Enzymatic functional assignment was extended to the paralogs of the ORFs by clustering ORFs using BLASTCLUST. In total, we assigned 911 enzymatic functions, including 886 EC numbers, to 1,427 transcripts. We further annotated the enzymatic ORFs by prediction of their subcellular localization. The majority of the ORFs are predicted to be compartmentalized in the cytosol and chloroplast. We verified the structure of the metabolism-related ORF models by reverse transcription-PCR of the functionally annotated ORFs. Following amplification and cloning, we carried out 454FLX and Sanger sequencing of the ORFs. Based on alignment of the 454FLX reads to the ORF predicted sequences, we obtained more than 90% coverage for more than 80% of the ORFs. In total, 1,087 ORF models were verified by 454 and Sanger sequencing methods. We obtained expression evidence for 98% of the metabolic ORFs in the algal cells grown under constant light in the presence of acetate. Conclusions: We functionally annotated approximately 1,400 JGI predicted metabolic ORFs that can facilitate the reconstruction and refinement of a genome-scale metabolic network. The unveiling of the metabolic potential of this organism, along with structural verification of the relevant ORFs, facilitates the selection of metabolic engineering targets with applications in bioenergy and biopharmaceuticals. The ORF clones are a resource for downstream studies. C1 [Ghamsari, Lila; Balaji, Santhanam; Shen, Yun; Yang, Xinping; Balcha, Dawit; Fan, Changyu; Hao, Tong; Salehi-Ashtiani, Kourosh] Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02115 USA. [Ghamsari, Lila; Balaji, Santhanam; Shen, Yun; Yang, Xinping; Balcha, Dawit; Fan, Changyu; Hao, Tong; Salehi-Ashtiani, Kourosh] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ghamsari, Lila; Balaji, Santhanam; Shen, Yun; Yang, Xinping; Balcha, Dawit; Fan, Changyu; Hao, Tong; Salehi-Ashtiani, Kourosh] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Yu, Haiyuan] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY 14853 USA. [Yu, Haiyuan] Cornell Univ, Weill Inst Cell & Mol Biol, Ithaca, NY 14853 USA. [Papin, Jason A.] Univ Virginia, Dept Biomed Engn, Charlottesville, VA 22908 USA. [Salehi-Ashtiani, Kourosh] NYU, Abu Dhabi, U Arab Emirates. [Salehi-Ashtiani, Kourosh] NYU, Dept Biol, Ctr Genom & Syst Biol, New York, NY 10003 USA. RP Yu, HY (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02115 USA. EM Haiyuan.Yu@cornell.edu; papin@virginia.edu; ksa3@nyu.edu OI Salehi-Ashtiani, Kourosh/0000-0002-6521-5243; Papin, Jason/0000-0002-2769-5805 FU Office of Science (Biological and Environmental Research), US Department of Energy [DE-FG02-07ER64496]; New York University; Dana-Farber Cancer Institute Strategic Initiative FX This research was supported by the Office of Science (Biological and Environmental Research), US Department of Energy, grant No. DE-FG02-07ER64496 (to J.P. and K.S.-A.), and additionally by New York University Abu Dhabi Research funds (to K.S.-A.), and Institute Sponsored Research funds from the Dana-Farber Cancer Institute Strategic Initiative (to CCSB). NR 44 TC 7 Z9 7 U1 0 U2 14 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 JUN 15 PY 2011 VL 12 SU 1 AR S4 DI 10.1186/1471-2164-12-S1-S4 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 940VH UT WOS:000303920700005 PM 21810206 ER PT J AU Parithivel, K Jagannathan, JP Krajewski, K O'Regan, K Quick, CM Ramaiya, N Campos, S AF Parithivel, Kavitha Jagannathan, Jyothi Priya Krajewski, Katherine O'Regan, Kevin Quick, Charles Matthew Ramaiya, Nikhil Campos, Susana TI Ovarian squamous cell carcinoma arising from mature cystic teratoma SO CANCER IMAGING LA English DT Article DE Ovarian squamous cell carcinoma; malignant transformation; ovarian mature cystic teratoma ID DERMOID CYSTS; NEOPLASMS; DIAGNOSIS; TUMORS AB Preoperative diagnosis of malignant transformation of an ovarian mature cystic teratoma to squamous cell carcinoma is difficult due to nonspecific tumor markers and imaging findings. This is an interesting case presentation that has prior imaging that demonstrates imaging characteristics of the transformation of a mature cystic teratoma to squamous cell carcinoma. C1 [Parithivel, Kavitha; Jagannathan, Jyothi Priya; Krajewski, Katherine; O'Regan, Kevin; Ramaiya, Nikhil] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [Quick, Charles Matthew] Brigham & Womens Hosp, Boston, MA 02115 USA. [Campos, Susana] Dana Farber Canc Inst, Dept Med Oncol Solid Tumor Oncol, Boston, MA 02115 USA. RP Parithivel, K (reprint author), Dana Farber Canc Inst, Dept Radiol, 44 Binney St, Boston, MA 02115 USA. EM kparithivel1@partners.org NR 11 TC 3 Z9 5 U1 0 U2 1 PU E-MED PI LONDON PA PO BOX 29761, LONDON, NW3 7ZS, ENGLAND SN 1470-7330 J9 CANCER IMAGING JI Cancer Imaging PD JUN 15 PY 2011 VL 11 IS 1 BP 67 EP 69 DI 10.1102/1470-7330.2011.0013 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 826DE UT WOS:000295330800003 PM 21684828 ER PT J AU Zhao, GP Moore, DJ Kim, JI Lee, KM O'Connor, MR Duff, PE Yang, MZ Lei, J Markmann, JF Deng, SP AF Zhao, Gaoping Moore, Daniel J. Kim, James I. Lee, Kang Mi O'Connor, Matthew R. Duff, Patrick E. Yang, Maozhu Lei, Ji Markmann, James F. Deng, Shaoping TI Inhibition of Transplantation Tolerance by Immune Senescence Is Reversed by Endocrine Modulation SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID REGULATORY T-CELLS; BREAST-CANCER PATIENTS; THYMIC INVOLUTION; B-CELL; INFLUENZA VACCINATION; THYMOCYTE DEVELOPMENT; SEX STEROIDS; IN-VITRO; AGE; LYMPHOCYTES AB The senescent immune system responds poorly to new stimuli; thymic involution, accumulation of memory cells against other specificities, and general refractoriness to antigen signaling all may contribute to poor resistance to infection. These same changes may pose a significant clinical barrier to organ transplantation, as transplantation tolerance requires thymic participation and integrated, tolerance-promoting responses to novel antigens. We found that after the age of 12 months, mice became resistant to the tolerance-inducing capacity of the monoclonal antibody therapy anti-CD45RB. This resistance to tolerance to cardiac allografts could be overcome by surgical castration of male mice, a procedure that led to thymic regeneration and long-term graft acceptance. The potential for clinical translation of this endocrine-immune interplay was confirmed by the ability of Lupron Depot injections, which temporarily disrupt gonadal function, to restore tolerance in aged mice. Furthermore, we demonstrated that the restoration of tolerance after surgical or chemical castration depended on thymic production of regulatory T cells (T(regs)); thymectomy or T(reg) depletion abrogated tolerance restoration. The aging of the immune system ("immune senescence") is a significant barrier to immune tolerance, but this barrier can be overcome by targeting sex steroid production with commonly used clinical therapeutics. C1 [Zhao, Gaoping; Kim, James I.; Lee, Kang Mi; O'Connor, Matthew R.; Duff, Patrick E.; Yang, Maozhu; Lei, Ji; Markmann, James F.; Deng, Shaoping] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Zhao, Gaoping; Yang, Maozhu; Deng, Shaoping] Sichuan Prov Peoples Hosp, Dept Surg, Chengdu 610072, Sichuan Prov, Peoples R China. [Zhao, Gaoping; Yang, Maozhu; Deng, Shaoping] Sichuan Acad Med Sci, Chengdu 610072, Sichuan Prov, Peoples R China. [Moore, Daniel J.] Vanderbilt Childrens Hosp, Dept Pediat, Ian Burr Div Endocrinol & Diabet, Nashville, TN 37232 USA. RP Deng, SP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM sdeng1@partners.org RI Moore, Daniel/A-4924-2008 OI Moore, Daniel/0000-0002-6889-9345 FU Vanderbilt Physician Scientist Development Program; [R01AI057851-06]; [2R56AI048820-10]; [NNSF30772042]; [K01DK079207-01]; [F32DK083161-03] FX This work was supported by grants R01AI057851-06 (J.F.M.), 2R56AI048820-10 (J.F.M.), NNSF30772042 (S. D.), K01DK079207-01 (J.I.K.), F32DK083161-03 (D.J.M.), and the Vanderbilt Physician Scientist Development Program (D.J.M.). NR 55 TC 6 Z9 6 U1 0 U2 3 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 JUN 15 PY 2011 VL 3 IS 87 AR 87ra52 DI 10.1126/scitranslmed.3002270 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 795NN UT WOS:000292981000003 PM 21677198 ER PT J AU Urick, ME Rudd, ML Godwin, AK Sgroi, D Merino, M Bell, DW AF Urick, Mary E. Rudd, Meghan L. Godwin, Andrew K. Sgroi, Dennis Merino, Maria Bell, Daphne W. TI PIK3R1 (p85 alpha) Is Somatically Mutated at High Frequency in Primary Endometrial Cancer SO CANCER RESEARCH LA English DT Article ID MUTATIONS; GENES; CARCINOMA; SUBUNIT AB Phosphoinositide 3-kinase (PI3K) is an important therapeutic target. Mutations in PIK3CA, which encodes p110 alpha, the catalytic subunit of PI3K, occur in endometrioid endometrial cancers (EEC) and nonendometrioid endometrial cancers (NEEC). The goal of this study was to determine whether PIK3R1, which encodes p85 alpha, the inhibitory subunit of PI3K, is mutated in endometrial carcinoma. We carried out exonic sequencing of PIK3R1 from 42 EECs and 66 NEECs. The pattern of PIK3R1 mutations was compared with the patterns of PIK3CA, PTEN, and KRAS mutations. The biochemical effect of seven PIK3R1 mutations was examined by stable expression in U2OS cells, followed by coimmunoprecipitation analysis of p110 alpha, and Western blotting of phospho-AKT(Ser473) (p-AKT(Ser473)). We found that PIK3R1 was somatically mutated in 43% of EECs and 12% of NEECs. The majority of mutations (93.3%) were localized to the p85 alpha-nSH2 and -iSH2 domains. Several mutations were recurrent. PIK3R1 mutations were significantly (P = 0.0015) more frequent in PIK3CA-wild type EECs (70%) than in PIK3CA mutant EECs (18%). Introduction of wild-type p85 alpha into U2OS cells reduced the level of p-AKT(Ser473) compared with the vector control. Five p85 alpha mutants, p85 alpha delH450-E451, p85 alpha delK459, p85 alpha delY463-L466, p85 alpha delR574-T576, and the p85 alpha N564D positive control, were shown to bind p110 alpha and led to increased levels of p-AKT(Ser473). The p85 alpha R348X and p85 alpha K511VfsX2 mutants did not bind p110 alpha and showed no appreciable change in p-AKT(Ser473) levels. In conclusion, our study has revealed a new mode of PI3K alteration in primary endometrial tumors and warrants future studies to determine whether PIK3R1 mutations correlate with clinical outcome to targeted therapies directed against the PI3K pathway in EEC and NEEC. Cancer Res; 71(12); 4061-7. (C)2011 AACR. C1 [Urick, Mary E.; Rudd, Meghan L.; Bell, Daphne W.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Merino, Maria] NCI, NIH, Bethesda, MD 20892 USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Sgroi, Dennis] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. RP Bell, DW (reprint author), NHGRI, Canc Genet Branch, NIH, Bldg 50,Room 5339,50 South Dr, Bethesda, MD 20892 USA. EM belldaph@mail.nih.gov FU NIH/National Human Genome Research Institute; NIH [R01 CA140323, U01 CA113916, RO1-1CA112021-01]; Ovarian Cancer Research Fund; NCI SPORE in breast cancer at Massachusetts General Hospital; Avon Foundation FX This study was funded by the Intramural Program of the NIH/National Human Genome Research Institute (D.W. Bell) and in part by NIH grants R01 CA140323 (A.K. Godwin), U01 CA113916 (A.K. Godwin), NIH RO1-1CA112021-01 (D.C. Sgroi), the Ovarian Cancer Research Fund (A.K. Godwin), the NCI SPORE in breast cancer at Massachusetts General Hospital (D.C. Sgroi), and the Avon Foundation (D.C. Sgroi). NR 21 TC 78 Z9 81 U1 2 U2 8 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 JUN 15 PY 2011 VL 71 IS 12 BP 4061 EP 4067 DI 10.1158/0008-5472.CAN-11-0549 PG 7 WC Oncology SC Oncology GA 777PZ UT WOS:000291637100002 PM 21478295 ER PT J AU Lustig, Y Ruas, JL Estall, JL Lo, JC Devarakonda, S Laznik, D Choi, JH Ono, H Olsen, JV Spiegelman, BM AF Lustig, Yaniv Ruas, Jorge L. Estall, Jennifer L. Lo, James C. Devarakonda, Srikripa Laznik, Dina Choi, Jang Hyun Ono, Hiraku Olsen, Jesper V. Spiegelman, Bruce M. TI Separation of the gluconeogenic and mitochondrial functions of PGC-1 alpha through S6 kinase SO GENES & DEVELOPMENT LA English DT Article DE PGC-1 alpha; gluconeogenesis; liver; S6K1 ID TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; HEPATIC GLUCONEOGENESIS; INSULIN-RESISTANCE; SKELETAL-MUSCLE; PPAR-GAMMA; ENERGY-METABOLISM; RECEPTOR-ALPHA; AMINO-ACIDS; ERR-ALPHA; PGC-1 AB PGC-1 alpha is a transcriptional coactivator that powerfully regulates many pathways linked to energy homeostasis. Specifically, PGC-1 alpha controls mitochondrial biogenesis in most tissues but also initiates important tissue-specific functions, including fiber type switching in skeletal muscle and gluconeogenesis and fatty acid oxidation in the liver. We show here that S6 kinase, activated in the liver upon feeding, can phosphorylate PGC-1 alpha directly on two sites within its arginine/serine-rich (RS) domain. This phosphorylation significantly attenuates the ability of PGC-1 alpha to turn on genes of gluconeogenesis in cultured hepatocytes and in vivo, while leaving the functions of PGC-1 alpha as an activator of mitochondrial and fatty acid oxidation genes completely intact. These phosphorylations interfere with the ability of PGC-1 alpha to bind to HNF4 alpha, a transcription factor required for gluconeogenesis, while leaving undisturbed the interactions of PGC-1 alpha with ERR alpha and PPAR alpha, factors important for mitochondrial biogenesis and fatty acid oxidation. These data illustrate that S6 kinase can modify PGC-1 alpha and thus allow molecular dissection of its functions, providing metabolic flexibility needed for dietary adaptation. C1 [Lustig, Yaniv; Ruas, Jorge L.; Estall, Jennifer L.; Lo, James C.; Devarakonda, Srikripa; Laznik, Dina; Choi, Jang Hyun; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ono, Hiraku] Saitama Med Univ, Dept Internal Med, Div Endo Diabet, Saitama 3500495, Japan. [Olsen, Jesper V.] Univ Copenhagen, Dept Prote, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth Sci, DK-2200 Copenhagen, Denmark. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu RI Choi, Jang Hyun/B-3055-2012; OI Olsen, Jesper/0000-0002-4747-4938; Ruas, Jorge/0000-0002-1110-2606 FU International Human Frontier Science Program Organization; Wenner-Gren Foundations (Sweden); Canadian Institutes of Health Research; National Research Council of Canada; NIH [T32 HL07604, DK54477, DK61562] FX We thank John Blenis for the S6K1 and S6K1ca plasmids, and Keyong Du for the HA-FOXO1 AAA plasmid. Y.L. is supported by a post-doctoral fellowship from the International Human Frontier Science Program Organization. J.L.R. was supported in part by a grant from the Wenner-Gren Foundations (Sweden). J.L.E. was supported by a post-doctoral fellowship from the Canadian Institutes of Health Research and the H. L. Holmes Award for Post-doctoral Studies from the National Research Council of Canada. J.C.L. was supported by NIH grant T32 HL07604. This work was supported by NIH grants DK54477 and DK61562 to B.M.S. NR 48 TC 49 Z9 50 U1 0 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 JUN 15 PY 2011 VL 25 IS 12 BP 1232 EP 1244 DI 10.1101/gad.2054711 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 778QG UT WOS:000291718800002 PM 21646374 ER PT J AU Chinai, JM Taylor, AB Ryno, LM Hargreaves, ND Morris, CA Hart, PJ Urbach, AR AF Chinai, Jordan M. Taylor, Alexander B. Ryno, Lisa M. Hargreaves, Nicholas D. Morris, Christopher A. Hart, P. John Urbach, Adam R. TI Molecular Recognition of Insulin by a Synthetic Receptor SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID AQUEOUS-SOLUTION; SUPRAMOLECULAR CHEMISTRY; SELECTIVE RECOGNITION; ARTIFICIAL RECEPTORS; LIGAND-BINDING; AMINO-ACID; PROTEINS; PEPTIDE; HOST; IMMOBILIZATION AB The discovery of molecules that bind tightly and selectively to desired proteins continues to drive innovation at the interface of chemistry and biology. This paper describes the binding of human insulin by the synthetic receptor cucurbit[7]uril (Q7) in vitro. Isothermal titration calorimetry and fluorescence spectroscopy experiments show that Q7 binds to insulin with an equilibrium association constant of 1.5 x 10(6) M-1 and with 50-100-fold selectivity versus proteins that are much larger but lack an N-terminal aromatic residue, and with >1000-fold selectivity versus an insulin variant lacking the N-terminal phenylalanine (Phe) residue. The crystal structure of the Q7 center dot insulin complex shows that binding occurs at the N-terminal Phe residue and that the N-terminus unfolds to enable binding. These findings suggest that site-selective recognition is based on the properties inherent to a protein terminus, including the unique chemical epitope presented by the terminal residue and the greater freedom of the terminus to unfold, like the end of a ball of string, to accommodate binding. Insulin recognition was predicted accurately from studies on short peptides and exemplifies an approach to protein recognition by targeting the terminus. C1 [Chinai, Jordan M.; Ryno, Lisa M.; Hargreaves, Nicholas D.; Morris, Christopher A.; Urbach, Adam R.] Trinity Univ, Dept Chem, San Antonio, TX 78212 USA. [Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, S Texas Hlth Care Syst, Dept Biochem, San Antonio, TX 78229 USA. [Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, S Texas Hlth Care Syst, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, S Texas Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Dept Vet Affairs, San Antonio, TX 78229 USA. RP Urbach, AR (reprint author), Trinity Univ, Dept Chem, 1 Trinity Pl, San Antonio, TX 78212 USA. EM aurbach@trinity.edu OI Dybdal-Hargreaves, Nicholas/0000-0002-5847-5231 FU National Science Foundation [CHE-0748483, DBI-0718766]; Welch Foundation [W-1640, AQ-1399]; W. M. Keck Foundation; Camille and Henry Dreyfus Foundation; National Center for Research Resources at the National Institutes of Health [RR-15301]; U.S. Department of Energy, Office of Basic Energy Sciences [DE-AC02-06CH11357]; Institutional Executive Research Council; San Antonio Cancer Institute FX This paper is dedicated to Prof. Jonathan L. Sessler on the occasion of his 55th birthday. Support for this work from the National Science Foundation (CHE-0748483, ARU) and Welch Foundation (W-1640, ARU and AQ-1399, PJH) is gratefully acknowledied. We thank Novo Nordisk for generous donation of the GluB1, GluB27 variant insulin 2. The circular dichroism spectropolarimeter was provided by a grant from the National Science Foundation (DBI-0718766, ARU). The fluorescence spectrometer and titration calorimeter were provided by a grant to Trinity University by the W. M. Keck Foundation. LMR had a Jean Dreyfus Boissevain Undergraduate Scholarship for Excellence in Chemistry from the Camille and Henry Dreyfus Foundation. This work is based on research conducted at the Advanced Photon Source on the Northeastern Collaborative Access Team (NE-CAT) beamlines, which are supported by award RR-15301 from the National Center for Research Resources at the National Institutes of Health. Use of the Advanced Photon Source is supported by the U.S. Department of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. We thank Dr. Jonathan P. Schuermann of NE-CAT for collecting the data for the Q7.1 complex. Support for the X-ray Crystallography Core Laboratory at the University of Texas Health Science Center by the Institutional Executive Research Council and the San Antonio Cancer Institute is gratefully acknowledged. NR 37 TC 104 Z9 104 U1 5 U2 72 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 JUN 15 PY 2011 VL 133 IS 23 BP 8810 EP 8813 DI 10.1021/ja201581x PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 777ZX UT WOS:000291667600010 PM 21473587 ER PT J AU Goodman, A AF Goodman, Annekathryn TI Measuring Success in Ovarian Cancer Risk Reducing Strategies SO CANCER LA English DT Editorial Material ID BRCA2 MUTATION CARRIERS; BREAST; WOMEN; OOPHORECTOMY C1 Massachusetts Gen Hosp, Gillette Ctr Womens Canc, Boston, MA 02114 USA. RP Goodman, A (reprint author), Massachusetts Gen Hosp, Gillette Ctr Womens Canc, Yawkey Bldg,9E, Boston, MA 02114 USA. EM agoodman@partners.org NR 15 TC 0 Z9 0 U1 0 U2 2 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 JUN 15 PY 2011 VL 117 IS 12 BP 2588 EP 2589 DI 10.1002/cncr.25946 PG 2 WC Oncology SC Oncology GA 775HR UT WOS:000291450100004 PM 21287539 ER PT J AU Mamon, HJ Niedzwiecki, D Hollis, D Tan, BR Mayer, RJ Tepper, JE Goldberg, RM Blackstock, AW Fuchs, CS AF Mamon, Harvey J. Niedzwiecki, Donna Hollis, Donna Tan, Benjamin R. Mayer, Robert J. Tepper, Joel E. Goldberg, Richard M. Blackstock, A. William Fuchs, Charles S. CA Canc Leukemia Grp B TI A Phase 2 Trial of Gemcitabine, 5-Fluorouracil, and Radiation Therapy in Locally Advanced Nonmetastatic Pancreatic Adenocarcinoma SO CANCER LA English DT Article; Proceedings Paper CT 102nd Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 02-06, 2011 CL Orlando, FL SP Amer Assoc Canc Res DE pancreatic cancer; gemcitabine; 5-fluorouracil; radiation; combined modality therapy ID COOPERATIVE-ONCOLOGY-GROUP; FULL-DOSE GEMCITABINE; GROWTH-FACTOR RECEPTOR; I TRIAL; CONCURRENT CHEMORADIOTHERAPY; CONSOLIDATIVE CHEMORADIATION; MAINTENANCE GEMCITABINE; MITOMYCIN-C; III TRIAL; CANCER AB BACKGROUND: The purpose of this study was to assess the efficacy and safety of 5-fluorouracil (5FU) and gemcitabine administered concurrently with radiation in patients with locally advanced, nonmetastatic pancreatic cancer. METHODS: Eligible patients had histologically confirmed pancreatic adenocarcinoma deemed locally unresectable without evidence of metastatic disease. In addition, all patients underwent laparoscopy or laparotomy before study entry to rule out peritoneal carcinomatosis. Patients received radiation therapy (50.4 Gy) with concurrent infusional 5FU (200 mg/m(2) 5 days/week) and weekly gemcitabine (200 mg/m(2)). After a 3-week break, patients received weekly gemcitabine at 1000 mg/m(2) for 3 of 4 weeks, for 4 cycles. The primary endpoint of the trial was the proportion of patients surviving 9 months from study entry. Secondary endpoints included objective tumor response, CA19-9 response, overall survival (OS) time to progression (TTP), and toxicity. RESULTS: Between November 2001 and October 2004, 81 patients were enrolled, 78 of whom were eligible for analysis. With a median follow-up of 55.2 months, the median OS was 12.2 months (95% confidence interval [CI], 10.9-14.9) and the median TTP was 10 months (95% CI, 6.4-12.0). An objective tumor response was seen in 19 patients (25%), and among 56 patients with an elevated CA19-9 at baseline, 29 (52%) had a sustained CA19-9 response. Overall, 41% of patients had grade 3 or greater treatment-related gastrointestinal adverse events. CONCLUSIONS: The combination of 5FU, gemcitabine, and radiation is well tolerated. Survival is comparable with the best results of other recent studies of 5FU and radiation or gemcitabine and radiation. Cancer 2011; 117: 2620-8. (C) 2010 American Cancer Society. C1 [Mamon, Harvey J.; Mayer, Robert J.; Fuchs, Charles S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mamon, Harvey J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Niedzwiecki, Donna; Hollis, Donna] Duke Univ, CALGB Stat Ctr, Durham, NC USA. [Tan, Benjamin R.] Washington Univ, St Louis, MO USA. [Tepper, Joel E.; Goldberg, Richard M.] Univ N Carolina, Chapel Hill, NC USA. [Blackstock, A. William] Wake Forest Univ, Winston Salem, NC 27109 USA. RP Mamon, HJ (reprint author), 75 Francis St, Boston, MA 02115 USA. EM hmamon@lroc.harvard.edu RI Goldberg , Richard/M-1311-2013 FU Christiana Care Health Services, Inc. CCOP, Wilmington, Delaware [CA45418]; Dana-Farber Cancer Institute, Boston, Massachusetts [CA32291]; Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, New Hampshire [CA04326]; Georgetown University Medical Center, Washington, DC [CA77597]; Hematology-Oncology Associates of Central New York CCOP, Syracuse, New York [CA45389]; Kansas City Community Clinical Oncology Program CCOP, Kansas City, Missouri; Long Island Jewish Medical Center, Lake Success, New York [CA35279]; Massachusetts General Hospital, Boston, Massachusetts [CA32291]; Mount Sinai Medical Center, Miami, Florida [CA45564]; New Hampshire Oncology-Hematology PA, Concord, New Hampshire; NorthShore University HealthSystem CCOP, Evanston, Illinois; Roswell Park Cancer Institute, Buffalo, New York [CA59518]; Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, North Carolina [CA45808]; Ohio State University Medical Center, Columbus, Ohio [CA77658]; University of California at San Diego, San Diego, California [CA11789]; University of Iowa, Iowa City, Iowa [CA47642]; University of Minnesota, Minneapolis, Minnesota [CA16450]; University of Missouri/Ellis Fischel Cancer Center, Columbia, Missouri [CA12046]; University of North Carolina at Chapel Hill, Chapel Hill, North Carolina [CA47559]; University of Vermont, Burlington, Vermont [CA77406]; Wake Forest University School of Medicine, Winston-Salem, North Carolina [CA03927]; Washington University School of Medicine, St. Louis, Missouri [CA77440]; Weill Medical College of Cornell University, New York, New York [CA07968] FX The following institutions participated in this study: Christiana Care Health Services, Inc. CCOP, Wilmington, Delaware (Stephen Grubbs, MD, supported by CA45418); Dana-Farber Cancer Institute, Boston, Massachusetts (Harold J. Burstein, MD, PhD, supported by CA32291); Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, New Hampshire (Konstantin Dragnev, MD, supported by CA04326); Georgetown University Medical Center, Washington, DC (Minetta C. Liu, MD, supported by CA77597); Hematology-Oncology Associates of Central New York CCOP, Syracuse, New York (Jeffrey Kirshner, MD, supported by CA45389); Kansas City Community Clinical Oncology Program CCOP, Kansas City, Missouri (Rakesh Gaur, MD); Long Island Jewish Medical Center, Lake Success, New York (Kanti R. Rai, MD, supported by CA35279); Massachusetts General Hospital, Boston, Massachusetts (Jeffrey W. Clark, MD, supported by CA32291); Mount Sinai Medical Center, Miami, Florida (Rogerio C. Lilenbaum, MD, supported by CA45564); New Hampshire Oncology-Hematology PA, Concord, New Hampshire (Douglas J. Weckstein); NorthShore University HealthSystem CCOP, Evanston, Illinois (David L Grinblatt, MD); Roswell Park Cancer Institute, Buffalo, New York (Ellis Levine, MD, supported by CA59518); Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, North Carolina (James N. Atkins, MD, supported by CA45808); The Ohio State University Medical Center, Columbus, Ohio (Clara D. Bloomfield, MD, supported by CA77658); University of California at San Diego, San Diego, California (Barbara A. Parker, MD, supported by CA11789); University of Iowa, Iowa City, Iowa (Daniel A. Vaena, MD, supported by CA47642); University of Minnesota, Minneapolis, Minnesota (Bruce A Peterson, MD, supported by CA16450); University of Missouri/Ellis Fischel Cancer Center, Columbia, Missouri (Michael C Perry, MD, supported by CA12046); University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (Thomas C. Shea, MD, supported by CA47559); University of Vermont, Burlington, Vermont (Steven M Grunberg, MD, supported by CA77406); Wake Forest University School of Medicine, Winston-Salem, North Carolina (David D Hurd, MD, supported by CA03927); Washington University School of Medicine, St. Louis, Missouri (Nancy Bartlett, MD, supported by CA77440); and Weill Medical College of Cornell University, New York, New York (John Leonard, MD, supported by CA07968). NR 57 TC 11 Z9 12 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUN 15 PY 2011 VL 117 IS 12 BP 2620 EP 2628 DI 10.1002/cncr.25742 PG 9 WC Oncology SC Oncology GA 775HR UT WOS:000291450100008 PM 21656739 ER PT J AU Heng, DYC Xie, WL Bjarnason, GA Vaishampayan, U Tan, MH Knox, J Donskov, F Wood, L Kollmannsberger, C Rini, BI Choueiri, TK AF Heng, Daniel Y. C. Xie, Wanling Bjarnason, Georg A. Vaishampayan, Ulka Tan, Min-Han Knox, Jennifer Donskov, Frede Wood, Lori Kollmannsberger, Christian Rini, Brian I. Choueiri, Toni K. TI Progression-Free Survival as a Predictor of Overall Survival in Metastatic Renal Cell Carcinoma Treated With Contemporary Targeted Therapy SO CANCER LA English DT Article; Proceedings Paper CT 102nd Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 02-06, 2011 CL Orlando, FL SP Amer Assoc Canc Res DE progression-free survival; overall survival; surrogate endpoints; vascular endothelial growth factor; metastatic renal cell carcinoma ID PHASE-III TRIAL; INTERFERON-ALPHA; COLORECTAL-CANCER; SUNITINIB; SURROGATE AB BACKGROUND. The majority of metastatic renal cell carcinoma (mRCC) clinical trials that examined targeted agents used progression-free survival (PFS) as the primary endpoint. Whether PFS can be used as a predictor of overall survival (OS) is unknown. METHODS. Patients from 12 cancer centers who received targeted therapy for mRCC were identified. Landmark analyses for progression at 3 months and 6 months after drug initiation were performed to minimize lead-time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS. RESULTS. In total, 1158 patients were included. The median follow-up was 30.6 months, the median age was 60 years, and the median Karnofsky performance status was 80%. For the entire cohort, the median PFS was 7.6 months, and the median OS was 19.7 months. In the landmark analysis, the median OS for patients who progressed at 3 months was 7.8 months compared with 23.6 months for patients who did not progress (log-rank test; P < .0001). Similarly, for patients who progressed at 6 months, the median OS was 8.6 months compared with 26 months for patients who did not progress (P < .0001). Compared with those who did not progress, for the patients who progressed at 3 months and at 6 months, the hazard ratios for death adjusted for adverse prognostic factors were 3.05 (95% confidence interval, 2.42-3.84) and 2.96 (95% confidence interval, 2.39-3.67), respectively. Similar results were demonstrated with landmark analyses at 9 months and at 12 months and in the bootstrap validation. Kendall tau rank correlation and a Fleischer model demonstrated a statistically significant dependent correlation. CONCLUSIONS. PFS at 3 months and at 6 months predicted OS, and the current results indicated that PFS may be a meaningful intermediate endpoint for OS in patients with mRCC who receive treatment with novel agents. Cancer 2011; 117: 2637-42. (C) 2010 American Cancer Society. C1 [Heng, Daniel Y. C.] Univ Calgary, Alberta Hlth Serv Canc Care, Tom Baker Canc Ctr, Calgary, AB T2N 4N2, Canada. [Choueiri, Toni K.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bjarnason, Georg A.] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Vaishampayan, Ulka] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Tan, Min-Han] Natl Canc Ctr, Singapore, Singapore. [Knox, Jennifer] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Donskov, Frede] Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. [Wood, Lori] Dalhousie Univ, Halifax, NS, Canada. [Kollmannsberger, Christian] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Rini, Brian I.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. RP Heng, DYC (reprint author), Univ Calgary, Alberta Hlth Serv Canc Care, Tom Baker Canc Ctr, 1331 29th St NW, Calgary, AB T2N 4N2, Canada. EM daniel.heng@albertahealthservices.ca OI Bjarnason, Georg Arnold/0000-0001-6903-5357; Donskov, Frede/0000-0002-8449-863X FU NCI NIH HHS [P30 CA022453] NR 18 TC 42 Z9 43 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUN 15 PY 2011 VL 117 IS 12 BP 2637 EP 2642 DI 10.1002/cncr.25750 PG 6 WC Oncology SC Oncology GA 775HR UT WOS:000291450100010 PM 21656741 ER PT J AU Maciejewski, ML Livingston, EH Smith, VA Kavee, AL Kahwati, LC Henderson, WG Arterburn, DE AF Maciejewski, Matthew L. Livingston, Edward H. Smith, Valerie A. Kavee, Andrew L. Kahwati, Leila C. Henderson, William G. Arterburn, David E. TI Survival Among High-Risk Patients After Bariatric Surgery SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LONG-TERM MORTALITY; QUALITY IMPROVEMENT PROGRAM; TREATMENT SELECTION BIAS; AFFAIRS MEDICAL-CENTERS; GASTRIC BYPASS-SURGERY; VETERANS-AFFAIRS; PROPENSITY-SCORE; OBESITY; PERFORMANCE; PREVALENCE AB Context Existing evidence of the survival associated with bariatric surgery is based on cohort studies of predominantly younger women with a low inherent obesity-related mortality risk. The association of survival and bariatric surgery for older men is less clear. Objective To determine whether bariatric surgery is associated with reduced mortality in a multisite cohort of predominantly older male patients who have a high baseline mortality rate. Design, Setting, and Participants Retrospective cohort study of bariatric surgery programs in Veterans Affairs medical centers. Mortality was examined for 850 veterans who had bariatric surgery in January 2000 to December 2006 (mean age 49.5 years; SD 8.3; mean body mass index [BMI] 47.4; SD 7.8) and 41 244 nonsurgical controls (mean age 54.7 years, SD 10.2; mean BMI 42.0, SD 5.0) from the same 12 Veteran Integrated Service Networks; the mean follow-up was 6.7 years. Four Cox proportional hazards models were assessed: unadjusted and controlled for baseline covariates on unmatched and propensity-matched cohorts. Main Outcome Measure All-cause mortality through December 2008. Results Among patients who had bariatric surgery, the 1-, 2-, and 6-year crude mortality rates were, respectively, 1.5%, 2.2%, and 6.8% compared with 2.2%, 4.6%, and 15.2% for nonsurgical controls. In unadjusted Cox regression, bariatric surgery was associated with reduced mortality (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.51-0.80). After covariate adjustment, bariatric surgery remained associated with reduced mortality (HR, 0.80; 95% CI, 0.63-0.995). In analysis of 1694 propensity-matched patients, bariatric surgery was no longer significantly associated with reduced mortality in unadjusted (HR, 0.83; 95% CI, 0.61-1.14) and time-adjusted (HR, 0.94; 95% CI, 0.64-1.39) Cox regressions. Conclusion In propensity score-adjusted analyses of older severely obese patients with high baseline mortality in Veterans Affairs medical centers, the use of bariatric surgery compared with usual care was not associated with decreased mortality during a mean 6.7 years of follow-up. JAMA. 2011;305(23):2419-2426 www.jama.com C1 [Maciejewski, Matthew L.; Smith, Valerie A.; Kavee, Andrew L.] 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. [Livingston, Edward H.] Univ Texas SW Med Ctr Dallas, Div Gastrointestinal & Endocrine Surg, Dallas, TX 75390 USA. [Livingston, Edward H.] Vet Adm N Texas Hlth Care Syst, Dallas, TX USA. [Livingston, Edward H.] Univ Texas Arlington, Arlington, TX USA. [Kahwati, Leila C.] US Dept Vet Affairs, Natl Ctr Hlth Promot & Dis Prevent, Off Patient Care Serv, Durham, NC USA. [Henderson, William G.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Henderson, William G.] Univ Colorado, Sch Publ Hlth, Dept Biostat & Informat, Aurora, CO USA. [Henderson, William G.] Univ Colorado, Colorado Hlth Outcomes Program, Aurora, CO USA. [Arterburn, David E.] Grp Hlth Res Inst, Seattle, WA 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 152, 411 W Chapel Hill St,Ste 600, Durham, NC 27705 USA. EM matthew.maciejewski@va.gov FU Takeda Pharmaceuticals; Novartis; Surgical Review Corporation; Research Data and Assistance Center at the University of Minnesota; Texas Instruments; Foundation for Informed Medical Decision Making [501[3]c] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Maciejewski reports receiving consultation funds from Takeda Pharmaceuticals, Novartis, the Surgical Review Corporation, and the Research Data and Assistance Center at the University of Minnesota and owns stock in Amgen. Dr Livingston reports receiving consulting funds from Texas Instruments. Dr Arterburn reports receiving research funding and has received salary support as a medical editor for the not-for-profit (501[3]c) 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 Veterans Affairs and Dr Livingston was formerly with the Dallas Veterans Affairs. No other disclosures were reported. NR 39 TC 86 Z9 87 U1 1 U2 7 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 JUN 15 PY 2011 VL 305 IS 23 BP 2419 EP 2426 DI 10.1001/jama.2011.817 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 777EB UT WOS:000291597300021 PM 21666276 ER PT J AU Abbs, B Liang, LC Makris, N Tsuang, M Seidman, LJ Goldstein, JM AF Abbs, Brandon Liang, Lichen Makris, Nikos Tsuang, Ming Seidman, Larry J. Goldstein, Jill M. TI Covariance modeling of MRI brain volumes in memory circuitry in schizophrenia: Sex differences are critical SO NEUROIMAGE LA English DT Article DE Verbal memory; Sex differences; Schizophrenia; Magnetic resonance imaging; Brain morphometry; Covariance ID VERBAL-LEARNING TEST; HUMAN CEREBRAL-CORTEX; INHIBIT GLUCOSE-TRANSPORT; MEDIAL PREFRONTAL CORTEX; LEFT TEMPORAL-LOBE; ADULT HUMAN BRAIN; EPISODIC MEMORY; GRAY-MATTER; NORMATIVE DATA; RHESUS-MONKEY AB Women have consistently demonstrated better verbal memory on tests that evaluate immediate and delayed free recall. In patients with schizophrenia, these verbal memory processes are relatively more preserved in women than men. However an understanding of the brain anatomy of the female advantage for verbal memory is still unclear. 29 females and 59 males with schizophrenia made comparable to 21 female and 27 male healthy volunteers were scanned using structural magnetic resonance imaging (sMRI) in order to assess volumes of regions across the entire brain. Sex differences within and between groups in the covariance structure of memory circuitry regions were evaluated using a novel approach to covariance analysis (the Box M Test). Brain areas of interest included the prefrontal cortex (PFC), inferior parietal lobule (iPAR), anterior cingulate gyrus (ACG), parahippocampus, and hippocampus (HIPP). Results showed significant differences in the covariance matrices of females and males with schizophrenia compared with their healthy counterparts, in particular the relationships between iPAR-PFC, iPAR-ACG, and HIPP-PFC. Sex differences in the iPAR-PFC relationship were significantly associated with sex differences in verbal memory performance. In control women, but not in men ACG volume correlated strongly with memory performance. In schizophrenia, ACG volume was reduced in females, but not in men, relative to controls. Findings suggest that the relationship between iPAR and PFC is particularly important for understanding the relative preservation of verbal memory processing in females with schizophrenia and may compensate for ACG volume reductions. These results illustrate the utility of a unique covariance structure modeling approach that yields important new knowledge for understanding the nature of schizophrenia. (C) 2011 Elsevier Inc. All rights reserved. C1 [Goldstein, Jill M.] Brigham & Womens Hosp, Div Womens Hlth, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02120 USA. [Abbs, Brandon; Goldstein, Jill M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02120 USA. [Abbs, Brandon; Liang, Lichen; Makris, Nikos; Seidman, Larry J.; Goldstein, Jill M.] MIT Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Liang, Lichen; Makris, Nikos; Seidman, Larry J.] MGH Ctr Morphometr Anal, Charlestown, MA 02129 USA. [Liang, Lichen; Makris, Nikos] Massachusetts Gen Hosp, Dept Psychiat & Neurol, Charlestown, MA 02129 USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr,Publ Psychiat Div, Boston, MA 02215 USA. [Tsuang, Ming] Univ Calif San Diego, Dept Psychiat, Inst Genom Med, Ctr Behav Genom, San Diego, CA 92103 USA. [Tsuang, Ming] Vet Affairs San Diego Healthcare Syst, La Jolla, CA 92037 USA. [Goldstein, Jill M.] Harvard Univ, Med Sch HMS, Dept Med, Boston, MA 02120 USA. RP Goldstein, JM (reprint author), Brigham & Womens Hosp, Div Womens Hlth, Connors Ctr Womens Hlth & Gender Biol, 1620 Tremont St,BC-3-34, Boston, MA 02120 USA. EM babbs@partners.org; lichenl@nmr.mgh.harvard.edu; nikos@cma.mgh.harvard.edu; mtsuang@ucsd.edu; lseidman@bidmc.harvard.edu; jill_goldstein@hms.harvard.edu FU National Institute of Mental Health (NIMH) [R01MH56956, T32MH16259-31, R01MH43518, R01MH46318]; Mental Health Centers for Intervention Development and Applied Research (CIDAR) [P50MH08272-02] FX This study was supported by National Institute of Mental Health (NIMH) grant R01MH56956 and Mental Health Centers for Intervention Development and Applied Research (CIDAR) grant P50MH08272-02 (JMG, P.I.