FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Carnevale, J Ross, L Puissant, A Banerji, V Stone, RM DeAngelo, DJ Ross, KN Stegmaier, K AF Carnevale, J. Ross, L. Puissant, A. Banerji, V. Stone, R. M. DeAngelo, D. J. Ross, K. N. Stegmaier, K. TI SYK regulates mTOR signaling in AML SO LEUKEMIA LA English DT Article DE AML; SYK; mTOR; RPS6; 4E-BP1; MAPK ID ACUTE MYELOID-LEUKEMIA; INDUCE GROWTH ARREST; TRANS-RETINOIC ACID; TYROSINE KINASE SYK; TRANSLATION INITIATION; CELL LYMPHOMA; THERAPEUTIC TARGET; HUMAN CANCER; DIFFERENTIATION; INHIBITOR AB Spleen tyrosine kinase (SYK) was recently identified as a new target in acute myeloid leukemia (AML); however, its mechanistic role in this disease is poorly understood. Based on the known interaction between SYK and mammalian target of rapamycin (mTOR) signaling in lymphoma, we hypothesized that SYK may regulate mTOR signaling in AML. Both small-molecule inhibition of SYK and SYK-directed shRNA suppressed mTOR and its downstream signaling effectors, as well as its upstream activator, AKT. Moreover, the inhibition of multiple nodes of the phosphatidylinositol 3'- kinase (PI3K) signaling pathway enhanced the effects of SYK suppression on AML cell viability and differentiation. Evaluation of the collateral mitogen-activated protein kinase (MAPK) pathway revealed a heterogeneous response to SYK inhibition in AML with downregulation of MEK and extracellular signal-regulated kinase (ERK) phosphorylation in some AML cell lines but a paradoxical increase in MEK/ERK phosphorylation in RAS-mutated AML. These studies reveal SYK as a regulator of mTOR and MAPK signaling in AML and demonstrate that inhibition of PI3K pathway activity enhances the effects of SYK inhibition on AML cell viability and differentiation. C1 [Carnevale, J.; Ross, L.; Puissant, A.; Banerji, V.; Stegmaier, K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Carnevale, J.; Ross, L.; Puissant, A.; Banerji, V.; Stegmaier, K.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA USA. [Banerji, V.] Univ Manitoba, Manitoba Inst Cell Biol, Winnipeg, MB, Canada. [Banerji, V.] Univ Manitoba, Dept Internal Med, Canc Care Manitoba, Winnipeg, MB, Canada. [Stone, R. M.; DeAngelo, D. J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ross, K. N.; Stegmaier, K.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Ross, K. N.; Stegmaier, K.] MIT, Cambridge, MA 02139 USA. RP Stegmaier, K (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave,D640C, Boston, MA 02215 USA. EM kimberly_stegmaier@dfci.harvard.edu RI PUISSANT, ALEXANDRE/O-9575-2016 OI PUISSANT, ALEXANDRE/0000-0002-3997-9282 FU National Cancer Institute [R01 CA140292]; American Cancer Society; Starr Cancer Consortium and Project Cupid FX We thank Gerhard Wagner for his generous contribution of the 4EGI-1 molecule and Rigel Pharmaceuticals and AstraZeneca for their kind gift of R406. We thank Margaret Shipp for her scientific advice, John Daley, Susan Lazo-Kallanian and Giovanni Roti for guidance regarding flow cytometry studies, Ilene Galinsky for primary patient sample support and Stacey Frumm for technical support. We thank Aaron Thorner for critical reading of the manuscript. This research was supported by grants from the National Cancer Institute (R01 CA140292), American Cancer Society, the Starr Cancer Consortium and Project Cupid (KS). JC was a Howard Hughes Medical Institute Medical Student Fellow and AP a Leukemia and Lymphoma Society Fellow. NR 65 TC 19 Z9 19 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD NOV PY 2013 VL 27 IS 11 BP 2118 EP 2128 DI 10.1038/leu.2013.89 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA 250UV UT WOS:000326882500002 PM 23535559 ER PT J AU Wei, Y Chen, R Dimicoli, S Bueso-Ramos, C Neuberg, D Pierce, S Wang, H Yang, H Jia, Y Zheng, H Fang, Z Nguyen, M Ganan-Gomez, I Ebert, B Levine, R Kantarjian, H Garcia-Manero, G AF Wei, Y. Chen, R. Dimicoli, S. Bueso-Ramos, C. Neuberg, D. Pierce, S. Wang, H. Yang, H. Jia, Y. Zheng, H. Fang, Z. Nguyen, M. Ganan-Gomez, I. Ebert, B. Levine, R. Kantarjian, H. Garcia-Manero, G. TI Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+cells SO LEUKEMIA LA English DT Article DE myelodysplastic syndromes; H3K4me3; CHIP-Seq; JMJD3; innate immunity ID HEMATOPOIETIC STEM-CELLS; DEMETHYLASE JMJD3; GENE-EXPRESSION; H3K27 DEMETHYLASE; MYELOID-LEUKEMIA; SCORING SYSTEM; NATURAL-KILLER; RECEPTOR; PROTEIN; DIFFERENTIATION AB The molecular bases of myelodysplastic syndromes (MDS) are not fully understood. Trimethylated histone 3 lysine 4 (H3K4me3) is present in promoters of actively transcribed genes and has been shown to be involved in hematopoietic differentiation. We performed a genome-wide H3K4me3 CHIP-Seq (chromatin immunoprecipitation coupled with whole genome sequencing) analysis of primary MDS bone marrow (BM) CD34+ cells. This resulted in the identification of 36 genes marked by distinct higher levels of promoter H3K4me3 in MDS. A majority of these genes are involved in nuclear factor (NF)-kappa B activation and innate immunity signaling. We then analyzed expression of histone demethylases and observed significant overexpression of the JmjC-domain histone demethylase JMJD3 (KDM6b) in MDS CD34+ cells. Furthermore, we demonstrate that JMJD3 has a positive effect on transcription of multiple CHIP-Seq identified genes involved in NF-kB activation. Inhibition of JMJD3 using shRNA in primary BM MDS CD34+ cells resulted in an increased number of erythroid colonies in samples isolated from patients with lower-risk MDS. Taken together, these data indicate the deregulation of H3K4me3 and associated abnormal activation of innate immunity signals have a role in the pathogenesis of MDS and that targeting these signals may have potential therapeutic value in MDS. C1 [Wei, Y.; Dimicoli, S.; Pierce, S.; Yang, H.; Jia, Y.; Zheng, H.; Fang, Z.; Ganan-Gomez, I.; Kantarjian, H.; Garcia-Manero, G.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Chen, R.; Wang, H.] Baylor Coll Med, Dept Human Genet, Houston, TX 77030 USA. [Bueso-Ramos, C.; Nguyen, M.] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA. [Neuberg, D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ganan-Gomez, I.] Univ Alcala de Henares, Fac Med, Dept Biochem & Mol Biol, Alcala De Henares, Spain. [Ebert, B.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Levine, R.] Mem Sloan Kettering Canc Ctr, Dept Leukemia, New York, NY 10021 USA. [Levine, R.] Mem Sloan Kettering Canc Ctr, Human Pathogenesis Program, New York, NY 10021 USA. RP Garcia-Manero, G (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Leukemia, 1515 Holcombe Blvd,Box 428, Houston, TX 77030 USA. EM ggarciam@mdanderson.org FU Cancer Prevention and Research Institute of Texas (CPRIT) [RP100202]; Ruth and Ken Arnold Fund; MD Anderson Cancer Center Leukemia SPORE grant [CA100632]; MD Anderson Cancer Center [CCSG CA016672]; Regional Ministry of Education of Castilla-la Mancha, Spain; European Social Fund (ESF) FX This work was supported by Grant RP100202 from the Cancer Prevention and Research Institute of Texas (CPRIT), the Ruth and Ken Arnold Fund (GGM), the MD Anderson Cancer Center Leukemia SPORE grant CA100632 and the MD Anderson Cancer Center CCSG CA016672. IG-G was funded by the Regional Ministry of Education of Castilla-la Mancha, Spain, supported by the European Social Fund (ESF). We are thankful for the efforts from Dr Hui Yao, Dr Lixia Diao and Dr Jing Wang (Department of Bioinformatics and Computational Biology, MDACC) for initial analysis of CHIP-Seq data. We are also thankful to Dr Sean Post and Dr Zeev Estrov for critical reading of the manuscript. NR 60 TC 23 Z9 24 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD NOV PY 2013 VL 27 IS 11 BP 2177 EP 2186 DI 10.1038/leu.2013.91 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 250UV UT WOS:000326882500008 PM 23538751 ER PT J AU Lee, HJ Yoon, C Schmidt, B Park, DJ Zhang, AY Erkizan, HV Toretsky, JA Kirsch, DG Yoon, SS AF Lee, Hae-June Yoon, Changhwan Schmidt, Benjamin Park, Do Joong Zhang, Alexia Y. Erkizan, Hayriye V. Toretsky, Jeffrey A. Kirsch, David G. Yoon, Sam S. TI Combining PARP-1 Inhibition and Radiation in Ewing Sarcoma Results in Lethal DNA Damage SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE; CANCER-TREATMENT; CELL-DEATH; TUMORS; SENSITIVITY; PATHWAYS; REPAIR; LUNG AB Ewing sarcomas (ES) harbor a chromosomal translocation that fuses the EWS gene to an ETS transcription factor, most commonly Friend leukemia integration 1 (FLI1). The EWS-FLI1 fusion protein acts in a positive feedback loop to maintain the expression of PARP-1, which is involved in repair of DNA damage. Here, we examine the effects of PARP-1 inhibition and radiation therapy on Ewing sarcomas. In proliferation assays, the Ewing sarcoma cell lines RD-ES and SK-N-MC were much more sensitive than non-Ewing sarcoma cell lines to the PARP-1 inhibitor olaparib (Ola; IC50 0.5-1 mu mol/L vs. >