-Sex Differences, Hormones and Memory Project). Dr. Abbs's time also was supported in part by NIMH grant T32MH16259-31. In addition, data collection was in part supported by NIMH grants R01MH43518 and R01MH46318 (MT, P.I.). The authors wish to thank George Papadimitriou for his assistance in figure preparation. NR 146 TC 15 Z9 16 U1 2 U2 12 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 JUN 15 PY 2011 VL 56 IS 4 BP 1865 EP 1874 DI 10.1016/j.neuroimage.2011.03.079 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 775KF UT WOS:000291457500002 PM 21497198 ER PT J AU Wu, W Chen, Z Gao, SK Brown, EN AF Wu, Wei Chen, Zhe Gao, Shangkai Brown, Emery N. TI A hierarchical Bayesian approach for learning sparse spatio-temporal decompositions of multichannel EEG SO NEUROIMAGE LA English DT Article DE Hierarchical Bayesian; Variational Bayesian; Common spatial patterns; Spatio-temporal decomposition; Inter-trial variability; Sparse learning; Brain-computer interface ID SINGLE-TRIAL EEG; INDEPENDENT COMPONENT ANALYSIS; BLIND SEPARATION; BRAIN RESPONSES; SCALE MIXTURES; FILTERS; ALPHA; MODEL; CLASSIFICATION; DISTRIBUTIONS AB Multichannel electroencephalography (EEG) offers a non-invasive tool to explore spatio-temporal dynamics of brain activity. With EEG recordings consisting of multiple trials, traditional signal processing approaches that ignore inter-trial variability in the data may fail to accurately estimate the underlying spatio-temporal brain patterns. Moreover, precise characterization of such inter-trial variability per se can be of high scientific value in establishing the relationship between brain activity and behavior. In this paper, a statistical modeling framework is introduced for learning spatio-temporal decompositions of multiple-trial EEG data recorded under two contrasting experimental conditions. By modeling the variance of source signals as random variables varying across trials, the proposed two-stage hierarchical Bayesian model is able to capture intertrial amplitude variability in the data in a sparse way where a parsimonious representation of the data can be obtained. A variational Bayesian (VB) algorithm is developed for statistical inference of the hierarchical model. The efficacy of the proposed modeling framework is validated with the analysis of both synthetic and real EEG data. In the simulation study we show that even at low signal-to-noise ratios our approach is able to recover with high precision the underlying spatio-temporal patterns and the dynamics of source amplitude across trials; on two brain-computer interface (BCI) data sets we show that our VB algorithm can extract physiologically meaningful spatio-temporal patterns and make more accurate predictions than other two widely used algorithms: the common spatial patterns (CSP) algorithm and the Infomax algorithm for independent component analysis (ICA). The results demonstrate that our statistical modeling framework can serve as a powerful tool for extracting brain patterns, characterizing trial-to-trial brain dynamics, and decoding brain states by exploiting useful structures in the data. (C) 2011 Elsevier Inc. All rights reserved. C1 [Wu, Wei; Chen, Zhe; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Wu, Wei; Gao, Shangkai] Tsinghua Univ, Dept Biomed Engn, Beijing 100084, Peoples R China. [Wu, Wei; Chen, Zhe; Brown, Emery N.] Harvard Univ, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp, Neurosci Stat Res Lab,Med Sch, Boston, MA 02114 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Wu, W (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. EM weiwu@neurostat.mit.edu OI Chen, Zhe/0000-0002-6483-6056 FU NIH [DP1-OD003646-01, R01-EB006385-01]; National Natural Science Foundation of China [30630022] FX This work was supported by NIH Grants DP1-OD003646-01, R01-EB006385-01, and the National Natural Science Foundation of China under Grant 30630022. We are grateful to Yijun Wang for providing Data Set 1 and to Klaus-Robert Muller, Benjamin Blankertz, and Gabriel Curio for providing the BCI competition data sets (Data Set 2). We thank Francis Bach for helpful discussions, and the anonymous reviewers for their constructive comments. NR 71 TC 28 Z9 29 U1 3 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 JUN 15 PY 2011 VL 56 IS 4 BP 1929 EP 1945 DI 10.1016/j.neuroimage.2011.03.032 PG 17 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 775KF UT WOS:000291457500008 PM 21420499 ER PT J AU Isci, S Ozturk, C Jones, J Otu, HH AF Isci, Senol Ozturk, Cengizhan Jones, Jon Otu, Hasan H. TI Pathway analysis of high-throughput biological data within a Bayesian network framework SO BIOINFORMATICS LA English DT Article ID RENAL-CELL CARCINOMA; GENE-EXPRESSION DATA; SET ENRICHMENT ANALYSIS; FUNCTIONAL-GROUPS; GLOBAL TEST; CANCER; GENOME; MODEL; KNOWLEDGE; TUMOR AB Motivation: Most current approaches to high-throughput biological data (HTBD) analysis either perform individual gene/protein analysis or, gene/protein set enrichment analysis for a list of biologically relevant molecules. Bayesian Networks (BNs) capture linear and nonlinear interactions, handle stochastic events accounting for noise, and focus on local interactions, which can be related to causal inference. Here, we describe for the first time an algorithm that models biological pathways as BNs and identifies pathways that best explain given HTBD by scoring fitness of each network. Results: Proposed method takes into account the connectivity and relatedness between nodes of the pathway through factoring pathway topology in its model. Our simulations using synthetic data demonstrated robustness of our approach. We tested proposed method, Bayesian Pathway Analysis (BPA), on human microarray data regarding renal cell carcinoma (RCC) and compared our results with gene set enrichment analysis. BPA was able to find broader and more specific pathways related to RCC. C1 [Otu, Hasan H.] Istanbul Bilgi Univ, Dept Bioengn, TR-34060 Istanbul, Turkey. [Isci, Senol; Ozturk, Cengizhan] Bogazici Univ, Inst Biomed Engn, TR-34342 Istanbul, Turkey. [Jones, Jon] Johannes Gutenberg Univ Mainz, Dept Urol, D-55131 Mainz, Germany. [Otu, Hasan H.] Harvard Univ, Sch Med, Dept Med, BIDMC Genom Ctr, Boston, MA 02115 USA. RP Otu, HH (reprint author), Istanbul Bilgi Univ, Dept Bioengn, TR-34060 Istanbul, Turkey. EM hotu@bidmc.harvard.edu RI isci, senol/E-7024-2012; Ozturk, Cengizhan/A-6177-2016; OI Ozturk, Cengizhan/0000-0002-6966-0774; Otu, Hasan/0000-0002-9253-8152 FU Dubai Harvard Foundation for Medical Research FX Funding: Grant from The Dubai Harvard Foundation for Medical Research (to H.H.O., in part). Associate Editor: Martin Bishop NR 46 TC 17 Z9 18 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2011 VL 27 IS 12 BP 1667 EP 1674 DI 10.1093/bioinformatics/btr269 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 772UD UT WOS:000291261300011 PM 21551144 ER PT J AU Bush, G AF Bush, George TI Cingulate, Frontal, and Parietal Cortical Dysfunction in Attention-Deficit/Hyperactivity Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE ADHD; attention; cingulate; cognition; decision; frontal; imaging; parietal; reward ID DEFICIT-HYPERACTIVITY DISORDER; FUNCTIONAL MAGNETIC-RESONANCE; EVENT-RELATED FMRI; MULTISOURCE INTERFERENCE TASK; PARENT-CHILD DYADS; ANTERIOR CINGULATE; DOPAMINE TRANSPORTER; INHIBITORY CONTROL; HUMAN BRAIN; COGNITIVE NEUROSCIENCE AB Functional and structural neuroimaging have identified abnormalities of the brain that are likely to contribute to the neuropathophysiology of attention-deficit/hyperactivity disorder (ADHD). In particular, hypofunction of the brain regions comprising the cingulo-frontal-parietal cognitive-attention network have been consistently observed across studies. These are major components of neural systems that are relevant to ADHD, including cognitive/attention networks, motor systems, and reward/feedback-based processing systems. Moreover, these areas interact with other brain circuits that have been implicated in ADHD, such as the "default mode" resting state network. The ADHD imaging data related to cingulo-frontal-parietal network dysfunction will be selectively highlighted here to help facilitate its integration with the other information presented in this special issue. Together, these reviews will help shed light on the neurobiology of ADHD. C1 Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Massachusetts Gen Hosp, Neurosci Div, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, MIT, Charlestown, MA USA. Massachusetts Gen Hosp, Athinoula A Martinos Ctr Funct & Struct Biomed Im, Charlestown, MA USA. RP Bush, G (reprint author), MGH East, Psychiat Neurosci Program, CNY2614,Bldg 149,13th St, Charlestown, MA 02129 USA. EM geo@nmr.mgh.harvard.edu FU Centers for Disease Control; National Institutes of Mental Health; National Science Foundation; Mental Illness and Neuroscience Discovery (MIND) Institute; National Alliance for Research on Schizophrenia and Depression (NARSAD); Benson-Henry Institute for Mind-Body Medicine at Massachusetts General Hospital; David Judah Fund; McIngvale Fund; Johnson and Johnson Center for the Study of Psychopathology; Center for Functional Neuroimaging Technologies [P41RR14075]; McNeil Pharmaceuticals; Pfizer Pharmaceuticals; Eli Lilly and Company FX This review was produced without direct support or compensation. Indirect support has been provided to the author for cingulate and attention-deficit/hyperactivity disorder-related work over the past decade in the form of grant or general support by the Centers for Disease Control, the National Institutes of Mental Health, the National Science Foundation, the Mental Illness and Neuroscience Discovery (MIND) Institute, the National Alliance for Research on Schizophrenia and Depression (NARSAD), the Benson-Henry Institute for Mind-Body Medicine at Massachusetts General Hospital, the David Judah Fund, the McIngvale Fund, the Johnson and Johnson Center for the Study of Psychopathology, the Center for Functional Neuroimaging Technologies (P41RR14075), McNeil Pharmaceuticals, Pfizer Pharmaceuticals, and Eli Lilly and Company. The author has, or has had in the past, a relationship with one or more organizations listed as follows: former advisory board member and speaker's honoraria from Eli Lilly and Company and Novartis Pharmaceuticals; and has received speaker's honoraria from Shire U.S., Janssen Pharmaceuticals, Johnson and Johnson, and McNeil Pharmaceuticals. The author does not now and has not at any time had a financial interest in any of these entities. NR 111 TC 97 Z9 101 U1 7 U2 50 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2011 VL 69 IS 12 BP 1160 EP 1167 DI 10.1016/j.biopsych.2011.01.022 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 772QI UT WOS:000291249200014 PM 21489409 ER PT J AU Seung, E Cho, JL Sparwasser, T Medoff, BD Luster, AD AF Seung, Edward Cho, Josalyn L. Sparwasser, Tim Medoff, Benjamin D. Luster, Andrew D. TI Inhibiting CXCR3-Dependent CD8(+) T Cell Trafficking Enhances Tolerance Induction in a Mouse Model of Lung Rejection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHEMOKINE RECEPTOR CXCR3; BRONCHIOLITIS OBLITERANS SYNDROME; CARDIAC ALLOGRAFT-REJECTION; TRANSPLANTATION TOLERANCE; IFN-GAMMA; ORGAN-TRANSPLANTATION; REGULATORY CELLS; INFLAMMATION; ASTHMA; HEART AB Lung transplantation remains the only effective therapy for patients with end-stage pulmonary diseases. Unfortunately, acute rejection of the lung remains a frequent complication and is an important cause of morbidity and mortality. The induction of transplant tolerance is thought to be dependent, in part, on the balance between allograft effector mechanisms mediated by effector T lymphocytes (Teff), and regulatory mechanisms mediated by FOXP3(+) regulatory T cells (Treg). In this study, we explored an approach to tip the balance in favor of regulatory mechanisms by modulating chemokine activity. We demonstrate in an adoptive transfer model of lung rejection that CXCR3-deficient CD8(+) Teff have impaired migration into the lungs compared with wild-type Teff, which results in a dramatic reduction in fatal pulmonary inflammation. The lungs of surviving mice contained tolerized CXCR3-deficient Teff, as well as a large increase in Treg. We confirmed that Treg were needed for tolerance and that their ability to induce tolerance was dependent on their numbers in the lung relative to the numbers of Teff. These data suggest that transplantation tolerance can be achieved by reducing the recruitment of some, but not necessarily all, CD8(+) Teff into the target organ and suggest a novel approach to achieve transplant tolerance. The Journal of Immunology, 2011, 186: 6830-6838. C1 [Seung, Edward; Cho, Josalyn L.; Medoff, Benjamin D.; Luster, Andrew D.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02129 USA. [Seung, Edward; Cho, Josalyn L.; Medoff, Benjamin D.; Luster, Andrew D.] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Seung, Edward; Luster, Andrew D.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02129 USA. [Cho, Josalyn L.; Medoff, Benjamin D.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02129 USA. [Sparwasser, Tim] Ctr Expt & Clin Infect Res, TWINCORE, Inst Infect Immunol, D-30625 Hannover, Germany. RP Luster, AD (reprint author), Massachusetts Gen Hosp E, 149 13th St, Boston, MA 02129 USA. EM bmedoff@partners.org; aluster@mgh.harvard.edu FU Roche Organ Transplantation Research Foundation; National Institutes of Health [R01CA069212]; International Society for Heart and Lung Transplantation FX This work was supported by the Roche Organ Transplantation Research Foundation, by National Institutes of Health Grant R01CA069212 (to A.D.L.), and by the International Society for Heart and Lung Transplantation (to E.S.). NR 66 TC 10 Z9 12 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2011 VL 186 IS 12 BP 6830 EP 6838 DI 10.4049/jimmunol.1001049 PG 9 WC Immunology SC Immunology GA 773LV UT WOS:000291309700024 PM 21555535 ER PT J AU Ndhlovu, ZM Piechocka-Trocha, A Vine, S McMullen, A Koofhethile, KC Goulder, PJR Ndung'u, T Barouch, DH Walker, BD AF Ndhlovu, Zaza M. Piechocka-Trocha, Alicja Vine, Seanna McMullen, Ashley Koofhethile, Kegakilwe C. Goulder, Phillip J. R. Ndung'u, Thumbi Barouch, Dan H. Walker, Bruce D. TI Mosaic HIV-1 Gag Antigens Can Be Processed and Presented to Human HIV-Specific CD8(+) T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LYMPHOCYTE RESPONSE; IMMUNE-RESPONSES; SUBDOMINANT EPITOPES; REPLICATION CAPACITY; VACCINE DEVELOPMENT; FLANKING SEQUENCES; AIDS VACCINE; INFECTION; ESCAPE; STEP AB Polyvalent mosaic HIV immunogens offer a potential solution for generating vaccines that can elicit immune responses against genetically diverse viruses. However, it is unclear whether key T cell epitopes can be processed and presented from these synthetic Ags and recognized by epitope-specific human T cells. In this study, we tested the ability of mosaic HIV immunogens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors to process and present major HIV clade B and clade C CD8 T cell epitopes in human cells. A bivalent mosaic vaccine expressing HIV Gag sequences was used to transduce PBMCs from 12 HIV-1-infected individuals from the United States and 10 HIV-1-infected individuals from South Africa; intracellular cytokine staining, together with tetramer staining, was used to assess the ability of mosaic Gag Ags to stimulate pre-existing memory responses compared with natural clade B and C vectors. Mosaic Gag Ags expressed all eight clade B epitopes tested in 12 United States subjects and all 5 clade C epitopes tested in 10 South African subjects. Overall, the magnitude of cytokine production induced by stimulation with mosaic Ags was comparable to clade B and clade C Ags tested, but the mosaic Ags elicited greater cross-clade recognition. Additionally, mosaic Ags induced HIV-specific CD4 T cell responses. Our studies demonstrate that mosaic Ags express major clade B and clade C viral T cell epitopes in human cells, as well as support the evaluation of mosaic HIV-1 vaccines in humans. The Journal of Immunology, 2011, 186: 6914-6924. C1 [Ndhlovu, Zaza M.; Piechocka-Trocha, Alicja; Vine, Seanna; McMullen, Ashley; Ndung'u, Thumbi; Barouch, Dan H.; Walker, Bruce D.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Charlestown, MA 02129 USA. [Ndhlovu, Zaza M.; Piechocka-Trocha, Alicja; Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Koofhethile, Kegakilwe C.; Goulder, Phillip J. R.; Ndung'u, Thumbi; Walker, Bruce D.] Univ KwaZulu Natal, HIV Pathogenesis Program, Doris Duke Med Res Inst, ZA-4013 Congella, Durban, South Africa. [Goulder, Phillip J. R.] Univ Oxford, Dept Pediat, Oxford OX1 3SY, England. [Barouch, Dan H.] Beth Israel Deaconess Med Ctr, Div Vaccine Res, Boston, MA 02215 USA. RP Walker, BD (reprint author), Ragon Inst Massachusetts Gen Hosp Massachusetts I, 149 13th St, Charlestown, MA 02149 USA. EM bwalker@partners.org OI Ndung'u, Thumbi/0000-0003-2962-3992 FU National Institutes of Health [R01 30914]; Bill and Melinda Gates Foundation; National Institute of Allergy and Infectious Disease [AI066924, AI078526]; Mark and Lisa Schwartz Foundation; Howard Hughes Medical Institute FX This work was supported by National Institutes of Health Grant R01 30914 (to B.D.W.), the Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation (to B.D.W.), National Institute of Allergy and Infectious Disease Grants AI066924 and AI078526 (to D.H.B.), the Mark and Lisa Schwartz Foundation (to B.D.W.), and the Howard Hughes Medical Institute (to B.D.W.). NR 47 TC 22 Z9 22 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2011 VL 186 IS 12 BP 6914 EP 6924 DI 10.4049/jimmunol.1004231 PG 11 WC Immunology SC Immunology GA 773LV UT WOS:000291309700032 PM 21576505 ER PT J AU Bonello, GB Pham, MH Begum, K Sigala, J Sataranatarajan, K Mummidi, S AF Bonello, Gregory B. Pham, Minh-Hieu Begum, Kazi Sigala, Jose Sataranatarajan, Kavithalakshmi Mummidi, Srinivas TI An Evolutionarily Conserved TNF-alpha-Responsive Enhancer in the Far Upstream Region of Human CCL2 Locus Influences Its Gene Expression SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BETA-GLOBIN LOCUS; NF-KAPPA-B; ACTIVE CHROMATIN HUB; CHEMOATTRACTANT PROTEIN-1 GENE; TRANSCRIPTION FACTOR-BINDING; TUMOR-NECROSIS-FACTOR; TH2 CYTOKINE LOCUS; IN-VIVO; REGULATORY REGIONS; SPATIAL-ORGANIZATION AB Comparative cross-species genomic analysis has served as a powerful tool to discover novel noncoding regulatory regions that influence gene expression in several cytokine loci. In this study, we have identified several evolutionarily conserved regions (ECRs) that are shared between human, rhesus monkey, dog, and horse and that are upstream of the promoter regions that have been previously shown to play a role in regulating CCL2 gene expression. Of these, an ECR that was similar to 16.5 kb (-16.5 ECR) upstream of its coding sequence contained a highly conserved NF-kappa B site. The region encompassing the -16.5 ECR conferred TNF-alpha responsiveness to homologous and heterologous promoters. In vivo footprinting demonstrated that specific nucleotide residues in the -16.5 ECR were protected or became hypersensitive after TNF-alpha treatment. The footprinted regions were found to bind NF-kappa B subunits in vitro and in vivo. Mutation/deletion of the conserved NF-kappa B binding site in the -16.5 ECR led to loss of TNF-alpha responsiveness. After TNF-alpha stimulation, the -16.5 ECR showed increased sensitivity to nuclease digestion and loss of histone signatures that are characteristic of a repressive chromatin. Chromosome conformation capture assays indicated that -16.5 ECR physically interacts with the CCL2 proximal promoter after TNF-alpha stimulation. Taken together, these results suggest that the -16.5 ECR may play a critical role in the regulation of CCL2. The Journal of Immunology, 2011, 186: 7025-7038. C1 [Bonello, Gregory B.; Pham, Minh-Hieu; Begum, Kazi; Sigala, Jose; Sataranatarajan, Kavithalakshmi; Mummidi, Srinivas] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Bonello, Gregory B.; Pham, Minh-Hieu; Begum, Kazi; Sigala, Jose; Mummidi, Srinivas] S Texas Vet Hlth Care Syst, Ctr Personalized Med, San Antonio, TX 78229 USA. RP Mummidi, S (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, 7703 Floyd Curl Dr,Mail Code 7881, San Antonio, TX 78229 USA. EM mummidi@uthscsa.edu RI Mummidi, Srinivas/C-1004-2008 OI Mummidi, Srinivas/0000-0002-4068-6380 FU Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development FX This work was supported by a Merit Review grant awarded by the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development (to S.M.). NR 79 TC 7 Z9 7 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2011 VL 186 IS 12 BP 7025 EP 7038 DI 10.4049/jimmunol.0900643 PG 14 WC Immunology SC Immunology GA 773LV UT WOS:000291309700044 PM 21551367 ER PT J AU Londono, D Carvajal, J Strle, K Kim, KS Cadavid, D AF Londono, Diana Carvajal, Jenny Strle, Klemen Kim, Kwang S. Cadavid, Diego TI IL-10 Prevents Apoptosis of Brain Endothelium during Bacteremia SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BORRELIA-BURGDORFERI LIPOPROTEINS; RELAPSING-FEVER BORRELIOSIS; PROGRAMMED CELL-DEATH; NECROSIS-FACTOR-ALPHA; INTERLEUKIN-10-DEFICIENT MICE; LYME NEUROBORRELIOSIS; PERSISTENT INFECTION; PLASMODIUM-CHABAUDI; MEDIATED APOPTOSIS; NEUROTROPIC STRAIN AB IL-10-deficient mice infected with the relapsing fever bacterium Borrelia turicatae rapidly succumb to a brain hemorrhage if they are unable to clear peak bacteremia. In this study, we investigated the protective role of IL-10 during relapsing-remitting bacteremia and explored the molecular events involved in the protection of brain endothelium by IL-10. Brain endothelial injury was measured with cytotoxicity and diverse apoptotic assays, whereas the signaling pathway analysis was done by quantitative PCR array. The results showed that severe endothelial cell injury leading to hemorrhage in the brain and other organs occurred in IL-10-deficient mice during relapsing-remitting infection. Human brain microvascular endothelial cells (HBMEC) produced abundant proinflammatory mediators upon exposure to whole bacteria or purified bacterial lipoprotein but did not produce any detectable IL-10. Whole bacteria and purified outer membrane lipoprotein rapidly killed HBMEC by apoptosis in a time-and concentration-dependent manner. Exogenous IL-10 protected HBMEC from apoptosis. HBMEC apoptosis during exposure to a low number of bacteria was associated with downregulation of TNF and TNFAIP3 and upregulation of BAX. In contrast, HBMEC apoptosis during exposure to high concentrations of purified outer membrane lipoprotein was associated with marked upregulation of FAS, FAS ligand, and the adaptor molecules RIPK1 and CFLAR. Exogenous IL-10 reversed all the apoptotic signaling changes induced by whole bacteria or its purified lipoprotein. The results indicate that prominent brain endothelial cell apoptosis occurs during relapsing-remitting bacteremia in the absence of IL-10 and point to a prominent role for bacterial lipoprotein-mediated activation of FAS and caspase-3 in this process. The Journal of Immunology, 2011, 186: 7176-7186. C1 [Londono, Diana; Strle, Klemen; Cadavid, Diego] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02144 USA. [Londono, Diana; Carvajal, Jenny; Cadavid, Diego] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Neurol & Neurosci, Newark, NJ 07103 USA. [Londono, Diana; Carvajal, Jenny; Cadavid, Diego] Univ Med & Dent New Jersey, New Jersey Med Sch, Ctr Emerging Pathogens, Newark, NJ 07103 USA. [Kim, Kwang S.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. RP Cadavid, D (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, 149 13th St,Room 8301, Boston, MA 02129 USA. EM dcadavid@partners.org FU National Institutes of Health [NS053997, 7R21NS057545-02]; Foundation of University of Medicine and Dentistry of New Jersey; Public Health Service [P30NS045776] FX This work was supported by National Institutes of Health Grants NS053997 and 7R21NS057545-02 (to D. C.), the Foundation of University of Medicine and Dentistry of New Jersey (to D. C.), and the Neuroscience Center PCR Core Facility at Massachusetts General Hospital, which is funded by Public Health Service Grant P30NS045776. NR 65 TC 17 Z9 19 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2011 VL 186 IS 12 BP 7176 EP 7186 DI 10.4049/jimmunol.1100060 PG 11 WC Immunology SC Immunology GA 773LV UT WOS:000291309700059 PM 21602495 ER PT J AU Dubielecka, PM Hwynn, N Sengun, C Lee, S Lomas-Francis, C Singer, C Fernandez, HH Walker, RH AF Dubielecka, Patrycja M. Hwynn, Nelson Sengun, Cenk Lee, Soohee Lomas-Francis, Christine Singer, Carlos Fernandez, Hubert H. Walker, Ruth H. TI Two McLeod patients with novel mutations in XK SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE McLeod syndrome; Neuroacanthocytosis; XK protein; Kell protein; Acanthocytosis; McLeod blood group; Kx erythrocyte antigen; Kell blood group antigens ID KELL BLOOD-GROUP; GROUP SYSTEM; MESSENGER-RNA; SPLICE SITES; MOUSE KELL; PHENOTYPE; PROTEINS; NEUROACANTHOCYTOSIS; ACANTHOCYTES; TRANSPORT AB McLeod syndrome (MIS) is a rare. X-linked, late-onset, disease involving hematological, brain, and neuromuscular systems, caused by mutations in XK that result in either defective XK or complete loss of XK protein. Acanthocytosis of erythrocytes is a typical feature. We report novel mutations in two patients who exhibited typical clinical characteristics of MIS. The coding and flanking intronic regions of XK were amplified by PCR, sequenced, and compared with the normal XK sequence. XK protein, and its complexed partner protein, Kell, were assessed by Western blot analysis. Patient 1 was found to have a single base insertion, 605insA at 175Ile creating a frame shift within the coding sequence of XK. Patient 2 had a single base substitution in the 3' splice sequence of intron 2 (IVS2-2a>g). In both cases mutations resulted in the absence of XK protein. (C) 2011 Elsevier B.V. All rights reserved. C1 [Hwynn, Nelson] Scripps Clin, Div Neurol, La Jolla, CA 92037 USA. [Dubielecka, Patrycja M.] New York Blood Ctr, Lindsley F Kimball Res Inst, Cell Signaling Lab, New York, NY 10065 USA. [Sengun, Cenk; Singer, Carlos] Univ Miami, Dept Neurol, Miami, FL 33136 USA. [Lomas-Francis, Christine] New York Blood Ctr, Lab Immunohematol, Long Isl City, NY 11101 USA. [Fernandez, Hubert H.] Cleveland Clin, Dept Neurol, Cleveland, OH 44195 USA. [Walker, Ruth H.] James J Peters VAMC, Dept Neurol, Movement Disorders Clin, Bronx, NY 10468 USA. [Walker, Ruth H.] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. RP Hwynn, N (reprint author), Scripps Clin, Div Neurol, 10666 N Torrey Pines Blvd,MS 313, La Jolla, CA 92037 USA. EM hwynn.nelson@scrippshealth.org FU NHLBI NIH HHS [R01 HL075716-01] NR 30 TC 3 Z9 4 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD JUN 15 PY 2011 VL 305 IS 1-2 BP 160 EP 164 DI 10.1016/j.jns.2011.02.028 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 773SN UT WOS:000291330800031 PM 21463873 ER PT J AU Mayhew, DL Hornberger, TA Lincoln, HC Bamman, MM AF Mayhew, David L. Hornberger, Troy A. Lincoln, Hannah C. Bamman, Marcas M. TI Eukaryotic initiation factor 2B epsilon induces cap-dependent translation and skeletal muscle hypertrophy SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID SIGNALING MOLECULE PHOSPHORYLATION; GUANINE-NUCLEOTIDE EXCHANGE; PROTEIN-SYNTHESIS; RESISTANCE EXERCISE; MYOFIBER HYPERTROPHY; CLUSTER-ANALYSIS; MAMMALIAN TARGET; MESSENGER-RNA; AMINO-ACIDS; YOUNG MEN AB The purpose of this study was to identify signalling components known to control mRNA translation initiation in skeletal muscle that are responsive to mechanical load and may be partly responsible for myofibre hypertrophy. To accomplish this, we first utilized a human cluster model in which skeletal muscle samples from subjects with widely divergent hypertrophic responses to resistance training were used for the identification of signalling proteins associated with the degree myofibre hypertrophy. We found that of 11 translational signalling molecules examined, the response of p(T421/S424)-p70S6K phosphorylation and total eukaryotic initiation factor 2B epsilon (eIF2B epsilon) protein abundance after a single bout of unaccustomed resistance exercise was associated with myofibre hypertrophy following 16 weeks of training. Follow up studies revealed that overexpression of eIF2B epsilon alone was sufficient to induce an 87% increase in cap-dependent translation in L6 myoblasts in vitro and 21% hypertrophy of myofibres in mouse skeletal muscle in vivo (P < 0.05). However, genetically altering p70S6K activity had no impact on eIF2B epsilon protein abundance in mouse skeletal muscle in vivo or multiple cell lines in vitro (P > 0.05), suggesting that the two phenomena were not directly related. These are the first data that mechanistically link eIF2B epsilon abundance to skeletal myofibre hypertrophy, and indicate that eIF2B epsilon abundance may at least partially underlie the widely divergent hypertrophic phenotypes in human skeletal muscle exposed to mechanical stimuli. C1 [Mayhew, David L.] Univ Alabama Birmingham, Med Scientist Training Program, Birmingham, AL 35294 USA. [Mayhew, David L.; Bamman, Marcas M.] Univ Alabama Birmingham, Dept Phys & Biophys, Birmingham, AL 35294 USA. [Mayhew, David L.; Bamman, Marcas M.] Birmingham VA Med Ctr, Geriatr Res Educ & Clin Ctr, Birmingham, AL 35233 USA. [Hornberger, Troy A.; Lincoln, Hannah C.] Univ Wisconsin, Dept Comparat Biosci, Madison, WI 53706 USA. RP Bamman, MM (reprint author), 966McCallum Bldg,1530 3rd Ave S, Birmingham, AL 35294 USA. EM mbamman@uab.edu OI Hornberger, Troy/0000-0002-2349-1899 FU NIH [AG017896, AG031623, AR057347] FX We would like to sincerely thank Shane Kelly (UAB) for technical assistance. This work was supported by NIH grants AG017896 to M. M. B., AG031623 to D. L. M., AR057347 to T. A. H. NR 56 TC 27 Z9 28 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUN 15 PY 2011 VL 589 IS 12 BP 3023 EP 3037 DI 10.1113/jphysiol.2010.202432 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 785CV UT WOS:000292205900014 PM 21486778 ER PT J AU Boucrot, E Howes, MT Kirchhausen, T Parton, RG AF Boucrot, Emmanuel Howes, Mark T. Kirchhausen, Tomas Parton, Robert G. TI Redistribution of caveolae during mitosis SO JOURNAL OF CELL SCIENCE LA English DT Article DE Caveolae; Caveolin-1; Cavin-1; Cell cycle; Mitosis; Total internal reflection fluorescence ID CLATHRIN-INDEPENDENT ENDOCYTOSIS; PLASMA-MEMBRANE; CELL-CYCLE; DYNAMIN; INTERNALIZATION; PROLIFERATION; POLARIZATION; MECHANISMS; MIGRATION; TRANSPORT AB Caveolae form a specialized platform within the plasma membrane that is crucial for an array of important biological functions, ranging from signaling to endocytosis. Using total internal reflection fluorescence (TIRF) and 3D fast spinning-disk confocal imaging to follow caveola dynamics for extended periods, and electron microscopy to obtain high resolution snapshots, we found that the vast majority of caveolae are dynamic with lifetimes ranging from a few seconds to several minutes. Use of these methods revealed a change in the dynamics and localization of caveolae during mitosis. During interphase, the equilibrium between the arrival and departure of caveolae from the cell surface maintains the steady-state distribution of caveolin-1 (Cav1) at the plasma membrane. During mitosis, increased dynamics coupled to an imbalance between the arrival and departure of caveolae from the cell surface induces a redistribution of Cav1 from the plasma membrane to intracellular compartments. These changes are reversed during cytokinesis. The observed redistribution of Cav1 was reproduced by treatment of interphase cells with nocodazole, suggesting that microtubule rearrangements during mitosis can mediate caveolin relocalization. This study provides new insights into the dynamics of caveolae and highlights precise regulation of caveola budding and recycling during mitosis. C1 [Boucrot, Emmanuel; Kirchhausen, Tomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Boucrot, Emmanuel; Kirchhausen, Tomas] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Howes, Mark T.; Parton, Robert G.] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. [Howes, Mark T.; Parton, Robert G.] Ctr Microscopy & Microanal, Brisbane, Qld 4072, Australia. RP Kirchhausen, T (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. EM kirchhausen@crystal.harvard.edu; r.parton@imb.uq.edu.au RI Parton, Robert/C-5673-2009 OI Parton, Robert/0000-0002-7494-5248 FU National Health and Medical Research Council of Australia; Human Frontier Science Program; US National Institutes of Health [GM 075252, GM 62566] FX We are grateful to Brigitte Joggerst, Nicole Schieber (R. G. P.) and Saveez Saffarian (E. B.) for technical assistance. R. G. P. made the initial observation and performed and analysed the electron microscopy experiments together with M. T. H. All the other experiments were performed and analyzed by E. B. The project was designed and supervised by R. G. P. and T. K. The paper was written by E. B. and R. G. P. with input from all the other authors. This work was supported by grants from the National Health and Medical Research Council of Australia (R. G. P.), the Human Frontier Science Program (R. G. P.) and the US National Institutes of Health grants GM 075252 and GM 62566 (T. K.). E. B. was a long-term fellow of the International Human Frontier Science Program Organization (HFSP). The authors acknowledge the use of facilities in the Australian Microscopy and Microanalysis Facility (AMMRF) at the Centre for Microscopy and Microanalysis at The University of Queensland. Deposited in PMC for release after 12 months. NR 29 TC 33 Z9 33 U1 2 U2 13 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JUN 15 PY 2011 VL 124 IS 12 BP 1965 EP 1972 DI 10.1242/jcs.076570 PG 8 WC Cell Biology SC Cell Biology GA 769WC UT WOS:000291048000002 PM 21625007 ER PT J AU Kotton, CN AF Kotton, Camille Nelson TI Judicious Choices: Outcomes of Organs From Seronegative Donors at Increased Risk for Viral Infection SO TRANSPLANTATION LA English DT Editorial Material ID PROVIDER UTILIZATION; TRANSPLANTATION C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. RP Kotton, CN (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, 55 Fruit St,Cox 5, Boston, MA 02114 USA. EM ckotton@partners.org NR 12 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUN 15 PY 2011 VL 91 IS 11 BP 1183 EP 1184 DI 10.1097/TP.0b013e318219796b PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 769JN UT WOS:000291008800006 PM 21464794 ER PT J AU Veillette, GR Sahara, H Meltzer, AJ Weiss, MJ Iwamoto, Y Kim, KM Rosengard, BR Allan, JS Houser, SL Sachs, DH Benichou, G Madsen, JC AF Veillette, Gregory R. Sahara, Hisashi Meltzer, Andrew J. Weiss, Mathew J. Iwamoto, Yoshiko Kim, Karen M. Rosengard, Bruce R. Allan, James S. Houser, Stuart L. Sachs, David H. Benichou, Gilles Madsen, Joren C. TI Autoimmune Sensitization to Cardiac Myosin Leads to Acute Rejection of Cardiac Allografts in Miniature Swine SO TRANSPLANTATION LA English DT Article DE Heart transplantation; Swine; Autoimmunity; Cardiac myosin ID MAJOR HISTOCOMPATIBILITY COMPLEX; HEART-TRANSPLANTATION; SELF-ANTIGEN; T-CELLS; MYOCARDITIS; ANTIBODIES; MICE; AUTOANTIBODIES; PATHOGENESIS; INDUCTION AB Background. Recent studies in mice and patients suggest that posttransplantation induction of autoimmune responses to tissue-specific antigens contributes to the rejection of major histocompatibility complex mismatched allotransplants. The relevance of this phenomenon to the rejection of major and minor histocompatibility-mismatched allografts performed in large-animal models remains to be established. Methods. Miniature swine were immunized with cardiac myosin (CM) in Freund's adjuvant and received heterotopic, minor antigen-mismatched heart transplants. T-cell (proliferation and delayed type hypersensitivity [DTH]) and B-cell (antibody) responses specific to CM were measured. The rejection of heart transplants was assessed histologically. Results. Three of four swine that were immunized with CM before receiving a minor antigen-mismatched heart transplant exhibited potent DTH, T-cell proliferation and antibody responses to CM and rejected their grafts acutely. The fourth swine, which failed to mount a significant DTH response to CM and displayed low and transient anti-CM antibody titers, demonstrated long-term allograft survival. Conclusions. This large-animal study supports the relevance of autoimmunity to CM in the rejection of minor antigen disparate cardiac allotransplants. C1 [Veillette, Gregory R.; Sahara, Hisashi; Meltzer, Andrew J.; Weiss, Mathew J.; Kim, Karen M.; Rosengard, Bruce R.; Allan, James S.; Houser, Stuart L.; Sachs, David H.; Madsen, Joren C.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Dept Surg, Boston, MA 02114 USA. [Veillette, Gregory R.; Sahara, Hisashi; Meltzer, Andrew J.; Weiss, Mathew J.; Iwamoto, Yoshiko; Kim, Karen M.; Rosengard, Bruce R.; Allan, James S.; Houser, Stuart L.; Sachs, David H.; Benichou, Gilles; Madsen, Joren C.] Harvard Univ, Sch Med, Boston, MA USA. [Iwamoto, Yoshiko; Benichou, Gilles] Massachusetts Gen Hosp, Transplantat Unit, Dept Surg, Boston, MA 02114 USA. [Rosengard, Bruce R.; Madsen, Joren C.] Massachusetts Gen Hosp, Div Cardiac Surg, Dept Surg, Boston, MA 02114 USA. [Allan, James S.] Massachusetts Gen Hosp, Div Thorac Surg, Dept Surg, Boston, MA 02114 USA. RP Madsen, JC (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Dept Surg, Cox 654,55 Fruit St, Boston, MA 02114 USA. EM jcmadsen@partners.org FU National Heart Lung and Blood Institute [RO1HL54211, PO1HL18646]; National Institute of Allergy and Infectious Disease of the National Institutes of Health [KO2AI53103] FX This work was supported, in part, by the National Heart Lung and Blood Institute grants RO1HL54211 and PO1HL18646 and the National Institute of Allergy and Infectious Disease grant KO2AI53103 of the National Institutes of Health. NR 30 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUN 15 PY 2011 VL 91 IS 11 BP 1187 EP 1191 DI 10.1097/TP.0b013e318218415d PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 769JN UT WOS:000291008800008 PM 21512437 ER PT J AU Turkmen, K Martin, J Akcay, A Nguyen, Q Ravichandran, K Faubel, S Pacic, A Ljubanovic, D Edelstein, CL Jani, A AF Turkmen, Kultigin Martin, Jessica Akcay, Ali Quocan Nguyen Ravichandran, Kameswaran Faubel, Sarah Pacic, Arijana Ljubanovic, Danica Edelstein, Charles L. Jani, Alkesh TI Apoptosis and Autophagy in Cold Preservation Ischemia SO TRANSPLANTATION LA English DT Article DE Autophagy; Apoptosis; Cold preservation ischemia ID TUBULAR EPITHELIAL-CELLS; DELAYED GRAFT FUNCTION; ACUTE-RENAL-FAILURE; REPERFUSION INJURY; RISK-FACTORS; INHIBITION; KIDNEY; RAT; TRANSPLANTATION; MACROAUTOPHAGY AB Background. Prolonged cold ischemia (CI) is a risk factor for the development of delayed graft function that predicts reduced 5-year kidney transplant survival. CI results in caspase-3 activation, tubular injury, and apoptosis. Autophagy, a highly conserved pathway that permits recycling of nutrients within the cell during stress, is linked to apoptosis. We hypothesized that CI during kidney preservation would induce autophagy. We sought to determine apoptosis and autophagic flux in CI. Methods. Autophagic flux and apoptosis were examined in kidneys of wild-type and green fluorescent protein (GFP)-microtubule-associated protein1 light chain 3 (LC3) transgenic mice that were subjected to 48 hr of CI. Autophagic flux was determined by performing experiments with and without bafilomycin A1. Results. CI alone significantly increased the number of apoptotic cells/hpf, caspase-3/7 activity, and protein expression of autophagy markers LC3 II and autophagy-related protein 5. To determine the effect of inhibiting autophagic flux on apoptosis, kidneys of wild-type and GFP-LC3 transgenic mice were subjected to 48 hr of CI in the presence of lysosomal inhibitor bafilomycin A1. The combination of CI and bafilomycin A1 suppressed autophagic flux and significantly reduced the number of apoptotic cells/hpf, caspase-3/7 activity, LC3 II (both by immunoblot and in GFP-LC3 transgenic mice), and autophagy-related protein 5 protein expression. Conclusion. In summary, we have shown that autophagy and autophagic flux are reduced in cold ischemic kidneys treated with bafilomycin A1. Reduced autophagy and autophagic flux were associated with a significant reduction in apoptotic cell death, which may provide a therapeutic rationale for including bafilomycin A1 in University of Wisconsin solution during organ preservation. C1 [Turkmen, Kultigin; Martin, Jessica; Akcay, Ali; Quocan Nguyen; Ravichandran, Kameswaran; Faubel, Sarah; Edelstein, Charles L.] Univ Colorado, Denver, CO 80202 USA. [Pacic, Arijana; Ljubanovic, Danica] Univ Zagreb, Hosp Dubrava, Univ Zagreb SOM, Zagreb 41000, Croatia. [Jani, Alkesh] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Jani, A (reprint author), Univ Colorado Denver, Div Renal Dis & Hypertens, 12700 E 19th Ave,C281, Aurora, CO 80045 USA. EM Alkesh.jani@ucdenver.edu FU NIH [RO1DK056851, RO1-DK-074835]; Turkish Society of Nephrology; [KO8DK069512]; [R01HL095363] FX This work was supported by KO8DK069512 (A.J.), R01HL095363 (S.F.), and NIH grants RO1DK056851 and RO1-DK-074835 (C.L.E.), and Turkish Society of Nephrology (K.T.). NR 32 TC 16 Z9 17 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUN 15 PY 2011 VL 91 IS 11 BP 1192 EP 1197 DI 10.1097/TP.0b013e31821ab9c8 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 769JN UT WOS:000291008800009 PM 21577181 ER PT J AU Reese, PP Halpern, SD Asch, DA Bloom, R Nathan, H Hasz, R Roth, J Reitsma, W Krefski, L Goerlitz, F DeLauro, G Blumberg, E Weng, FL Caplan, A Thomasson, A Shults, J Feldman, HI AF Reese, Peter P. Halpern, Scott D. Asch, David A. Bloom, Roy Nathan, Howard Hasz, Richard Roth, Joseph Reitsma, William Krefski, Louis Goerlitz, Fred DeLauro, Gina Blumberg, Emily Weng, Francis L. Caplan, Arthur Thomasson, Arwin Shults, Justine Feldman, Harold I. TI Longer-Term Outcomes After Kidney Transplantation From Seronegative Deceased Donors at Increased Risk for Blood-Borne Viral Infection SO TRANSPLANTATION LA English DT Article DE Kidney transplantation; Viral transmission; Human immunodeficiency virus; High-risk donor ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; ACID TESTING NAT; LIVER-TRANSPLANTATION; INFORMING CANDIDATES; TRANSMISSION; SURVIVAL; RECIPIENTS AB Background. Transmission of human immunodeficiency virus and hepatitis C to transplant recipients has drawn attention of the use of allografts from seronegative donors at increased risk for blood-borne viral infection (DIRVI). Methods. We performed a cohort study of 7803 kidney transplant recipients whose kidneys were recovered through one of two organ procurement organizations from 1996 to 2007. Detailed organ procurement organization data on donor risk factors were linked to recipient data from the Organ Procurement and Transplantation Network. Results. Median recipient follow-up was 3.9 years. Three hundred sixty-eight (5%) patients received DIRVI kidneys, a third of which were procured from donors with a history of injection drug use or commercial sex work. Compared with standard criteria kidney recipients, DIRVI kidney recipients were more likely to be human immunodeficiency virus positive or black. In multivariable Cox regression, using DIRVI recipients as the reference, recipients of standard criteria donor kidneys had lower mortality (hazard ratio [HR] 0.71, P < 0.01) and no difference in death-censored allograft failure(HR 1.09, P = 0.62), whereas recipients of expanded criteria donor kidneys had no significant difference in mortality (HR 0.98, P = 0.83) but a higher allograft failure rate (HR 1.93, P < 0.01). High-quality data on posttransplant recipient viral testing were not available. Conclusions. DIRVI kidney recipients experienced higher mortality than standard criteria kidney recipients. This finding could be explained if sicker patients received DIRVI kidneys (i.e., residual confounding) or the less likely possibility of undetected transmission of viral infections. Given the limitations of registry data used in this analysis, prospective studies are needed to further elucidate these findings. C1 [Reese, Peter P.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Reese, Peter P.; Halpern, Scott D.; Asch, David A.; Caplan, Arthur; Feldman, Harold I.] Univ Penn, Leonard Davis Inst, Philadelphia, PA 19104 USA. [Reese, Peter P.; Bloom, Roy; Feldman, Harold I.] Hosp Univ Penn, Div Renal, Philadelphia, PA 19104 USA. [Asch, David A.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Halpern, Scott D.] Univ Penn, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Nathan, Howard; Hasz, Richard] Gift Life Inst, Philadelphia, PA USA. [Roth, Joseph; Reitsma, William; Krefski, Louis; Goerlitz, Fred; DeLauro, Gina] New Jersey Sharing Network, Springfield, NJ USA. [Blumberg, Emily] Univ Penn, Div Infect Dis, Philadelphia, PA 19104 USA. [Weng, Francis L.] St Barnabas Hosp, Livingston, NJ USA. [Halpern, Scott D.; Caplan, Arthur] Univ Penn, Ctr Bioeth, Philadelphia, PA 19104 USA. RP Reese, PP (reprint author), Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, 908 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM peter.reese@uphs.upenn.edu OI Asch, David/0000-0002-7970-286X FU NIH [K23-DK078688-01, K24-DK002651]; Greenwall Foundation; Health Resources and Services Administration [234-2005-370011C] FX This work was supported by NIH Career Development Award, K23-DK078688-01 (P.P.R.), a Greenwall Foundation Faculty Scholar Award in Bioethics (S.D.H.), NIH grant K24-DK002651 (H.I.F.), and in part by Health Resources and Services Administration contract 234-2005-370011C. NR 19 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUN 15 PY 2011 VL 91 IS 11 BP 1211 EP 1217 DI 10.1097/TP.0b013e318218d59a PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 769JN UT WOS:000291008800012 PM 21527872 ER PT J AU Reis, SA Thompson, MN Lee, JM Fossale, E Kim, HH Liao, JK Moskowitz, MA Shaw, SY Dong, L Haggarty, SJ MacDonald, ME Seong, IS AF Reis, Surya A. Thompson, Morgan N. Lee, Jong-Min Fossale, Elisa Kim, Hyung-Hwan Liao, James K. Moskowitz, Michael A. Shaw, Stanley Y. Dong, Linda Haggarty, Stephen J. MacDonald, Marcy E. Seong, Ihn Sik TI Striatal neurons expressing full-length mutant huntingtin exhibit decreased N-cadherin and altered neuritogenesis SO HUMAN MOLECULAR GENETICS LA English DT Article ID CELL-CELL ADHESION; ISCHEMIA-INDUCED CLEAVAGE; KNOCK-IN MOUSE; SYNAPTIC PLASTICITY; ENERGY DEFICIT; HD MUTATION; NRK CELLS; DISEASE; COMPLEX; REPEAT AB The expanded CAG repeat that causes striatal cell vulnerability in Huntington's disease (HD) encodes a polyglutamine tract in full-length huntingtin that is correlated with cellular [ATP] and [ATP/ADP]. Since striatal neurons are vulnerable to energy deficit, we have investigated, in Hdh CAG knock-in mice and striatal cells, the hypothesis that decreased energetics may affect neuronal (N)-cadherin, a candidate energy-sensitive adhesion protein that may contribute to HD striatal cell sensitivity. In vivo, N-cadherin was sensitive to ischemia and to the effects of full-length mutant huntingtin, progressively decreasing in Hdh(Q111) striatum with age. In cultured striatal cells, N-cadherin was decreased by ATP depletion and ST Hdh(Q111) striatal cells exhibited dramatically decreased N-cadherin, due to decreased Cdh2 mRNA and enhanced N-cadherin turnover, which was partially normalized by adenine supplementation to increase [ATP] and [ATP/ADP]. Consistent with decreased N-cadherin function, ST Hdh(Q111) striatal cells displayed profound deficits in calcium-dependent N-cadherin-mediated cell clustering and cell-substratum adhesion, and primary Hdh(Q111) striatal neuronal cells exhibited decreased N-cadherin and an abundance of immature neurites, featuring diffuse, rather than clustered, staining for N-cadherin and synaptic vesicle markers, which was partially rescued by adenine treatment. Thus, mutant full-length huntingtin, via energetic deficit, contributes to decreased N-cadherin levels in striatal neurons, with detrimental effects on neurite maturation, strongly suggesting that N-cadherin-mediated signaling merits investigation early in the HD pathogenic disease process. C1 [Reis, Surya A.; Thompson, Morgan N.; Lee, Jong-Min; Fossale, Elisa; Dong, Linda; MacDonald, Marcy E.; Seong, Ihn Sik] Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. [Shaw, Stanley Y.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Chem Biol Program, Boston, MA 02114 USA. [Kim, Hyung-Hwan; Liao, James K.] Brigham & Womens Hosp, Vasc Med Res Unit, Cambridge, MA 02139 USA. [Kim, Hyung-Hwan; Liao, James K.] Harvard Univ, Sch Med, Cambridge, MA 02139 USA. [Moskowitz, Michael A.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Seong, IS (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, 185 Cambridge St, Boston, MA 02114 USA. EM iseong@chgr.mgh.harvard.edu OI Haggarty, Stephen J./0000-0002-7872-168X FU National Institute of Neurological Disorders and Stroke [NS32765, NS070001]; Massachusetts HD Center Without Walls [NS16367]; Huntington's Disease Society of America Coalition for the Cure Normal Function Team; de Gunzburg Family Foundation at Massachusetts General Hospital; American Heart Association [0930202N] FX This work was supported by the National Institute of Neurological Disorders and Stroke (NS32765 to M.E.M., NS070001 to J.K.L.); the Massachusetts HD Center Without Walls [NS16367 (Project 3) to M.E.M.]; the Huntington's Disease Society of America Coalition for the Cure Normal Function Team to M.E.M.; the de Gunzburg Family Foundation at Massachusetts General Hospital to S.Y.S.; National Scientist Develoment Grant of the American Heart Association (0930202N to H.-H.K.); and an anonymous donor. NR 59 TC 13 Z9 13 U1 0 U2 3 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 JUN 15 PY 2011 VL 20 IS 12 BP 2344 EP 2355 DI 10.1093/hmg/ddr127 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 767IK UT WOS:000290849200005 PM 21447599 ER PT J AU O'Seaghdha, CM Parekh, RS Hwang, SJ Li, M Kottgen, A Coresh, J Yang, Q Fox, CS Kao, WHL AF O'Seaghdha, Conall M. Parekh, Rulan S. Hwang, Shih-Jen Li, Man Koettgen, Anna Coresh, Josef Yang, Qiong Fox, Caroline S. Kao, W. H. Linda TI The MYH9/APOL1 region and chronic kidney disease in European-Americans SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; STAGE RENAL-DISEASE; 9 GENE MYH9; AFRICAN-AMERICANS; NATURAL-SELECTION; POPULATION; FRAMINGHAM; ANCESTRY; COMPONENTS; COMMUNITY AB Polymorphisms in the MYH9 and adjacent APOL1 gene region demonstrate a strong association with nondiabetic kidney disease in African-Americans. However, it is not known to what extent these polymorphisms are present in other ethnic groups. To examine the association of genetic polymorphisms in this region with chronic kidney disease (CKD; estimated glomerular filtration rate <60 ml/min/1.73 m(2)) in individuals of European ancestry, we examined rs4821480, an MYH9 single-nucleotide polymorphism (SNP) recently identified as associated with kidney disease in African-Americans, in 13 133 participants from the Framingham Heart Study (FHS) and Atherosclerosis Risk in Communities (ARIC) Study. In addition, we further interrogated the MYH9/APOL1 gene region using 282 SNPs for association with CKD using age-, sex- and center-adjusted models and performed a meta-analysis of the results from both studies. Because of prior data linking rs4821480 and kidney disease, we used a P-value of <0.05 to test the association with CKD. In the meta-analysis, rs4821480 (minor allele frequency 4.45 and 3.96% in FHS and ARIC, respectively) was associated with higher CKD prevalence in participants free of diabetes (odds ratio 1.44; 95% confidence interval 1.15-1.80; P = 0.001). No other SNPs achieved significance after adjusting for multiple testing. Results utilizing directly genotyped data confirmed the results of the primary analysis. Recently identified APOL1 risk variants were also directly genotyped, but did not account for the observed MYH9 signal. These data suggest that the MYH9 polymorphism rs4821480 is associated with an increased risk of non-diabetic CKD in individuals of European ancestry. C1 [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBIs Framingham Heart Study, Framingham, MA 01702 USA. [O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA 01702 USA. [O'Seaghdha, Conall M.] Massachusetts Gen Hosp, Div Renal, Brigham & Womens Hosp, Boston, MA 02114 USA. [O'Seaghdha, Conall M.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Hwang, Shih-Jen] Univ Toronto, Hosp Sick Children, Dept Pediat & Med, Div Nephrol, Toronto, ON M5G 1X8, Canada. [Parekh, Rulan S.] Univ Toronto, Univ Hlth Network, Toronto, ON M5G 1X8, Canada. [Parekh, Rulan S.; Li, Man; Koettgen, Anna; Coresh, Josef; Kao, W. H. Linda] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Coresh, Josef; Kao, W. H. Linda] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Coresh, Josef; Kao, W. H. Linda] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Sch Med, Baltimore, MD 21205 USA. [Yang, Qiong] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Koettgen, Anna] Freiburg Univ Hosp, Dept Med, Div Nephrol, Freiburg, Germany. RP Fox, CS (reprint author), NHLBIs Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov; wkao@jhsph.edu RI Kottgen, Anna/D-2920-2012; Yang, Qiong/G-5438-2014 FU National Heart, Lung and Blood Institute [N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694]; Affymetrix, Inc. [N02-HL-6-4278]; Department of Medicine at Boston University School of Medicine and Boston Medical Center; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005]; NIH Roadmap for Medical Research FX This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart, Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect the intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc., for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Atherosclerosis Risk in Communities Study. The ARIC Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant No. UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. NR 35 TC 46 Z9 48 U1 2 U2 6 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 JUN 15 PY 2011 VL 20 IS 12 BP 2450 EP 2456 DI 10.1093/hmg/ddr118 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 767IK UT WOS:000290849200014 PM 21429915 ER PT J AU Zhang, JJ Zhang, LJ Zhou, KY Ye, XX Liu, CN Zhang, LT Kang, JX Cai, C AF Zhang, Jun-jie Zhang, Lijian Zhou, Keyuan Ye, Xiaoxia Liu, Chunan Zhang, Liangtao Kang, Jingxuan Cai, Chun TI Analysis of global DNA methylation by hydrophilic interaction ultra high-pressure liquid chromatography tandem mass spectrometry SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE DNA methylation; Mass spectrum; Hydrophilic interaction chromatography (HILIC); Ultra high-pressure liquid chromatography (UHPLC) ID RAPID QUANTIFICATION; HYPOMETHYLATION; ACID AB We developed and validated a rapid, sensitive, and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) method for determination of global DNA methylation in tissue. DNA was extracted by phenol-chloroform, hydrolyzed using 88% formic acid at 140 degrees C, spiked with cytosine-2,4-(CN2)-C-13-N-15 as internal standard, evaporated under nitrogen, reconstituted in methanol, and analyzed by LC-MS/MS in multiple reaction monitoring mode to reflect the global DNA methylation of the tissue. The method was linear throughout the range of clinical interest and had good sensitivity, with a limit of quantification of 0.5 pg for both cytosine (Cyt) and 5-methylcytosine (5mCyt). The linear range of calibration curve was 1-50 and 1-100 ng/ml for 5mCyt and Cyt, respectively, with a correlation coefficient higher than 0.99. The relative standard deviation (RSD) was 0.70-4.09% and 0.60-4.81% for Cyt and 5mCyt, respectively. The intraday precision expressed as RSD ranged from 1.86% to 4.67%, whereas the interday values ranged from 3.72% to 4.68%. The recovery of the method varied from 86.52% to 105.14%. This yielded a simple and reliable LC-MS/MS assay for detection of Cyt and 5mCyt, thereby enabling the evaluation of global DNA methylation. (C) 2011 Elsevier Inc. All rights reserved. C1 [Zhang, Jun-jie; Zhang, Lijian; Zhou, Keyuan; Ye, Xiaoxia; Liu, Chunan; Zhang, Liangtao; Cai, Chun] Guangdong Med Coll, Zhanjiang 524023, Guangdong, Peoples R China. [Kang, Jingxuan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. RP Cai, C (reprint author), Guangdong Med Coll, Zhanjiang 524023, Guangdong, Peoples R China. EM caichun2006@tom.com NR 29 TC 30 Z9 35 U1 0 U2 28 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUN 15 PY 2011 VL 413 IS 2 BP 164 EP 170 DI 10.1016/j.ab.2011.01.029 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 757HZ UT WOS:000290077400011 PM 21303652 ER PT J AU Sudarshan, S Shanmugasundaram, K Naylor, SL Lin, S Livi, CB O'Neill, CF Parekh, DJ Yeh, IT Sun, LZ Block, K AF Sudarshan, Sunil Shanmugasundaram, Karthigayan Naylor, Susan L. Lin, Shu Livi, Carolina B. O'Neill, Christine F. Parekh, Dipen J. Yeh, I-Tien Sun, Lu-Zhe Block, Karen TI Reduced Expression of Fumarate Hydratase in Clear Cell Renal Cancer Mediates HIF-2 alpha Accumulation and Promotes Migration and Invasion SO PLOS ONE LA English DT Article ID HYPOXIA-INDUCIBLE FACTORS; TUMOR-SUPPRESSOR GENE; PROLYL HYDROXYLATION; HIF-ALPHA; CARCINOMA; MUTATIONS; PARAGANGLIOMA; PROTEIN; OVEREXPRESSION; SUSCEPTIBILITY AB Germline mutations of FH, the gene that encodes for the tricarboxylic acid TCA (TCA) cycle enzyme fumarate hydratase, are associated with an inherited form of cancer referred to as Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). Individuals with HLRCC are predisposed to the development of highly malignant and lethal renal cell carcinoma (RCC). The mechanisms of tumorigenesis proposed have largely focused on the biochemical consequences of loss of FH enzymatic activity. While loss of the tumor suppressor gene von Hippel Lindau (VHL) is thought to be an initiating event for the majority of RCCs, a role for FH in sporadic renal cancer has not been explored. Here we report that FH mRNA and protein expression are reduced in clear cell renal cancer, the most common histologic variant of kidney cancer. Moreover, we demonstrate that reduced FH leads to the accumulation of hypoxia inducible factor-2 alpha (HIF-2 alpha), a transcription factor known to promote renal carcinogenesis. Finally, we demonstrate that overexpression of FH in renal cancer cells inhibits cellular migration and invasion. These data provide novel insights into the tumor suppressor functions of FH in sporadic kidney cancer. C1 [Sudarshan, Sunil; Shanmugasundaram, Karthigayan; O'Neill, Christine F.; Parekh, Dipen J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Naylor, Susan L.; Lin, Shu; Sun, Lu-Zhe] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Livi, Carolina B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Livi, Carolina B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Yeh, I-Tien] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Block, Karen] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Sudarshan, Sunil; Shanmugasundaram, Karthigayan; Naylor, Susan L.; Lin, Shu; Livi, Carolina B.; O'Neill, Christine F.; Parekh, Dipen J.; Yeh, I-Tien; Sun, Lu-Zhe; Block, Karen] S Texas Vet Hlth Care Syst, Audie L Murphy Mem Hosp Div, San Antonio, TX USA. RP Sudarshan, S (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. EM sudarshan@uthscsa.edu RI Lin, Shu/C-3790-2013 FU Cancer Therapy and Research Center (CTRC) at the University of Texas Health Science Center (National Institutes of Health ) [P30 CA054174-17]; NIH, AUA Foundation, HEB [K08 CA138774]; CTRC; NIH [U01 CA86402, R01 CA079683, R01 NCI CA131272]; Veterans Administration [CDA-2] FX This work was supported in part by the Cancer Therapy and Research Center (CTRC) at the University of Texas Health Science Center (National Institutes of Health P30 CA054174-17). SS is supported by NIH K08 CA138774, Voelcker Fund Young Investigator Award, AUA Foundation/Astellas Rising Star Award, and a special gift from Mr. Charles Butt and the employees of HEB. SLN is supported by the CTRC and NIH U01 CA86402. LZS is supported by NIH R01 CA079683. KB is supported by Veterans Administration Career Development Award (CDA-2) and NIH R01 NCI CA131272. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 16 Z9 18 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 14 PY 2011 VL 6 IS 6 AR e21037 DI 10.1371/journal.pone.0021037 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 778EB UT WOS:000291682300024 PM 21695080 ER PT J AU Hochholzer, W Wiviott, SD Antman, EM Contant, CF Guo, JP Giugliano, RP Dalby, AJ Montalescot, G Braunwald, E AF Hochholzer, Willibald Wiviott, Stephen D. Antman, Elliott M. Contant, Charles F. Guo, Jianping Giugliano, Robert P. Dalby, Anthony J. Montalescot, Gilles Braunwald, Eugene TI Predictors of Bleeding and Time Dependence of Association of Bleeding With Mortality Insights From the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) SO CIRCULATION LA English DT Article DE clopidogrel; prasugrel; hemorrhage; mortality ID ACUTE CORONARY SYNDROMES; CLOPIDOGREL; ASPIRIN; IMPACT; RISK; INTERVENTION; ELEVATION; METAANALYSIS; PREVENTION; RESIDUALS AB Background-The balance between benefit (ischemia protection) and risk (bleeding) is a key consideration in choosing the intensity of antiplatelet therapy for patients with acute coronary syndromes. The goals of this analysis were to identify baseline characteristics that independently predict bleeding and to determine how bleeding events impact the subsequent mortality in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). Methods and Results-Multivariable Cox regression analyses adjusted for treatment, baseline, and procedural variables were used to determine the predictors for serious (TIMI major or minor) bleeding. To analyze the hazard ratio and time dependency of bleeding on mortality, we used iterative day-to-day landmark analyses after the bleed. From the 13 420 patients with acute coronary syndromes included in this analysis, 534 (4.0%) experienced a serious bleeding event. Variables with the highest strength of association with risk of serious bleeding were female sex, use of a glycoprotein IIb/IIIa inhibitor, duration of intervention, age, assignment to prasugrel, regional characteristics, admission diagnosis of ST-elevation myocardial infarction, femoral access for angiography, creatinine clearance, hypercholesterolemia, and arterial hypertension. Serious bleeding was associated with a significantly increased adjusted hazard ratio of 5.84 (95% confidence interval 4.11 to 8.29) for mortality. However, the hazard ratio did not differ statistically from baseline risk by 40 days after the bleeding event. Conclusions-The major predictors of serious bleeding were a combination of patient and procedural characteristics and antiplatelet therapies. Although serious bleeding was strongly associated with mortality within the first month of the bleeding event, this association was not significant beyond 40 days. C1 [Hochholzer, Willibald; Wiviott, Stephen D.; Antman, Elliott M.; Contant, Charles F.; Guo, Jianping; Giugliano, Robert P.; Braunwald, Eugene] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Hochholzer, Willibald; Wiviott, Stephen D.; Antman, Elliott M.; Contant, Charles F.; Guo, Jianping; Giugliano, Robert P.; Braunwald, Eugene] Harvard Univ, Sch Med, Boston, MA USA. [Dalby, Anthony J.] Milpk Hosp, Johannesburg, South Africa. [Montalescot, Gilles] Univ Paris 06, Inst Cardiol, Paris, France. [Montalescot, Gilles] Pitie Salpetriere Univ Hosp, INSERM CMRS 937, Paris, France. RP Wiviott, SD (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM swiviott@partners.org FU Eli Lilly and Company; Daiichi Sankyo Company Ltd.; German Heart Foundation; Bristol-Myers-Squibb; Daiichi Sankyo Ltd; Eli Lilly; Sanofi-Aventis; Daiichi Sankyo; Schering Plough; Merck; Bristol Myers Squibb; Ortho McNeil; Abbott Vascular; Boston Scientific; Cordis; Federation Francaise de Cardiologie; Fondation de France; Guerbet Medical; INSERM; ITC Edison; Medtronic; Pfizer; Societe Francaise de Cardiologie; Stago; Bayer; Portola; Medicines Company; Accumetrics; Cardiovascular Research Foundation; Cleveland Clinic Research Foundation; Duke Institute; Institut de Cardiologie de Montreal; Menarini; Sharpe Dohme; Nanospheres; TIMI Study Group FX TRITON-TIMI 38 received funding from Eli Lilly and Company and Daiichi Sankyo Company Ltd. No additional funding for this analysis was provided. Dr Hochholzer was supported by the German Heart Foundation.; The TIMI Study Group has received significant research grant support from Bristol-Myers-Squibb, Daiichi Sankyo Ltd, Eli Lilly, and Sanofi-Aventis. Dr Hochholzer reports receiving consulting fees or paid advisory board fees from Sanofi-Aventis. Drs Braunwald and Antman report receiving research grants from Eli Lilly, Daiichi Sankyo, and Sanofi-Aventis. In addition, Dr Braunwald reports consulting fees or paid advisory board fees from Daiichi Sankyo and Sanofi-Aventis and lecture fees from Eli Lilly. Dr Antman reports receiving consulting fees or paid advisory board fees from Sanofi-Aventis and lecture fees from Eli Lilly and Sanofi-Aventis. Dr Wiviott reports receiving research grants from Schering Plough, Merck, Eli Lilly, Daiichi Sankyo, and Sanofi-Aventis; consulting fees or paid advisory board fees from Bristol Myers Squibb, AstraZeneca, and Sanofi-Aventis and lecture fees from Eli Lilly and Daiichi Sankyo. Dr Giugliano reports grant support from Daiichi-Sankyo and Merck, as well as honoraria for lectures and consulting from Bristol-Myers-Squibb, Daiichi Sankyo, Merck, Ortho McNeil, and Sanofi-Aventis. Dr Dalby reports receiving paid advisory board fees and lecture fees from Eli Lilly and Sanofi-Aventis. Dr Montalescot and his research units have received significant research grant support from Abbott Vascular, Bristol-Myers-Squibb, Boston Scientific, Cordis, Eli Lilly, Federation Francaise de Cardiologie, Fondation de France, Guerbet Medical, INSERM, ITC Edison, Medtronic, Pfizer, Sanofi-Aventis, Societe Francaise de Cardiologie, and Stago. Dr Montalescot reports honoraria for consulting from Astra-Zeneca, Bayer, Bristol-Myers-Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Eisai, Eli Lilly, Menarini, Nanospheres, Novartis, Pfizer, Portola, Sanofi-Aventis, Schering-Plough, and The Medicines Company; lecture fees from Abbott Vascular, Accumetrics, AstraZeneca, Bristol-Myers-Squibb, Cardiovascular Research Foundation, Cleveland Clinic Research Foundation, Cordis, Daiichi Sankyo, Duke Institute, Eli Lilly, Europa, Lead-up, GlaxoSmithKline, Institut de Cardiologie de Montreal, Menarini, Merck, Sharpe & Dohme, Nanospheres, Pfizer, Sanofi-Aventis, Schering-Plough, and the TIMI Study Group. The other authors report no conflicts. NR 26 TC 87 Z9 92 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 JUN 14 PY 2011 VL 123 IS 23 BP 2681 EP U70 DI 10.1161/CIRCULATIONAHA.110.002683 PG 21 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 776PZ UT WOS:000291550600011 PM 21606391 ER PT J AU Baggish, AL Wood, MJ AF Baggish, Aaron L. Wood, Malissa J. TI Athlete's Heart and Cardiovascular Care of the Athlete Scientific and Clinical Update SO CIRCULATION LA English DT Article DE athlete's heart; death, cardiac, sudden; exercise; ventricular remodeling ID LEFT-VENTRICULAR HYPERTROPHY; LONE ATRIAL-FIBRILLATION; PHYSIOLOGICAL CARDIAC-HYPERTROPHY; PROFESSIONAL SOCCER PLAYERS; FLOW PROPAGATION VELOCITY; DIASTOLIC FUNCTION; TISSUE DOPPLER; EUROPEAN-SOCIETY; SUDDEN-DEATH; FOLLOW-UP C1 [Baggish, Aaron L.] Massachusetts Gen Hosp, Cardiovasc Performance Program, Div Cardiol, Boston, MA 02114 USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Cardiovasc Performance Program, Div Cardiol, Yawkey Ste 5B,55 Fruit St, Boston, MA 02114 USA. EM abaggish@partners.org NR 128 TC 81 Z9 83 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 14 PY 2011 VL 123 IS 23 BP 2723 EP 2735 DI 10.1161/CIRCULATIONAHA.110.981571 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 776PZ UT WOS:000291550600016 PM 21670241 ER PT J AU Turer, AT Addo, TA Martin, JL Sabatine, MS Lewis, GD Gerszten, RE Keeley, EC Cigarroa, JE Lange, RA Hillis, LD de Lemos, JA AF Turer, Aslan T. Addo, Tayo A. Martin, Justin L. Sabatine, Marc S. Lewis, Gregory D. Gerszten, Robert E. Keeley, Ellen C. Cigarroa, Joaquin E. Lange, Richard A. Hillis, L. David de Lemos, James A. TI Myocardial Ischemia Induced by Rapid Atrial Pacing Causes Troponin T Release Detectable by a Highly Sensitive Assay Insights From a Coronary Sinus Sampling Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiac biomarkers; coronary artery disease; ischemia; rapid pacing; troponin T ID PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA; ST-SEGMENT DEPRESSION; ARTERY-DISEASE; EARLY-DIAGNOSIS; INFARCTION; MORTALITY; ELEVATION; POPULATION; BLOOD AB Objectives The purpose of this study was to assess whether: 1) very small increases in troponin T, measured by a new highly sensitive cardiac troponin T (hs-cTnT), may reflect ischemia without necrosis; and 2) serial changes can discriminate ischemia from other causes of cardiac troponin T (cTnT) release. Background A new hs-cTnT assay offers greater sensitivity than current assays. Methods Nineteen patients referred for diagnostic catheterization underwent cannulation of the coronary sinus (CS). Serial CS and peripheral plasma samples were obtained at multiple time points during and after incremental rapid atrial pacing. cTnT was quantified using both a standard and a pre-commercial highly sensitive assay. Ischemia was determined by the presence of significant coronary artery disease (CAD) and myocardial lactate release with pacing. Results cTnT concentrations in CS blood increased from a median of 6.8 pg/ml prior to pacing to 15.6 pg/ml 60 min after termination of rapid atrial pacing (p < 0.0001), changes that were mirrored at 180 min in peripheral blood (5.1 to 11.8 pg/ml, p < 0.0001). Although peripheral cTnT concentrations tended to be higher at 180 min following pacing for patients with CAD and lactate elution (n = 7) when compared with those without either marker (n = 5) (25.0 pg/ml vs. 10.2 pg/ml, p = 0.10), relative (1.7-fold vs. 5.2-fold) and absolute (6.8 pg/ml vs. 8.8 pg/ml, p = 0.50) changes were not different between groups. Conclusions Brief periods of ischemia, without frank infarction, cause low-level cTnT release, and small increases are common after periods of increased myocardial work, even among patients without objective evidence of myocardial ischemia or obstructive CAD. Additional research is needed before hs-cTnT assays are widely adopted in the management of subjects with chest pain syndromes. (J Am Coll Cardiol 2011;57:2398-405) (C) 2011 by the American College of Cardiology Foundation C1 [Turer, Aslan T.; Addo, Tayo A.; de Lemos, James A.] Univ Texas SW Med Ctr Dallas, Div Cardiol, Dept Med, Dallas, TX 75390 USA. [de Lemos, James A.] Univ Texas SW Med Ctr Dallas, Donald W Reynolds Cardiovasc Clin Res Ctr, Dallas, TX 75390 USA. [Martin, Justin L.] Consultants Cardiol, Ft Worth, TX USA. [Lange, Richard A.; Hillis, L. David] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Sabatine, Marc S.] Harvard Univ, Sch Med, Dept Med, Div Cardiovasc Med, Boston, MA USA. [Sabatine, Marc S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp, Boston, MA 02115 USA. [Keeley, Ellen C.] Univ Virginia, Dept Internal Med, Div Cardiol, Charlottesville, VA USA. [Cigarroa, Joaquin E.] Oregon Hlth & Sci Univ, Div Cardiol, Dept Internal Med, Portland, OR 97201 USA. RP Turer, AT (reprint author), Univ Texas SW, Dept Med, 5323 Harry Hines Blvd,Box 9047, Dallas, TX 75230 USA. EM aslan.turer@utsouthwestern.edu FU National Institutes of Health [R01-HL098280-01]; AstraZeneca; BRAHMS; Bristol-Myers Squibb/sanofi-aventis; Daiichi-Sankyo; Ortho-Clinical Diagnostics; Schering-Plough; Biosite; Roche Diagnostics; Johnson Johnson; Tethys FX From the *Department of Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas; dagger Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; double dagger Consultants in Cardiology, Forth Worth, Texas; Department of Medicine, University of Texas Health Science Center, San Antonio, Texas; parallel to Department of Medicine, Division of Cardiovascular Medicine and the TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; #Department of Internal Medicine, Division of Cardiology, University of Virginia, Charlottesville, Virginia; and the **Department of Internal Medicine, Division of Cardiology, Oregon Health and Science University, Portland, Oregon. This work was supported by National Institutes of Health grant R01-HL098280-01 (Drs. Gerszten and Sabatine). Troponin T assays were provided by Roche Diagnostics. Dr. Addo is a speaker for Eli Lilly and Daiichi Sankyo. Dr. Sabatine has received research support from AstraZeneca, BRAHMS, Bristol-Myers Squibb/sanofi-aventis, Daiichi-Sankyo, Ortho-Clinical Diagnostics, and Schering-Plough; is on the scientific advisory board for Bristol-Myers Squibb/sanofi-aventis; Daiichi-Sankyo/Lilly Partnership, and sanofi-aventis; and has received honoraria from Eli Lilly. Dr. de Lemos has received grant support from Biosite and Roche Diagnostics; and consulting fees from Johnson & Johnson and Tethys. Drs. Gerszten and Sabatine have received grant funding from the National Institutes of Health pertaining to biomarker research. All other authors have reported that they have no relationships to disclose. NR 26 TC 48 Z9 51 U1 1 U2 4 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 JUN 14 PY 2011 VL 57 IS 24 BP 2398 EP 2405 DI 10.1016/j.jacc.2010.11.066 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 774ZA UT WOS:000291424100004 PM 21658559 ER PT J AU Bamberg, F Sommer, WH Hoffmann, V Achenbach, S Nikolaou, K Conen, D Reiser, MF Hoffmann, U Becker, CR AF Bamberg, Fabian Sommer, Wieland H. Hoffmann, Verena Achenbach, Stephan Nikolaou, Konstantin Conen, David Reiser, Maximilian F. Hoffmann, Udo Becker, Christoph R. TI Meta-Analysis and Systematic Review of the Long-Term Predictive Value of Assessment of Coronary Atherosclerosis by Contrast-Enhanced Coronary Computed Tomography Angiography SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE cardiac computed tomography; coronary calcification; meta-analysis; noninvasive imaging; prognostic value ID MULTIDETECTOR CT ANGIOGRAPHY; ARTERY-DISEASE; PROGNOSTIC VALUE; HEART-DISEASE; MORTALITY; OUTCOMES; EVENTS; BIAS AB Objectives We conducted a systematic review and meta-analysis to determine the predictive value of findings of coronary computed tomography angiography for incident cardiovascular events. Background Initial studies indicate a prognostic value of the technique; however, the level of evidence as well as exact independent risk estimates remain unclear. Methods We searched PubMed, EMBASE, and the Cochrane Library through January 2010 for studies that followed up >= 100 subjects for >1 year and reported at >1 hazard ratio (HR) of interest. Risk estimates for the presence of significant coronary stenosis (primary endpoint; >= 50% diameter stenosis), left main coronary artery stenosis, each coronary stenosis, 3-vessel disease, any plaque, per coronary segment containing plaque, and noncalcified plaque were derived in random effect regression analysis, and causes of heterogeneity were determined in meta-regression analysis. Results We identified 11 eligible articles including 7,335 participants (age 59.1 +/- 2.6 years, 62.8% male) with suspected coronary artery disease. The presence of >= 1 significant coronary stenosis (9 studies, 3,670 participants, and 252 outcome events [6.8%] with 62% revascularizations) was associated with an annualized event rate of 11.9% (6.4% in studies excluding revascularization). The corresponding HR was 10.74 (98% confidence interval [CI]: 6.37 to 18.11) and 6.15 (95% CI: 3.22 to 11.74) in studies excluding revascularization. Adjustment for coronary calcification did not attenuate the prognostic significance (p = 0.79). The estimated HRs for left main stenosis, presence of plaque, and each coronary segment containing plaque were 6.64 (95% CI: 2.6 to 17.3), 4.51 (95% CI: 2.2 to 9.3), and 1.23 (95% CI: 1.17 to 1.29), respectively. Conclusions Presence and extent of coronary artery disease on coronary computed tomography angiography are strong, independent predictors of cardiovascular events despite heterogeneity in endpoints, categorization of computed tomography findings, and study population. (J Am Coll Cardiol 2011;57:2426-36) (C) 2011 by the American College of Cardiology Foundation C1 [Bamberg, Fabian; Hoffmann, Udo] Univ Munich, Dept Clin Radiol, Klinikum Grosshadern, D-81377 Munich, Germany. [Bamberg, Fabian; Sommer, Wieland H.; Nikolaou, Konstantin; Reiser, Maximilian F.; Becker, Christoph R.] Harvard Univ, Sch Med, Div Cardiol, Cardiac MR PET CT Program, Boston, MA USA. [Bamberg, Fabian; Sommer, Wieland H.; Nikolaou, Konstantin; Reiser, Maximilian F.; Becker, Christoph R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Hoffmann, Verena] Univ Munich, Inst Biomed Informat Biometry & Epidemiol, D-81377 Munich, Germany. [Achenbach, Stephan] Univ Erlangen Nurnberg, Dept Internal Med 2, Erlangen, Germany. [Conen, David] Univ Basel Hosp, Dept Med, CH-4031 Basel, Switzerland. RP Bamberg, F (reprint author), Univ Munich, Dept Clin Radiol, Klinikum Grosshadern, Grosshadern Campus,Marchioninistr 15, D-81377 Munich, Germany. EM fbamberg@post.harvard.edu OI Nikolaou, Konstantin/0000-0003-2668-7325 FU Siemens FX From the *Department of Clinical Radiology, Ludwig-Maximilians University, Klinikum Grosshadern, Munich, Germany; dagger Cardiac MR PET CT Program, Division of Cardiology and Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; double dagger Institute of Biomedical Informatics, Biometry and Epidemiology, Ludwig-Maximilians University, Munich, Germany; Department of Internal Medicine II, University of Erlangen, Erlangen, Germany; and the parallel to Department of Medicine, University Hospital Basel, Basel, Switzerland. Dr. Bamberg has received grant support from Siemens. All other authors have reported that they have no relationships to disclose. NR 28 TC 78 Z9 80 U1 1 U2 6 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 JUN 14 PY 2011 VL 57 IS 24 BP 2426 EP 2436 DI 10.1016/j.jacc.2010.12.043 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 774ZA UT WOS:000291424100009 PM 21658564 ER PT J AU Emanuele, MJ Ciccia, A Elia, AEH Elledge, SJ AF Emanuele, Michael J. Ciccia, Alberto Elia, Andrew E. H. Elledge, Stephen J. TI Proliferating cell nuclear antigen (PCNA)-associated KIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA replication; proteolysis ID DNA-DAMAGE; MITOTIC PHOSPHORYLATION; MAMMALIAN-CELLS; KEN-BOX; PCNA; REPLICATION; DEGRADATION; P15(PAF); IDENTIFICATION; LOCALIZATION AB The anaphase-promoting complex/cyclosome (APC/C) is a cell cycle-regulated E3 ubiquitin ligase that controls the degradation of substrate proteins at mitotic exit and throughout the G1 phase. We have identified an APC/C substrate and cell cycle-regulated protein, KIAA0101/PAF15. PAF15 protein levels peak in the G2/M phase of the cell cycle and drop rapidly at mitotic exit in an APC/C- and KEN-box-dependent fashion. PAF15 associates with proliferating cell nuclear antigen (PCNA), and depletion of PAF15 decreases the number of cells in S phase, suggesting a role for it in cell cycle regulation. Following irradiation, PAF15 colocalized with gamma H2AX foci at sites of DNA damage through its interaction with PCNA. Finally, PAF15 depletion led to an increase in homologous recombination-mediated DNA repair, and overexpression caused sensitivity to UV-induced DNA damage. We conclude that PAF15 is an APC/C-regulated protein involved in both cell cycle progression and the DNA damage response. C1 [Emanuele, Michael J.; Ciccia, Alberto; Elia, Andrew E. H.; Elledge, Stephen J.] Brigham & Womens Hosp, Howard Hughes Med Inst, Div Genet, Boston, MA 02115 USA. [Emanuele, Michael J.; Ciccia, Alberto; Elia, Andrew E. H.; Elledge, Stephen J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Elia, Andrew E. H.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Elledge, SJ (reprint author), Brigham & Womens Hosp, Howard Hughes Med Inst, Div Genet, Boston, MA 02115 USA. EM selledge@genetics.med.harvard.edu FU Jane Coffin Childs Foundation; American Society for Radiation Oncology; European Molecular Biology Organization; National Institutes of Health FX We thank the members of the S.J.E. laboratory for helpful discussions and insights. Special thanks to Britt Adamson for help with the homologous recombination reporter assay and Anna Burrows for help with quantitative RT-PCR. We thank Steve Gygi for access to MS/MS analysis software and Stephen Taylor for providing the Cdh1 null MEFs. M.J.E. is the Philip O'Bryan Montgomery, Jr., MD fellow of the Damon Runyon Cancer Research Foundation (DRG-1996-08). A. E. H. E. is supported by fellowships from the Jane Coffin Childs Foundation and the American Society for Radiation Oncology. A. C. is a recipient of a European Molecular Biology Organization long-term fellowship. This work was supported by a National Institutes of Health grant (to S.J.E.). S.J.E. is an investigator with the Howard Hughes Medical Institute. NR 30 TC 36 Z9 41 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 14 PY 2011 VL 108 IS 24 BP 9845 EP 9850 DI 10.1073/pnas.1106136108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 777DD UT WOS:000291594000027 PM 21628590 ER PT J AU Kulke, MH Bendell, J Kvols, L Picus, J Pommier, R Yao, J AF Kulke, Matthew H. Bendell, Johanna Kvols, Larry Picus, Joel Pommier, Rodney Yao, James TI Evolving Diagnostic and Treatment Strategies for Pancreatic Neuroendocrine Tumors SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Review ID ZOLLINGER-ELLISON SYNDROME; NEURO ENDOCRINE TUMORS; ISLET-CELL-CARCINOMA; NEOPLASIA TYPE-I; LIVER METASTASES; PHASE-II; RADIOFREQUENCY ABLATION; GLUCAGONOMA SYNDROME; PROGNOSTIC-FACTORS; GRADING SYSTEM AB Pancreatic neuroendocrine tumors (NET) have diverse clinical presentations. Patients with symptoms of hormone secretion may require specific medical interventions to control those symptoms prior to antitumor intervention. In some patients, tumors in the pancreas may be occult and specialized diagnostic imaging or surgery may be required for diagnosis. Other patients may present with more advanced disease, presenting with symptoms of tumor bulk rather than hormone secretion. Treatment options for patients with advanced pancreatic neuroendocrine tumors include surgical resection and hepatic directed therapies, including partial hepatectomy, hepatic artery embolization, or other ablative techniques. Streptozocin or temozolomide-based chemotherapy regimens are active against pancreatic NET, and can also play an important role in the palliation of patients with advanced disease. A number of biologically targeted agents targeting the VEGF and mTOR signaling pathways have recently shown promise, with recent trials showing treatment with the VEGFR tyrosine kinase inhibitor sunitinib or the mTOR inhibitor everolimus improves progression-free survival in patients with advanced NET. C1 [Kulke, Matthew H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bendell, Johanna] Sarah Cannon Res Inst, Nashville, TN USA. [Kvols, Larry] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Picus, Joel] Siteman Canc Ctr, St Louis, MO USA. [Pommier, Rodney] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Yao, James] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Kulke, MH (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM matthew_kulke@dfci.harvard.edu FU Pfizer Inc.; Novartis; Pfizer FX The authors thank Lindy Morde (Dana-Farber Cancer Institute) for providing editorial assistance. Medical writing support was also provided by Susanne Gilbert and Keith Lantz (ACUMED (R), New York, USA) and was funded by Pfizer Inc.; MK has served as a consultant for Pfizer, Novartis, Ipsen, Lexicon Pharmaceuticals, and Molecular Insight Pharmaceuticals. JB has no competing interests. LK has served as a consultant and/or received honorarium from Novartis, Pfizer, and Delcath. JP has received research funding and honorarium, and served as a consultant and as a speaker for Novartis and Pfizer. JY has served as a consultant for Ipsen, Novartis, and Pfizer. NR 67 TC 38 Z9 41 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD JUN 14 PY 2011 VL 4 AR 29 DI 10.1186/1756-8722-4-29 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 786OG UT WOS:000292317200001 PM 21672194 ER PT J AU Wu, YN Munhall, AC Johnson, SW AF Wu, Yan-Na Munhall, Adam C. Johnson, Steven W. TI Mitochondrial uncoupling agents antagonize rotenone actions in rat substantia nigra dopamine neurons SO BRAIN RESEARCH LA English DT Article DE Coenzyme Q(10); 2,4-dinitrophenol; FCCP; N-methyl-D-aspartate; Dopamine neuron; Uncoupling agent ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; METHYL-D-ASPARTATE; K-ATP CHANNELS; PARKINSONS-DISEASE; COMPLEX-I; COENZYME Q(10); OXIDATIVE STRESS; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE MPTP; GLUTAMATE EXCITOTOXICITY; SUPEROXIDE-PRODUCTION AB Mild uncoupling of oxidative phosphorylation has been reported to reduce generation of reactive oxygen species (ROS) and therefore may be neuroprotective. We reported previously that the mitochondrial poison rotenone enhanced currents evoked by N-methyl-D-aspartate (NMDA) by a ROS-dependent mechanism in rat midbrain dopamine neurons. Thus, rotenone, which produces a model of Parkinson's disease in rodents, may increase the risk of dopamine neuron excitotoxicity. The purpose of this study was to test the hypothesis that oxidative phosphorylation uncoupling agents would antagonize the effect of rotenone on NMDA current. We used patch pipettes to record whole-cell currents under voltage-clamp (-60 mV) in substantia nigra dopamine neurons in slices of rat brain. Rotenone, NMDA and uncoupling agents were added to the brain slice superfusate. Inward currents evoked by NMDA (30 mu M) more than doubled in amplitude after slices were superfused for 30 min with 100 nM rotenone. Continuous superfusion with the uncoupling agent carbonyl cyanide-p-trifluoromethoxy-phenylhydrazone (1-3 nM) or 2,4-dinitrophenol (100 nM) significantly antagonized and delayed the ability of rotenone to potentiate NMDA currents. Coenzyme Q(10) (1-10 nM), which has been reported to facilitate uncoupling protein activity, also antagonized this action of rotenone. These results suggest that mild uncoupling of oxidative phosphorylation may protect dopamine neurons against injury from mitochondrial poisons such as rotenone. Published by Elsevier B.V. C1 [Wu, Yan-Na; Munhall, Adam C.; Johnson, Steven W.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Johnson, Steven W.] Portland VA Med Ctr, Portland, OR 97207 USA. RP Johnson, SW (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. EM johnsost@ohsu.edu FU Veterans Affairs Merit Review grant [0383]; Portland Veterans Affairs Parkinson's Disease Research, Education, and Clinical Center FX This research was supported by Veterans Affairs Merit Review grant 0383 and by the Portland Veterans Affairs Parkinson's Disease Research, Education, and Clinical Center. NR 56 TC 9 Z9 9 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 13 PY 2011 VL 1395 BP 86 EP 93 DI 10.1016/j.brainres.2011.04.032 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 788DQ UT WOS:000292426000010 PM 21550595 ER PT J AU Spyra, M Kluwe, L Hagel, C Nguyen, R Panse, J Kurtz, A Mautner, VF Rabkin, SD Demestre, M AF Spyra, Melanie Kluwe, Lan Hagel, Christian Nguyen, Rosa Panse, Jens Kurtz, Andreas Mautner, Victor Felix Rabkin, Samuel David Demestre, Maria TI Cancer Stem Cell-Like Cells Derived from Malignant Peripheral Nerve Sheath Tumors SO PLOS ONE LA English DT Article ID MAMMALIAN NEURAL CREST; IDENTIFICATION; GLIOBLASTOMA AB This study aims to examine whether or not cancer stem cells exist in malignant peripheral nerve sheath tumors ( MPNST). Cells of established lines, primary cultures and freshly dissected tumors were cultured in serum free conditions supplemented with epidermal and fibroblast growth factors. From one established human MPNST cell line, S462, cells meeting the criteria for cancer stem cells were isolated. Clonal spheres were obtained, which could be passaged multiple times. Enrichment of stem cell-like cells in these spheres was also supported by increased expression of stem cell markers such as CD133, Oct4, Nestin and NGFR, and decreased expression of mature cell markers such as CD90 and NCAM. Furthermore, cells of these clonal S462 spheres differentiated into Schwann cells, smooth muscle/fibroblast and neurons-like cells under specific differentiation-inducing cultural conditions. Finally, subcutaneous injection of the spheres into immunodeficient nude mice led to tumor formation at a higher rate compared to the parental adherent cells (66% versus 10% at 2.5x10(5)). These results provide evidence for the existence of cancer stem cell-like cells in malignant peripheral nerve sheath tumors. C1 [Spyra, Melanie; Kluwe, Lan; Nguyen, Rosa; Mautner, Victor Felix; Demestre, Maria] Univ Med Ctr Hamburg Eppendorf, Dept Maxillofacial Surg, Hamburg, Germany. [Hagel, Christian] Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany. [Panse, Jens] Univ Med Ctr Hamburg Eppendorf, Dept Hematol & Oncol, Hamburg, Germany. [Kurtz, Andreas] Charite, Berlin Brandenburg Ctr Regenerat Therapies BCRT, D-13353 Berlin, Germany. [Kurtz, Andreas] Seoul Natl Univ, Coll Vet Med, Seoul, South Korea. [Rabkin, Samuel David] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Rabkin, Samuel David] Harvard Univ, Sch Med, Boston, MA USA. RP Spyra, M (reprint author), Univ Med Ctr Hamburg Eppendorf, Dept Maxillofacial Surg, Hamburg, Germany. EM andreas.kurtz@charite.de.com; mariademestre@hotmail.com RI rabkin, samuel/C-2443-2012 OI rabkin, samuel/0000-0003-2344-2795 FU Department of Defense [W81XWH-07-0359 to SDR]; "Bundesministerium fur Bildung und Forschung'' (BMBF) [01GM0480] FX These studies were supported in part by a grant from the Department of Defense neurofibromatosis program (W81XWH-07-0359 to SDR) and "Bundesministerium fur Bildung und Forschung'' (BMBF) (01GM0480 to AK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 17 Z9 18 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 13 PY 2011 VL 6 IS 6 AR e21099 DI 10.1371/journal.pone.0021099 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 777ZG UT WOS:000291663300041 PM 21695156 ER PT J AU Pararas, EEL Chen, ZQ Fiering, J Mescher, MJ Kim, ES McKenna, MJ Kujawa, SG Borenstein, JT Sewell, WF AF Pararas, Erin E. Leary Chen, Zhiqiang Fiering, Jason Mescher, Mark J. Kim, Ernest S. McKenna, Michael J. Kujawa, Sharon G. Borenstein, Jeffrey T. Sewell, William F. TI Kinetics of reciprocating drug delivery to the inner ear SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Intracochlear; Guinea pig; Microfluidic; Implantable; Regeneration; Cochlea ID PLGA NANOPARTICLES; ROUND-WINDOW; GUINEA-PIG; SYSTEM; COCHLEA; MOUSE; FLUID AB Reciprocating drug delivery is a means of delivering soluble drugs directly to closed fluid spaces in the body via a single cannula without an accompanying fluid volume change. It is ideally suited for drug delivery into small, sensitive and unique fluid spaces such as the cochlea. We characterized the pharmacokinetics of reciprocating drug delivery to the scala tympani within the cochlea by measuring the effects of changes in flow parameters on the distribution of drug throughout the length of the cochlea. Distribution was assessed by monitoring the effects of DNQX, a reversible glutamate receptor blocker, delivered directly to the inner ear of guinea pigs using reciprocating flow profiles. We then modeled the effects of those parameters on distribution using both an iterative curve-fitting approach and a computational fluid dynamic model. Our findings are consistent with the hypothesis that reciprocating delivery distributes the drug into a volume in the base of the cochlea, and suggest that the primary determinant of distribution throughout more distal regions of the cochlea is diffusion. Increases in flow rate distributed the drug into a larger volume that extended more apically. Over short time courses (less than 2 h), the apical extension, though small, significantly enhanced apically directed delivery of drug. Over longer time courses (>5 h) or greater distances (>3 mm), maintenance of drug concentration in the basal scala tympani may prove more advantageous for extending apical delivery than increases in flow rate. These observations demonstrate that this reciprocating technology is capable of providing controlled delivery kinetics to the closed fluid space in the cochlea, and may be suitable for other applications such as localized brain and retinal delivery. (C) 2011 Elsevier B.V. All rights reserved. C1 [Pararas, Erin E. Leary; Chen, Zhiqiang; McKenna, Michael J.; Kujawa, Sharon G.; Sewell, William F.] Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. [Pararas, Erin E. Leary; Chen, Zhiqiang; McKenna, Michael J.; Kujawa, Sharon G.; Sewell, William F.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Pararas, Erin E. Leary; Fiering, Jason; Mescher, Mark J.; Kim, Ernest S.; Borenstein, Jeffrey T.] Charles Stark Draper Lab Inc, Cambridge, MA 02139 USA. RP Sewell, WF (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM wfs@epl.meei.harvard.edu FU National Institute on Deafness and Other Communication Disorders [R01DC006848] FX The project described was supported by Award Number R01DC006848 from the National Institute on Deafness and Other Communication Disorders. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institute on Deafness and other Communication Disorders or the National Institutes of Health. NR 28 TC 12 Z9 12 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD JUN 10 PY 2011 VL 152 IS 2 BP 270 EP 277 DI 10.1016/j.jconrel.2011.02.021 PG 8 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 791KX UT WOS:000292665200008 PM 21385596 ER PT J AU Gusev, A Kenny, EE Lowe, JK Salit, J Saxena, R Kathiresan, S Altshuler, DM Friedman, JM Breslow, JL Pe'er, I AF Gusev, Alexander Kenny, Eimear E. Lowe, Jennifer K. Salit, Jaqueline Saxena, Richa Kathiresan, Sekar Altshuler, David M. Friedman, Jeffrey M. Breslow, Jan L. Pe'er, Itsik TI DASH: A Method for Identical-by-Descent Haplotype Mapping Uncovers Association with Recent Variation SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENOTYPE-IMPUTATION; UNRELATED INDIVIDUALS; HUMAN-POPULATIONS; TRAITS; ALGORITHM; VARIANTS; POWERFUL; ACCURACY; KOSRAE AB Rare variants affecting phenotype pose a unique challenge for human genetics. Although genome-wide association studies have successfully detected many common causal variants, they are underpowered in identifying disease variants that are too rare or population-specific to be imputed from a general reference panel and thus are poorly represented on commercial SNP arrays. We set out to overcome these challenges and detect association between disease and rare alleles using SNP arrays by relying on long stretches of genomic sharing that are identical by descent. We have developed an algorithm, DASH, which builds upon pairwise identical-by-descent shared segments to infer clusters of individuals likely to be sharing a single haplotype. DASH constructs a graph with nodes representing individuals and links on the basis of such segments spanning a locus and uses an iterative minimum cut algorithm to identify densely connected components. We have applied DASH to simulated data and diverse GWAS data sets by constructing haplotype clusters and testing them for association. In simulations we show this approach to be significantly more powerful than single-marker testing in an isolated population that is from Kosrae, Federated States of Micronesia and has abundant IBD, and we provide orthogonal information for rare, recent variants in the outbred Wellcome Trust Case-Control Consortium (WTCCC) data. In both cohorts, we identified a number of haplotype associations, five such loci in the WTCCC data and ten in the isolated, that were conditionally significant beyond any individual nearby markers. We have replicated one of these loci in an independent European cohort and identified putative structural changes in low-pass whole-genome sequence of the cluster carriers. C1 [Gusev, Alexander; Kenny, Eimear E.; Pe'er, Itsik] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA. [Kenny, Eimear E.; Salit, Jaqueline; Friedman, Jeffrey M.; Breslow, Jan L.] Rockefeller Univ, New York, NY 10065 USA. [Lowe, Jennifer K.; Altshuler, David M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Lowe, Jennifer K.; Saxena, Richa; Kathiresan, Sekar; Altshuler, David M.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Cardiovasc Dis Prevent Ctr, Cardiol Div,Dept Med,Med Sch, Boston, MA 02114 USA. [Altshuler, David M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Altshuler, David M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Pe'er, I (reprint author), Columbia Univ, Dept Comp Sci, New York, NY 10027 USA. EM itsik@cs.columbia.edu RI Breslow, Jan/B-7544-2008; Altshuler, David/A-4476-2009; OI Altshuler, David/0000-0002-7250-4107; Kenny, Eimear/0000-0001-9198-759X FU National Science Foundation [0845677, 0829882]; National Institutes of Health [U54-CA121852]; National Science Foundation FX We thank the reviewers for comments and suggestions that have greatly improved this manuscript. This study makes use of genotype data from the WTCCC as well as genotype and sequence data from the island of Kosrae, Federated States of Micronesia. This work has been supported by National Science Foundation grants 0845677 and 0829882, National Institutes of Health award U54-CA121852 and the National Science Foundation Graduate Research Fellowship Program. NR 37 TC 36 Z9 36 U1 0 U2 8 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 JUN 10 PY 2011 VL 88 IS 6 BP 706 EP 717 DI 10.1016/j.ajhg.2011.04.023 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 779HK UT WOS:000291768500003 PM 21620352 ER PT J AU Mulligan, P Yang, FJ Di Stefano, L Ji, JY Ouyang, J Nishikawa, JL Toiber, D Kulkarni, M Wang, Q Najafi-Shoushtari, SH Mostoslavsky, R Gygi, SP Gill, G Dyson, NJ Naar, AM AF Mulligan, Peter Yang, Fajun Di Stefano, Luisa Ji, Jun-Yuan Ouyang, Jian Nishikawa, Joy L. Toiber, Debra Kulkarni, Madhura Wang, Qun Najafi-Shoushtari, S. Hani Mostoslavsky, Raul Gygi, Steven P. Gill, Grace Dyson, Nicholas J. Naeaer, Anders M. TI A SIRT1-LSD1 Corepressor Complex Regulates Notch Target Gene Expression and Development SO MOLECULAR CELL LA English DT Article ID MEDIATED TRANSCRIPTIONAL REPRESSION; HISTONE DEMETHYLASE LSD1; DEACETYLASE SIRT1; TUMOR-SUPPRESSOR; CONSERVED ROLE; IN-VIVO; HAIRLESS; DROSOPHILA; BINDING; INHIBITION AB Epigenetic regulation of gene expression by histone-modifying corepressor complexes is central to normal animal development. The NAD+-dependent deacetylase and gene repressor SIRT1 removes histone H4K16 acetylation marks and facilitates heterochromatin formation. However, the mechanistic contribution of SIRT1 to epigenetic regulation at euchromatic loci and whether it acts in concert with other chromatin-modifying activities to control developmental gene expression programs remain unclear. We describe here a SIRT1 corepressor complex containing the histone H3K4 demethylase LSD1/KDM1A and several other LSD1-associated proteins. SIRT1 and LSD1 interact directly and play conserved and concerted roles in H4K16 deacetylation and H3K4 demethylation to repress genes regulated by the Notch signaling pathway. Mutations in Drosophila SIRT1 and LSD1 orthologs result in similar developmental phenotypes and genetically interact with the Notch pathway in Drosophila. These findings offer new insights into conserved mechanisms of epigenetic gene repression and regulation of development by SIRT1 in metazoans. C1 [Mulligan, Peter; Yang, Fajun; Di Stefano, Luisa; Ji, Jun-Yuan; Nishikawa, Joy L.; Toiber, Debra; Kulkarni, Madhura; Najafi-Shoushtari, S. Hani; Mostoslavsky, Raul; Dyson, Nicholas J.; Naeaer, Anders M.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Mulligan, Peter; Yang, Fajun; Di Stefano, Luisa; Ji, Jun-Yuan; Nishikawa, Joy L.; Toiber, Debra; Kulkarni, Madhura; Najafi-Shoushtari, S. Hani; Mostoslavsky, Raul; Dyson, Nicholas J.; Naeaer, Anders M.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Mulligan, Peter; Yang, Fajun; Nishikawa, Joy L.; Kulkarni, Madhura; Najafi-Shoushtari, S. Hani; Gygi, Steven P.; Naeaer, Anders M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Wang, Qun] Texas A&M Hlth Sci Ctr, Coll Med, Dept Mol & Cellular Med, College Stn, TX 77843 USA. [Ouyang, Jian; Gill, Grace] Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. RP Naar, AM (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,13th St, Charlestown, MA 02129 USA. EM naar@helix.mgh.harvard.edu OI Najafi-Shoushtari, Hani/0000-0002-7562-4083 FU National Institutes of Health [R01GM071449, R01GM53203, R01GM077689, R01GM093072-01, R01DK088190-01A1]; MGH-AstraZeneca Strategic Alliance; Sidney Kimmel Cancer Research Foundation; Massachusetts Life Sciences Center; AFAR; MGH Executive Committee on Research Fund for Medical Discovery; Leukemia and Lymphoma Society; Brain Power for Israel Fund FX We thank Amy Walker for critical reading of the manuscript and Luhan Yang for valuable assistance and discussion. We express our gratitude to the groups of Vittorio Sartorelli and Mark Leid for sharing with us SIRT1 deletion constructs, Stephen Helfand and Kent Golic for dSir2 mutant flies, Spyros Artavanis-Tsakonas for Notch and Su(H) mutant flies, the Bloomington Drosophila Stock Center for various fly strains, Jon C. Aster for providing the pMigRI-ICN1 plasmid, John R. Whetstine for kind assistance in performing LSD1 demethylase assays, and members of the Massachusetts General Hospital (MGH) Cancer Center and Artavanis-Tsakonas' lab for helpful discussions. These studies were supported by National Institutes of Health grants R01GM071449 (A.M.N.), R01GM53203 (N.J.D.), R01GM077689 (G.G.), R01GM093072-01 (R.M.), and R01DK088190-01A1 (R.M.), the MGH-AstraZeneca Strategic Alliance (A.M.N.), the Sidney Kimmel Cancer Research Foundation (R.M.), a New Investigator Grant from the Massachusetts Life Sciences Center (R.M.), and an AFAR Research Grant (R.M.). P.M. was supported by a fellowship from the MGH Executive Committee on Research Fund for Medical Discovery, L.D.S. was supported by a Leukemia and Lymphoma Society fellowship, and D.T. was supported by the Brain Power for Israel Fund. NR 67 TC 91 Z9 92 U1 2 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUN 10 PY 2011 VL 42 IS 5 BP 689 EP 699 DI 10.1016/j.molcel.2011.04.020 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 778AY UT WOS:000291670600016 PM 21596603 ER PT J AU Orkin, SH Hochedlinger, K AF Orkin, Stuart H. Hochedlinger, Konrad TI Chromatin Connections to Pluripotency and Cellular Reprogramming SO CELL LA English DT Review ID EMBRYONIC STEM-CELLS; X-CHROMOSOME INACTIVATION; PRIMORDIAL GERM-CELLS; LONG NONCODING RNAS; TRANSCRIPTIONAL REGULATORY CIRCUITRY; POLYCOMB REPRESSIVE COMPLEX-2; PROTEIN-INTERACTION NETWORK; GROUND-STATE PLURIPOTENCY; CXXC FINGER PROTEIN-1; HUMAN SOMATIC-CELLS AB The pluripotent state of embryonic stem cells (ESCs) provides a unique perspective on regulatory programs that govern self-renewal and differentiation and somatic cell reprogramming. Here, we review the highly connected protein and transcriptional networks that maintain pluripotency and how they are intertwined with factors that affect chromatin structure and function. The complex interrelationships between pluripotency and chromatin factors are illustrated by X chromosome inactivation, regulatory control by noncoding RNAs, and environmental influences on cell states. Manipulation of cell state through the process of transdifferentiation suggests that environmental cues may direct transcriptional programs as cells enter a transiently "plastic" state during reprogramming. C1 [Orkin, Stuart H.; Hochedlinger, Konrad] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Orkin, Stuart H.] Childrens Hosp, Boston, MA 02115 USA. [Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Hochedlinger, Konrad] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Hochedlinger, Konrad] Ctr Regenerat Med, Boston, MA 02114 USA. [Orkin, Stuart H.; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Orkin, SH (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu; khochedlinger@helix.mgh.harvard.edu RI liang, yan/H-3894-2011 FU NIH [DP2OD003266-01, R01HD058013-01A1] FX We thank Joost Gribnau, Raul Mostoslavsky, Bernhard Payer, and members of the Orkin and Hochedlinger labs for critical reading of the manuscript. Due to space limitations, we apologize to those colleagues whose publications could not be cited. Support to K.H. is from NIH grants DP2OD003266-01 and R01HD058013-01A1. NR 154 TC 196 Z9 199 U1 3 U2 48 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUN 10 PY 2011 VL 145 IS 6 BP 835 EP 850 DI 10.1016/j.cell.2011.05.019 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 775LS UT WOS:000291461600012 PM 21663790 ER PT J AU Rabbani, P Takeo, M Chou, WC Myung, P Bosenberg, M Chin, L Taketo, MM Ito, M AF Rabbani, Piul Takeo, Makoto Chou, WeiChin Myung, Peggy Bosenberg, Marcus Chin, Lynda Taketo, M. Mark Ito, Mayumi TI Coordinated Activation of Wnt in Epithelial and Melanocyte Stem Cells Initiates Pigmented Hair Regeneration SO CELL LA English DT Article ID BETA-CATENIN GENE; NEURAL CREST; FOLLICLE MORPHOGENESIS; TRANSCRIPTION FACTOR; SIGNALING PATHWAY; MOUSE SKIN; DIFFERENTIATION; BULGE; GROWTH; NICHE AB Melanocyte stem cells (McSCs) intimately interact with epithelial stem cells (EpSCs) in the hair follicle bulge and secondary hair germ (sHG). Together, they undergo activation and differentiation to regenerate pigmented hair. However, the mechanisms behind this coordinated stem cell behavior have not been elucidated. Here, we identified Wnt signaling as a key pathway that couples the behavior of the two stem cells. EpSCs and McSCs coordinately activate Wnt signaling at the onset of hair follicle regeneration within the sHG. Using genetic mouse models that specifically target either EpSCs or McSCs, we show that Wnt activation in McSCs drives their differentiation into pigment-producing melanocytes, while EpSC Wnt signaling not only dictates hair follicle formation but also regulates McSC proliferation during hair regeneration. Our data define a role for Wnt signaling in the regulation of McSCs and also illustrate a mechanism for regeneration of complex organs through collaboration between heterotypic stem cell populations. C1 [Rabbani, Piul; Takeo, Makoto; Chou, WeiChin; Ito, Mayumi] NYU, Sch Med, Dept Dermatol, New York, NY 10016 USA. [Rabbani, Piul; Takeo, Makoto; Chou, WeiChin; Ito, Mayumi] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. [Myung, Peggy] Univ Hosp Case Western Reserve, Dept Dermatol, Cleveland, OH USA. [Bosenberg, Marcus] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA. [Chin, Lynda] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Taketo, M. Mark] Kyoto Univ, Dept Pharmacol, Grad Sch Med, Kyoto 6068501, Japan. RP Ito, M (reprint author), NYU, Sch Med, Dept Dermatol, New York, NY 10016 USA. EM mayumi.ito@nyumc.org FU Department of Dermatology; Helen and Martin Kimmel Center for Stem Cell Biology at New York University (NYU); Dermatology Foundation; Ellison Medical Foundation; Yan Deng; Microscopy Core of NYU [NCRR S10 RR023704-01A1, NCRR S10 RR024708] FX We thank funds from the Department of Dermatology and the Helen and Martin Kimmel Center for Stem Cell Biology at New York University (NYU), the Dermatology Foundation Career Development Award, and the New Scholar Award in aging from the Ellison Medical Foundation to M.I. We thank Tung-Tien Sun for critical reading of the manuscript. We thank Seth Orlow and Prashiela Manga for providing Melan-a cells and helpful advice. We thank our mentors George Cotsarelis and Sarah Millar for their helpful advice and constant encouragement. We thank Radhika Atit for her input and collaboration for this work. We thank Yan Deng and the Microscopy Core of NYU for use of confocal microscopes (grants NCRR S10 RR023704-01A1 and NCRR S10 RR024708). NR 58 TC 104 Z9 114 U1 2 U2 30 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUN 10 PY 2011 VL 145 IS 6 BP 941 EP 955 DI 10.1016/j.cell.2011.05.004 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 775LS UT WOS:000291461600020 PM 21663796 ER PT J AU Chen, AB Neville, BA Sher, DJ Chen, K Schrag, D AF Chen, Aileen B. Neville, Bridget A. Sher, David J. Chen, Kun Schrag, Deborah TI Survival Outcomes After Radiation Therapy for Stage III Non-Small-Cell Lung Cancer After Adoption of Computed Tomography-Based Simulation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HIGH-DOSE RADIATION; LOCAL TUMOR-CONTROL; 3-DIMENSIONAL RADIOTHERAPY; CONFORMAL RADIOTHERAPY; COMORBIDITY INDEX; RANDOMIZED TRIAL; PHASE-III; CHEMOTHERAPY; VALIDATION; CONCURRENT AB Purpose Technical studies suggest that computed tomography (CT) - based simulation improves the therapeutic ratio for thoracic radiation therapy (TRT), although few studies have evaluated its use or impact on outcomes. Methods We used the Surveillance, Epidemiology and End Results (SEER) - Medicare linked data to identify CT-based simulation for TRT among Medicare beneficiaries diagnosed with stage III non-small-cell lung cancer (NSCLC) between 2000 and 2005. Demographic and clinical factors associated with use of CT simulation were identified, and the impact of CT simulation on survival was analyzed by using Cox models and propensity score analysis. Results The proportion of patients treated with TRT who had CT simulation increased from 2.4% in 1994 to 34.0% in 2000 to 77.6% in 2005. Of the 5,540 patients treated with TRT from 2000 to 2005, 60.1% had CT simulation. Geographic variation was seen in rates of CT simulation, with lower rates in rural areas and in the South and West compared with those in the Northeast and Midwest. Patients treated with chemotherapy were more likely to have CT simulation (65.2% v 51.2%; adjusted odds ratio, 1.67; 95% CI, 1.48 to 1.88; P < .01), although there was no significant association between use of surgery and CT simulation. Controlling for demographic and clinical characteristics, CT simulation was associated with lower risk of death (adjusted hazard ratio, 0.77; 95% CI, 0.73 to 0.82; P < .01) compared with conventional simulation. Conclusion CT-based simulation has been widely, although not uniformly, adopted for the treatment of stage III NSCLC and is associated with higher survival among patients receiving TRT. J Clin Oncol 29: 2305-2311. (C) 2011 by American Society of Clinical Oncology C1 [Chen, Aileen B.] Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Chen, AB (reprint author), Dana Farber Canc Inst, 44 Binney St,Smith 255, Boston, MA 02115 USA. EM achen7@partners.org OI Chen, Aileen/0000-0002-5385-3360 FU Joint Center for Radiation Therapy Foundation FX Supported by a grant from the Joint Center for Radiation Therapy Foundation. NR 30 TC 30 Z9 30 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 JUN 10 PY 2011 VL 29 IS 17 BP 2305 EP 2311 DI 10.1200/JCO.2010.33.4466 PG 7 WC Oncology SC Oncology GA 774KT UT WOS:000291385200019 PM 21537034 ER PT J AU Temel, JS Greer, JA Admane, S Gallagher, ER Jackson, VA Lynch, TJ Lennes, IT Dahlin, CM Pirl, WF AF Temel, Jennifer S. Greer, Joseph A. Admane, Sonal Gallagher, Emily R. Jackson, Vicki A. Lynch, Thomas J. Lennes, Inga T. Dahlin, Connie M. Pirl, William F. TI Longitudinal Perceptions of Prognosis and Goals of Therapy in Patients With Metastatic Non-Small-Cell Lung Cancer: Results of a Randomized Study of Early Palliative Care SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol ID QUALITY-OF-LIFE; PHASE-III TRIAL; TREATMENT PREFERENCES; TREATMENT INTENT; CHEMOTHERAPY; END; DISCLOSURE; PHYSICIANS; PROVIDERS; DECISIONS AB Purpose Understanding of prognosis among terminally ill patients impacts medical decision making. The aims of this study were to explore perceptions of prognosis and goals of therapy in patients with metastatic non-small-cell lung cancer (NSCLC) and to examine the effect of early palliative care on these views over time. Patients and Methods Patients with newly diagnosed metastatic NSCLC were randomly assigned to receive either early palliative care integrated with standard oncology care or standard oncology care alone. Participants completed baseline and longitudinal assessments of their perceptions of prognosis and the goals of cancer therapy over a 6-month period. Results We enrolled 151 participants on the study. Despite having terminal cancer, one third of patients (46 of 145 patients) reported that their cancer was curable at baseline, and a majority (86 of 124 patients) endorsed getting rid of all of the cancer as a goal of therapy. Baseline perceptions of prognosis (ie, curability) and goals of therapy did not differ significantly between study arms. A greater percentage of patients assigned to early palliative care retained or developed an accurate assessment of their prognosis over time (82.5% v 59.6%; P = .02) compared with those receiving standard care. Patients receiving early palliative care who reported an accurate perception of their prognosis were less likely to receive intravenous chemotherapy near the end of life (9.4% v 50%; P = .02). Conclusion Many patients with newly diagnosed metastatic NSCLC hold inaccurate perceptions of their prognoses. Early palliative care significantly improves patient understanding of prognosis over time, which may impact decision making about care near the end of life. J Clin Oncol 29: 2319- 2326. (C) 2011 by American Society of Clinical Oncology C1 [Temel, Jennifer S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. SUNY Buffalo, Buffalo, NY 14260 USA. Yale Univ, Ctr Canc, New Haven, CT USA. RP Temel, JS (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM jtemel@partners.org NR 42 TC 170 Z9 171 U1 3 U2 13 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 JUN 10 PY 2011 VL 29 IS 17 BP 2319 EP 2326 DI 10.1200/JCO.2010.32.4459 PG 8 WC Oncology SC Oncology GA 774KT UT WOS:000291385200021 PM 21555700 ER PT J AU Hendrickson, WK Flavin, R Kasperzyk, JL Fiorentino, M Fang, F Lis, R Fiore, C Penney, KL Ma, J Kantoff, PW Stampfer, MJ Loda, M Mucci, LA Giovannucci, E AF Hendrickson, Whitney K. Flavin, Richard Kasperzyk, Julie L. Fiorentino, Michelangelo Fang, Fang Lis, Rosina Fiore, Christopher Penney, Kathryn L. Ma, Jing Kantoff, Philip W. Stampfer, Meir J. Loda, Massimo Mucci, Lorelei A. Giovannucci, Edward TI Vitamin D Receptor Protein Expression in Tumor Tissue and Prostate Cancer Progression SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SUBSEQUENT DEVELOPMENT; GENE POLYMORPHISMS; PHYSICIANS HEALTH; CYTOSOLIC CALCIUM; UNITED-STATES; D METABOLITES; KINASE-C; RISK; 1,25-DIHYDROXYVITAMIN-D; D-3 AB Purpose Data suggest that circulating 25-hydroxyvitamin D [25(OH)D] interacts with the vitamin D receptor (VDR) to decrease proliferation and increase apoptosis for some malignancies, although evidence for prostate cancer is less clear. How VDR expression in tumor tissue may influence prostate cancer progression has not been evaluated in large studies. Patients and Methods We examined protein expression of VDR in tumor tissue among 841 patients with prostate cancer in relation to risk of lethal prostate cancer within two prospective cohorts, the Physicians' Health Study and Health Professionals Follow-Up Study. We also examined the association of VDR expression with prediagnostic circulating 25(OH) D and 1,25-dihydroxyvitamin D levels and with two VDR single nucleotide polymorphisms, FokI and BsmI. Results Men whose tumors had high VDR expression had significantly lower prostate-specific antigen (PSA) at diagnosis (P for trend < .001), lower Gleason score (P for trend < .001), and less advanced tumor stage (P for trend < .001) and were more likely to have tumors harboring the TMPRSS2:ERG fusion (P for trend = .009). Compared with the lowest quartile, men whose tumors had the highest VDR expression had significantly reduced risk of lethal prostate cancer (hazard ratio [HR], 0.17; 95% CI, 0.07 to 0.41). This association was only slightly attenuated after adjustment for Gleason score and PSA at diagnosis (HR, 0.33; 95% CI, 0.13 to 0.83) or, additionally, for tumor stage (HR, 0.37; 95% CI, 0.14 to 0.94). Neither prediagnostic plasma vitamin D levels nor VDR polymorphisms were associated with VDR expression. Conclusion High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression. J Clin Oncol 29:2378-2385. (C) 2011 by American Society of Clinical Oncology C1 [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hendrickson, Whitney K.; Kasperzyk, Julie L.; Penney, Kathryn L.; Ma, Jing; Stampfer, Meir J.; Mucci, Lorelei A.; Giovannucci, Edward] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Flavin, Richard; Fiorentino, Michelangelo; Lis, Rosina; Fiore, Christopher; Kantoff, Philip W.; Loda, Massimo] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Flavin, Richard] Natl Univ Ireland, Galway, Ireland. [Fang, Fang] Karolinska Inst, Stockholm, Sweden. RP Giovannucci, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 655 Huntington Ave, Boston, MA 02115 USA. EM egiovann@hsph.harvard.edu OI Fang, Fang/0000-0002-3310-6456 FU National Institutes of Health (NIH) [R01 CA133891, CA136578]; US Army [W81XWH-05-1-0562]; National Cancer Institute (NCI) [CA-34933, CA-40360, CA-091793]; National Heart, Lung, and Blood Institute, Bethesda, MD [HL-26490, HL-34595]; NCI/NIH [P01 CA055075]; Prostate Cancer Foundation; NCI National Research Service [T32 CA09001] FX Supported by National Institutes of Health (NIH) Grants No. R01 CA133891 (E. G.) and CA136578 (L. A. M.) and US Army Prostate Cancer Program Grant No. W81XWH-05-1-0562 (L. A. M.). The Physicians' Health Study is supported by Grants No. CA-34933, CA-40360, and CA-091793 from the National Cancer Institute (NCI) and Grants No. HL-26490 and HL-34595 from the National Heart, Lung, and Blood Institute, Bethesda, MD. Health Professionals Follow-Up Study is supported by NCI/NIH Grant No. P01 CA055075. L. A. M. is supported by the Prostate Cancer Foundation. J.L.K. and K. L. P. are supported by the NCI National Research Service Award No. T32 CA09001 (primary investigator, M.J.S.). NR 46 TC 49 Z9 52 U1 0 U2 6 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 JUN 10 PY 2011 VL 29 IS 17 BP 2378 EP 2384 DI 10.1200/JCO.2010.30.9880 PG 7 WC Oncology SC Oncology GA 774KT UT WOS:000291385200029 PM 21537045 ER PT J AU Penney, KL Sinnott, JA Fall, K Pawitan, Y Hoshida, Y Kraft, P Stark, JR Fiorentino, M Perner, S Finn, S Calza, S Flavin, R Freedman, ML Setlur, S Sesso, HD Andersson, SO Martin, N Kantoff, PW Johansson, JE Adami, HO Rubin, MA Loda, M Golub, TR Andren, O Stampfer, MJ Mucci, LA AF Penney, Kathryn L. Sinnott, Jennifer A. Fall, Katja Pawitan, Yudi Hoshida, Yujin Kraft, Peter Stark, Jennifer R. Fiorentino, Michelangelo Perner, Sven Finn, Stephen Calza, Stefano Flavin, Richard Freedman, Matthew L. Setlur, Sunita Sesso, Howard D. Andersson, Swen-Olof Martin, Neil Kantoff, Philip W. Johansson, Jan-Erik Adami, Hans-Olov Rubin, Mark A. Loda, Massimo Golub, Todd R. Andren, Ove Stampfer, Meir J. Mucci, Lorelei A. TI mRNA Expression Signature of Gleason Grade Predicts Lethal Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID POPULATION-BASED COHORT; GENE-EXPRESSION; PROGNOSTIC-SIGNIFICANCE; PROGRESSION; SCORE; CARCINOMA; DISEASE; TISSUES; DEATH AB Purpose Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis. Patients and Methods Using the complementary DNA-mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason <= 6 to those with Gleason >= 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases. Results We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006). Conclusion Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment. J Clin Oncol 29:2391-2396. (C) 2011 by American Society of Clinical Oncology C1 Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Radiat Oncol Program, Boston, MA USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Broad Inst, Cambridge, MA USA. Uppsala Univ, Uppsala, Sweden. Karolinska Inst, Stockholm, Sweden. Orebro Univ Hosp, Orebro, Sweden. Univ Hosp Tuebingen, Ctr Comprehens Canc, Tubingen, Germany. Univ Brescia, Brescia, Italy. Weill Cornell Med Coll, New York, NY USA. [Penney, Kathryn L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Penney, KL (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM kpenney@hsph.harvard.edu RI Martin, Neil/E-2193-2014; Calza, Stefano/B-1915-2010; OI Martin, Neil/0000-0002-8164-8516; Calza, Stefano/0000-0003-4996-7995; Rubin, Mark/0000-0002-8321-9950; Rider, Jennifer/0000-0002-2637-6036; Finn, Stephen/0000-0002-8628-5814; Fall, Katja/0000-0002-3649-2639 FU Dana-Farber/Harvard Cancer Center [5P50CA090381-08]; National Cancer Institute [5R01CA141298, CA-34944, CA-40360, CA-097193]; National Heart, Lung, and Blood Institute [HL-26490, HL-34595]; Swedish Cancer Foundation; Orebro County Council Research Foundation; National Research Service [T32 CA009001-32, GM-074897]; Prostate Cancer Foundation FX Supported by Grants No. 5P50CA090381-08 from the Dana-Farber/Harvard Cancer Center Prostate Specialized Programs of Research Excellence program and No. 5R01CA141298 from the National Cancer Institute. The Physicians' Health Study was supported by Grants No. CA-34944, CA-40360, and CA-097193 from the National Cancer Institute and HL-26490 and HL-34595 from the National Heart, Lung, and Blood Institute. The Swedish Watchful Waiting cohort was supported by the Swedish Cancer Foundation and The Orebro County Council Research Foundation. Supported by National Research Service Award T32 CA009001-32 (K. L. P.), Grant No. GM-074897 (J.A.S.), and the Prostate Cancer Foundation (L.A.M.). NR 33 TC 57 Z9 57 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 JUN 10 PY 2011 VL 29 IS 17 BP 2391 EP 2396 DI 10.1200/JCO.2010.32.6421 PG 6 WC Oncology SC Oncology GA 774KT UT WOS:000291385200031 PM 21537050 ER PT J AU Galsky, MD Hahn, NM Rosenberg, J Sonpavde, G Hutson, T Oh, WK Dreicer, R Vogelzang, N Sternberg, CN Bajorin, DF Bellmunt, J AF Galsky, Matthew D. Hahn, Noah M. Rosenberg, Jonathan Sonpavde, Guru Hutson, Thomas Oh, William K. Dreicer, Robert Vogelzang, Nicholas Sternberg, Cora N. Bajorin, Dean F. Bellmunt, Joaquim TI Treatment of Patients With Metastatic Urothelial Cancer "Unfit" for Cisplatin-Based Chemotherapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; COOPERATIVE-ONCOLOGY-GROUP; ADVANCED BLADDER-CARCINOMA; PHASE-II TRIAL; PACLITAXEL PLUS CARBOPLATIN; COLONY-STIMULATING FACTOR; QUALITY-OF-LIFE; ELDERLY-PATIENTS; PROGNOSTIC-FACTORS; EUROPEAN ORGANIZATION AB Purpose Cisplatin-based combination chemotherapy is considered standard first-line treatment for patients with metastatic urothelial carcinoma. However, a large proportion of patients with metastatic urothelial carcinoma are considered "unfit" for cisplatin. The purpose of this review is to define unfit patients and to identify treatment options for this subgroup of patients. Patients and Methods In this review, the criteria used to define unfit patients are explored and the results of prospective clinical trials evaluating chemotherapeutic regimens in unfit patients are summarized. Results Several phase II trials and a single, large phase III trial have explored chemotherapeutic regimens for the treatment of unfit patients with metastatic urothelial carcinoma. Heterogeneous eligibility criteria have been used to define unfit patients in these studies. A uniform definition of unfit is proposed on the basis of the results of a survey of genitourinary medical oncologists. According to this definition, unfit patients would meet at least one of the following criteria: Eastern Cooperative Oncology Group performance status of 2, creatinine clearance less than 60 mL/min, grade >= 2 hearing loss, grade >= 2 neuropathy, and/or New York Heart Association Class III heart failure. Conclusion Additional studies to optimize treatment for this important subset of patients are needed. A uniform definition of unfit patients will lead to more uniform clinical trials, enhanced ability to interpret the results of these trials, and a greater likelihood of developing a viable strategy for regulatory approval. J Clin Oncol 29:2432-2438. (C) 2011 by American Society of Clinical Oncology C1 [Galsky, Matthew D.] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Bajorin, Dean F.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Hahn, Noah M.] Indiana Univ, Indianapolis, IN 46204 USA. [Rosenberg, Jonathan] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sonpavde, Guru] Texas Oncol & Vet Affairs Med Ctr, Houston, TX USA. [Sonpavde, Guru] Baylor Coll Med, Houston, TX 77030 USA. [Hutson, Thomas] Baylor Sammons Canc Ctr, Dallas, TX USA. [Dreicer, Robert] Cleveland Clin, Cleveland, OH 44106 USA. [Vogelzang, Nicholas] Comprehens Canc Ctr Nevada, Las Vegas, NV USA. [Sternberg, Cora N.] San Camillo Forlanini Hosp, Rome, Italy. [Bellmunt, Joaquim] Univ Hosp Del Mar, Inst Municipal Invest Med, Barcelona, Spain. RP Galsky, MD (reprint author), Mt Sinai Sch Med, Tisch Canc Inst, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM matthew.galsky@mssm.edu RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 59 TC 80 Z9 80 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 JUN 10 PY 2011 VL 29 IS 17 BP 2432 EP 2438 DI 10.1200/JCO.2011.34.8433 PG 7 WC Oncology SC Oncology GA 774KT UT WOS:000291385200037 PM 21555688 ER PT J AU Steensma, DP Sloan, JA Loprinzi, CL AF Steensma, David P. Sloan, Jeff A. Loprinzi, Charles L. TI Too-Low Iron Doses and Too Many Dropouts in Negative Iron Trial? Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID ANEMIC PATIENTS; PHASE-III C1 [Steensma, David P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sloan, Jeff A.; Loprinzi, Charles L.] Mayo Clin, Rochester, MN USA. RP Steensma, DP (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 12 TC 3 Z9 3 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 JUN 10 PY 2011 VL 29 IS 17 BP E527 EP E528 DI 10.1200/JCO.2011.35.4597 PG 2 WC Oncology SC Oncology GA 774KT UT WOS:000291385200014 ER PT J AU Franco, GCN Kajiya, M Nakanishi, T Ohta, K Rosalen, PL Groppo, FC Ernst, CWO Boyesen, JL Bartlett, JD Stashenko, P Taubman, MA Kawai, T AF Franco, Gilson C. N. Kajiya, Mikihito Nakanishi, Tadashi Ohta, Kouji Rosalen, Pedro L. Groppo, Francisco C. Ernst, Cory W. O. Boyesen, Janie L. Bartlett, John D. Stashenko, Philip Taubman, Martin A. Kawai, Toshihisa TI Inhibition of matrix metalloproteinase-9 activity by doxycycline ameliorates RANK ligand-induced osteoclast differentiation in vitro and in vivo SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Doxycycline; Osteoclast; RANK ligand; MMP-9; MAPKs; NFATc1 ID PERIODONTAL-DISEASE; BONE-RESORPTION; MATRIX METALLOPROTEINASES; ADULT PERIODONTITIS; MEMBRANE-PROTEINS; GENE-EXPRESSION; LONG BONES; TETRACYCLINES; ACTIVATION; MARROW AB Tetracycline antibiotics, including doxycycli\e (DOX), have been used to treat bone resorptive diseases, partially because of their activity to suppress osteoclastogenesis induced by receptor activator of nuclear factor kappa B ligand (RANKL). However, their precise inhibitory mechanism remains unclear. Therefore, the present study examined the effect of Dox on osteoclastogenesis signaling induced by RANKL, both in vitro and in vivo. Although Dox inhibited RANKL-induced osteoclastogenesis and down-modulated the mRNA expression, of functional osteoclast markers, including tartrate-resistant acid phosphatase (TRAP) and cathepsin K. Dox neither affected RANKL-induced MAPKs phosphorylation nor NFATc1 gene expression in RAW264.7 murine monocytic cells. Gelatin zymography and Western blot analyses showed that Dox down-regulated the enzyme activity of RANKL-induced MMP-9, but without affecting its protein expression. Furthermore, MMP-9 enzyme inhibitor also attenuated both RANKL-induced osteoclastogenesis and up-regulation of TRAP and cathepsin K mRNA expression, indicating that MMP-9 enzyme action is engaged in the promotion of RANKL-induced osteoclastogenesis. Finally, Dox treatment abrogated RANKL-induced osteoclastogenesis and TRAP activity in mouse calvaria along with the suppression of MMP9 enzyme activity, again without affecting the expression of MMP9 protein. These findings suggested that Dox inhibits RANKL-induced osteoclastogenesis by its inhibitory effect on MMP-9 enzyme activity independent of the MAPK-NFATc1 signaling cascade. (C) 2011 Elsevier Inc. All rights reserved. C1 [Franco, Gilson C. N.; Kajiya, Mikihito; Nakanishi, Tadashi; Ohta, Kouji; Ernst, Cory W. O.; Boyesen, Janie L.; Taubman, Martin A.; Kawai, Toshihisa] Forsyth Inst, Dept Immunol, Cambridge, MA 02142 USA. [Bartlett, John D.; Stashenko, Philip] Forsyth Inst, Dept Cytokine Biol, Cambridge, MA 02142 USA. [Kajiya, Mikihito; Ohta, Kouji; Kawai, Toshihisa] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Franco, Gilson C. N.; Rosalen, Pedro L.; Groppo, Francisco C.] FOP UNICAMP, Dept Pharmacol, Piracicaba, SP, Brazil. RP Kawai, T (reprint author), Forsyth Inst, Dept Immunol, 245 1st St, Cambridge, MA 02142 USA. EM tkawai@forsyth.org RI Groppo, Francisco/C-3516-2012; Rosalen, Pedro/I-3718-2012; Franco, Gilson/F-9312-2012 OI Groppo, Francisco/0000-0002-8513-773X; FU NIDCR [DE-016276, DE-03420, DE-09018, DE-14551, DE-18499, DE-19917]; FAPESP [05/54580] FX This research study was supported by NIDCR grants DE-016276, DE-03420, DE-09018, DE-14551, DE-18499 and DE-19917 and FAPESP 05/54580. NR 40 TC 23 Z9 25 U1 0 U2 7 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD JUN 10 PY 2011 VL 317 IS 10 BP 1454 EP 1464 DI 10.1016/j.yexcr.2011.03.014 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 771TY UT WOS:000291184800012 PM 21420951 ER PT J AU Hamouda, AK Stewart, DS Husain, SS Cohen, JB AF Hamouda, Ayman K. Stewart, Deirdre S. Husain, S. Shaukat Cohen, Jonathan B. TI Multiple Transmembrane Binding Sites for p-Trifluoromethyldiazirinyl-etomidate, a Photoreactive Torpedo Nicotinic Acetylcholine Receptor Allosteric Inhibitor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GATED ION-CHANNEL; NONCOMPETITIVE ANTAGONISTS; MOLECULAR-MECHANISMS; ANESTHETIC ETOMIDATE; OPEN-STATE; IDENTIFICATION; AGONIST; TIME; SUBUNIT; PROTON AB Photoreactive derivatives of the general anesthetic etomidate have been developed to identify their binding sites in gamma-aminobutyric acid, type A and nicotinic acetylcholine receptors. One such drug, [(3)H]TDBzl-etomidate (4-[3-(trifluoromethyl)3H-diazirin-3-yl]benzyl-[(3)H]1-(1-phenylethyl)-1H-imidazole-5- carboxylate), acts as a positive allosteric potentiator of Torpedo nACh receptor (nAChR) and binds to a novel site in the transmembrane domain at the gamma-alpha subunit interface. To extend our understanding of the locations of allosteric modulator binding sites in the nAChR, we now characterize the interactions of a second aryl diazirine etomidate derivative, TFD-etomidate (ethyl-1-(1-(4-(3-trifluoromethyl)-3H-diazirin-3-yl)phenylethyl)1H-imidazole-5-carboxylate). TFD-etomidate inhibited acetylcholine-induced currents with an IC(50) = 4 mu M, whereas it inhibited the binding of [(3)H]phencyclidine to the Torpedo nAChR ion channel in the resting and desensitized states with IC(50) values of 2.5 and 0.7 mM, respectively. Similar to [(3)H] TDBzl-etomidate, [(3)H]TFD-etomidate bound to a site at the gamma-alpha subunit interface, photolabeling alpha M2-10 (alpha Ser-252) and gamma Met-295 and gamma Met-299 within gamma M3, and to a site in the ion channel, photolabeling amino acids within each subunit M2 helix that line the lumen of the ion channel. In addition, [(3)H]TFD-etomidate photolabeled in an agonist-dependent manner amino acids within the delta subunit M2-M3 loop (delta Ile-288) and the delta subunit transmembrane helix bundle (delta Phe-232 and delta Cys-236 within delta M1). The fact that TFD-etomidate does not compete with ion channel blockers at concentrations that inhibit acetylcholine responses indicates that binding to sites at the gamma-alpha subunit interface and/or within delta subunit helix bundle mediates the TFD-etomidate inhibitory effect. These results also suggest that the gamma-alpha subunit interface is a binding site for Torpedo nAChR negative allosteric modulators (TFD-etomidate) and for positive modulators (TDBzl-etomidate). C1 [Hamouda, Ayman K.; Cohen, Jonathan B.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Stewart, Deirdre S.; Husain, S. Shaukat] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Cohen, JB (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA. EM Jonathan_Cohen@hms.harvard.edu OI Hamouda, Ayman/0000-0001-7819-3074 FU United States Public Health Service [GM-58448]; Howard Hughes Biomedical Research Support Program for Medical Schools FX This work was supported in part by United States Public Health Service Grant GM-58448 (to J. B. C., Stuart Forman, and Keith W. Miller) and by an award to Harvard Medical School from the Howard Hughes Biomedical Research Support Program for Medical Schools. NR 43 TC 21 Z9 21 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 JUN 10 PY 2011 VL 286 IS 23 BP 20466 EP 20477 DI 10.1074/jbc.M111.219071 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 772WC UT WOS:000291267600034 PM 21498509 ER PT J AU Zamborlini, A Coiffic, A Beauclair, G Delelis, O Paris, J Koh, Y Magne, F Giron, ML Tobaly-Tapiero, J Deprez, E Emiliani, S Engelman, A de The, H Saib, A AF Zamborlini, Alessia Coiffic, Audrey Beauclair, Guillaume Delelis, Olivier Paris, Joris Koh, Yashuiro Magne, Fabian Giron, Marie-Lou Tobaly-Tapiero, Joelle Deprez, Eric Emiliani, Stephane Engelman, Alan de The, Hugues Saib, Ali TI Impairment of Human Immunodeficiency Virus Type-1 Integrase SUMOylation Correlates with an Early Replication Defect SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIV-1 INTEGRASE; REVERSE-TRANSCRIPTASE; DNA-BINDING; IN-VITRO; NONDIVIDING CELLS; VIRAL INTEGRATION; SUMO MODIFICATION; GENE-EXPRESSION; TERMINAL DOMAIN; RETROVIRAL DNA AB HIV-1 integrase (IN) orchestrates the integration of the reverse transcribed viral cDNA into the host cell genome and participates also in other steps of HIV-1 replication. Cellular and viral factors assist IN in performing its multiple functions, and post-translational modifications contribute to modulate its activities. Here, we show that HIV-1 IN is modified by SUMO proteins and that phylogenetically conserved SUMOylation consensus motifs represent major SUMO acceptor sites. Viruses harboring SUMOylation site IN mutants displayed a replication defect that was mapped during the early stages of infection, before integration but after reverse transcription. Because SUMOylation-defective IN mutants retained WT catalytic activity, we hypothesize that SUMOylation might regulate the affinity of IN for co-factors, contributing to efficient HIV-1 replication. C1 [Zamborlini, Alessia; Coiffic, Audrey; Beauclair, Guillaume; Paris, Joris; Magne, Fabian; Giron, Marie-Lou; Tobaly-Tapiero, Joelle; de The, Hugues; Saib, Ali] Univ Paris 07, CNRS, INSERM, Inst Univ Hematol,UMR7212,U944, F-75475 Paris, France. [Zamborlini, Alessia; Magne, Fabian; Saib, Ali] Conservatoire Arts & Metiers, Paris, France. [Delelis, Olivier; Deprez, Eric] Ecole Normale Super, Lab Biotechnol & Pharmacol Genet Appl, CNRS, UMR8113, F-94235 Cachan, France. [Emiliani, Stephane] Univ Paris 05, INSERM, CNRS, Inst Cochin,U1016,UMR8104, F-75014 Paris, France. [Koh, Yashuiro; Engelman, Alan] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. RP Saib, A (reprint author), Univ Paris 07, CNRS, INSERM, Inst Univ Hematol,UMR7212,U944, F-75475 Paris, France. EM ali.saib@cnam.fr RI Magne, Fabien/F-1393-2014 FU National Institutes of Health [AI052014]; Agence Nationale pour la Recherche sur le SIDA et les Hepatites Virales (ANRS); Sidaction; French Research Ministry; Mitsubishi Pharma Foundation; Conseil Regional d'Ile de France FX This work was supported, in whole or in part, by National Institutes of Health Grant AI052014 (to A. E.). This work was also supported by Sidaction and by Agence Nationale pour la Recherche sur le SIDA et les Hepatites Virales (ANRS).; Supported by the French Research Ministry.; Supported by the Mitsubishi Pharma Foundation.; We thank D. Gabuzda, R. Niedenthal, F. Mammano, R. Hay, and D. Trono for reagents; P. Lesage, S. Basmaciogullari, V. Lallemand-Breitenbach, and M. Benkirane for discussion and critical reading of the manuscript; and F. Lacoste for informatics supplies. We thank N. Setterblad and C. Doliger at the Imagery and Cell Sorting Department of the Institut Universitaire d'Hematologie-Hopital St-Louis IFR105 (supported by grants from the Conseil Regional d'Ile de France and the French Research Ministry) for technical assistance. NR 70 TC 26 Z9 26 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 JUN 10 PY 2011 VL 286 IS 23 BP 21013 EP 21022 DI 10.1074/jbc.M110.189274 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 772WC UT WOS:000291267600085 PM 21454548 ER PT J AU Hsu, PP Kang, SA Rameseder, J Zhang, Y Ottina, KA Lim, D Peterson, TR Choi, YM Gray, NS Yaffe, MB Marto, JA Sabatini, DM AF Hsu, Peggy P. Kang, Seong A. Rameseder, Jonathan Zhang, Yi Ottina, Kathleen A. Lim, Daniel Peterson, Timothy R. Choi, Yongmun Gray, Nathanael S. Yaffe, Michael B. Marto, Jarrod A. Sabatini, David M. TI The mTOR-Regulated Phosphoproteome Reveals a Mechanism of mTORC1-Mediated Inhibition of Growth Factor Signaling SO SCIENCE LA English DT Article ID MESSENGER-RNA TRANSLATION; P-BODIES; PROTEIN; KINASE; GRB10; DISRUPTION; AUTOPHAGY; SPECIFICITY; ACTIVATION; REPRESSION AB The mammalian target of rapamycin (mTOR) protein kinase is a master growth promoter that nucleates two complexes, mTORC1 and mTORC2. Despite the diverse processes controlled by mTOR, few substrates are known. We defined the mTOR-regulated phosphoproteome by quantitative mass spectrometry and characterized the primary sequence motif specificity of mTOR using positional scanning peptide libraries. We found that the phosphorylation response to insulin is largely mTOR dependent and that mTOR exhibits a unique preference for proline, hydrophobic, and aromatic residues at the +1 position. The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1. Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology. C1 [Hsu, Peggy P.; Kang, Seong A.; Ottina, Kathleen A.; Peterson, Timothy R.; Sabatini, David M.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Hsu, Peggy P.; Peterson, Timothy R.; Yaffe, Michael B.; Sabatini, David M.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Rameseder, Jonathan] MIT, Computat & Syst Biol Initiat, Cambridge, MA 02139 USA. [Rameseder, Jonathan; Lim, Daniel; Yaffe, Michael B.; Sabatini, David M.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Zhang, Yi; Choi, Yongmun; Gray, Nathanael S.; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zhang, Yi; Marto, Jarrod A.] DFCI, Blais Prote Ctr, Boston, MA 02115 USA. [Ottina, Kathleen A.; Sabatini, David M.] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Choi, Yongmun; Gray, Nathanael S.; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Sabatini, DM (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM sabatini@wi.mit.edu FU National Institutes of Health [CA103866, AI47389, ES015339, GM68762, CA112967]; Department of Defense [W81XWH-07-0448]; W.M. Keck Foundation; LAM Foundation; Dana-Farber Cancer Institute; International Fulbright Science and Technology Award; American Cancer Society FX We thank members of the Sabatini Lab for helpful discussion, especially B. Joughin, G. Bell, H. Keys, K. Birsoy, N. Kory, C. Thoreen, J. Claessen, and D. Wagner for assistance with technical or conceptual aspects of this project. This work was supported by the National Institutes of Health (grants CA103866 and AI47389 to D. M. S.; ES015339, GM68762, and CA112967 to M.B.Y.), Department of Defense (W81XWH-07-0448 to D. M. S.), the W.M. Keck Foundation (D. M. S.), LAM Foundation (D. M. S.), Dana-Farber Cancer Institute (N. S. G, J. M), the International Fulbright Science and Technology Award (J. R.), and American Cancer Society (S. A. K.). D. M. S. is an investigator of the Howard Hughes Medical Institute. Torin1, the drug used in this paper, is part of a Whitehead-DFCI patent application on which N. S. G. and D. M. S. are inventors. Shared reagents are subject to a Materials Transfer Agreement. NR 31 TC 434 Z9 446 U1 6 U2 53 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUN 10 PY 2011 VL 332 IS 6035 BP 1317 EP 1322 DI 10.1126/science.1199498 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 775EP UT WOS:000291441700044 PM 21659604 ER PT J AU Figueira, CP Croda, J Choy, HA Haake, DA Reis, MG Ko, AI Picardeau, M AF Figueira, Claudio Pereira Croda, Julio Choy, Henry A. Haake, David A. Reis, Mitermayer G. Ko, Albert I. Picardeau, Mathieu TI Heterologous expression of pathogen-specific genes ligA and ligB in the saprophyte Leptospira biflexa confers enhanced adhesion to cultured cells and fibronectin SO BMC MICROBIOLOGY LA English DT Article ID IMMUNOGLOBULIN-LIKE PROTEIN; PROTECTIVE IMMUNITY; TARGETED MUTAGENESIS; ESCHERICHIA-COLI; HOST-CELLS; MDCK CELLS; C-TERMINUS; INTERROGANS; BINDING; INFECTION AB Background: In comparison to other bacterial pathogens, our knowledge of the molecular basis of the pathogenesis of leptospirosis is extremely limited. An improved understanding of leptospiral pathogenetic mechanisms requires reliable tools for functional genetic analysis. Leptospiral immunoglobulin-like (Lig) proteins are surface proteins found in pathogenic Leptospira, but not in saprophytes. Here, we describe a system for heterologous expression of the Leptospira interrogans genes ligA and ligB in the saprophyte Leptospira biflexa serovar Patoc. Results: The genes encoding LigA and LigB under the control of a constitutive spirochaetal promoter were inserted into the L. biflexa replicative plasmid. We were able to demonstrate expression and surface localization of LigA and LigB in L. biflexa. We found that the expression of the lig genes significantly enhanced the ability of transformed L. biflexa to adhere in vitro to extracellular matrix components and cultured cells, suggesting the involvement of Lig proteins in cell adhesion. Conclusions: This work reports a complete description of the system we have developed for heterologous expression of pathogen-specific proteins in the saprophytic L. biflexa. We show that expression of LigA and LigB proteins from the pathogen confers a virulence-associated phenotype on L. biflexa, namely adhesion to eukaryotic cells and fibronectin in vitro. This study indicates that L. biflexa can serve as a surrogate host to characterize the role of key virulence factors of the causative agent of leptospirosis. C1 [Picardeau, Mathieu] Inst Pasteur, Unite Biol Spirochetes, F-75724 Paris 15, France. [Figueira, Claudio Pereira; Croda, Julio; Reis, Mitermayer G.; Ko, Albert I.] Brazilian Minist Hlth, Oswaldo Cruz Fdn, Goncalo Moniz Res Ctr, BR-40295001 Salvador, BA, Brazil. [Choy, Henry A.; Haake, David A.] Vet Affairs Greater Los Angeles Hlth Care Syst, Div Infect Dis, Los Angeles, CA 90073 USA. [Choy, Henry A.; Haake, David A.] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Ko, Albert I.] Yale Univ, Sch Med, Div Epidemiol Microbial Dis, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Croda, Julio] Fed Univ Grande Dourados, Fac Hlth Sci, Dourados, Brazil. RP Picardeau, M (reprint author), Inst Pasteur, Unite Biol Spirochetes, 28 Rue Docteur Roux, F-75724 Paris 15, France. EM mpicard@pasteur.fr RI Vacinas, Inct/J-9431-2013; Ko, Albert/P-2343-2015 FU Institut Pasteur, Paris, France; French Ministry of Research [ANR-08-MIE-018]; Oswaldo Cruz Foundation [PDTIS RVR05]; Brazilian National Research Council (INCTV); VA Medical Research Funds; National Institutes of Health [D43 TW00919, R01 AI34431, U01 AI088752] FX This work was supported by the Institut Pasteur, Paris, France; the French Ministry of Research ANR-08-MIE-018, the Fiocruz-Pasteur Scientific Cooperation Agreement, Oswaldo Cruz Foundation (PDTIS RVR05), Brazilian National Research Council (INCTV), VA Medical Research Funds, and the National Institutes of Health (grants D43 TW00919, R01 AI34431 and U01 AI088752). This research was conducted by C. P. Figueira in partial fulfillment of the requirements for a Ph.D. from Goncalo Moniz Research Center, Oswaldo Cruz Foundation, Brazil. NR 52 TC 29 Z9 30 U1 0 U2 4 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 JUN 9 PY 2011 VL 11 AR 129 DI 10.1186/1471-2180-11-129 PG 9 WC Microbiology SC Microbiology GA 790UK UT WOS:000292614500001 PM 21658265 ER PT J AU Jirawatnotai, S Hu, YD Michowski, W Elias, JE Becks, L Bienvenu, F Zagozdzon, A Goswami, T Wang, YYE Clark, AB Kunkel, TA van Harn, T Xia, B Correll, M Quackenbush, J Livingston, DM Gygi, SP Sicinski, P AF Jirawatnotai, Siwanon Hu, Yiduo Michowski, Wojciech Elias, Joshua E. Becks, Lisa Bienvenu, Frederic Zagozdzon, Agnieszka Goswami, Tapasree Wang, Yaoyu E. Clark, Alan B. Kunkel, Thomas A. van Harn, Tanja Xia, Bing Correll, Mick Quackenbush, John Livingston, David M. Gygi, Steven P. Sicinski, Piotr TI A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers SO NATURE LA English DT Article ID HUMAN RAD51 PROTEIN; DOUBLE-STRAND BREAK; RETINOBLASTOMA-PROTEIN; MAMMALIAN-CELLS; IN-VITRO; DAMAGE; PHOSPHORYLATION; OVEREXPRESSION; RECOMBINATION; EXPRESSION AB Cyclin D1 is a component of the core cell cycle machinery(1). Abnormally high levels of cyclin D1 are detected in many human cancer types(2). To elucidate the molecular functions of cyclin D1 in human cancers, we performed a proteomic screen for cyclin D1 protein partners in several types of human tumours. Analyses of cyclin D1 interactors revealed a network of DNA repair proteins, including RAD51, a recombinase that drives the homologous recombination process(3). We found that cyclin D1 directly binds RAD51, and that cyclin D1-RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2-dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination-mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein, which do not require D-cyclins for proliferation(4,5). These findings reveal an unexpected function of a core cell cycle protein in DNA repair and suggest that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers which are currently thought to be unaffected by cyclin D1 inhibition. C1 [Jirawatnotai, Siwanon; Hu, Yiduo; Michowski, Wojciech; Becks, Lisa; Bienvenu, Frederic; Zagozdzon, Agnieszka; van Harn, Tanja; Livingston, David M.; Sicinski, Piotr] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Jirawatnotai, Siwanon; Hu, Yiduo; Michowski, Wojciech; Becks, Lisa; Bienvenu, Frederic; Zagozdzon, Agnieszka; van Harn, Tanja; Livingston, David M.; Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA. [Jirawatnotai, Siwanon] Mahidol Univ, Inst Mol Biosci, Salaya 73170, Nakhon Prathom, Thailand. [Elias, Joshua E.; Goswami, Tapasree; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Becks, Lisa] Massachusetts Coll Pharm & Hlth Sci, Dept Pharmacol, Boston, MA 02115 USA. [Wang, Yaoyu E.; Correll, Mick; Quackenbush, John] Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02215 USA. [Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Xia, Bing] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ 08903 USA. [Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Quackenbush, John] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. RP Sicinski, P (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM peter_sicinski@dfci.harvard.edu FU NIH [R01 CA083688, P01 CA080111, P01 CA109901]; Thailand Research Fund [MRG5280248]; Foundation for Polish Science; CCCB; Dana-Farber Strategic Plan Initiative; Division of Intramural Research of the NIH, NIEHS [Z01 ES065089] FX We thank the members of the Sicinski lab for help and advice, N. Li for help with initial experiments, S Panyim and Y. Geng for discussions and reading the manuscript, P. Nakatani for pOZ-FH-N construct, M. Jasin for DR-GFP system, D. Bulavin and E. Appella for anti-phospho-CDC25A antibodies, A. Smogorzewska for anti-FANCI antibody, A. Venkitaraman and M. Lee for GST-BRCA2 fragments, and DFCI Confocal and Light Microscopy Core Facility for assisting with confocal microscopy. This work was supported by R01 CA083688, P01 CA080111 and P01 CA109901 grants from NIH (to P.S.). S.J. is supported by The Thailand Research Fund MRG5280248, W.M. by Foundation for Polish Science, Y.E.W. through the CCCB and the Dana-Farber Strategic Plan Initiative, A.B.C. and T.A.K. by Project Z01 ES065089 (to T.A.K.) from the Division of Intramural Research of the NIH, NIEHS. NR 29 TC 130 Z9 133 U1 2 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 9 PY 2011 VL 474 IS 7350 BP 230 EP 234 DI 10.1038/nature10155 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 774PE UT WOS:000291397800054 PM 21654808 ER PT J AU Sanders, SJ Ercan-Sencicek, AG Hus, V Luo, R Murtha, MT Moreno-De-Luca, D Chu, SH Moreau, MP Gupta, AR Thomson, SA Mason, CE Bilguvar, K Celestino-Soper, PBS Choi, M Crawford, EL Davis, L Wright, NRD Dhodapkar, RM DiCola, M DiLullo, NM Fernandez, TV Fielding-Singh, V Fishman, DO Frahm, S Garagaloyan, R Goh, GS Kammela, S Klei, L Lowe, JK Lund, SC McGrew, AD Meyer, KA Moffat, WJ Murdoch, JD O'Roak, BJ Ober, GT Pottenger, RS Raubeson, MJ Song, Y Wang, Q Yaspan, BL Yu, TW Yurkiewicz, LR Beaudet, AL Cantor, RM Curland, M Grice, DE Gunel, M Lifton, RP Mane, SM Martin, DM Shaw, CA Sheldon, M Tischfield, JA Walsh, CA Morrow, EM Ledbetter, DH Fombonne, E Lord, C Martin, CL Brooks, AI Sutcliffe, JS Cook, EH Geschwind, D Roeder, K Devlin, B State, MW AF Sanders, Stephan J. Ercan-Sencicek, A. Gulhan Hus, Vanessa Luo, Rui Murtha, Michael T. Moreno-De-Luca, Daniel Chu, Su H. Moreau, Michael P. Gupta, Abha R. Thomson, Susanne A. Mason, Christopher E. Bilguvar, Kaya Celestino-Soper, Patricia B. S. Choi, Murim Crawford, Emily L. Davis, Lea Wright, Nicole R. Davis Dhodapkar, Rahul M. DiCola, Michael DiLullo, Nicholas M. Fernandez, Thomas V. Fielding-Singh, Vikram Fishman, Daniel O. Frahm, Stephanie Garagaloyan, Rouben Goh, Gerald S. Kammela, Sindhuja Klei, Lambertus Lowe, Jennifer K. Lund, Sabata C. McGrew, Anna D. Meyer, Kyle A. Moffat, William J. Murdoch, John D. O'Roak, Brian J. Ober, Gordon T. Pottenger, Rebecca S. Raubeson, Melanie J. Song, Youeun Wang, Qi Yaspan, Brian L. Yu, Timothy W. Yurkiewicz, Liana R. Beaudet, Arthur L. Cantor, Rita M. Curland, Martin Grice, Dorothy E. Guenel, Murat Lifton, Richard P. Mane, Shrikant M. Martin, Donna M. Shaw, Chad A. Sheldon, Michael Tischfield, Jay A. Walsh, Christopher A. Morrow, Eric M. Ledbetter, David H. Fombonne, Eric Lord, Catherine Martin, Christa Lese Brooks, Andrew I. Sutcliffe, James S. Cook, Edwin H., Jr. Geschwind, Daniel Roeder, Kathryn Devlin, Bernie State, Matthew W. TI Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism SO NEURON LA English DT Article ID COPY NUMBER VARIATION; RARE CHROMOSOMAL DELETIONS; HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; SPECTRUM DISORDERS; GENETIC DISORDER; BEUREN-SYNDROME; INCREASE RISK; EARLY-ONSET; GENOME AB We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 x 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1. C1 [Sanders, Stephan J.; Ercan-Sencicek, A. Gulhan; Murtha, Michael T.; Bilguvar, Kaya; Guenel, Murat; State, Matthew W.] Yale Univ, Sch Med, Program Neurogenet, New Haven, CT 06520 USA. [Sanders, Stephan J.; Ercan-Sencicek, A. Gulhan; Murtha, Michael T.; Gupta, Abha R.; Wright, Nicole R. Davis; Dhodapkar, Rahul M.; DiLullo, Nicholas M.; Fernandez, Thomas V.; Kammela, Sindhuja; Moffat, William J.; Ober, Gordon T.; Song, Youeun; Yurkiewicz, Liana R.; State, Matthew W.] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06520 USA. [Sanders, Stephan J.; Ercan-Sencicek, A. Gulhan; Murtha, Michael T.; State, Matthew W.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Sanders, Stephan J.; Ercan-Sencicek, A. Gulhan; Murtha, Michael T.; Bilguvar, Kaya; Choi, Murim; Goh, Gerald S.; Murdoch, John D.; Guenel, Murat; Lifton, Richard P.; State, Matthew W.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Hus, Vanessa; Lund, Sabata C.; Lord, Catherine] Univ Michigan, Autism & Commun Disorders Ctr, Ann Arbor, MI 48109 USA. [Luo, Rui; Cantor, Rita M.] Univ Calif Los Angeles, Dept Human Genet, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Moreno-De-Luca, Daniel; Martin, Christa Lese] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. [Chu, Su H.; Roeder, Kathryn] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA. [Moreau, Michael P.; DiCola, Michael; Frahm, Stephanie; Wang, Qi; Brooks, Andrew I.] Rutgers State Univ, Environm & Occupat Hlth Sci Inst, Piscataway, NJ 08854 USA. [Gupta, Abha R.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. [Thomson, Susanne A.; Crawford, Emily L.; McGrew, Anna D.; Yaspan, Brian L.; Sutcliffe, James S.] Vanderbilt Univ, Ctr Mol Neurosci, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Mason, Christopher E.] Weill Cornell Med Coll, Dept Physiol Biophys, New York, NY 10021 USA. [Mason, Christopher E.] Weill Cornell Med Coll, Inst Computat Biomed, New York, NY 10021 USA. [Bilguvar, Kaya; Guenel, Murat] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT 06510 USA. [Bilguvar, Kaya; Guenel, Murat] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06510 USA. [Celestino-Soper, Patricia B. S.; Beaudet, Arthur L.; Shaw, Chad A.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Davis, Lea; Cook, Edwin H., Jr.] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60608 USA. [Fielding-Singh, Vikram] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Fishman, Daniel O.] Vanderbilt Univ, Sch Med, Nashville, TN 37232 USA. [Garagaloyan, Rouben; Curland, Martin] Microangelo Associates LLC, Pacific Palisades, CA 90272 USA. [Klei, Lambertus; Devlin, Bernie] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Lowe, Jennifer K.; Geschwind, Daniel] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Neurogenet Program, Los Angeles, CA 90095 USA. [Meyer, Kyle A.] Yale Univ, Interdept Neurosci Program, New Haven, CT 06510 USA. [O'Roak, Brian J.; Raubeson, Melanie J.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Pottenger, Rebecca S.] Princeton Univ, Princeton, NJ 08544 USA. [Yu, Timothy W.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Childrens Hosp Boston,Dept Neurol,Div Genet, Boston, MA 02115 USA. [Cantor, Rita M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Los Angeles, CA 90095 USA. [Grice, Dorothy E.] Columbia Univ, Dept Psychiat, Div Child & Adolescent Psychiat, New York, NY 10032 USA. [Grice, Dorothy E.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Choi, Murim; Lifton, Richard P.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. [Mane, Shrikant M.] Yale Ctr Genome Anal, Orange, CT 06477 USA. [Martin, Donna M.] Univ Michigan, Med Ctr, Dept Pediat, Ann Arbor, MI 48109 USA. [Martin, Donna M.] Univ Michigan, Med Ctr, Dept Human Genet, Ann Arbor, MI 48109 USA. [Sheldon, Michael; Tischfield, Jay A.] Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA. [Sheldon, Michael; Tischfield, Jay A.] Rutgers State Univ, Inst Human Genet, Piscataway, NJ 08854 USA. [Walsh, Christopher A.] Harvard Univ, Sch Med, Ctr Life Sci, Howard Hughes Med Inst, Boston, MA 02115 USA. [Walsh, Christopher A.] Harvard Univ, Sch Med, Ctr Life Sci, Div Genet,Childrens Hosp Boston, Boston, MA 02115 USA. [Morrow, Eric M.] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA. [Morrow, Eric M.] Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Ledbetter, David H.] Geisinger Hlth Syst, Danville, PA 17822 USA. [Fombonne, Eric] McGill Univ, Montreal Childrens Hosp, Dept Psychiat, Montreal, PQ H3Z 1P2, Canada. [Lord, Catherine] Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. [Lord, Catherine] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Lord, Catherine] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Lord, Catherine] Univ Michigan, Ctr Human Growth & Dev, Ann Arbor, MI 48109 USA. RP State, MW (reprint author), Yale Univ, Sch Med, Program Neurogenet, 230 S Frontage Rd, New Haven, CT 06520 USA. EM matthew.state@yale.edu RI Morrow, Eric/J-2767-2013; Sutcliffe, James/C-1348-2012; Goh, Gerald/N-1684-2015; OI Sutcliffe, James/0000-0001-5200-6007; Goh, Gerald/0000-0002-3832-6466; Shaw, Chad/0000-0001-7267-5398; Martin, Donna/0000-0002-8070-2007; Fernandez, Thomas V/0000-0003-0830-022X; O'Roak, Brian/0000-0002-4141-0095; Sanders, Stephan/0000-0001-9112-5148; Tischfield, Jay/0000-0003-3217-8287; Fombonne, Eric/0000-0002-8605-3538 FU Simons Foundation [SFARI 124827] FX We are most grateful to all of the families at the participating Simons Foundation Autism Research Initiative (SFARI) Simplex Collection (SSC) sites. This work was supported by a grant from the Simons Foundation (SFARI 124827). C.A. Walsh and R.P. Lifton are Investigators of the Howard Hughes Medical Institute. We wish to thank the SSC principal investigators A.L. Beaudet, R. Bernier, J. Constantino, E.H. Cook, Jr., E. Fombonne, D. Geschwind, D.E. Grice, A. Klin, D.H. Ledbetter, C. Lord, C.L. Martin, D.M. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M.W. State, W. Stone, J.S. Sutcliffe, C.A. Walsh, and E. Wijsman; the coordinators and staff at the SSC sites; the SFARI staff (M. Greenup and S. Johnson); R. Smith and Z. Galfayan at Microangelo Associates for bioinformatics support; Prometheus Research; the Yale Center of Genomic Analysis staff, in particular S. Umlauf and C. Castaldi; T. Brooks-Boone and M. Wojciechowski for their help in administering the project at Yale; and J. Krystal, G.D. Fischbach, A. Packer, J. Spiro, and M. Benedetti for their suggestions throughout and very helpful comments during the preparation of this manuscript. Approved researchers can obtain the SSC population data set described in this study by applying at https://base.sfari.org. D.H. Ledbetter acts as a consultant for Roche Diagnostics and BioReference Laboratories; M.W. State, R.P. Lifton, and B.J. O'Roak hold a patent relating to the gene CNTNAP2. NR 71 TC 545 Z9 556 U1 8 U2 71 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUN 9 PY 2011 VL 70 IS 5 BP 863 EP 885 DI 10.1016/j.neuron.2011.05.002 PG 23 WC Neurosciences SC Neurosciences & Neurology GA 780GW UT WOS:000291843500008 PM 21658581 ER PT J AU Tanwar, PS Zhang, LH Kaneko-Tarui, T Curley, MD Taketo, MM Rani, P Roberts, DJ Teixeira, JM AF Tanwar, Pradeep S. Zhang, LiHua Kaneko-Tarui, Tomoko Curley, Michael D. Taketo, Makoto M. Rani, Poonam Roberts, Drucilla J. Teixeira, Jose M. TI Mammalian Target of Rapamycin Is a Therapeutic Target for Murine Ovarian Endometrioid Adenocarcinomas with Dysregulated Wnt/beta-Catenin and PTEN SO PLOS ONE LA English DT Article ID MULLERIAN-INHIBITING SUBSTANCE; TRANSGENIC MOUSE MODEL; CELL TUMOR-DEVELOPMENT; BETA-CATENIN; SURFACE EPITHELIUM; FOLLICULAR DEVELOPMENT; REPRODUCTIVE-TRACT; GRANULOSA-CELLS; BREAST-CANCER; EXPRESSION AB Despite the fact that epithelial ovarian cancers are the leading cause of death from gynecological cancer, very little is known about the pathophysiology of the disease. Mutations in the WNT and PI3K pathways are frequently observed in the human ovarian endometrioid adenocarcinomas (OEAs). However, the role of WNT/beta-catenin and PTEN/AKT signaling in the etiology and/or progression of this disease is currently unclear. In this report we show that mice with a gain-of-function mutation in beta-catenin that leads to dysregulated nuclear accumulation of beta-catenin expression in the ovarian surface epithelium (OSE) cells develop indolent, undifferentiated tumors with both mesenchymal and epithelial characteristics. Combining dysregulated beta-catenin with homozygous deletion of PTEN in the OSE resulted in development of significantly more aggressive tumors, which was correlated with inhibition of p53 expression and cellular senescence. Induced expression of both mTOR kinase, a master regulator of proliferation, and phosphorylation of its downstream target, S6Kinase was also observed in both the indolent and aggressive mouse tumors, as well as in human OEA with nuclear beta-catenin accumulation. Ectopic allotransplants of the mouse ovarian tumor cells with a gain-of-function mutation in beta-catenin and PTEN deletion developed into tumors with OEA histology, the growth of which were significantly inhibited by oral rapamycin treatment. These studies demonstrate that rapamycin might be an effective therapeutic for human ovarian endometrioid patients with dysregulated Wnt/beta-catenin and Pten/PI3K signaling. C1 [Tanwar, Pradeep S.; Zhang, LiHua; Kaneko-Tarui, Tomoko; Curley, Michael D.; Rani, Poonam; Teixeira, Jose M.] Massachusetts Gen Hosp, Dept Obstet Gynecol & Reprod Biol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Tanwar, Pradeep S.; Zhang, LiHua; Kaneko-Tarui, Tomoko; Curley, Michael D.; Rani, Poonam; Roberts, Drucilla J.; Teixeira, Jose M.] Harvard Univ, Sch Med, Boston, MA USA. [Taketo, Makoto M.] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Kyoto, Japan. [Roberts, Drucilla J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Teixeira, JM (reprint author), Massachusetts Gen Hosp, Dept Obstet Gynecol & Reprod Biol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. EM teixeira@helix.mgh.harvard.edu FU NIH [HD052701] FX This study was supported in part by an NIH grant to JMT (HD052701) and by Vincent Memorial Research Funds. 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 56 TC 29 Z9 30 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 9 PY 2011 VL 6 IS 6 AR e20715 DI 10.1371/journal.pone.0020715 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 777JX UT WOS:000291612900021 PM 21695255 ER PT J AU Antin, JH AF Antin, Joseph H. TI T-cell depletion in GVHD: less is more? SO BLOOD LA English DT Editorial Material ID HOST-DISEASE PROPHYLAXIS; TRANSPLANTATION C1 Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. RP Antin, JH (reprint author), Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. NR 8 TC 7 Z9 7 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 JUN 9 PY 2011 VL 117 IS 23 BP 6061 EP 6062 DI 10.1182/blood-2011-04-348409 PG 3 WC Hematology SC Hematology GA 775DI UT WOS:000291438000005 PM 21659553 ER PT J AU Cavo, M Rajkumar, SV Palumbo, A Moreau, P Orlowski, R Blade, J Sezer, O Ludwig, H Dimopoulos, MA Attal, M Sonneveld, P Boccadoro, M Anderson, KC Richardson, PG Bensinger, W Johnsen, HE Kroeger, N Gahrton, G Bergsagel, PL Vesole, DH Einsele, H Jagannath, S Niesvizky, R Durie, BGM San Miguel, J Lonial, S AF Cavo, Michele Rajkumar, S. Vincent Palumbo, Antonio Moreau, Philippe Orlowski, Robert Blade, Joan Sezer, Orhan Ludwig, Heinz Dimopoulos, Meletios A. Attal, Michel Sonneveld, Pieter Boccadoro, Mario Anderson, Kenneth C. Richardson, Paul G. Bensinger, William Johnsen, Hans E. Kroeger, Nicolaus Gahrton, Gosta Bergsagel, P. Leif Vesole, David H. Einsele, Hermann Jagannath, Sundar Niesvizky, Ruben Durie, Brian G. M. San Miguel, Jesus Lonial, Sagar CA Int Myeloma Working Grp TI International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation SO BLOOD LA English DT Article ID HIGH-DOSE THERAPY; BORTEZOMIB PLUS DEXAMETHASONE; BONE-MARROW-TRANSPLANTATION; INDUCTION TREATMENT PRIOR; TERM-FOLLOW-UP; PERIPHERAL NEUROPATHY; CLINICAL-IMPLICATIONS; RANDOMIZED-TRIAL; PHASE-II; STANDARD CHEMOTHERAPY AB The role of high-dose therapy followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional chemotherapy to newer regimens incorporating the immunomodulatory derivatives thalidomide or lenalidomide and the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various doublet, triplet, and quadruplet regimens. Up-front use of these induction treatments, in particular 3-drug combinations, has affected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the depth of response, a gain that translates into extended progression-free survival and, potentially, overall survival. High activity shown by immunomodulatory derivatives and bortezomib before ASCT has recently led to their use as consolidation and maintenance therapies after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This article reviews the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current management of younger, transplantation-eligible MM patients. (Blood. 2011;117(23):6063-6073) C1 [Cavo, Michele] Univ Bologna, Sch Med, Seragnoli Inst Hematol, Bologna, Italy. [Rajkumar, S. Vincent] Mayo Clin, Dept Hematol, Rochester, MN USA. [Palumbo, Antonio] Univ Turin, Div Hematol, Turin, Italy. [Moreau, Philippe] Univ Hosp, Dept Hematol, Nantes, France. [Orlowski, Robert] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA. [Blade, Joan] Hosp Clin Barcelona, Dept Hematol, Barcelona, Spain. [Sezer, Orhan] Univ Hamburg, Univ Med Ctr, Hamburg, Germany. [Ludwig, Heinz] Wilhelminenspital Hosp, Med Dept & Med Oncol 1, Vienna, Austria. [Dimopoulos, Meletios A.] Univ Athens, Sch Med, Dept Clin Therapeut, GR-11527 Athens, Greece. [Attal, Michel] Hop Purpan, Serv Hematol, Toulouse, France. [Sonneveld, Pieter] Erasmus MC, Dept Hematol, Rotterdam, Netherlands. [Boccadoro, Mario] Univ Turin, Dept Med & Expt Oncol, Turin, Italy. [Anderson, Kenneth C.; Richardson, Paul G.] Dana Farber Canc Inst, Div Hematol Malignancy, Boston, MA 02115 USA. [Bensinger, William] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Johnsen, Hans E.] Aarhus Univ Hosp, Med Ctr, Dept Hematol, DK-8000 Aarhus, Denmark. [Kroeger, Nicolaus] Univ Hamburg Hosp, Dept Stem Cell Transplantat, D-2000 Hamburg, Germany. [Gahrton, Gosta] Huddinge Univ Hosp, Dept Med, Stockholm, Sweden. [Bergsagel, P. Leif] Mayo Clin Scottsdale, Dept Hematol Oncol, Scottsdale, AZ USA. [Vesole, David H.] Hackensack Univ Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Einsele, Hermann] Wuertzburg Univ Hosp, Dept Hematol & Oncol, Wuertzburg, Germany. [Jagannath, Sundar] Mt Sinai Canc Inst, New York, NY USA. [Niesvizky, Ruben] Cornell Univ, Ctr Lymphoma & Myeloma, Weill Med Coll, New York, NY 10021 USA. [Durie, Brian G. M.] Aptium Oncol, Hematol Malignancies & Multiple Myeloma, Los Angeles, CA USA. [San Miguel, Jesus] Univ Salamanca, Conscjo Super Invest Cient USAL CSIC, Hosp Univ Salamanca, CIC,IBMCC, E-37008 Salamanca, Spain. [Lonial, Sagar] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. RP Cavo, M (reprint author), Azienda Osped Univ, Policlin S Orsola Malpighi, Ist Ematol Seragnoli, Via Massarenti 9, I-40138 Bologna, Italy. EM michele.cavo@unibo.it; rajks@mayo.edu RI Bergsagel, Peter/A-7842-2011; 2011, Secribsal/D-9425-2012; richard, chrystelle/K-8595-2015; OI Bergsagel, Peter/0000-0003-1523-7388; SAN MIGUEL, JESUS/0000-0002-9183-4857; CAVO, MICHELE/0000-0003-4514-3227; Rajkumar, S. Vincent/0000-0002-5862-1833 FU Celgene; Millennium; Jansen; Janssen; Novartis; Onyx FX R.O. was supported by Celgene and Millennium (research funding). J.B. was supported by Jansen and Celgene. O.S. was supported by Janssen and Novartis (research funding). P.S. was supported by Janssen, Celgene, and Onyx (research support). R.N. was supported by Millenium and Celgene (research support). NR 113 TC 135 Z9 141 U1 1 U2 8 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 JUN 9 PY 2011 VL 117 IS 23 BP 6063 EP 6073 DI 10.1182/blood-2011-02-297325 PG 11 WC Hematology SC Hematology GA 775DI UT WOS:000291438000006 PM 21447828 ER PT J AU Neri, P Ren, L Azab, AK Brentnall, M Gratton, K Klimowicz, AC Lin, C Duggan, P Tassone, P Mansoor, A Stewart, DA Boise, LH Ghobrial, IM Bahlis, NJ AF Neri, Paola Ren, Li Azab, Abdel Kareem Brentnall, Matthew Gratton, Kathy Klimowicz, Alexander C. Lin, Charles Duggan, Peter Tassone, Pierfrancesco Mansoor, Adnan Stewart, Douglas A. Boise, Lawrence H. Ghobrial, Irene M. Bahlis, Nizar J. TI Integrin beta 7-mediated regulation of multiple myeloma cell adhesion, migration, and invasion SO BLOOD LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MEDIATED DRUG-RESISTANCE; MARROW STROMAL CELLS; NF-KAPPA-B; TUMOR MICROENVIRONMENT; PLASMA-CELLS; E-CADHERIN; T-CELLS; CAM-DR; C-MAF AB Integrin-beta 7 (ITGB7) mRNA is detected in multiple myeloma (MM) cells and its presence is correlated with MAF gene activation. Although the involvement of several integrin family members in MM-stoma cell interaction is well documented, the specific biologic functions regulated by integrin-beta 7 in MM are largely unknown. Clinically, we have correlated integrin-beta 7 expression in MM with poor survival outcomes post autologous stem cell transplantation and postsalvage therapy with bortezomib. Functionally, we have found that shRNA-mediated silencing of ITGB7 reduces MM-cell adhesion to extracellular matrix elements (fibronectin, E-cadherin) and reverses cell-adhesion-mediated drug resistance (CAM-DR) sensitizing them to bortezomib and melphalan. In addition, ITGB7 silencing abrogated MM-cell transwell migration in response to SDF1 alpha gradients, reduced vessel density in xenografted tumors, and altered MM cells in vivo homing into the BM. Mechanistically, ITGB7 knockdown inhibited focal adhesion kinase (FAK) and Src phosphorylation, Rac1 activation, and SUMOylation, reduced VEGF production in MM-BM stem cell cocultures and attenuated p65-NF-kappa B activity. Our findings support a role for integrin-beta 7 in MM-cell adhesion, migration, and BM homing, and pave the way for a novel therapeutic approach targeting this molecule. (Blood. 2011;117(23):6202-6213) C1 [Neri, Paola; Duggan, Peter; Stewart, Douglas A.; Bahlis, Nizar J.] Univ Calgary, Div Hematol, Calgary, AB T2N 2T9, Canada. [Neri, Paola; Tassone, Pierfrancesco] Magna Graecia Univ Catanzaro, Med Oncol Unit, Catanzaro, Italy. [Neri, Paola; Gratton, Kathy; Klimowicz, Alexander C.; Stewart, Douglas A.; Bahlis, Nizar J.] SACRI, Calgary, AB, Canada. [Azab, Abdel Kareem; Ghobrial, Irene M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Brentnall, Matthew; Boise, Lawrence H.] Emory Univ, Dept Hematol Oncol, Winship Canc Inst, Atlanta, GA 30322 USA. [Brentnall, Matthew] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Lin, Charles] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Mansoor, Adnan] Univ Calgary, Div Hematopathol, Calgary Lab Serv, Calgary, AB T2N 2T9, Canada. RP Bahlis, NJ (reprint author), Univ Calgary, Div Hematol, 1403 29th St NW,Rm 681, Calgary, AB T2N 2T9, Canada. EM nbahlis@ucalgary.ca FU Leukemia & Lymphoma Society of Canada; Alberta Cancer Foundation; Multiple Myeloma Research Foundation; Terry Fox Foundation; Italian Association of Cancer Research FX This work has been supported by research grants from the Leukemia & Lymphoma Society of Canada (N.J.B. and P.N.), Alberta Cancer Foundation (P.N. and N.J.B.), Multiple Myeloma Research Foundation (A.C.K. and N.J.B.), Terry Fox Foundation (D.A.S. and N.J.B.), and Italian Association of Cancer Research (P.N.). NR 50 TC 36 Z9 38 U1 1 U2 13 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 JUN 9 PY 2011 VL 117 IS 23 BP 6202 EP 6213 DI 10.1182/blood-2010-06-292243 PG 12 WC Hematology SC Hematology GA 775DI UT WOS:000291438000022 PM 21474670 ER PT J AU Chen, W Huang, FW de Renshaw, TB Andrews, NC AF Chen, Wenjie Huang, Franklin W. de Renshaw, Tomasa Barrientos Andrews, Nancy C. TI Skeletal muscle hemojuvelin is dispensable for systemic iron homeostasis SO BLOOD LA English DT Article ID ANTIMICROBIAL PEPTIDE HEPCIDIN; JUVENILE HEMOCHROMATOSIS; SOLUBLE HEMOJUVELIN; DEFICIENCY ANEMIA; EXPRESSION; OVERLOAD; HYPOXIA; LIVER; GENE; MICE AB Hepcidin, a hormone produced mainly by the liver, has been shown to inhibit both intestinal iron absorption and iron release from macrophages. Hemojuvelin, a glycophosphatidyl inositol-linked membrane protein, acts as a bone morphogenetic protein coreceptor to activate hepcidin expression through a SMAD signaling pathway in hepatocytes. In the present study, we show in mice that loss of hemojuvelin specifically in the liver leads to decreased liver hepcidin production and increased tissue and serum iron levels. Although it does not have any known function outside of the liver, hemojuvelin is expressed at very high levels in cardiac and skeletal muscle. To explore possible roles for hemojuvelin in skeletal muscle, we analyzed conditional knockout mice that lack muscle hemojuvelin. The mutant animals had no apparent phenotypic abnormalities. We found that systemic iron homeostasis and liver hepcidin expression were not affected by loss of hemojuvelin in skeletal muscle regardless of dietary iron content. We conclude that, in spite of its expression pattern, hemojuvelin is primarily important in the liver. (Blood. 2011; 117(23): 6319-6325) C1 [Chen, Wenjie; de Renshaw, Tomasa Barrientos; Andrews, Nancy C.] Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Andrews, Nancy C.] Duke Univ, Sch Med, Dept Pediat, Durham, NC 27710 USA. [Huang, Franklin W.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Andrews, NC (reprint author), Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, DUMC 2927, Durham, NC 27710 USA. EM nancy.andrews@duke.edu OI Andrews, Nancy/0000-0003-0243-4462 FU Cooley's Anemia Foundation; Roche Foundation for Anemia Research; National Institutes of Health [R01 DK066373] FX This work was supported by a Cooley's Anemia Foundation Research Fellowship (to W.C.), by a Roche Foundation for Anemia Research grant (to N.C.A.), and by National Institutes of Health grant R01 DK066373 (to N.C.A.). NR 29 TC 29 Z9 30 U1 0 U2 3 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 JUN 9 PY 2011 VL 117 IS 23 BP 6319 EP 6325 DI 10.1182/blood-2010-12-327957 PG 7 WC Hematology SC Hematology GA 775DI UT WOS:000291438000034 PM 21493799 ER PT J AU Flick, MJ Chauhan, AK Frederick, M Talmage, KE Kombrinck, KW Miller, W Mullins, ES Palumbo, JS Zheng, XZ Esmon, NL Esmon, CT Thornton, S Becker, A Pelc, LA Di Cera, E Wagner, DD Degen, JL AF Flick, Matthew J. Chauhan, Anil K. Frederick, Malinda Talmage, Kathryn E. Kombrinck, Keith W. Miller, Whitney Mullins, Eric S. Palumbo, Joseph S. Zheng, Xunzhen Esmon, Naomi L. Esmon, Charles T. Thornton, Sherry Becker, Ann Pelc, Leslie A. Di Cera, Enrico Wagner, Denisa D. Degen, Jay L. TI The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A SO BLOOD LA English DT Article ID ACTIVATED PROTEIN-C; COLLAGEN-INDUCED ARTHRITIS; RHEUMATOID-ARTHRITIS; POTENT ANTICOAGULANT; THROMBIN INHIBITION; EMBRYONIC LETHALITY; ISCHEMIC-STROKE; SYNOVIAL TISSUE; IN-VIVO; CELLS AB Thrombin is a positive mediator of thrombus formation through the proteolytic activation of protease-activated receptors (PARs), fibrinogen, factor XI (fXI), and other substrates, and a negative regulator through activation of protein C, a natural anticoagulant with anti-inflammatory/ cytoprotective properties. Protease-engineering studies have established that 2 active-site substitutions, W215A and E217A (fII(WE)), result in dramatically reduced catalytic efficiency with procoagulant substrates while largely preserving thrombomodulin (TM)-dependent protein C activation. To explore the hypothesis that a prothrombin variant favoring anti-thrombotic pathways would be compatible with development but limit inflammatory processes in vivo, we generated mice carrying the fII(WE) mutations within the endogenous prothrombin gene. Unlike fII(WE) embryos, fII(WE/WE) mice uniformly developed to term. Nevertheless, these mice ultimately succumbed to spontaneous bleeding events shortly after birth. Heterozygous fII(WT/WE) mice were viable and fertile despite a shift toward an anti-thrombotic phenotype exemplified by prolonged tail-bleeding times and times-to-occlusion after FeCl(3) vessel injury. More interestingly, prothrombin(WE) expression significantly ameliorated the development of inflammatory joint disease in mice challenged with collagen-induced arthritis (CIA). The administration of active recombinant thrombin(WE) also suppressed the development of CIA in wildtype mice. These studies provide a proof-of-principle that pro/thrombin variants engineered with altered substrate specificity may offer therapeutic opportunities for limiting inflammatory disease processes. (Blood. 2011; 117(23): 6326-6337) C1 [Flick, Matthew J.; Frederick, Malinda; Talmage, Kathryn E.; Kombrinck, Keith W.; Miller, Whitney; Mullins, Eric S.; Palumbo, Joseph S.; Thornton, Sherry; Becker, Ann; Degen, Jay L.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH USA. [Chauhan, Anil K.; Wagner, Denisa D.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. [Chauhan, Anil K.; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Zheng, Xunzhen; Esmon, Naomi L.; Esmon, Charles T.] Oklahoma Med Res Fdn, Cardiovasc Biol Res Program, Oklahoma City, OK 73104 USA. [Esmon, Charles T.] Howard Hughes Med Inst, Oklahoma City, OK USA. [Pelc, Leslie A.; Di Cera, Enrico] St Louis Univ, Sch Med, Dept Biochem & Mol Biol, St Louis, MO 63104 USA. RP Degen, JL (reprint author), Cincinnati Childrens Hosp Res Fdn, Div Expt Hematol, 3333 Burnet Ave, Cincinnati, OH 45255 USA. EM jay.degen@cchmc.org FU National Institutes of Health [R01 AR056990, R01 HL085357, R01 HL096126, R01 HL041002, R01 HL049413, R01 HL058141, R01 HL073813, R44 HL095315]; Howard Hughes Medical Institute; Cincinnati Rheumatic Diseases Center [P30 AR047363] FX This work was supported by grants from the National Institutes of Health (R01 AR056990 to M.J.F.; R01 HL085357 and R01 HL096126 to J.L.D.; R01 HL041002 to D. D. W.; and R01 HL049413, R01 HL058141, R01 HL073813, and R44 HL095315 to E. D. C.), by the Howard Hughes Medical Institute (to C. T. E.), and by the Cincinnati Rheumatic Diseases Center (P30 AR047363). NR 50 TC 18 Z9 18 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 JUN 9 PY 2011 VL 117 IS 23 BP 6326 EP 6337 DI 10.1182/blood-2010-08-304915 PG 12 WC Hematology SC Hematology GA 775DI UT WOS:000291438000035 PM 21436072 ER PT J AU Apostolou, E Hochedlinger, K AF Apostolou, Effie Hochedlinger, Konrad TI STEM CELLS iPS cells under attack SO NATURE LA English DT Editorial Material C1 [Apostolou, Effie; Hochedlinger, Konrad] Massachusetts Gen Hosp, Howard Hughes Med Inst, Ctr Regenerat Med, Boston, MA 02114 USA. [Apostolou, Effie; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Apostolou, Effie; Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Apostolou, Effie; Hochedlinger, Konrad] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Apostolou, E (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Ctr Regenerat Med, Boston, MA 02114 USA. EM khochedlinger@helix.mgh.harvard.edu NR 7 TC 25 Z9 27 U1 3 U2 14 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 JUN 9 PY 2011 VL 474 IS 7350 BP 165 EP 166 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 774PE UT WOS:000291397800035 PM 21654792 ER PT J AU Fujisaki, J Wu, J Carlson, AL Silberstein, L Putheti, P Larocca, R Gao, WD Saito, TI Lo Celso, C Tsuyuzaki, H Sato, T Cote, D Sykes, M Strom, TB Scadden, DT Lin, CP AF Fujisaki, Joji Wu, Juwell Carlson, Alicia L. Silberstein, Lev Putheti, Prabhakar Larocca, Rafael Gao, Wenda Saito, Toshiki I. Lo Celso, Cristina Tsuyuzaki, Hitoshi Sato, Tatsuyuki Cote, Daniel Sykes, Megan Strom, Terry B. Scadden, David T. Lin, Charles P. TI In vivo imaging of T-reg cells providing immune privilege to the haematopoietic stem-cell niche SO NATURE LA English DT Article ID BONE-MARROW NICHE; ENGRAFTMENT AB Stem cells reside in a specialized regulatory microenvironment or niche(1,2), where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity(1-3). The niche may also protect stem cells from environmental insults(3) including cytotoxic chemotherapy and perhaps pathogenic immunity(4). The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression(4). We sought to determine if somatic stem-cell niches more broadly are immune-privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche(1,2,5-7) in the bone marrow, a site where immune reactivity exists(8,9). We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30 days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T (T-reg) cells. High-resolutionin vivo imaging over time demonstrated marked co-localization of HSPCs with T-reg cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. T-reg cells seem to participate in creating a localized zone where HSPCs reside and where T-reg cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack. C1 [Fujisaki, Joji; Wu, Juwell; Carlson, Alicia L.; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol,Adv Microscopy Program, Boston, MA 02114 USA. [Fujisaki, Joji; Wu, Juwell; Carlson, Alicia L.; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Fujisaki, Joji; Wu, Juwell; Silberstein, Lev; Lo Celso, Cristina; Scadden, David T.; Lin, Charles P.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Wu, Juwell] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Silberstein, Lev; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Putheti, Prabhakar; Larocca, Rafael; Gao, Wenda; Strom, Terry B.] Beth Israel Deaconess Med Ctr, Inst Transplantat, Boston, MA 02215 USA. [Putheti, Prabhakar; Larocca, Rafael; Gao, Wenda; Strom, Terry B.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Saito, Toshiki I.; Sykes, Megan] Massachusetts Gen Hosp E, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Bone Marrow Transplantat Sect, Boston, MA 02129 USA. [Tsuyuzaki, Hitoshi; Sato, Tatsuyuki] Univ Tokyo, Fac Med, Bunkyo Ku, Tokyo 1130033, Japan. [Cote, Daniel] Dept Phys Genie Phys & Opt, Quebec City, PQ G1J 2G3, Canada. [Cote, Daniel] Univ Laval Robert Giffard, Ctr Rech, Quebec City, PQ G1J 2G3, Canada. RP Fujisaki, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol,Adv Microscopy Program, CPZN 8238,185 Cambridge St, Boston, MA 02114 USA. EM jfujisaki@partners.org; lin@helix.mgh.harvard.edu RI Cote, Daniel/D-5185-2011; Larocca, Rafael/J-9557-2012; Assumpcao Larocca, Rafael/H-1655-2015; OI Assumpcao Larocca, Rafael/0000-0002-9995-1804; Lo Celso, Cristina/0000-0002-1163-4207 FU Bullock fellowship; Harvard Stem Cell Institute; DoD [W81XWH-10-1-0217]; NIH [HL097748, HL97794, CA111519, AI041521]; EMBO; HFSP; philanthropic sources FX This work was supported by Bullock fellowship (to J.F.), the Harvard Stem Cell Institute and DoD W81XWH-10-1-0217 (to J.F. and C.P.L.), NIH HL097748 (to C.P.L.), HL97794 (to D.T.S.), CA111519 (to M.S.), AI041521 (to T.B.S), EMBO (to C.L.C.), HFSP (to C.L.C.), philanthropic sources (to D.T.S. and C.L.C.), and the National Institutes of Health. We acknowledge J. Zhao and D. Cao for cell sorting. NR 19 TC 166 Z9 173 U1 3 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 9 PY 2011 VL 474 IS 7350 BP 216 EP U256 DI 10.1038/nature10160 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 774PE UT WOS:000291397800051 PM 21654805 ER PT J AU Overmoyer, BA Lee, JM Lerwill, MF AF Overmoyer, Beth A. Lee, Janie M. Lerwill, Melinda F. TI Case 17-2011: A 49-Year-Old Woman with a Mass in the Breast and Overlying Skin Changes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID E-CADHERIN EXPRESSION; CANCER; CARCINOMA; CHEMOTHERAPY; THERAPY; IDENTIFICATION; ANGIOGENESIS; MASTECTOMY; INDUCTION; SIGNATURE C1 [Overmoyer, Beth A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Overmoyer, Beth A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Lee, Janie M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Lerwill, Melinda F.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Lee, Janie M.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Overmoyer, Beth A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Lerwill, Melinda F.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Overmoyer, BA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. FU Harvard Medical School Department of Continuing Education; Dana-Farber/Brigham and Women's Cancer Center; Massachusetts General Hospital Cancer Center FX This case was presented at the postgraduate course Breast Cancer: New Horizons Current Controversies (2010), Judy E. Garber, M.D., M.P.H., Barbara L. Smith, M.D., Ph.D., and Eric P. Winer, M.D., course directors; sponsored by the Harvard Medical School Department of Continuing Education, Dana-Farber/Brigham and Women's Cancer Center, and Massachusetts General Hospital Cancer Center. NR 28 TC 0 Z9 0 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 JUN 9 PY 2011 VL 364 IS 23 BP 2246 EP 2254 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 774NA UT WOS:000291392100013 PM 21651397 ER PT J AU Nadazdin, O Boskovic, S Murakami, T Tocco, G Smith, RN Colvin, RB Sachs, DH Allan, J Madsen, JC Kawai, T Cosimi, AB Benichou, G AF Nadazdin, Ognjenka Boskovic, Svjetlan Murakami, Toru Tocco, Georges Smith, Rex-Neal Colvin, Robert B. Sachs, David H. Allan, James Madsen, Joren C. Kawai, Tatsuo Cosimi, A. Benedict Benichou, Gilles TI Host Alloreactive Memory T Cells Influence Tolerance to Kidney Allografts in Nonhuman Primates SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID TRANSPLANTATION TOLERANCE; CYNOMOLGUS MONKEYS; MIXED CHIMERISM; HETEROLOGOUS IMMUNITY; CD154 BLOCKADE; REJECTION; INDUCTION; SURVIVAL; PROLIFERATION; HOMEOSTASIS AB Transplant tolerance, defined as indefinite allograft survival without immunosuppression, has been regularly achieved in laboratory mice but not in nonhuman primates or humans. In contrast to laboratory mice, primates regularly have high frequencies of alloreactive memory T cells (TMEMs) before transplantation. These TMEMs are poorly sensitive to conventional immunosuppression and costimulation blockade, and the presence of donor-reactive TMEMs in primates may account for their resistance to transplant tolerance protocols that have proven consistently effective in mice. We measured the frequencies of anti-donor TMEMs before and after transplantation in a series of rejecting and tolerant monkeys that underwent nonmyeloablative conditioning, short-term immunosuppression, and combined allogeneic kidney/cell transplantation. Transplants were acutely rejected in all the monkeys with high numbers of donor-specific TMEMs before transplantation. In contrast, long-term survival was observed in the recipients harboring lower frequencies of anti-donor TMEMs before transplantation. Similar amounts of TMEM homeostatic expansion were recorded in all transplanted monkeys upon hematopoietic reconstitution; however, only the tolerant monkeys had no expansion or activation of donor-reactive TMEMs after transplantation. These results indicate that the presence of high frequencies of host donor-reactive TMEMs before transplantation impairs tolerance induction to kidney allografts in this nonhuman primate model. Indeed, recipients harboring a low anamnestic reactivity to their donor before transplantation were successfully rendered tolerant via infusion of donor cells and short-term immunosuppression. This suggests that selection of allogeneic donors with low memory responses in recipients may be essential to successful transplant tolerance induction in patients. C1 [Nadazdin, Ognjenka; Boskovic, Svjetlan; Murakami, Toru; Tocco, Georges; Allan, James; Madsen, Joren C.; Kawai, Tatsuo; Cosimi, A. Benedict; Benichou, Gilles] Massachusetts Gen Hosp, Dept Surg, Transplant Ctr, Boston, MA 02114 USA. [Nadazdin, Ognjenka; Boskovic, Svjetlan; Murakami, Toru; Tocco, Georges; Smith, Rex-Neal; Colvin, Robert B.; Allan, James; Madsen, Joren C.; Kawai, Tatsuo; Cosimi, A. Benedict; Benichou, Gilles] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Smith, Rex-Neal; Colvin, Robert B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sachs, David H.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. RP Benichou, G (reprint author), Massachusetts Gen Hosp, Dept Surg, Transplant Ctr, Boston, MA 02114 USA. EM gbenichou@partners.org FU National Institute of Allergy and Infectious Diseases [U19 AI066705]; NIH [19 DK080652, HL018446, U191066705, PO1HL18646]; Massachusetts General Hospital Executive Committee on Research FX Funding: This work was supported by grants from the Massachusetts General Hospital Executive Committee on Research and National Institute of Allergy and Infectious Diseases grant U19 AI066705 to G. B., NIH grants 19 DK080652 and HL018446 to A. B. C., and NIH grants U191066705 and PO1HL18646 to J.C.M. NR 46 TC 38 Z9 38 U1 0 U2 1 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 JUN 8 PY 2011 VL 3 IS 86 AR 86ra51 DI 10.1126/scitranslmed.3002093 PG 6 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 795NG UT WOS:000292980300004 PM 21653831 ER PT J AU Sakai, Y Shaw, CA Dawson, BC Dugas, DV Al-Mohtaseb, Z Hill, DE Zoghbi, HY AF Sakai, Yasunari Shaw, Chad A. Dawson, Brian C. Dugas, Diana V. Al-Mohtaseb, Zaina Hill, David E. Zoghbi, Huda Y. TI Protein Interactome Reveals Converging Molecular Pathways Among Autism Disorders SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID COPY NUMBER VARIATION; POSTSYNAPTIC DENSITY PROTEINS; TUBEROUS SCLEROSIS GENE; SPECTRUM DISORDERS; MENTAL-RETARDATION; INTERACTION NETWORK; MOUSE MODEL; IDENTIFICATION; MECP2; MUTATIONS AB To uncover shared pathogenic mechanisms among the highly heterogeneous autism spectrum disorders (ASDs), we developed a protein interaction network that identified hundreds of new interactions among proteins encoded by ASD-associated genes. We discovered unexpectedly high connectivity between SHANK and TSC1, previously implicated in syndromic autism, suggesting that common molecular pathways underlie autistic phenotypes in distinct syndromes. ASD patients were more likely to harbor copy number variations that encompass network genes than were control subjects. We also identified, in patients with idiopathic ASD, three de novo lesions (deletions in 16q23.3 and 15q22 and one duplication in Xq28) that involve three network genes (NECAB2, PKM2, and FLNA). The protein interaction network thus provides a framework for identifying causes of idiopathic autism and for understanding molecular pathways that underpin both syndromic and idiopathic ASDs. C1 [Sakai, Yasunari; Shaw, Chad A.; Dawson, Brian C.; Dugas, Diana V.; Al-Mohtaseb, Zaina; Zoghbi, Huda Y.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Sakai, Yasunari; Dawson, Brian C.; Zoghbi, Huda Y.] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA. [Hill, David E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Hill, David E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Hill, David E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Zoghbi, Huda Y.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Zoghbi, Huda Y.] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. [Zoghbi, Huda Y.] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA. RP Shaw, CA (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. EM cashaw@bcm.tmc.edu; hzoghbi@bcm.tmc.edu RI Hill, David/B-6617-2011; OI Shaw, Chad/0000-0001-7267-5398 FU Howard Hughes Medical Institute; Simons Foundation Autism Research Initiative (SFARI); Ellison Foundation FX Funding: Supported by the Howard Hughes Medical Institute (H.Y.Z.), the Simons Foundation Autism Research Initiative (SFARI award to H.Y.Z.), and the Ellison Foundation (D. E. H.; awarded to M. Vidal). We are grateful to all of the families at the participating SFARI Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, and E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. Approved researchers can obtain the SSC population data set described in this study by applying at https://base.sfari.org. The array CGH data for the probands analyzed in the study have been deposited in National Center for Biotechnology Information's Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE29576 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE29576). NR 54 TC 61 Z9 62 U1 1 U2 16 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 JUN 8 PY 2011 VL 3 IS 86 AR 86ra49 DI 10.1126/scitranslmed.3002166 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 795NG UT WOS:000292980300002 PM 21653829 ER PT J AU Hernandez-Corbacho, MJ Jenkins, RW Clarke, CJ Hannun, YA Obeid, LM Snider, AJ Siskind, LJ AF Hernandez-Corbacho, Maria Jose Jenkins, Russell W. Clarke, Christopher J. Hannun, Yusuf A. Obeid, Lina M. Snider, Ashley J. Siskind, Leah J. TI Accumulation of Long-Chain Glycosphingolipids during Aging Is Prevented by Caloric Restriction SO PLOS ONE LA English DT Article ID RENAL-CELL CARCINOMA; MEMBRANE-ASSOCIATED SIALIDASE; OXIDATIVE STRESS; INSULIN SENSITIVITY; RAT-KIDNEY; T-CELLS; NUTRITIONAL INFLUENCES; DIABETIC-NEPHROPATHY; ALZHEIMERS-DISEASE; FISCHER-344 RATS AB Background: Chronic kidney disease and end-stage renal disease are major causes of morbidity and mortality that are seen far more commonly in the aged population. Interestingly, kidney function declines during aging even in the absence of underlying renal disease. Declining renal function has been associated with age-related cellular damage and dysfunction with reports of increased levels of apoptosis, necrosis, and inflammation in the aged kidney. Bioactive sphingolipids have been shown to regulate these same cellular processes, and have also been suggested to play a role in aging and cellular senescence. Methodology/Principal Findings: We hypothesized that alterations in kidney sphingolipids play a role in the declining kidney function that occurs during aging. To begin to address this, the sphingolipid profile was measured in young (3 mo), middle aged (9 mo) and old (17 mo) C57BL/6 male mice. Interestingly, while modest changes in ceramides and sphingoid bases were evident in kidneys from older mice, the most dramatic elevations were seen in long-chain hexosylceramides (HexCer) and lactosylceramides (LacCer), with C14-and C16-lactosylceramides elevated as much as 8 and 12-fold, respectively. Increases in long-chain LacCers during aging are not exclusive to the kidney, as they also occur in the liver and brain. Importantly, caloric restriction, previously shown to prevent the declining kidney function seen in aging, inhibits accumulation of long-chain HexCer/LacCers and prevents the age-associated elevation of enzymes involved in their synthesis. Additionally, long-chain LacCers are also significantly elevated in human fibroblasts isolated from elderly individuals. Conclusion/Significance: This study demonstrates accumulation of the glycosphingolipids HexCer and LacCer in several different organs in rodents and humans during aging. In addition, data demonstrate that HexCer and LacCer metabolism is regulated by caloric restriction. Taken together, data suggest that HexCer/LacCers are important mediators of cellular processes fundamental to mammalian aging. C1 [Hernandez-Corbacho, Maria Jose; Obeid, Lina M.; Snider, Ashley J.; Siskind, Leah J.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Jenkins, Russell W.; Clarke, Christopher J.; Hannun, Yusuf A.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Obeid, Lina M.; Snider, Ashley J.; Siskind, Leah J.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Hernandez-Corbacho, MJ (reprint author), Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. EM siskind@musc.edu OI obeid, lina/0000-0002-0734-0847 FU VA Merit; VA; VA REAP; American Cancer Society [IRG-97-219-11]; NIH/NCRR [P30 CA138313, P20 RR17677]; American Heart Association [AHA 081509E]; NIH [GM08716, GM-43825]; MUSC Hollings Cancer Center Abney Foundation; NIH/NIA [R01 AG016583] FX This work is supported by: VA Merit (to L.M.O.), VA CDA-2 Awards (to L.J.S. and A.J.S.), pilot project from the VA REAP (to L.J.S., A.J.S., and L.M.O.), the American Cancer Society Institutional Research Grant # IRG-97-219-11 (subaward to L.J.S.), Lipidomics Shared Resource of the Hollings Cancer Center supported by a Cancer Center Support Grant (P30 CA138313), pilot project (to L.J.S) from the NIH/NCRR P20 RR17677 COBRE in Lipidomics and Pathobiology, American Heart Association Pre-Doctoral Fellowship (AHA 081509E - to R.W.J.), NIH MSTP Training Grant (GM08716 - to R.W.J.), MUSC Hollings Cancer Center Abney Foundation Scholarship (to R.W.J.), and NIH/NIA R01 AG016583 (L.M.O.) and NIH GM-43825 (YAH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 88 TC 12 Z9 13 U1 1 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 JUN 8 PY 2011 VL 6 IS 6 AR e20411 DI 10.1371/journal.pone.0020411 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 777JJ UT WOS:000291611500023 PM 21687659 ER PT J AU Maia, S Pelletier, M Ding, JX Hsu, YM Sallan, SE Rao, SP Nadler, LM Cardoso, AA AF Maia, Sara Pelletier, Marc Ding, Jixin Hsu, Yen-Ming Sallan, Stephen E. Rao, Sambasiva P. Nadler, Lee M. Cardoso, Angelo A. TI Aberrant Expression of Functional BAFF-System Receptors by Malignant B-Cell Precursors Impacts Leukemia Cell Survival SO PLOS ONE LA English DT Article ID NECROSIS-FACTOR FAMILY; ACUTE LYMPHOBLASTIC-LEUKEMIA; BONE-MARROW MICROENVIRONMENT; NF-KAPPA-B; MYELOMA CELLS; LYMPHOCYTE STIMULATOR; AUTOIMMUNE-DISEASE; MATURATION ANTIGEN; TNF RECEPTOR; T-CELLS AB Despite exhibiting oncogenic events, patient's leukemia cells are responsive and dependent on signals from their malignant bone marrow (BM) microenvironment, which modulate their survival, cell cycle progression, trafficking and resistance to chemotherapy. Identification of the signaling pathways mediating this leukemia/microenvironment interplay is critical for the development of novel molecular targeted therapies. We observed that primary leukemia B-cell precursors aberrantly express receptors of the BAFF-system, BAFF-R, BCMA, and TACI. These receptors are functional as their ligation triggers activation of NF-kappa B, MAPK/JNK, and Akt signaling. Leukemia cells express surface BAFF and APRIL ligands, and soluble BAFF is significantly higher in leukemia patients in comparison to age-matched controls. Interestingly, leukemia cells also express surface APRIL, which seems to be encoded by APRIL-delta, a novel isoform that lacks the furin convertase domain. Importantly, we observed BM microenvironmental cells express the ligands BAFF and APRIL, including surface and secreted BAFF by BM endothelial cells. Functional studies showed that signals through BAFF-system receptors impact the survival and basal proliferation of leukemia B-cell precursors, and support the involvement of both homotypic and heterotypic mechanisms. This study shows an unforeseen role for the BAFF-system in the biology of precursor B-cell leukemia, and suggests that the target disruption of BAFF signals may constitute a valid strategy for the treatment of this cancer. C1 [Maia, Sara; Nadler, Lee M.; Cardoso, Angelo A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sallan, Stephen E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Ding, Jixin; Cardoso, Angelo A.] Indiana Univ Sch Med, Div Hematol Oncol, Indianapolis, IN USA. [Pelletier, Marc; Hsu, Yen-Ming] Biogen Idec Inc, Dept Prot Engn, Cambridge, MA USA. [Rao, Sambasiva P.] Biogen Idec Inc, Dept Immunobiol Autoimmun, Cambridge, MA USA. [Maia, Sara; Cardoso, Angelo A.] Inst Mol Med, Lisbon, Portugal. RP Maia, S (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM aacardos@iupui.edu RI Maia, Sara/B-2513-2013 OI Maia, Sara/0000-0001-8638-0566 FU National Institutes of Health [P01-CA68484]; Fundacao Ciencia e Tecnologia (FCT-Portugal) FX The work was supported by National Institutes of Health (P01-CA68484), Fundacao Ciencia e Tecnologia (FCT-Portugal); SM was supported by a FCT-Portugal scholarship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 14 Z9 16 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 8 PY 2011 VL 6 IS 6 AR e20787 DI 10.1371/journal.pone.0020787 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 777JJ UT WOS:000291611500044 PM 21687682 ER PT J AU Zhong, L Mostoslavsky, R AF Zhong, Lei Mostoslavsky, Raul TI Fine Tuning Our Cellular Factories: Sirtuins in Mitochondrial Biology SO CELL METABOLISM LA English DT Review ID FATTY-ACID OXIDATION; SIRT3-MEDIATED DEACETYLATION; UREA CYCLE; SIRT3; RESTRICTION; STRESS; CELLS; METABOLISM; ACTIVATION; HIF1-ALPHA C1 [Zhong, Lei; Mostoslavsky, Raul] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. RP Mostoslavsky, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. EM rmostoslavsky@mgh.harvard.edu FU Massachusetts Life Science Center; Howard Goodman Awardee; AFAR; National Institutes of Health [RO1DK088190-01A1, RO1GM093072-01] FX We apologize to those authors whose original work could not be referenced due to space constraints. We would like to thank Nabeel Bardeesy and all the members of the Mostoslavsky's lab for helpful comments. R.M. is a Sidney Kimmel Scholar, the recipient of the Massachusetts Life Science Center New Investigator Award, a Howard Goodman Awardee, and the recipient of a Young Investigator AFAR Grant. Work in the Mostoslavsky's lab is funded in part by National Institutes of Health grants RO1DK088190-01A1 and RO1GM093072-01. NR 28 TC 39 Z9 39 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD JUN 8 PY 2011 VL 13 IS 6 BP 621 EP 626 DI 10.1016/j.cmet.2011.05.004 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 776VR UT WOS:000291567300005 PM 21641544 ER PT J AU Miller, FG Joffe, S AF Miller, Franklin G. Joffe, Steven TI Balancing Access and Evaluation in the Approval of New Cancer Drugs SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID ACCELERATED APPROVAL; CLINICAL-TRIALS C1 [Miller, Franklin G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Joffe, Steven] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Joffe, Steven] Childrens Hosp, Dept Med, Boston, MA 02115 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov OI Joffe, Steven/0000-0002-0667-7384 NR 10 TC 6 Z9 6 U1 0 U2 0 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 JUN 8 PY 2011 VL 305 IS 22 BP 2345 EP 2346 DI 10.1001/jama.2011.784 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 773YV UT WOS:000291349100029 PM 21642688 ER PT J AU Jeon, SJ Fujioka, M Kim, SC Edge, ASB AF Jeon, Sang-Jun Fujioka, Masato Kim, Shi-Chan Edge, Albert S. B. TI Notch Signaling Alters Sensory or Neuronal Cell Fate Specification of Inner Ear Stem Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DEVELOPING NERVOUS-SYSTEM; NEURAL PROGENITOR CELLS; HAIR-CELLS; MAMMALIAN COCHLEA; SUBTYPE SPECIFICATION; LATERAL INHIBITION; ORGAN DEVELOPMENT; XENOPUS RETINA; NULL MICE; DIFFERENTIATION AB Multipotent progenitor cells in the otic placode give rise to the specialized cell types of the inner ear, including neurons, supporting cells, and hair cells. The mechanisms governing acquisition of specific fates by the cells that form the cochleovestibular organs remain poorly characterized. Here we show that whereas blocking Notch signaling with a gamma-secretase inhibitor increased the conversion of inner ear stem cells to hair cells by a mechanism that involved the upregulation of bHLH transcription factor, Math1 ( mouse Atoh1), differentiation to a neuronal lineage was increased by expression of the Notch intracellular domain. The shift to a neuronal lineage could be attributed in part to continued cell proliferation in cells that did not undergo sensory cell differentiation due to the high Notch signaling, but also involved upregulation of Ngn1. The Notch intracellular domain influenced Ngn1 indirectly by upregulation of Sox2, a transcription factor expressed in many neural progenitor cells, and directly by an interaction with an RBP-J binding site in the Ngn1 promoter/enhancer. The induction of Ngn1 was blocked partially by mutation of the RBP-J site and nearly completely when the mutation was combined with inhibition of Sox2 expression. Thus, Notch signaling had a significant role in the fate specification of neurons and hair cells from inner ear stem cells, and decisions about cell fate were mediated in part by a differential effect of combinatorial signaling by Notch and Sox2 on the expression of bHLH transcription factors. C1 [Jeon, Sang-Jun; Fujioka, Masato; Kim, Shi-Chan; Edge, Albert S. B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Jeon, Sang-Jun; Fujioka, Masato; Kim, Shi-Chan; 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 [RO1 DC007174, P30 DC05209]; Harvard Neurodiscovery Center FX This work was supported by grants from the National Institute on Deafness and Other Communicative Disorders (RO1 DC007174 and P30 DC05209) and from the Harvard Neurodiscovery Center. We thank Oksana Berezovska, John Kessler, Haeyoung Suh-Kim, and Federico Kalinec for cells and plasmids. NR 51 TC 43 Z9 47 U1 0 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 8 PY 2011 VL 31 IS 23 BP 8351 EP 8358 DI 10.1523/JNEUROSCI.6366-10.2011 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 774LJ UT WOS:000291387200004 PM 21653840 ER PT J AU Dutt, A Ramos, AH Hammerman, PS Mermel, C Cho, J Sharifnia, T Chande, A Tanaka, KE Stransky, N Greulich, H Gray, NS Meyerson, M AF Dutt, Amit Ramos, Alex H. Hammerman, Peter S. Mermel, Craig Cho, Jeonghee Sharifnia, Tanaz Chande, Ajit Tanaka, Kumiko Elisa Stransky, Nicolas Greulich, Heidi Gray, Nathanael S. Meyerson, Matthew TI Inhibitor-Sensitive FGFR1 Amplification in Human Non-Small Cell Lung Cancer SO PLOS ONE LA English DT Article ID GROWTH-FACTOR RECEPTOR-3; POLYMORPHISM ARRAY ANALYSIS; BREAST-CANCER; ACTIVATING MUTATIONS; THERAPEUTIC TARGET; KINASE INHIBITORS; MULTIPLE-MYELOMA; BLADDER-CANCER; OVARIAN-CANCER; RESISTANCE AB Background: Squamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma. Methodology/Principal Findings: Using SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes-WHSC1L1, LETM2, and FGFR1-is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas. Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition. Conclusions/Significance: These studies show that FGFR1 amplification is common in squamous cell lung cancer, and that FGFR1 may represent a promising therapeutic target in non-small cell lung cancer. C1 [Dutt, Amit; Ramos, Alex H.; Hammerman, Peter S.; Mermel, Craig; Cho, Jeonghee; Sharifnia, Tanaz; Tanaka, Kumiko Elisa; Greulich, Heidi; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dutt, Amit; Ramos, Alex H.; Mermel, Craig; Sharifnia, Tanaz; Tanaka, Kumiko Elisa; Stransky, Nicolas; Greulich, Heidi; Meyerson, Matthew] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Greulich, Heidi] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Greulich, Heidi] Harvard Univ, Sch Med, Boston, MA USA. [Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Ramos, Alex H.; Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Dutt, Amit] Tata Mem Hosp, Adv Ctr Treatment Res & Educ, Kharghar, Navi Mumbai, India. RP Dutt, A (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM adutt@actrec.gov.in; matthew_meyerson@dfci.harvard.edu RI Meyerson, Matthew/E-7123-2012; Dutt, Amit/I-1911-2013; Chande, Ajit/K-5031-2014 OI Dutt, Amit/0000-0002-1119-4774; Chande, Ajit/0000-0003-2210-5180 FU Novartis Pharmaceuticals; American Lung Association; Uniting Against Lung Cancer; Sarah Thomas Monopoli Fund; Seaman Foundation; Genentech; Department of Biotechnology, Ministry of Science, Government of India; National Lung Cancer Partnership; Novartis FX Funding sources for this work include support from Novartis Pharmaceuticals, the American Lung Association, Uniting Against Lung Cancer, the Sarah Thomas Monopoli Fund, the Seaman Foundation and Genentech to M. M. A. D. is supported by a Ramalingaswami fellowship from the Department of Biotechnology, Ministry of Science, Government of India. P. S. H. is supported by a Young Investigator Award from the National Lung Cancer Partnership. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; M. M. is a consultant to Novartis and receives research support from Novartis, receives research support from Genentech, and is a founding advisor and consultant, and an equity holder in Foundation Medicine. N.G. laboratory receives sponsored research from Novartis. However, this does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. NR 61 TC 189 Z9 198 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 7 PY 2011 VL 6 IS 6 AR e20351 DI 10.1371/journal.pone.0020351 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 777HR UT WOS:000291607000005 PM 21666749 ER PT J AU Malik, WQ Schummers, J Sur, M Brown, EN AF Malik, Wasim Q. Schummers, James Sur, Mriganka Brown, Emery N. TI Denoising Two-Photon Calcium Imaging Data SO PLOS ONE LA English DT Article ID VISUAL-CORTEX; IN-VIVO; NEURONAL-ACTIVITY; COLORED NOISE; FIRING RATE; RESPONSES; SIGNALS; MODEL; ORIENTATION; POTENTIALS AB Two-photon calcium imaging is now an important tool for in vivo imaging of biological systems. By enabling neuronal population imaging with subcellular resolution, this modality offers an approach for gaining a fundamental understanding of brain anatomy and physiology. Proper analysis of calcium imaging data requires denoising, that is separating the signal from complex physiological noise. To analyze two-photon brain imaging data, we present a signal plus colored noise model in which the signal is represented as harmonic regression and the correlated noise is represented as an order p autoregressive process. We provide an efficient cyclic descent algorithm to compute approximate maximum likelihood parameter estimates by combing a weighted least-squares procedure with the Burg algorithm. We use Akaike information criterion to guide selection of the harmonic regression and the autoregressive model orders. Our flexible yet parsimonious modeling approach reliably separates stimulus-evoked fluorescence response from background activity and noise, assesses goodness of fit, and estimates confidence intervals and signal-to-noise ratio. This refined separation leads to appreciably enhanced image contrast for individual cells including clear delineation of subcellular details and network activity. The application of our approach to in vivo imaging data recorded in the ferret primary visual cortex demonstrates that our method yields substantially denoised signal estimates. We also provide a general Volterra series framework for deriving this and other signal plus correlated noise models for imaging. This approach to analyzing two-photon calcium imaging data may be readily adapted to other computational biology problems which apply correlated noise models. C1 [Malik, Wasim Q.; Brown, Emery N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02115 USA. [Malik, Wasim Q.; Schummers, James; Sur, Mriganka; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Schummers, James; Sur, Mriganka] MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Malik, WQ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02115 USA. EM wqm@mit.edu FU U.S. National Institutes of Health [DP1 OD003646-01, R01 EB006385-01, EY07023, EY017098] FX This work was supported by U.S. National Institutes of Health DP1 OD003646-01, R01 EB006385-01, EY07023 and EY017098. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 9 Z9 9 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 JUN 7 PY 2011 VL 6 IS 6 AR e20490 DI 10.1371/journal.pone.0020490 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 777HR UT WOS:000291607000008 PM 21687727 ER PT J AU Anderson, KS Wong, J D'Souza, G Riemer, AB Lorch, J Haddad, R Pai, SI Longtine, J McClean, M LaBaer, J Kelsey, KT Posner, M AF Anderson, K. S. Wong, J. D'Souza, G. Riemer, A. B. Lorch, J. Haddad, R. Pai, S. I. Longtine, J. McClean, M. LaBaer, J. Kelsey, K. T. Posner, M. TI Serum antibodies to the HPV16 proteome as biomarkers for head and neck cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE autoantibodies; biomarker; Luminex; HPV; head and neck cancer ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS INFECTION; HUMORAL IMMUNE-RESPONSES; CERVICAL-CANCER; NEUTRALIZING EPITOPES; OROPHARYNGEAL CANCER; UNITED-STATES; ORAL-CANCER; SURVIVAL; TYPE-16 AB BACKGROUND: Human papillomavirus (HPV) type 16 is associated with oropharyngeal carcinomas (OPC). Antibodies (Abs) to HPV16 E6 and E7 oncoproteins have been detected in patient sera; however, Abs to other early HPV-derived proteins have not been well explored. METHODS: Antibodies to the HPV16 proteome were quantified using a novel multiplexed bead assay, using C-terminal GST-fusion proteins captured onto Luminex beads. Sera were obtained from untreated patients with OPC (N=40), partners of patients with HPV16 + OPC (N = 11), and healthy controls (N = 50). RESULTS: Oropharyngeal carcinomas patients with known virus-like capsid particle + Abs had elevated serum Abs to HPV16 E1, E2, E4, E6, and E7, and L1 antibody levels, but not E5. The ratios of specific median fluorescence intensity to p21-GST compared with controls were E1: 50.7 vs 2.1; E4: 14.6 vs 1.3; E6: 11.3 vs 2.4; E7: 43.1 vs 2.6; and L1: 10.3 vs 2.6 (each P <= 0.01). In a validation cohort, HPV16 E1, E2, and E7 antibody levels were significantly elevated compared with healthy control samples (P <= 0.02) and partners of OPC patients (P <= 0.01). CONCLUSION: Patients with HPV16 + OPC have detectable Abs to E1, E2, and E7 proteins, which are potential biomarkers for HPV-associated OPC. British Journal of Cancer (2011) 104, 1896-1905. doi:10.1038/bjc.2011.171 www.bjcancer.com (C) 2011 Cancer Research UK C1 [Anderson, K. S.; Wong, J.; Riemer, A. B.] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Anderson, K. S.; Lorch, J.; Haddad, R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [D'Souza, G.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Pai, S. I.] Johns Hopkins Med Inst, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. [Longtine, J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [McClean, M.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02118 USA. [LaBaer, J.] Arizona State Univ, Biodesign Inst, Ctr Personalized Diagnost, Tempe, AZ 85287 USA. [Kelsey, K. T.] Brown Univ, Bio Med Ctr Environm Hlth & Technol, Providence, RI 02912 USA. [Posner, M.] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. RP Anderson, KS (reprint author), Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. EM kanderson@partners.org RI Kelsey, Karl/I-1252-2014 FU Early Detection Research Network [5U01CA117374]; Friends of the Dana-Farber Head and Neck Cancer Research Fund [CA078609, CA100679] FX This study was supported by a research grant from the Early Detection Research Network 5U01CA117374 (KSA and JL), the Friends of the Dana-Farber Head and Neck Cancer Research Fund (KSA and MP), CA078609 (KTK) and CA100679 (KTK). We thank Dr Elizabeth Unger at the Centers for Disease Control for providing serum samples from patients with HPV16+ cervical infection. NR 57 TC 26 Z9 27 U1 2 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 7 PY 2011 VL 104 IS 12 BP 1896 EP 1905 DI 10.1038/bjc.2011.171 PG 10 WC Oncology SC Oncology GA 774KP UT WOS:000291384700015 PM 21654689 ER PT J AU Kinlay, S AF Kinlay, Scott TI Fire in the Hole Carotid Stenting Versus Endarterectomy SO CIRCULATION LA English DT Editorial Material DE carotid arteries; carotid artery stenting; carotid endarterectomy; carotid stenting ID HIGH-RISK PATIENTS; STROKE PREVENTION; RANDOMIZED-TRIAL; ARTERY STENOSIS; ANGIOPLASTY; METAANALYSIS; SURGERY C1 [Kinlay, Scott] Harvard Univ, Brigham & Womens Hosp, Sch Med, VA Boston Healthcare Syst, Boston, MA 02115 USA. RP Kinlay, S (reprint author), VA Boston Healthcare Syst, Cardiac Catheterizat Lab, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM scott.kinlay@va.gov NR 31 TC 7 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 7 PY 2011 VL 123 IS 22 BP 2522 EP 2525 DI 10.1161/CIRCULATIONAHA.111.034314 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 773KR UT WOS:000291306600013 PM 21606395 ER PT J AU deGoma, EM Wright, CD Pelikan, PC Leal, JE Karlsberg, RP AF deGoma, Emil M. Wright, Cameron D. Pelikan, Peter C. Leal, John E. Karlsberg, Ronald P. TI Surgically Corrected Right-Sided Aortic Arch SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material C1 [deGoma, Emil M.] Univ Penn, Dept Cardiovasc Med, Philadelphia, PA 19104 USA. [Wright, Cameron D.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Pelikan, Peter C.] Pacific Heart Inst, Santa Monica, CA USA. [Leal, John E.; Karlsberg, Ronald P.] Cardiovasc Res Fdn So Calif, Beverly Hills, CA USA. RP deGoma, EM (reprint author), Univ Penn, Dept Cardiovasc Med, Philadelphia, PA 19104 USA. NR 1 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 7 PY 2011 VL 57 IS 23 BP 2375 EP 2375 DI 10.1016/j.jacc.2010.07.070 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 771HG UT WOS:000291147200012 PM 21636040 ER PT J AU Sanchez-Aguilera, A Lee, YJ Lo Celso, C Ferraro, F Brumme, K Mondal, S Kim, C Dorrance, A Luo, HBR Scadden, DT Williams, DA AF Sanchez-Aguilera, Abel Lee, Yun-Jung Lo Celso, Cristina Ferraro, Francesca Brumme, Kristina Mondal, Subhanjan Kim, Chaekyun Dorrance, Adrienne Luo, Hongbo R. Scadden, David T. Williams, David A. TI Guanine nucleotide exchange factor Vav1 regulates perivascular homing and bone marrow retention of hematopoietic stem and progenitor cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NOD/SCID MICE; RHO-GTPASES; T-CELLS; B-CELLS; NICHE; CXCR4; ENGRAFTMENT; RECEPTORS; VLA-4; SDF-1 AB Engraftment and maintenance of hematopoietic stem and progenitor cells (HSPC) depend on their ability to respond to extracellular signals from the bone marrow microenvironment, but the critical intracellular pathways integrating these signals remain poorly understood. Furthermore, recent studies provide contradictory evidence of the roles of vascular versus osteoblastic niche components in HSPC function. To address these questions and to dissect the complex upstream regulation of Rac GTPase activity in HSPC, we investigated the role of the hematopoietic-specific guanine nucleotide exchange factor Vav1 in HSPC localization and engraftment. Using intravital microscopy assays, we demonstrated that transplanted Vav1(-/-) HSPC showed impaired early localization near nestin(+) perivascular mesenchymal stem cells; only 6.25% of Vav1(-/-) HSPC versus 45.8% of wild-type HSPC were located less than 30 mu m from a nestin(+) cell. Abnormal perivascular localization correlated with decreased retention of Vav1(-/-) HSPC in the bone marrow (44-60% reduction at 48 h posttransplant, compared with wild-type) and a very significant defect in short- and long-term engraftment in competitive and noncompetitive repopulation assays (<1.5% chimerism of Vav1(-/-) cells vs. 53-63% for wild-type cells). The engraftment defect of Vav1(-/-) HSPC was not related to alterations in proliferation, survival, or integrin-mediated adhesion. However, Vav1(-/-) HSPC showed impaired responses to SDF1 alpha, including reduced in vitro migration in time-lapse microscopy assays, decreased circadian and pharmacologically induced mobilization in vivo, and dysregulated Rac/Cdc42 activation. These data suggest that Vav1 activity is required specifically for SDF1 alpha-dependent perivascular homing of HSPC and suggest a critical role for this localization in retention and subsequent engraftment. C1 [Sanchez-Aguilera, Abel; Brumme, Kristina; Kim, Chaekyun; Dorrance, Adrienne; Williams, David A.] Childrens Hosp Boston, Div Hematol Oncol, Boston, MA 02115 USA. [Sanchez-Aguilera, Abel; Brumme, Kristina; Kim, Chaekyun; Dorrance, Adrienne; Williams, David A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lee, Yun-Jung] Univ Cincinnati, Dept Pathol & Lab med, Cincinnati, OH 45267 USA. [Lo Celso, Cristina; Ferraro, Francesca; Scadden, David T.; Williams, David A.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Lo Celso, Cristina; Ferraro, Francesca; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Mondal, Subhanjan; Luo, Hongbo R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Mondal, Subhanjan; Luo, Hongbo R.] Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. [Mondal, Subhanjan; Luo, Hongbo R.] Childrens Hosp Boston, Dept Lab Med, Boston, MA 02115 USA. [Kim, Chaekyun] Inha Univ, Sch Med, Inchon 400712, South Korea. [Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Williams, DA (reprint author), Childrens Hosp Boston, Div Hematol Oncol, Boston, MA 02115 USA. EM dawilliams@childrens.harvard.edu OI Lo Celso, Cristina/0000-0002-1163-4207 FU National Institutes of Health [DK62757, HL44851, HL097794, HL081030] FX We thank Stuart Orkin, Leonard Zon, Jose Cancelas, and members of our laboratories for discussing and critically reading the manuscript. Charles P. Lin and Joel Spencer assisted with intravital microscopy, Ronald Mathieu assisted with cell sorting, Chad Harris and Megan Bariteau provided technical support, and Elise Porter provided administrative assistance. This work was supported by National Institutes of Health Grants DK62757 (to D.A.W.) and HL44851, HL097794, and HL081030 (to D.T.S.). NR 39 TC 24 Z9 24 U1 0 U2 1 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 JUN 7 PY 2011 VL 108 IS 23 BP 9607 EP 9612 DI 10.1073/pnas.1102018108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773WE UT WOS:000291341400059 PM 21606370 ER PT J AU Keating, NL Landrum, MB Lamont, EB Bozeman, SR Krasnow, SH Shulman, LN Brown, JR Earle, CC Oh, WK Rabin, M McNeil, BJ AF Keating, Nancy L. Landrum, Mary Beth Lamont, Elizabeth B. Bozeman, Samuel R. Krasnow, Steven H. Shulman, Lawrence N. Brown, Jennifer R. Earle, Craig C. Oh, William K. Rabin, Michael McNeil, Barbara J. TI Quality of Care for Older Patients With Cancer in the Veterans Health Administration Versus the Private Sector A Cohort Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CELL LUNG-CANCER; III COLON-CANCER; PROSTATE-CANCER; ADJUVANT CHEMOTHERAPY; MYOCARDIAL-INFARCTION; PROPENSITY SCORE; ADVERSE EVENTS; SENSITIVITY; MEDICARE; SYSTEM AB Background: The Veterans Health Administration (VHA) is the largest integrated health care system in the United States. Studies suggest that the VHA provides better preventive care and care for some chronic illnesses than does the private sector. Objective: To assess the quality of cancer care for older patients provided by the VHA versus fee-for-service Medicare. Design: Observational study of patients with cancer that was diagnosed between 2001 and 2004 who were followed through 2005. Setting: VHA and non-VHA hospitals and office-based practices. Patients: Men older than 65 years with incident colorectal, lung, or prostate cancer; lymphoma; or multiple myeloma. Measurements: Rates of processes of care for colorectal, lung, or prostate cancer; lymphoma; or multiple myeloma. Rates were adjusted by using propensity score weighting. Results: Compared with the fee-for-service Medicare population, the VHA population received diagnoses of colon (P < 0.001) and rectal (P = 0.007) cancer at earlier stages and had higher adjusted rates of curative surgery for colon cancer (92.7% vs. 90.5%; P < 0.010), standard chemotherapy for diffuse large B-cell non-Hodgkin lymphoma (71.1% vs. 59.3%; P < 0.001), and bisphosphonate therapy for multiple myeloma (62.1% vs. 50.4%; P < 0.001). The VHA population had lower adjusted rates of 3-dimensional conformal or intensity-modulated radiation therapy for prostate cancer treated with external-beam radiation therapy (61.6% vs. 86.0%; P < 0.001). Adjusted rates were similar for 9 other measures. Sensitivity analyses suggest that if patients with cancer in the VHA system have more severe comorbid illness than other patients, rates for most indicators would be higher in the VHA population than in the fee-for-service Medicare population. Limitation: This study included only older men and did not include information about performance status, severity of comorbid illness, or patient preferences. Conclusion: Care for older men with cancer in the VHA system was generally similar to or better than care for fee-for-service Medicare beneficiaries, although adoption of some expensive new technologies may be delayed in the VHA system. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Massachusetts Gen Hosp,Ctr Canc, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Abt Associates Inc, Cambridge, MA USA. Vet Affairs Med Ctr, Washington, DC 20422 USA. Inst Clin Evaluat Sci, Toronto, ON, Canada. Mt Sinai Med Ctr, New York, NY 10029 USA. RP Keating, NL (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. EM keating@hcp.med.harvard.edu RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 FU Department of Veterans Affairs; Department of Veterans Affairs through the Office of Policy and Planning [101-35-04] FX Department of Veterans Affairs.r By contract 101-35-04 from the Department of Veterans Affairs through the Office of Policy and Planning. NR 40 TC 47 Z9 47 U1 0 U2 4 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 JUN 7 PY 2011 VL 154 IS 11 DI 10.7326/0003-4819-154-11-201106070-00004 PG 90 WC Medicine, General & Internal SC General & Internal Medicine GA 773MV UT WOS:000291312300003 PM 21646556 ER PT J AU Ryoo, JJ Malin, JL AF Ryoo, Joan J. Malin, Jennifer L. TI Reconsidering the Veterans Health Administration: A Model and a Moment for Publicly Funded Health Care Delivery SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID QUALITY-OF-CARE; MYOCARDIAL-INFARCTION; SYSTEM; PROSTATE; TRANSFORMATION; MORTALITY; TRIAL C1 [Malin, Jennifer L.] Vet Affairs Greater Los Angeles Healthcare Syst, W Angeles Med Ctr, Div Hematol Oncol, Dept Internal Med, Los Angeles, CA 90073 USA. [Ryoo, Joan J.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. RP Malin, JL (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, W Angeles Med Ctr, Div Hematol Oncol, Dept Internal Med, 11301 Wilshire Blvd,4th Floor, Los Angeles, CA 90073 USA. EM jennifer.malin@va.gov NR 19 TC 4 Z9 4 U1 1 U2 4 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 JUN 7 PY 2011 VL 154 IS 11 DI 10.7326/0003-4819-154-11-201106070-00010 PG 34 WC Medicine, General & Internal SC General & Internal Medicine GA 773MV UT WOS:000291312300009 PM 21646560 ER PT J AU Slatore, CG Gould, MK Au, DH Deffebach, ME White, E AF Slatore, Christopher G. Gould, Michael K. Au, David H. Deffebach, Mark E. White, Emily TI Lung cancer stage at diagnosis: Individual associations in the prospective VITamins and lifestyle (VITAL) cohort SO BMC CANCER LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; GUIDELINES 2ND EDITION; SURVIVAL; CT; OVERDIAGNOSIS; SURVEILLANCE; MANAGEMENT; EDUCATION; OUTCOMES; SOCIETY AB Background: Lung cancer is the leading cause of cancer death in the United States. Identifying factors associated with stage of diagnosis can improve our understanding of biologic and behavioral pathways of lung cancer development and detection. We used data from a prospective cohort study to evaluate associations of demographic, health history, and health behaviors with early versus late stage at diagnosis of non-small cell lung cancer (NSCLC). Methods: We calculated odds ratios (ORs) for the association of patient-level characteristics with advanced stage of diagnosis for NSCLC. The OR's were then adjusted for age, gender, race/ethnicity, smoking status, income, education, chronic obstructive pulmonary disease, and a comorbidity index. Results: We identified 612 cases of NSCLC among 77,719 adults, aged 50 to 76 years from Washington State recruited in 2000-2002, with followup through December 2007. In univariate analyses, subjects who quit smoking <10 years (OR 2.56, 95% CI 1.17 - 5.60) and were college graduates (OR 1.67, 95% CI, 1.00 - 2.76) had increased risks of being diagnosed with advanced stage NSCLC, compared to never smokers and non-college graduates, respectively. Receipt of sigmoidoscopy/colonoscopy, compared to no receipt, was associated with a decreased risk of advanced stage (OR 0.65, 95% CI, 0.43 - 0.99). The adjusted OR for receipt of sigmoidoscopy/colonoscopy was 0.55 (95% CI, 0.36 - 0.86). There was evidence that increasing the number of screening activities was associated with a decreased risk of advanced stage NSCLC (P for trend = 0.049). Conclusions: Smoking status, education, and a screening activity were associated with stage at diagnosis of NSCLC. These results may guide future studies of the underlying mechanisms that influence how NSCLC is detected and diagnosed. C1 [Slatore, Christopher G.; Deffebach, Mark E.] Portland VA Med Ctr, Portland, OR USA. [Slatore, Christopher G.; Deffebach, Mark E.] Oregon Hlth & Sci Univ, Div Pulm & Crit Care Med, Portland, OR 97201 USA. [Gould, Michael K.] Univ So Calif, Keck Sch Med, Div Pulm & Crit Care Med, Los Angeles, CA 90033 USA. [Au, David H.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Au, David H.] Univ Washington, Div Pulm & Crit Care, Seattle, WA 98195 USA. [White, Emily] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [White, Emily] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. RP Slatore, CG (reprint author), Portland VA Med Ctr, Portland, OR USA. EM christopher.slatore@va.gov OI Slatore, Christopher/0000-0003-0958-8122 FU CHEST Foundation of the American College of Chest Physicians; LUNGevity Foundation; National Institutes of Health [CA74846]; Department of Veterans Affairs; Portland VA Medical Center, Portland, OR; VA Puget Sound Health Care System, Seattle, Washington FX This work was completed with grant support from the CHEST Foundation of the American College of Chest Physicians and the LUNGevity Foundation to C. S. This work was also supported by the National Institutes of Health [CA74846 to EW]. Drs. Slatore, Au, and Deffebach were supported by the Department of Veterans Affairs. This study is the result of work supported by resources from the Portland VA Medical Center, Portland, OR, and VA Puget Sound Health Care System, Seattle, Washington. The study sponsors had no role in the conduct of the study, in the collection, management, analysis, or interpretation of data, or in the preparation, review, or approval of the manuscript. NR 31 TC 5 Z9 5 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUN 7 PY 2011 VL 11 AR 228 DI 10.1186/1471-2407-11-228 PG 7 WC Oncology SC Oncology GA 786VF UT WOS:000292335300001 PM 21649915 ER PT J AU Thomas, SY Scanlon, ST Griewank, KG Constantinides, MG Savage, AK Barr, KA Meng, FY Luster, AD Bendelac, A AF Thomas, Seddon Y. Scanlon, Seth T. Griewank, Klaus G. Constantinides, Michael G. Savage, Adam K. Barr, Kenneth A. Meng, Fanyong Luster, Andrew D. Bendelac, Albert TI PLZF induces an intravascular surveillance program mediated by long-lived LFA-1-ICAM-1 interactions SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NKT CELL LINEAGE; KILLER T-CELLS; BORRELIA-BURGDORFERI; INKT CELLS; MICE; ANTIGENS; CD1D; GLYCOSPHINGOLIPIDS; INFLAMMATION; RECOGNITION AB Innate-like NKT cells conspicuously accumulate within the liver microvasculature of healthy mice, crawling on the luminal side of endothelial cells, but their general recirculation pattern and the mechanism of their intravascular behavior have not been elucidated. Using parabiotic mice, we demonstrated that, despite their intravascular location, most liver NKT cells failed to recirculate. Antibody blocking experiments established that they were retained locally through constitutive LFA-1-intercellular adhesion molecule (ICAM) 1 interactions. This unprecedented lifelong intravascular residence could be induced in conventional CD4 T cells by the sole expression of promyelocytic leukemia zinc finger (PLZF), a transcription factor specifically expressed in the NKT lineage. These findings reveal the unique genetic and biochemical pathway that underlies the innate intravascular surveillance program of NKT cells. C1 [Thomas, Seddon Y.; Scanlon, Seth T.; Griewank, Klaus G.; Constantinides, Michael G.; Savage, Adam K.; Barr, Kenneth A.; Meng, Fanyong; Bendelac, Albert] Univ Chicago, Howard Hughes Med Inst, Comm Immunol, Chicago, IL 60637 USA. [Thomas, Seddon Y.; Scanlon, Seth T.; Griewank, Klaus G.; Constantinides, Michael G.; Savage, Adam K.; Barr, Kenneth A.; Meng, Fanyong; Bendelac, Albert] Univ Chicago, Howard Hughes Med Inst, Dept Pathol, Chicago, IL 60637 USA. [Luster, Andrew D.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Charlestown, MA 02129 USA. RP Bendelac, A (reprint author), Univ Chicago, Howard Hughes Med Inst, Comm Immunol, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM abendela@bsd.uchicago.edu RI Griewank, Klaus/A-9097-2017; OI Scanlon, Seth Thomas/0000-0002-1792-6382; Constantinides, Michael/0000-0003-4770-7751; Thomas, Seddon/0000-0003-0075-0744 FU National Institutes of Health [AI038339, AI053725, CA69212]; Sandler Program for Asthma Research FX This work was supported by National Institutes of Health grants AI038339 and AI053725 (A. Bendelac), CA69212 (A.D. Luster), and the Sandler Program for Asthma Research (A. Bendelac). A. Bendelac is a Howard Hughes Medical Institute Investigator. NR 48 TC 64 Z9 64 U1 2 U2 5 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 JUN 6 PY 2011 VL 208 IS 6 BP 1179 EP 1188 DI 10.1084/jem.20102630 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 774ZB UT WOS:000291424200006 PM 21624939 ER PT J AU Chakraborty, R Vepuri, V Mhatre, SD Paddock, BE Miller, S Michelson, SJ Delvadia, R Desai, A Vinokur, M Melicharek, DJ Utreja, S Khandelwal, P Ansaloni, S Goldstein, LE Moir, RD Lee, JC Tabb, LP Saunders, AJ Marenda, DR AF Chakraborty, Ranjita Vepuri, Vidya Mhatre, Siddhita D. Paddock, Brie E. Miller, Sean Michelson, Sarah J. Delvadia, Radha Desai, Arkit Vinokur, Marianna Melicharek, David J. Utreja, Suruchi Khandelwal, Preeti Ansaloni, Sara Goldstein, Lee E. Moir, Robert D. Lee, Jeremy C. Tabb, Loni P. Saunders, Aleister J. Marenda, Daniel R. TI Characterization of a Drosophila Alzheimer's Disease Model: Pharmacological Rescue of Cognitive Defects SO PLOS ONE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; SHORT-TERM-MEMORY; TRANSGENIC DROSOPHILA; PRESENILIN HOMOLOG; DIMETHYL-SULFOXIDE; COURTSHIP BEHAVIOR; OXIDATIVE STRESS; MUSHROOM BODIES; NERVOUS-SYSTEM; CALCIUM STORES AB Transgenic models of Alzheimer's disease (AD) have made significant contributions to our understanding of AD pathogenesis, and are useful tools in the development of potential therapeutics. The fruit fly, Drosophila melanogaster, provides a genetically tractable, powerful system to study the biochemical, genetic, environmental, and behavioral aspects of complex human diseases, including AD. In an effort to model AD, we over-expressed human APP and BACE genes in the Drosophila central nervous system. Biochemical, neuroanatomical, and behavioral analyses indicate that these flies exhibit aspects of clinical AD neuropathology and symptomology. These include the generation of A beta(40) and A beta(42), the presence of amyloid aggregates, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. In addition, these flies exhibit external morphological abnormalities. Treatment with a gamma-secretase inhibitor suppressed these phenotypes. Further, all of these phenotypes are present within the first few days of adult fly life. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification of AD therapeutic interventions. C1 [Chakraborty, Ranjita; Vepuri, Vidya; Mhatre, Siddhita D.; Paddock, Brie E.; Miller, Sean; Michelson, Sarah J.; Delvadia, Radha; Desai, Arkit; Vinokur, Marianna; Melicharek, David J.; Utreja, Suruchi; Khandelwal, Preeti; Ansaloni, Sara; Saunders, Aleister J.; Marenda, Daniel R.] Drexel Univ, Dept Biol, Philadelphia, PA 19104 USA. [Vepuri, Vidya] Univ Sci Philadelphia, Dept Biol Sci, Philadelphia, PA USA. [Goldstein, Lee E.] Boston Univ, Dept Psychiat, Boston, MA 02215 USA. [Moir, Robert D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Genet & Aging Res Unit,MIND, Boston, MA USA. [Lee, Jeremy C.] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA. [Tabb, Loni P.] Drexel Univ, Dept Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Saunders, Aleister J.] Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Philadelphia, PA 19104 USA. [Saunders, Aleister J.; Marenda, Daniel R.] Drexel Univ, Coll Med, Dept Neurobiol & Anat, Philadelphia, PA 19104 USA. RP Chakraborty, R (reprint author), Drexel Univ, Dept Biol, Philadelphia, PA 19104 USA. EM Aleister.Saunders@drexel.edu; dm562@drexel.edu OI Goldstein, Lee/0000-0001-8419-9800 FU Drexel University; Cure Alzheimer's Fund Investigator Award; National Institutes of Health (NIH) [1R01AI081990-01A1, R21RR026074, R01NS057295] FX This work is supported by grants from Drexel University's Human Cognition Enhancement Program (to DRM), Cure Alzheimer's Fund Investigator Award and National Institutes of Health (NIH) grant 1R01AI081990-01A1 (to RDM), NIH R21RR026074 (to DRM), and NIH R01NS057295 (to AJS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 21 Z9 24 U1 1 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 6 PY 2011 VL 6 IS 6 AR e20799 DI 10.1371/journal.pone.0020799 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 774BN UT WOS:000291356400030 PM 21673973 ER PT J AU Gebregziabher, M Lynch, CP Mueller, M Gilbert, GE Echols, C Zhao, YM Egede, LE AF Gebregziabher, Mulugeta Lynch, Cheryl P. Mueller, Martina Gilbert, Gregory E. Echols, Carrae Zhao, Yumin Egede, Leonard E. TI Using quantile regression to investigate racial disparities in medication non-adherence SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE Medication adherence; Quantile regression; Diabetes; Health disparities ID RETROSPECTIVE COHORT; DENSITY REGRESSION; DIABETES-MELLITUS; CLAIMS DATA; ADHERENCE; HOSPITALIZATION; PREVALENCE; PREDICTORS; ALGORITHM; DATABASES AB Background: Many studies have investigated racial/ethnic disparities in medication non-adherence in patients with type 2 diabetes using common measures such as medication possession ratio (MPR) or gaps between refills. All these measures including MPR are quasi-continuous and bounded and their distribution is usually skewed. Analysis of such measures using traditional regression methods that model mean changes in the dependent variable may fail to provide a full picture about differential patterns in non-adherence between groups. Methods: A retrospective cohort of 11,272 veterans with type 2 diabetes was assembled from Veterans Administration datasets from April 1996 to May 2006. The main outcome measure was MPR with quantile cutoffs Q1-Q4 taking values of 0.4, 0.6, 0.8 and 0.9. Quantile-regression (QReg) was used to model the association between MPR and race/ethnicity after adjusting for covariates. Comparison was made with commonly used ordinary-least-squares (OLS) and generalized linear mixed models (GLMM). Results: Quantile-regression showed that Non-Hispanic-Black (NHB) had statistically significantly lower MPR compared to Non-Hispanic-White (NHW) holding all other variables constant across all quantiles with estimates and p-values given as -3.4% (p = 0.11), -5.4% (p = 0.01), -3.1% (p = 0.001), and -2.00% (p = 0.001) for Q1 to Q4, respectively. Other racial/ethnic groups had lower adherence than NHW only in the lowest quantile (Q1) of about -6.3% (p = 0.003). In contrast, OLS and GLMM only showed differences in mean MPR between NHB and NHW while the mean MPR difference between other racial groups and NHW was not significant. Conclusion: Quantile regression is recommended for analysis of data that are heterogeneous such that the tails and the central location of the conditional distributions vary differently with the covariates. QReg provides a comprehensive view of the relationships between independent and dependent variables (i.e. not just centrally but also in the tails of the conditional distribution of the dependent variable). Indeed, without performing QReg at different quantiles, an investigator would have no way of assessing whether a difference in these relationships might exist. C1 [Lynch, Cheryl P.; Gilbert, Gregory E.; Echols, Carrae; Egede, Leonard E.] Ralph H Johnson Vet Affairs Med Ctr, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston, SC USA. [Gebregziabher, Mulugeta; Lynch, Cheryl P.; Zhao, Yumin; Egede, Leonard E.] Med Univ S Carolina, Ctr Hlth Dispar Res, Dept Med, Charleston, SC USA. [Gebregziabher, Mulugeta; Mueller, Martina] Med Univ S Carolina, Div Biostat & Epidemiol, Charleston, SC USA. [Mueller, Martina] Med Univ S Carolina, Coll Nursing, Charleston, SC USA. RP Egede, LE (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston, SC USA. EM egedel@musc.edu RI Gilbert, Gregory/C-7735-2016; OI Gilbert, Gregory/0000-0003-0879-5496; Gebregziabher, Mulugeta/0000-0002-4826-481X FU Veterans Affairs Health Services Research and Development [REA 08-261] FX This study was supported by Grant # REA 08-261, Center for Disease Prevention and Health Interventions for Diverse Populations funded by Veterans Affairs Health Services Research and Development (PI - Leonard Egede). NR 40 TC 15 Z9 15 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD JUN 6 PY 2011 VL 11 AR 88 DI 10.1186/1471-2288-11-88 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 781QT UT WOS:000291949300002 PM 21645379 ER PT J AU Kashiwagi, A Fein, MJ Shimada, M AF Kashiwagi, Aki Fein, Mikaela J. Shimada, Masako TI A high fat diet-induced impaired glucose metabolism in mice with targeted deletion of calpain in osteoblasts SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Osteoporosis; Bone resorption; High fat diet; Glucose metabolism ID BONE-MINERAL DENSITY; INVOLUTIONAL OSTEOPOROSIS; POSTMENOPAUSAL WOMEN; ENERGY-METABOLISM; SMALL-SUBUNIT; CELL; OSTEOCALCIN; CAPN4; GENE; MASS AB The ubiquitously expressed Calpains 1 and 2 belong to a family of calcium-dependent intracellular cysteine proteases. Both calpains are heterodimers consisting of a large subunit and a small regulatory subunit encoded by the gene Capns1. To investigate a role for the calpain small subunit in cells of the osteoblast lineage in vivo, we previously generated osteoblast-specific Capns1 knockout mice and characterized their bone phenotype. In this study, we further examined effects of low calcium and high fat diets on their bone, fat, and glucose homeostasis. Osteoblast-specific Capns1 knockout mice showed significantly reduced serum levels of total and uncarboxylated osteocalcin, and this was presumably due to their impaired bone formation and bone resorption. The reduced bone resorptive function of the mutant mice was also significant under a low calcium diet. Thus, these results suggest that reduced uncarboxylated osteocalcin levels of mutant mice were, at least in part, due to their osteoporotic bone with impaired bone resorptive function. Interestingly, unlike osteocalcin knockout mice, mutant mice on a normal chow diet were leaner than control littermates: this was likely due to their reduced food intake and overall lower energy homeostasis. To test this hypothesis, we next provided mutant mice with a high fat diet and further examined an effect of their reduced uncarboxylated osteocalcin levels on body composition and glucose metabolism. The average mean body weight of mutant mice became indistinguishable with that of controls after 2 weeks on a high fat diet, and continued to show an upward trend, at least, up to 6 weeks. Moreover, mutant mice on a high fat diet exhibited a significant increase in serum levels of leptin and resistin, adipocyte-specific adipokines, and developed impaired glucose tolerance. Collectively, mice with osteoporosis and reduced bone resorptive function showed reduced serum uncarboxylated osteocalcin levels and were susceptible to increase body adiposity and develop impaired glucose tolerance under a high fat diet. (C) 2011 Elsevier Inc. All rights reserved. C1 [Shimada, Masako] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Dept Med, Sch Med, Boston, MA 02114 USA. RP Shimada, M (reprint author), Thier 10,50 Blossom St, Boston, MA 02114 USA. EM shimada@helix.mgh.harvard.edu FU National Institutes of Health [R01 DK072102]; BADERC [NIH P30 DK057521]; MGH FX We are grateful to Dr. Mary L. Bouxsein and Leeann Louis for mu CT analysis. We also thank Yuko Sumiyama and Kimberly Atkin for technical supports. This work was partially supported by National Institutes of Health Grants R01 DK072102, BADERC Pilot and Feasibility Grant Award (a part of NIH P30 DK057521), and MGH interim support fund (to M.S.). NR 22 TC 3 Z9 3 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 3 PY 2011 VL 409 IS 2 BP 235 EP 240 DI 10.1016/j.bbrc.2011.04.134 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 779LM UT WOS:000291779100015 PM 21569760 ER PT J AU Han, T Sui, JH Bennett, AS Liddington, RC Donis, RO Zhu, Q Marasco, WA AF Han, Thomas Sui, Jianhua Bennett, Andrew S. Liddington, Robert C. Donis, Ruben O. Zhu, Quan Marasco, Wayne A. TI Fine epitope mapping of monoclonal antibodies against hemagglutinin of a highly pathogenic H5N1 influenza virus using yeast surface display SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Yeast surface display; Fine epitope mapping; Influenza; H5N1 ID VACCINES AB Highly pathogenic H5N1 avian influenza viruses pose a debilitating pandemic threat. Thus, understanding mechanisms of antibody-mediated viral inhibition and neutralization escape is critical. Here, a robust yeast display system for fine epitope mapping of viral surface hemagglutinin (HA)-specific antibodies is demonstrated. The full-length H5 subtype HA (HA0) was expressed on the yeast surface in a correctly folded conformation, determined by binding of a panel of extensively characterized neutralizing human monoclonal antibodies (mAbs). These mAbs target conformationally-dependent epitopes of influenza A HA, which are highly conserved across H5 clades and group 1 serotypes. By separately displaying HA1 and HA2 subunits on yeast, domain mapping of two anti-H5 mAbs, NR2728 and H5-2A, localized their epitopes to HA1. These anti-H5 mAb epitopes were further fine mapped by using a library of yeast-displayed HA1 mutants and selecting for loss of binding without prior knowledge of potential contact residues. By overlaying key mutant residues that impacted binding onto a crystal structure of HA, the NR2728 mAb was found to interact with a fully surface-exposed contiguous patch of residues at the receptor binding site (RBS), giving insight into the mechanism underlying its potent inhibition of virus binding. The non-neutralizing H5-2A mAb was similarly mapped to a highly conserved H5 strain-specific but poorly accessible location on a loop at the trimer HA interface. These data further augment our tool-chest for studying HA antigenicity, epitope diversity and accessibility in response to natural and experimental influenza infection and vaccines. (C) 2011 Elsevier Inc. All rights reserved. C1 [Han, Thomas; Sui, Jianhua; Bennett, Andrew S.; Zhu, Quan; Marasco, Wayne A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Liddington, Robert C.] Burnham Inst Med Res, Infect & Inflammatory Dis Ctr, La Jolla, CA 92037 USA. [Donis, Ruben O.] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. RP Marasco, WA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 450 Brookline Ave, Boston, MA 02215 USA. EM wayne_marasco@dfci.harvard.edu OI SUI, JIANHUA/0000-0002-1272-9662 FU National Institutes of Health [U01-AI074518-01, 1K01AI073861] FX This work was supported by Grants from the National Institutes of Health: U01-AI074518-01 to W.A.M. and 1K01AI073861 to T.H. The findings and conclusions in this report are those of the authors and do not necessarily reflect the views of the funding agency. NR 12 TC 21 Z9 21 U1 0 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 3 PY 2011 VL 409 IS 2 BP 253 EP 259 DI 10.1016/j.bbrc.2011.04.139 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 779LM UT WOS:000291779100018 PM 21569761 ER PT J AU Sawers, A Hahn, ME AF Sawers, Andrew Hahn, Michael E. TI Trajectory of the center of rotation in non-articulated energy storage and return prosthetic feet SO JOURNAL OF BIOMECHANICS LA English DT Article DE Prosthetic feet; Helical axis; Link-segment model; Amputee; Artificial limb ID HUMAN JOINT KINEMATICS; HELICAL AXIS; CENTER LOCATION; AMPUTEE GAIT; KNEE; MOTION; PARAMETERS; AMPUTATION; MARKERS; MOMENT AB Non-articulated energy storage and return prosthetic feet lack any true articulation or obvious point of rotation. This makes it difficult to select a joint center about which to estimate their kinetics. Despite this absence of any clear point of rotation, methods for estimating the kinetic performance of this class of prosthetic feet typically assume that they possess a fixed center of rotation and that its location is well approximated by the position of the contralateral lateral malleolus. To evaluate the validity of this assumption we used a finite helical axis approach to determine the position of the center of rotation in the sagittal plane for a series of non-articulated energy storage and return prosthetic feet. We found that over the course of stance phase, the sagittal finite helical axis position diverged markedly from the typically assumed fixed axis location. These results suggest that researchers may need to review center of rotation assumptions when assessing prosthetic foot kinetics, while clinicians may need to reconsider the criteria by which they prescribe these prosthetic feet. Published by Elsevier Ltd. C1 [Sawers, Andrew; Hahn, Michael E.] VA Puget Sound, Rehabil Res & Dev Ctr Excellence Limb Loss Preven, Dept Vet Affairs VA, Seattle, WA 98108 USA. [Sawers, Andrew] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Hahn, Michael E.] Univ Washington, Dept Mech Engn, Seattle, WA 98105 USA. RP Hahn, ME (reprint author), VA Puget Sound, Rehabil Res & Dev Ctr Excellence Limb Loss Preven, Dept Vet Affairs VA, 1660 S Columbian Way, Seattle, WA 98108 USA. EM mehahn@uw.edu FU American Society of Biomechanics; Orthotic and Prosthetic Education and Research Foundation [OPERF-2009-FA-1]; Center for Orthotics and Prosthetics Learning and Outcomes/Evidence-Based Practice (COPL); Department of Veterans Affairs, Rehabilitation Research and Development Service [A4883C] FX This research was supported in part by a Graduate Student Grant-in-Aid from the American Society of Biomechanics, a Graduate Fellow Research Award from the Orthotic and Prosthetic Education and Research Foundation (OPERF-2009-FA-1), a Research Award from the Center for Orthotics and Prosthetics Learning and Outcomes/Evidence-Based Practice (COPL) and a Center of Excellence grant (A4883C), Department of Veterans Affairs, Rehabilitation Research and Development Service. NR 28 TC 7 Z9 7 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD JUN 3 PY 2011 VL 44 IS 9 BP 1673 EP 1677 DI 10.1016/j.jbiomech.2011.03.028 PG 5 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 780HY UT WOS:000291846300006 PM 21481878 ER PT J AU Kendall, RT Strungs, EG Rachidi, SM Lee, MH El-Shewy, HM Luttrell, DK Janech, MG Luttrell, LM AF Kendall, Ryan T. Strungs, Erik G. Rachidi, Saleh M. Lee, Mi-Hye El-Shewy, Hesham M. Luttrell, Deirdre K. Janech, Michael G. Luttrell, Louis M. TI The beta-Arrestin Pathway-selective Type 1A Angiotensin Receptor (AT(1A)) Agonist [Sar(1), Ile(4), Ile(8)] Angiotensin II Regulates a Robust G Protein-independent Signaling Network SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SMOOTH-MUSCLE-CELLS; ACTIVATION; PHOSPHORYLATION; KINASE; SET; CYCLOOXYGENASE-1; BETA-ARRESTIN-2; STIMULATION; COMPLEXES; SYNTHASE AB The angiotensin II peptide analog [Sar(1), Ile(4), Ile(8)] AngII (SII) is a biased AT(1A) receptor agonist that stimulates receptor phosphorylation, beta-arrestin recruitment, receptor internalization, and beta-arrestin-dependent ERK1/2 activation without activating heterotrimeric G-proteins. To determine the scope of G-protein- independent AT(1A) receptor signaling, we performed a gelbased phosphoproteomic analysis of AngII and SII-induced signaling in HEK cells stably expressing AT(1A) receptors. A total of 34 differentially phosphorylated proteins were detected, of which 16 were unique to SII and eight to AngII stimulation. MALDI-TOF/TOF mass fingerprinting was employed to identify 24 SII-sensitive phosphoprotein spots, of which three (two peptide inhibitors of protein phosphatase 2A (I1PP2A and I2PP2A) and prostaglandin E synthase 3 (PGES3)) were selected for validation and further study. We found that phosphorylation of I2PP2A was associated with rapid and transient inhibition of a beta-arrestin 2-associated pool of protein phosphatase 2A, leading to activation of Akt and increased phosphorylation of glycogen synthase kinase 3 beta in an arrestin signalsome complex. SII-stimulated PGES3 phosphorylation coincided with an increase in beta-arrestin 1-associated PGES3 and an arrestin-dependent increase in cyclooxygenase 1-dependent prostaglandin E-2 synthesis. These findings suggest that AT(1A) receptors regulate a robust G protein-independent signaling network that affects protein phosphorylation and autocrine/paracrine prostaglandin production and that these pathways can be selectively modulated by biased ligands that antagonize G protein activation. C1 [Kendall, Ryan T.; Strungs, Erik G.; Rachidi, Saleh M.; Lee, Mi-Hye; El-Shewy, Hesham M.; Luttrell, Louis M.] Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. [Luttrell, Deirdre K.; Janech, Michael G.] Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. [Janech, Michael G.; Luttrell, Louis M.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Luttrell, LM (reprint author), Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, 96 Jonathan Lucas St,MSC 624, Charleston, SC 29425 USA. EM luttrell@musc.edu OI Janech, Michael/0000-0002-3202-4811 FU National Institutes of Health [R01 DK055524, T32 HL07260]; Research Service of the Ralph H. Johnson Veterans Affairs Medical Center; Nephcure Young Investigator Award; Cancer Center [P30 CA138313]; Department of Veterans Affairs FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 DK055524 (to L. M. L.) and T32 HL07260 (to R. T. K.). This work was also supported by the Research Service of the Ralph H. Johnson Veterans Affairs Medical Center (to L. M. L. and M. G. J.) and the Nephcure Young Investigator and Department of Veterans Affairs Career Development Awards (to M. G. J.). Imaging facilities for this research were supported, in part, by Cancer Center Support Grant P30 CA138313 (to the Hollings Cancer Center, Medical University of South Carolina). NR 33 TC 31 Z9 32 U1 1 U2 6 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 JUN 3 PY 2011 VL 286 IS 22 BP 19880 EP 19891 DI 10.1074/jbc.M111.233080 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 769OZ UT WOS:000291027700068 PM 21502318 ER PT J AU Salas, A Ponnusamy, S Senkal, CE Meyers-Needham, M Selvam, SP Saddoughi, SA Apohan, E Sentelle, RD Smith, C Gault, CR Obeid, LM El-Shewy, HM Oaks, J Santhanam, R Marcucci, G Baran, Y Mahajan, S Fernandes, D Stuart, R Perrotti, D Ogretmen, B AF Salas, Arelis Ponnusamy, Suriyan Senkal, Can E. Meyers-Needham, Marisa Selvam, Shanmugam Panneer Saddoughi, Sahar A. Apohan, Elif Sentelle, R. David Smith, Charles Gault, Christopher R. Obeid, Lina M. El-Shewy, Hesham M. Oaks, Joshua Santhanam, Ramasamy Marcucci, Guido Baran, Yusuf Mahajan, Sandeep Fernandes, Daniel Stuart, Robert Perrotti, Danilo Ogretmen, Besim TI Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A SO BLOOD LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; IMATINIB-INDUCED APOPTOSIS; ABL TYROSINE KINASE; BCR-ABL; INHIBITOR STI571; CANCER-CELLS; GENE; SPHINGOSINE-1-PHOSPHATE; MECHANISMS AB The mechanisms by which sphingosine kinase-1 (SK-1)/sphingosine 1-phosphate (S1P) activation contributes to imatinib resistance in chronic myeloid leukemia (CML) are unknown. We show herein that increased SK-1/S1P enhances Bcr-Abl1 protein stability, through inhibition of its proteasomal degradation in imatinibresistant K562/IMA-3 and LAMA-4/IMA human CML cells. In fact, Bcr-Abl1 stability was enhanced by ectopic SK-1 expression. Conversely, siRNA-mediated SK-1 knockdown in K562/IMA-3 cells, or its genetic loss in SK-1(-/-) MEFs, significantly reduced Bcr-Abl1 stability. Regulation of Bcr-Abl1 by SK-1/S1P was dependent on S1P receptor 2 (S1P2) signaling, which prevented Bcr-Abl1 dephosphorylation, and degradation via inhibition of PP2A. Molecular or pharmacologic interference with SK-1/S1P2 restored PP2A-dependent Bcr-Abl1 dephosphorylation, and enhanced imatinib-or nilotinib-induced growth inhibition in primary CD34(+) mononuclear cells obtained from chronic phase and blast crisis CML patients, K562/IMA-3 or LAMA4/IMA cells, and 32Dcl3 murine progenitor cells, ex-pressing the wild-type or mutant (Y253H or T315I) Bcr-Abl1 in situ. Accordingly, impaired SK-1/S1P2 signaling enhanced the growth-inhibitory effects of nilotinib against 32D/T315I-Bcr-Abl1-derived mouse allografts. Since SK-1/S1P/S1P2 signaling regulates Bcr-Abl1 stability via modulation of PP2A, inhibition of SK-1/S1P2 axis represents a novel approach to target wild-type-ormutant-Bcr-Abl1 thereby overcoming drug resistance. (Blood. 2011; 117(22): 5941-5952) C1 [Salas, Arelis; Ponnusamy, Suriyan; Senkal, Can E.; Meyers-Needham, Marisa; Selvam, Shanmugam Panneer; Saddoughi, Sahar A.; Apohan, Elif; Sentelle, R. David; Gault, Christopher R.; Baran, Yusuf; Mahajan, Sandeep; Fernandes, Daniel; Ogretmen, Besim] Ralph H Johnson Vet Adm Hosp, Dept Biochem & Mol Biol, Charleston, SC USA. [Salas, Arelis; Ponnusamy, Suriyan; Senkal, Can E.; Meyers-Needham, Marisa; Selvam, Shanmugam Panneer; Saddoughi, Sahar A.; Apohan, Elif; Sentelle, R. David; Smith, Charles; Gault, Christopher R.; Obeid, Lina M.; Baran, Yusuf; Mahajan, Sandeep; Fernandes, Daniel; Stuart, Robert; Ogretmen, Besim] Ralph H Johnson Vet Adm Hosp, Hollings Canc Ctr, Charleston, SC USA. [Smith, Charles] Ralph H Johnson Vet Adm Hosp, Dept Pharmaceut Sci, Charleston, SC USA. [Obeid, Lina M.] Ralph H Johnson Vet Adm Hosp, Div Internal Med, Charleston, SC USA. [El-Shewy, Hesham M.; Perrotti, Danilo] Med Univ S Carolina, Div Endocrinol Diabet & Med Genet, Dept Med, Charleston, SC 29425 USA. [Oaks, Joshua; Santhanam, Ramasamy; Marcucci, Guido] Ohio State Univ, Human Canc Genet Program, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. RP Ogretmen, B (reprint author), 86 Jonathan Lucas St,Rm HO512A-B, Charleston, SC 29425 USA. EM ogretmen@musc.edu RI Perrotti, Danilo/E-3852-2011; OI Stuart, Robert/0000-0001-7549-8008; obeid, lina/0000-0002-0734-0847 FU National Institutes of Health (NIH) [CA088932, DE016572, CA097132, CA095512]; US Army [W81XWH-07-1-0270]; NIH, National Center for Research Resources [C06 RR015455] FX This work was supported by research grants from the National Institutes of Health (NIH; CA088932, DE016572, and CA097132 to B.O., and CA095512 to D.P.) and the US Army (CML Research Program, W81XWH-07-1-0270 to D. P.). D.P. is a Scholar of The Leukemia & Lymphoma Society. A.S. was supported by the Minority Fellowship grant from the NIH. Lipid measurements and animal studies were conducted in facilities constructed with support from the NIH (C06 RR015455), at the Extramural Research Facilities Program of the National Center for Research Resources. NR 50 TC 49 Z9 50 U1 1 U2 17 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 JUN 2 PY 2011 VL 117 IS 22 BP 5941 EP 5952 DI 10.1182/blood-2010-08-300772 PG 12 WC Hematology SC Hematology GA 772BA UT WOS:000291203200022 PM 21527515 ER PT J AU Smith, NL Rice, KM Bovill, EG Cushman, M Bis, JC McKnight, B Lumley, T Glazer, NL Vlieg, AV Tang, WH Dehghan, A Strachan, DP O'Donnell, CJ Rotter, JI Heckbert, SR Psaty, BM Rosendaal, FR AF Smith, Nicholas L. Rice, Kenneth M. Bovill, Edwin G. Cushman, Mary Bis, Joshua C. McKnight, Barbara Lumley, Thomas Glazer, Nicole L. Vlieg, Astrid van Hylckama Tang, Weihong Dehghan, Abbas Strachan, David P. O'Donnell, Christopher J. Rotter, Jerome I. Heckbert, Susan R. Psaty, Bruce M. Rosendaal, Frits R. TI Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis SO BLOOD LA English DT Article ID GENOME-WIDE ASSOCIATION; DEEP-VEIN THROMBOSIS; POSTMENOPAUSAL WOMEN; AGING RESEARCH; FACTOR-VIII; DISEASE; DESIGN; HEART; OBJECTIVES; CONSORTIUM AB In a recent genome-wide association study, variants in 8 genes were associated with VWF level, a risk factor for venous thrombosis (VT). In an independent, population-based, case-control study of incident VT, we tested hypotheses that variants in these genes would be associated with risk. Cases were 656 women who experienced an incident VT, and controls comprised 710 women without a history of VT. DNA was obtained from whole blood. Logistic regression was used to test associations between incident VT and single nucleotide polymorphisms (SNPs) in 7 genes not previously shown to be associated with VT. Associations with P<.05 were candidates for replication in an independent case-control study of VT in both sexes. Two of the 7 SNPs tested yielded P<.05: rs1039084 (P=.005) in STXBP5, a novel candidate gene for VT, and rs1063856 (P=.04) in VWF, a gene whose protein level is associated with VT risk. Association results for the remaining 5 variants in SCARA5, STAB2, STX2, TC2N, and CLEC4M were not significant. Both STXBP5 and VWF findings were replicated successfully. Variation in genes associated with VWF levels in the genome-wide association study was found to be independently associated with incident VT. (Blood. 2011; 117(22): 6007-6011) C1 [Smith, Nicholas L.; Heckbert, Susan R.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Dept Vet Affairs, Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Smith, Nicholas L.; Heckbert, Susan R.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Rice, Kenneth M.; McKnight, Barbara; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Bovill, Edwin G.; Cushman, Mary] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT 05405 USA. [Bis, Joshua C.; Glazer, Nicole L.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Vlieg, Astrid van Hylckama; Rosendaal, Frits R.] Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands. [Tang, Weihong] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Dehghan, Abbas] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Strachan, David P.] St Georges Univ London, Div Populat Hlth Sci & Educ, London, England. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Rosendaal, Frits R.] Leiden Univ, Med Ctr, Dept Thrombosis & Haemostasis, Leiden, Netherlands. RP Smith, NL (reprint author), Cardiovasc Hlth Res Unit, 1730 Minor Ave,Ste 1360, Seattle, WA 98101 USA. EM nlsmith@u.washington.edu RI Rice, Kenneth/A-4150-2013; van Hylckama Vlieg, Astrid/A-3323-2017; OI Rice, Kenneth/0000-0001-5779-4495; Dehghan, Abbas/0000-0001-6403-016X FU National Heart, Lung, and Blood Institute (National Institutes of Health, Bethesda, MD) [HL43201, HL60739, HL68986, HL73410, HL74745, HL85251, HL95080]; Leducq Foundation (Paris, France); Netherlands Heart Foundation [NHS 98.113]; Dutch Cancer Foundation [RUL 99/1992]; Netherlands Organization for Scientific Research [912-03-033/2003]; National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Leducq Foundation FX The Heart and Vascular Health Study is supported by National Heart, Lung, and Blood Institute (National Institutes of Health, Bethesda, MD) grants HL43201, HL60739, HL68986, HL73410, HL74745, HL85251, and HL95080, and by a grant from the Leducq Foundation (Paris, France) for the development of Transatlantic Networks of Excellence in Cardiovascular Research. The Multiple Environmental and Genetic Assessment (MEGA) study is funded by the Netherlands Heart Foundation (NHS 98.113), the Dutch Cancer Foundation (RUL 99/1992), and the Netherlands Organization for Scientific Research (912-03-033/2003). DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. A. v. H. V. is a recipient of a Leducq Transatlantic Fellowship from the Leducq Foundation. The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. N.L.S. 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. NR 25 TC 40 Z9 41 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 JUN 2 PY 2011 VL 117 IS 22 BP 6007 EP 6011 DI 10.1182/blood-2010-10-315473 PG 5 WC Hematology SC Hematology GA 772BA UT WOS:000291203200028 PM 21163921 ER PT J AU Rich, JD Wakeman, SE Dickman, SL AF Rich, Josiah D. Wakeman, Sarah E. Dickman, Samuel L. TI Medicine and the Epidemic of Incarceration in the United States SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID FORMER INMATES C1 [Rich, Josiah D.; Dickman, Samuel L.] Miriam Hosp, Dept Med, Div Infect Dis, Providence, RI 02906 USA. [Rich, Josiah D.; Dickman, Samuel L.] Brown Med Sch, Providence, RI USA. [Wakeman, Sarah E.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Rich, JD (reprint author), Miriam Hosp, Dept Med, Div Infect Dis, Providence, RI 02906 USA. FU NIDA NIH HHS [K24 DA022112, K24 DA022112-01A2] NR 6 TC 44 Z9 45 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 2 PY 2011 VL 364 IS 22 BP 2081 EP 2083 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 772AB UT WOS:000291200700001 PM 21631319 ER PT J AU Goodman, A Schorge, J Greene, MF AF Goodman, Annekathryn Schorge, John Greene, Michael F. TI The Long-Term Effects of In Utero Exposures - The DES Story SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID DIETHYLSTILBESTROL DES C1 [Goodman, Annekathryn; Schorge, John; Greene, Michael F.] Harvard Univ, Sch Med, Boston, MA 02163 USA. [Goodman, Annekathryn; Schorge, John; Greene, Michael F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Goodman, A (reprint author), Harvard Univ, Sch Med, Boston, MA 02163 USA. NR 5 TC 16 Z9 16 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 2 PY 2011 VL 364 IS 22 BP 2083 EP 2084 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 772AB UT WOS:000291200700002 PM 21506735 ER PT J AU Ciaranello, AL Perez, F Maruva, M Chu, J Engelsmann, B Keatinge, J Walensky, RP Mushavi, A Mugwagwa, R Dabis, F Freedberg, KA AF Ciaranello, Andrea L. Perez, Freddy Maruva, Matthews Chu, Jennifer Engelsmann, Barbara Keatinge, Jo Walensky, Rochelle P. Mushavi, Angela Mugwagwa, Rumbidzai Dabis, Francois Freedberg, Kenneth A. CA CEPAC Int Investigators TI WHO 2010 Guidelines for Prevention of Mother-to-Child HIV Transmission in Zimbabwe: Modeling Clinical Outcomes in Infants and Mothers SO PLOS ONE LA English DT Article ID SINGLE-DOSE NEVIRAPINE; RESOURCE-LIMITED SETTINGS; ANTIRETROVIRAL THERAPY PROGRAMS; TREATMENT INTERRUPTION STRATEGY; PLACEBO-CONTROLLED TRIAL; SUB-SAHARAN AFRICA; DAR-ES-SALAAM; SOUTH-AFRICA; COST-EFFECTIVENESS; RANDOMIZED-TRIAL AB Background: The Zimbabwean national prevention of mother-to-child HIV transmission (PMTCT) program provided primarily single-dose nevirapine (sdNVP) from 2002-2009 and is currently replacing sdNVP with more effective antiretroviral (ARV) regimens. Methods: Published HIV and PMTCT models, with local trial and programmatic data, were used to simulate a cohort of HIV-infected, pregnant/breastfeeding women in Zimbabwe (mean age 24.0 years, mean CD4 451 cells/mu L). We compared five PMTCT regimens at a fixed level of PMTCT medication uptake: 1) no antenatal ARVs (comparator); 2) sdNVP; 3) WHO 2010 guidelines using "Option A" (zidovudine during pregnancy/infant NVP during breastfeeding for women without advanced HIV disease; lifelong 3-drug antiretroviral therapy (ART) for women with advanced disease); 4) WHO "Option B" (ART during pregnancy/breastfeeding without advanced disease; lifelong ART with advanced disease); and 5) "Option B+:" lifelong ART for all pregnant/breastfeeding, HIV-infected women. Pediatric (4-6 week and 18-month infection risk, 2-year survival) and maternal (2-and 5-year survival, life expectancy from delivery) outcomes were projected. Results: Eighteen-month pediatric infection risks ranged from 25.8% (no antenatal ARVs) to 10.9% (Options B/B+). Although maternal short-term outcomes (2-and 5-year survival) varied only slightly by regimen, maternal life expectancy was reduced after receipt of sdNVP (13.8 years) or Option B (13.9 years) compared to no antenatal ARVs (14.0 years), Option A (14.0 years), or Option B+ (14.5 years). Conclusions: Replacement of sdNVP with currently recommended regimens for PMTCT (WHO Options A, B, or B+) is necessary to reduce infant HIV infection risk in Zimbabwe. The planned transition to Option A may also improve both pediatric and maternal outcomes. C1 [Ciaranello, Andrea L.; Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Perez, Freddy; Dabis, Francois] Univ Bordeaux 2, INSERM, U897, Africa Team,ISPED, F-33076 Bordeaux, France. [Perez, Freddy] Pan Amer Hlth Org, HIV AIDS Unit, Washington, DC USA. [Maruva, Matthews; Keatinge, Jo] Elizabeth Glaser Pediat AIDS Fdn Zimbabwe Cty Off, Harare, Zimbabwe. [Chu, Jennifer; Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Engelsmann, Barbara] Org Publ Hlth Intervent & Dev OPHID Trust, Harare, Zimbabwe. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Walensky, Rochelle P.; Freedberg, Kenneth A.] Harvard Univ, Sch Med, Ctr AIDS Res, Boston, MA USA. [Mushavi, Angela; Mugwagwa, Rumbidzai] Minist Hlth & Child Welf, Harare, Zimbabwe. RP Ciaranello, AL (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM aciaranello@partners.org RI Anglaret, Xavier/F-7333-2013; OI Walensky, Rochelle P./0000-0002-8795-379X; , International Journal of Business and Applied Social Science/0000-0001-7850-0193; Lipsitch, Marc/0000-0003-1504-9213 FU Elizabeth Glaser Pediatric AIDS Foundation; National Institute of Allergy and Infectious Disease [K01 AI078754, K24 AI062476, R01 AI058736] FX Funding for this work was provided by the Elizabeth Glaser Pediatric AIDS Foundation (all authors) and the National Institute of Allergy and Infectious Disease (K01 AI078754 (ALC), K24 AI062476 (KAF), and R01 AI058736 (KAF, RPW, RW, JC)). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 89 TC 24 Z9 24 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 2 PY 2011 VL 6 IS 6 AR e20224 DI 10.1371/journal.pone.0020224 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773ME UT WOS:000291310600006 PM 21655097 ER PT J AU Granot, T Venticinque, L Tseng, JC Meruelo, D AF Granot, Tomer Venticinque, Lisa Tseng, Jen-Chieh Meruelo, Daniel TI Activation of Cytotoxic and Regulatory Functions of NK Cells by Sindbis Viral Vectors SO PLOS ONE LA English DT Article ID NATURAL-KILLER-CELLS; INTERFERON-GAMMA PRODUCTION; VESICULAR STOMATITIS-VIRUS; IN-VIVO; IMMUNODEFICIENT MICE; ANTITUMOR IMMUNITY; STIMULATORY FACTOR; OVARIAN-CANCER; TUMOR-CELLS; IFN-GAMMA AB Oncolytic viruses (OVs) represent a relatively novel anti-cancer modality. Like other new cancer treatments, effective OV therapy will likely require combination with conventional treatments. In order to design combinatorial treatments that work well together, a greater scrutiny of the mechanisms behind the individual treatments is needed. Sindbis virus (SV) based vectors have previously been shown to target and kill tumors in xenograft, syngeneic, and spontaneous mouse models. However, the effect of SV treatment on the immune system has not yet been studied. Here we used a variety of methods, including FACS analysis, cytotoxicity assays, cell depletion, imaging of tumor growth, cytokine blockade, and survival experiments, to study how SV therapy affects Natural Killer (NK) cell function in SCID mice bearing human ovarian carcinoma tumors. Surprisingly, we found that SV anti-cancer efficacy is largely NK cell-dependent. Furthermore, the enhanced therapeutic effect previously observed from Sin/IL12 vectors, which carry the gene for interleukin 12, is also NK cell dependent, but works through a separate IFN gamma-dependent mechanism, which also induces the activation of peritoneal macrophages. These results demonstrate the multimodular nature of SV therapy, and open up new possibilities for potential synergistic or additive combinatorial therapies with other treatments. C1 [Granot, Tomer; Venticinque, Lisa; Meruelo, Daniel] NYU, Sch Med, Inst Canc, Gene Therapy Ctr, New York, NY 10016 USA. [Granot, Tomer; Venticinque, Lisa; Meruelo, Daniel] NYU, Sch Med, Dept Pathol, New York, NY USA. [Tseng, Jen-Chieh] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Granot, T (reprint author), NYU, Sch Med, Inst Canc, Gene Therapy Ctr, New York, NY 10016 USA. EM DM01@mac.com FU U. S. Public Health [CA100687]; National Cancer Institute; National Institutes of Health; Department of Health and Human Services; Litwin Foundation FX This work was supported by U. S. Public Health grants CA100687 from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. Funding was also provided by a gift from the Litwin Foundation and a Research and License agreement between NYU and CynVec. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 6 Z9 6 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 2 PY 2011 VL 6 IS 6 AR e20598 DI 10.1371/journal.pone.0020598 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 773ME UT WOS:000291310600018 PM 21674047 ER PT J AU Huang, PG Westmoreland, SV Jain, RK Fukumura, D AF Huang, Peigen Westmoreland, Susan V. Jain, Rakesh K. Fukumura, Dai TI Spontaneous Nonthymic Tumors in SCID Mice SO COMPARATIVE MEDICINE LA English DT Article ID COMBINED IMMUNODEFICIENT MICE; INBRED LABORATORY MICE; SPONTANEOUS OSTEOSARCOMA; RADIATION SENSITIVITY; METASTATIC BEHAVIOR; MOUSE; MUTATION; CELL; GROWTH; CANCER AB SCID mice provide an excellent platform for cancer research. Because of their lack of immunity, SOD mice readily succumb to infectious pathogens and therefore must be maintained in an SPF, barrier-protected environment. Although SPF and barrier facilities prevent infection, SOD mice remain prone to premature death due in part to a high prevalence of spontaneous thymic lymphomas. However, little is known about spontaneous nonthymic tumors in SCID mice. We therefore analyzed the incidence of nonthymic tumor in our defined-flora C.B-17/Icr-SCID/Sed mice and examined their histopathologic characteristics. We necropsied 1060 retired SCID breeders (506 males, 554 females; average ages of 325 and 320 d, respectively) and found that 24 mice had developed nonthymic tumors, yielding an incidence of 2.26% (1.78% in males; 2.71% in females). The incidence of nonthymic tumors was substantially lower than that of thymic lymphomas in our retired SCID breeders (12.3% in males; 4.15% in females). Based on histopathology, 9 nonthymic tumors in male SCID mice consisted of 4 salivary gland myoepitheliomas, 2 rhabdomyosarcomas, and 3 cases of leukemia involving multiple organs. Female SCID mice had 15 nonthymic tumors consisting of 8 mammary adenocarcinomas, 4 salivary gland myoepitheliomas, and 1 case each of leukemia, rhabdomyosarcoma, and fibrosarcoma. In addition, we tested in vivo transplantability and characterized the growth behavior of several of these tumors. To our knowledge, this report is the first comprehensive description of spontaneous nonthymic tumors, including 8 myoepitheliomas and 3 rhabdomyosarcomas, from the same SCID mouse colony. C1 [Huang, Peigen; Jain, Rakesh K.; Fukumura, Dai] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Edwin L Steele Lab,Dept Radiat Oncol, Boston, MA 02114 USA. [Westmoreland, Susan V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Westmoreland, Susan V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Comparat Med, Boston, MA USA. RP Huang, PG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Edwin L Steele Lab,Dept Radiat Oncol, Boston, MA 02114 USA. EM peigen@steele.mgh.harvard.edu FU NIH [P01-CA080124, R01-CA085140, R01-CA115767, R01-CA126642, R01-CA096915]; Federal Share/National Cancer Institute; Department of Defense [W81XWH-10-1-0016] FX This work was supported by NIH grants P01-CA080124, R01-CA085140, R01-CA115767, and R01-CA126642 and Federal Share/National Cancer Institute Proton Beam Program Income (to RKJ); and NIH grant R01-CA096915 (to DF). RKJ is the recipient of Department of Defense Breast Cancer Research Innovator Award W81XWH-10-1-0016. NR 36 TC 6 Z9 6 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD JUN PY 2011 VL 61 IS 3 BP 227 EP 234 PG 8 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 915QQ UT WOS:000302042900006 PM 21819692 ER PT J AU Kang, JH Wiggs, JL Rosner, BA Haines, J Abdrabou, W Pasquale, LR AF Kang, Jae Hee Wiggs, Janey L. Rosner, Bernard A. Haines, Jonathan Abdrabou, Wael Pasquale, Louis R. TI Endothelial Nitric Oxide Synthase Gene Variants and Primary Open-Angle Glaucoma Interactions With Hypertension, Alcohol Intake, and Cigarette Smoking SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID OPTIC-NERVE HEAD; HUMOR OUTFLOW FACILITY; MESHWORK CELL-VOLUME; RETINAL BLOOD-FLOW; TRABECULAR MESHWORK; RELAXING FACTOR; INTRAOCULAR-PRESSURE; RISK-FACTORS; SMOOTH-MUSCLE; RED WINE AB Objective: To evaluate whether an association between risk of any of the factors of hypertension, alcohol intake, and cigarette smoking and the risk of primary open-angle glaucoma (POAG) depended on nitric oxide synthase 3 (NOS3) gene variants. Methods: Two functional single-nucleotide polymorphisms (SNPs) (T-786C [rs2070744] and Glu298Asp [rs1799983]) and 2 tagging SNPs (rs7830 and rs3918188) were evaluated in nested case-control studies from the Nurses' Health Study (1980-2002) and the Health Professionals' Follow-up Study (1986-2002). Participants were 40 years of age or older and white, and were followed up biennially. We included 527 incident case patients with POAG and 1539 control participants, matched by cohort, age, and eye examination at the matched case patients' diagnosis dates. Cohort-specific relative risks were estimated using multivariable conditional logistic regression and were pooled using meta-analytic methods. Results: The association between hypertension and POAG depended on T-786C SNP variants. Compared with TT homozygotes without hypertension, the TT homozygotes with hypertension were at significantly higher risk of POAG (relative risk, 1.45 [95% confidence interval, 1.01-2.08]); however, among carriers of the variant (C) allele, hypertension was not associated with POAG (P interaction = .007). Similarly, compared with CC homozygotes with the rs7830 tagging SNP who never smoked, CC homozygotes who were past or current smokers were at significantly higher risk of POAG(relative risk, 1.63 [95% confidence interval, 1.15-2.31]); however, among carriers of the variant allele (A), smoking was not associated with POAG (P interaction = .004). Interactions were not observed with alcohol intake. Conclusions: The associations between hypertension and cigarette smoking in relation to POAG depended on NOS3 SNPs. C1 [Kang, Jae Hee; Rosner, Bernard A.] Harvard Univ, Sch Med, Channing Lab, Dept Med,Brigham & Womens Hosp, Boston, MA 02114 USA. [Wiggs, Janey L.; Abdrabou, Wael; Pasquale, Louis R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Rosner, Bernard A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Haines, Jonathan] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37212 USA. RP Pasquale, LR (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM louis_pasquale@meei.harvard.edu RI Haines, Jonathan/C-3374-2012 FU Wyeth Pharmaceuticals; National Institutes of Health [CA87969, CA55075, CA49449, EY09611, HL35464, EY015473]; Research to Prevent Blindness Physician Scientist award FX Dr Kang has received research funding (2008-2009) from Wyeth Pharmaceuticals.; This work was supported by grants CA87969, CA55075, CA49449, EY09611, HL35464, and EY015473 from the National Institutes of Health. Dr Pasquale is also supported by a Research to Prevent Blindness Physician Scientist award. NR 60 TC 24 Z9 25 U1 0 U2 3 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 JUN PY 2011 VL 129 IS 6 BP 773 EP 780 PG 8 WC Ophthalmology SC Ophthalmology GA 776UJ UT WOS:000291563500013 PM 21670344 ER PT J AU Bostrom, P Mann, N Wu, J Quintero, PA Plovie, ER Panakova, DR Gupta, RK Xiao, CK MacRae, CA Rosenzweig, A Spiegelman, BM AF Bostrom, P. Mann, N. Wu, J. Quintero, P. A. Plovie, E. R. Panakova, D. R. Gupta, R. K. Xiao, C. K. MacRae, C. A. Rosenzweig, A. Spiegelman, B. M. TI C/EBP beta CONTROLS EXERCISE-INDUCED CARDIAC GROWTH AND PROTECTS AGAINST PATHOLOGICAL CARDIAC REMODELING SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 79th Congress of the European-Atherosclerosis-Society (EAS) CY JUN 26-29, 2011 CL Gothenburg, SWEDEN SP European Atherosclerosis Soc (EAS) C1 [Bostrom, P.; Wu, J.; Gupta, R. K.; Spiegelman, B. M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Mann, N.; Quintero, P. A.; Xiao, C. K.; Rosenzweig, A.] Harvard Univ, Sch Med, BIDMC, Boston, MA 02115 USA. [Mann, N.; Quintero, P. A.; Xiao, C. K.; Rosenzweig, A.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Plovie, E. R.; Panakova, D. R.; MacRae, C. A.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD JUN PY 2011 VL 12 IS 1 MA 51 BP 11 EP 11 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 890QG UT WOS:000300159000052 ER PT J AU Motazacker, MM Huijgen, R Peter, J Defesche, JC Kastelein, JJP Hovingh, GK Kathiresan, S Zelcer, N Fouchier, SW AF Motazacker, M. M. Huijgen, R. Peter, J. Defesche, J. C. Kastelein, J. J. P. Hovingh, G. K. Kathiresan, S. Zelcer, N. Fouchier, S. W. TI COMBINING EXOME SEQUENCING WITH EXCLUSION LINKAGE ANALYSIS AS A TOOL TO UNRAVEL THE MOLECULAR BASIS OF A COMMON GENETIC DISEASE SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 79th Congress of the European-Atherosclerosis-Society (EAS) CY JUN 26-29, 2011 CL Gothenburg, SWEDEN SP European Atherosclerosis Soc (EAS) C1 [Motazacker, M. M.; Huijgen, R.; Kastelein, J. J. P.; Hovingh, G. K.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Motazacker, M. M.; Peter, J.; Defesche, J. C.; Fouchier, S. W.] Univ Amsterdam, Acad Med Ctr, Dept Expt Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Kathiresan, S.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Zelcer, N.; Fouchier, S. W.] Univ Amsterdam, Acad Med Ctr, Dept Med Biochem, NL-1105 AZ Amsterdam, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD JUN PY 2011 VL 12 IS 1 MA 603 BP 127 EP 127 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 890QG UT WOS:000300159000599 ER PT J AU Smedbakken, LM Jensen, JK Hallen, J Atar, D Januzzi, JL Halvorsen, B Aukrust, P Ueland, T AF Smedbakken, L. M. Jensen, J. K. Hallen, J. Atar, D. Januzzi, J. L. Halvorsen, B. Aukrust, P. Ueland, T. TI ACTIVATED LEUKOCYTE CELL ADHESION MOLECULE (ALCAM) AND PROGNOSIS IN ACUTE ISCHEMIC STROKE SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 79th Congress of the European-Atherosclerosis-Society (EAS) CY JUN 26-29, 2011 CL Gothenburg, SWEDEN SP European Atherosclerosis Soc (EAS) C1 [Smedbakken, L. M.; Halvorsen, B.; Aukrust, P.; Ueland, T.] Univ Oslo, Rikshosp, Oslo Univ Hosp, Internal Med Res Inst, N-0027 Oslo, Norway. [Jensen, J. K.] Odense Univ Hosp, Dept Cardiol, DK-5000 Odense, Denmark. [Hallen, J.; Atar, D.] Oslo Univ Hosp, Div Cardiol, Oslo, Norway. [Januzzi, J. L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Aukrust, P.] Univ Oslo, Rikshosp, Oslo Univ Hosp, Sect Clin Immunol & Infect Dis, N-0027 Oslo, Norway. [Aukrust, P.] Univ Oslo, Fac Med, Oslo, Norway. [Ueland, T.] Univ Oslo, Rikshosp, Oslo Univ Hosp, Sect Specialized Endocrinol, N-0027 Oslo, Norway. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD JUN PY 2011 VL 12 IS 1 MA 610 BP 128 EP 129 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 890QG UT WOS:000300159000606 ER PT J AU Holm, S Ueland, T Dahl, TB Michelsen, AE Skjelland, M Russell, D Krogh-Sorensen, K Clausen, OP Atar, D Januzzi, JL Aukrust, P Jensen, JK Halvorsen, B AF Holm, S. Ueland, T. Dahl, T. B. Michelsen, A. E. Skjelland, M. Russell, D. Krogh-Sorensen, K. Clausen, O. P. Atar, D. Januzzi, J. L. Aukrust, P. Jensen, J. K. Halvorsen, B. TI FATTY ACID BINDING PROTEIN 4 AS A BIOMARKER OF CAROTID ATHEROSCLEROSIS AND OUTCOME IN PATIENTS WITH ACUTE ISCHEMIC STROKE SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract CT 79th Congress of the European-Atherosclerosis-Society (EAS) CY JUN 26-29, 2011 CL Gothenburg, SWEDEN SP European Atherosclerosis Soc (EAS) C1 [Holm, S.; Ueland, T.; Dahl, T. B.; Michelsen, A. E.; Skjelland, M.; Russell, D.; Krogh-Sorensen, K.; Clausen, O. P.; Aukrust, P.; Halvorsen, B.] Univ Oslo, Rikshosp, Oslo Univ Hosp, N-0027 Oslo, Norway. [Atar, D.] Oslo Univ Hosp, Oslo, Norway. [Januzzi, J. L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jensen, J. K.] Odense Univ Hosp, DK-5000 Odense, Denmark. RI Skjelland, Mona/B-7362-2016 NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD JUN PY 2011 VL 12 IS 1 MA 614 BP 129 EP 129 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 890QG UT WOS:000300159000610 ER PT J AU Kang, D Yoo, H Jillella, P Bouma, BE Tearney, GJ AF Kang, DongKyun Yoo, Hongki Jillella, Priyanka Bouma, Brett E. Tearney, Guillermo J. TI Comprehensive volumetric confocal microscopy with adaptive focusing SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID DOUBLE-CLAD FIBER; IN-VIVO; BARRETTS-ESOPHAGUS; LASER ENDOMICROSCOPY; ENDOSCOPY; NEOPLASIA; MINIPROBE; CANCER; VIDEO AB Comprehensive microscopy of distal esophagus could greatly improve the screening and surveillance of esophageal diseases such as Barrett's esophagus by providing histomorphologic information over the entire region at risk. Spectrally encoded confocal microscopy (SECM) is a high-speed reflectance confocal microscopy technology that can be configured to image the entire distal esophagus by helically scanning the beam using optics within a balloon-centering probe. It is challenging to image the human esophagus in vivo with balloon-based SECM, however, because patient motion and anatomic tissue surface irregularities decenter the optics, making it difficult to keep the focus at a predetermined location within the tissue as the beam is scanned. In this paper, we present a SECM probe equipped with an adaptive focusing mechanism that can compensate for tissue surface irregularity and dynamic focal variation. A tilted arrangement of the objective lens is employed in the SECM probe to provide feedback signals to an adaptive focusing mechanism. The tilted configuration also allows the probe to obtain reflectance confocal data from multiple depth levels, enabling the acquisition of three-dimensional volumetric data during a single scan of the probe. A tissue phantom with a surface area of 12.6 cm(2) was imaged using the new SECM probe, and 8 large-area reflectance confocal microscopy images were acquired over the depth range of 56 mu m in 20 minutes. Large-area SECM images of excised swine small intestine tissue were also acquired, enabling the visualization of villous architecture, epithelium, and lamina propria. The adaptive focusing mechanism was demonstrated to enable acquisition of in-focus images even when the probe was not centered and the tissue surface was irregular. (C)2011 Optical Society of America C1 [Kang, DongKyun; Yoo, Hongki; Jillella, Priyanka; Bouma, Brett E.; Tearney, Guillermo J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Kang, DongKyun; Yoo, Hongki; Jillella, Priyanka; Bouma, Brett E.; Tearney, Guillermo J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Bouma, Brett E.; Tearney, Guillermo J.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Kang, D (reprint author), Harvard Univ, Sch Med, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM gtearney@partners.org 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 National Institute of Health/National Cancer Institute [R21CA122161, R21 CA141884] FX This research was sponsored by National Institute of Health/National Cancer Institute (Grants R21CA122161 and R21 CA141884). Priyanka Jillella is currently with the University of Arizona. NR 32 TC 10 Z9 10 U1 0 U2 6 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD JUN 1 PY 2011 VL 2 IS 6 BP 1412 EP 1422 PG 11 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 886UG UT WOS:000299878800002 PM 21698005 ER PT J AU Desjardins, AE Hendriks, BHW van der Voort, M Nachabe, R Bierhoff, W Braun, G Babic, D Rathmell, JP Holmin, S Soderman, M Holmstrom, B AF Desjardins, Adrien E. Hendriks, Benno H. W. van der Voort, Marjolein Nachabe, Rami Bierhoff, Walter Braun, Guus Babic, Drazenko Rathmell, James P. Holmin, Staffan Soderman, Michael Holmstrom, Bjorn TI Epidural needle with embedded optical fibers for spectroscopic differentiation of tissue: ex vivo feasibility study SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID COHERENCE TOMOGRAPHY; DIFFUSE-REFLECTANCE; SPECTRAL RANGE; IN-VIVO; SPACE; PROBE; HEMOGLOBIN; MYOGLOBIN AB Epidural injection is commonly used to provide intraoperative anesthesia, postoperative and obstetric analgesia, and to treat acute radicular pain. Identification of the epidural space is typically carried out using the loss of resistance (LOR) technique, but the usefulness of this technique is limited by false LOR and the inability to reliably detect intravascular or subarachnoid needle placement. In this study, we present a novel epidural needle that allows for the acquisition of optical reflectance spectra from tissue close to the beveled surface. This needle has optical fibers embedded in the cannula that deliver and receive light. With two spectrometers, light received from tissue is resolved across the wavelength range of 500 to 1600 nm. To determine the feasibility of optical tissue differentiation, spectra were acquired from porcine tissues during a post mortem laminectomy. The spectra were processed with an algorithm that derives estimates of the hemoglobin and lipid concentrations. The results of this study suggest that the optical epidural needle has the potential to improve the accuracy of epidural space identification. (C)2010 Optical Society of America C1 [Desjardins, Adrien E.; Hendriks, Benno H. W.; van der Voort, Marjolein; Nachabe, Rami; Bierhoff, Walter; Braun, Guus] Philips Res, Minimally Invas Healthcare Dept, Amsterdam, Netherlands. [Babic, Drazenko] Philips Healthcare, Best, Netherlands. [Rathmell, James P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Holmin, Staffan; Soderman, Michael] Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden. [Holmin, Staffan; Soderman, Michael] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Holmstrom, Bjorn] Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden. [Holmstrom, Bjorn] Karolinska Univ Hosp, Dept Anesthesiol & Intens Care, Huddinge, Sweden. RP Desjardins, AE (reprint author), Philips Res, Minimally Invas Healthcare Dept, Amsterdam, Netherlands. EM bjorn.holmstrom@karolinska.se NR 34 TC 18 Z9 18 U1 2 U2 12 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD JUN 1 PY 2011 VL 2 IS 6 BP 1452 EP 1461 PG 10 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 886UG UT WOS:000299878800006 PM 21698009 ER PT J AU Mazhar, A Cuccia, DJ Rice, TB Carp, SA Durkin, AJ Boas, DA Choi, B Tromberg, BJ AF Mazhar, Amaan Cuccia, David J. Rice, Tyler B. Carp, Stefan A. Durkin, Anthony J. Boas, David A. Choi, Bernard Tromberg, Bruce J. TI Laser speckle imaging in the spatial frequency domain SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID TURBID MEDIA; CONTRAST; LIGHT; SPECTROSCOPY; TOMOGRAPHY; SCATTERING; PERFUSION; TOOL AB Laser Speckle Imaging (LSI) images interference patterns produced by coherent addition of scattered laser light to map subsurface tissue perfusion. However, the effect of longer path length photons is typically unknown and poses a limitation towards absolute quantification. In this work, LSI is integrated with spatial frequency domain imaging (SFDI) to suppress multiple scattering and absorption effects. First, depth sensitive speckle contrast is shown in phantoms by separating a deep source (4 mm) from a shallow source (2 mm) of speckle contrast by using a high spatial frequency of illumination (0.24 mm(-1)). We develop an SFD adapted correlation diffusion model and show that with high frequency (0.24 mm(-1)) illumination, doubling of absorption contrast results in only a 1% change in speckle contrast versus 25% change using a planar unmodulated (0 mm(-1)) illumination. Similar absorption change is mimicked in vivo imaging a finger occlusion and the relative speckle contrast change from baseline is 10% at 0.26 mm(-1) versus 60% at 0 mm(-1) during a finger occlusion. These results underscore the importance of path length and optical properties in determining speckle contrast. They provide an integrated approach for simultaneous mapping of blood flow (speckle contrast) and oxygenation (optical properties) which can be used to inform tissue metabolism. (C)2011 Optical Society of America C1 [Mazhar, Amaan; Choi, Bernard; Tromberg, Bruce J.] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92612 USA. [Mazhar, Amaan; Rice, Tyler B.; Durkin, Anthony J.; Choi, Bernard; Tromberg, Bruce J.] Univ Calif Irvine, Beckman Laser Inst, Irvine, CA 92612 USA. [Cuccia, David J.] Modulated Imaging Inc, Technol Incubator Off, Irvine, CA 92612 USA. [Carp, Stefan A.; Boas, David A.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Carp, Stefan A.; Boas, David A.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Mazhar, A (reprint author), Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92612 USA. EM bjtrombe@uci.edu OI Durkin, Anthony/0000-0001-9124-6388 FU NIH Biomedical Technology Resource [P41-RR01192]; Military Photomedicine Program, AFOSR [FA9550-08-1-0384] FX In addition to the co-authors, the primary author would like to thank Professor Vasan Venugopalan, Dr. Soren Konecky, Dr. Eugene Huang, and the Virtual Photonics group at Beckman Laser Institute for their insight regarding concepts/models presented in this work. This research was made possible by the Laser Microbeam and Medical Program (LAMMP), an NIH Biomedical Technology Resource, Grant No. P41-RR01192, the Beckman Foundation, and the Military Photomedicine Program, AFOSR Grant No. FA9550-08-1-0384. NR 31 TC 22 Z9 22 U1 1 U2 17 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD JUN 1 PY 2011 VL 2 IS 6 BP 1553 EP 1563 PG 11 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 886UG UT WOS:000299878800015 PM 21698018 ER PT J AU Tohen, M Bowden, C Nierenberg, A AF Tohen, M. Bowden, C. Nierenberg, A. TI International Society for Bipolar Disorder (ISBD) task force reports: clinical trial design SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA C1 [Tohen, M.; Bowden, C.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Nierenberg, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nierenberg, A.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 19 EP 19 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400022 ER PT J AU Iosifescu, DV Leon, AC Sylvia, LG Thase, ME Bowden, CL Ostacher, MJ Calabrese, JR Friedman, ES Reilly-Harrington, N Ketter, TA Pencina, M Nierenberg, AA AF Iosifescu, D. V. Leon, A. C. Sylvia, L. G. Thase, M. E. Bowden, C. L. Ostacher, M. J. Calabrese, J. R. Friedman, E. S. Reilly-Harrington, N. Ketter, T. A. Pencina, M. Nierenberg, A. A. TI Cognitive deficits are an important determinant of functional deficits in bipolar disorder: baseline results from LiTMUS SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE bipolar; cognition; attention; memory; functional deficits C1 [Iosifescu, D. V.] Mt Sinai Sch Med, New York, NY USA. [Iosifescu, D. V.; Sylvia, L. G.; Reilly-Harrington, N.; Nierenberg, A. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Leon, A. C.] Weill Cornell Med Coll, New York, NY USA. [Thase, M. E.] Univ Penn, Philadelphia, PA 19104 USA. [Bowden, C. L.] Univ Texas Hlth Sci, San Antonio, TX USA. [Ostacher, M. J.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Ostacher, M. J.; Ketter, T. A.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Calabrese, J. R.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Friedman, E. S.; Pencina, M.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Pencina, M.] Harvard Clin Res Inst, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 22 EP 22 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400028 ER PT J AU Vizueta, N Townsend, JD Torrisi, S Moody, TD Fischer, J Aquino, AR Bookheimera, SY Altshuler, LL AF Vizueta, N. Townsend, J. D. Torrisi, S. Moody, T. D. Fischer, J. Aquino, A. R. Bookheimera, S. Y. Altshuler, L. L. TI Emotion regulation and functional magnetic resonance imaging in bipolar II depression vs. major depressive disorder SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE bipolar II disorder; functional MRI; emotional faces; major depressive disorder C1 [Vizueta, N.; Townsend, J. D.; Torrisi, S.; Moody, T. D.; Fischer, J.; Aquino, A. R.; Altshuler, L. L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Vizueta, N.; Townsend, J. D.; Torrisi, S.; Moody, T. D.; Fischer, J.; Aquino, A. R.; Altshuler, L. L.] Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Altshuler, L. L.] VA Greater Los Angeles Healthcare Syst, W Los Angeles Healthcare Ctr, Dept Psychiat, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 26 EP 26 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400038 ER PT J AU Casamassima, F Fava, M Cassano, GB Clain, A Kansky, MSC Perlis, RH AF Casamassima, F. Fava, M. Cassano, G. B. Clain, A. Kansky, M. S. Christine Perlis, R. H. TI Predictive value of bipolar-spectrum clinical features in a large cohort of fluoxetine treated patients with major depressive disorder SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE major depressive disorder (MDD); fluoxetine; bipolar spectrum C1 [Casamassima, F.; Fava, M.; Clain, A.; Kansky, M. S. Christine; Perlis, R. H.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Casamassima, F.; Cassano, G. B.] Univ Pisa, Div Psychiat, Pisa, Italy. [Perlis, R. H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Fava, M.; Perlis, R. H.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 34 EP 34 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400061 ER PT J AU Deckersbach, T Peters, AT Peckham, AD Duffy, AM Rodman, AM Perlis, R Rauch, S Nierenberg, A Dougherty, D AF Deckersbach, T. Peters, A. T. Peckham, A. D. Duffy, A. M. Rodman, A. M. Perlis, R. Rauch, S. Nierenberg, A. Dougherty, D. TI Characteristics of everyday functioning difficulties in bipolar disorder SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE bipolar; executive functioning C1 [Deckersbach, T.; Peters, A. T.; Peckham, A. D.; Duffy, A. M.; Rodman, A. M.; Perlis, R.; Rauch, S.; Nierenberg, A.; Dougherty, D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Deckersbach, T.; Perlis, R.; Rauch, S.; Nierenberg, A.; Dougherty, D.] Harvard Univ, Sch Med, Boston, MA USA. [Rauch, S.] McLean Hosp, Belmont, MA 02178 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 38 EP 39 PG 2 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400074 ER PT J AU Deckersbach, T Duffy, AM Peters, AT Peckham, AD Rodman, AM Rauch, S Nierenberg, A Dougherty, D AF Deckersbach, T. Duffy, A. M. Peters, A. T. Peckham, A. D. Rodman, A. M. Rauch, S. Nierenberg, A. Dougherty, D. TI Neural correlates of real-world functioning difficulties in patients with bipolar disorder SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE bipolar disorder; fMRI; executive functioning C1 [Deckersbach, T.; Duffy, A. M.; Peters, A. T.; Peckham, A. D.; Rodman, A. M.; Rauch, S.; Nierenberg, A.; Dougherty, D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Deckersbach, T.; Rauch, S.; Nierenberg, A.; Dougherty, D.] Harvard Univ, Sch Med, Boston, MA USA. [Rauch, S.] McLean Hosp, Belmont, MA 02178 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 39 EP 39 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400075 ER PT J AU Dupuy, J McMurrich, S Peters, AT Ariel, AH Deckersbach, T Perlis, RH AF Dupuy, J. McMurrich, S. Peters, A. T. Ariel, A. H. Deckersbach, T. Perlis, R. H. TI Characterizing pilot data to establish a clinical profile of patients with bipolar disorder following a first episode of mania SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE first episode; demographics; bipolar disorder C1 [Dupuy, J.; McMurrich, S.; Peters, A. T.; Ariel, A. H.; Deckersbach, T.; Perlis, R. H.] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. [Dupuy, J.; McMurrich, S.; Deckersbach, T.; Perlis, R. H.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 40 EP 40 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400078 ER PT J AU Friedman, ES Calabrese, JR Ketter, TA Bowden, CL Thase, ME Leon, AC Sylvia, LG Ostacher, MJ Iosifescu, DV Reilly-Harrington, NA Severe, J Nierenberg, AA AF Friedman, E. S. Calabrese, J. R. Ketter, T. A. Bowden, C. L. Thase, M. E. Leon, A. C. Sylvia, L. G. Ostacher, M. J. Iosifescu, D. V. Reilly-Harrington, N. A. Severe, J. Nierenberg, A. A. TI Using comparative effectiveness design to improve the generalizability of bipolar treatment trials data: contrasting LiTMUS baseline data with pre-existing placebo controlled trials SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE comparative effectiveness; bipolar; baseline characteristics; generalizability; external validity C1 [Friedman, E. S.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Calabrese, J. R.] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Ketter, T. A.; Ostacher, M. J.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Bowden, C. L.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Thase, M. E.] Univ Penn, Philadelphia, PA 19104 USA. [Leon, A. C.] Weill Cornell Med Coll, New York, NY USA. [Sylvia, L. G.; Reilly-Harrington, N. A.; Nierenberg, A. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Iosifescu, D. V.] Mt Sinai Sch Med, New York, NY USA. [Severe, J.] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 46 EP 47 PG 2 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400097 ER PT J AU Ketter, TA Calabrese, JR Friedman, ES Bowden, CL Thase, ME Sylvia, LG Ostacher, MJ Nierenberg, AA Reilly-Harrington, NA Leon, AC Pencina, M Iosifescu, DV AF Ketter, T. A. Calabrese, J. R. Friedman, E. S. Bowden, C. L. Thase, M. E. Sylvia, L. G. Ostacher, M. J. Nierenberg, A. A. Reilly-Harrington, N. A. Leon, A. C. Pencina, M. Iosifescu, D. V. TI Depressive symptom burden in bipolar disorder: baseline observations from LiTMUS SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE bipolar disorder; depression; severity; gender C1 [Ketter, T. A.; Ostacher, M. J.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Calabrese, J. R.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Friedman, E. S.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Bowden, C. L.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Thase, M. E.] Univ Penn, Philadelphia, PA 19104 USA. [Sylvia, L. G.; Nierenberg, A. A.; Reilly-Harrington, N. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ostacher, M. J.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Leon, A. C.] Weill Cornell Med Coll, New York, NY USA. [Pencina, M.] Harvard Clin Res Inst, Boston, MA USA. [Iosifescu, D. V.] Mt Sinai Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 61 EP 62 PG 2 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 889VH UT WOS:000300102400141 ER PT J AU Magalhaes, PV Dodd, S Nierenberg, AA Berk, M AF Magalhaes, P. V. Dodd, S. Nierenberg, A. A. Berk, M. TI Cumulative morbidity and prognostic staging of illness in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 9th International Conference on Bipolar Disorder CY JUN 09-11, 2011 CL Pittsburgh, PA DE bipolar disorder; staging; prognosis C1 [Magalhaes, P. V.] Hosp Clin Porto Alegre, Natl Inst Translat Med, Porto Alegre, RS, Brazil. [Magalhaes, P. V.; Dodd, S.; Berk, M.] Univ Melbourne, Dept Clin & Biomed Sci Barwon Hlth, Geelong, Vic, Australia. [Dodd, S.; Berk, M.] Deakin Univ, Geelong, Vic 3217, Australia. [Nierenberg, A. A.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Berk, M.] Mental Hlth Res Inst Victoria, Parkville, Vic, Australia. RI Magalhaes, Pedro/A-8519-2008 OI Magalhaes, Pedro/0000-0002-5644-6357 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD JUN PY 2011 VL 13 SU 1 SI SI BP 68 EP 68 PG 1 WC Clinical Neur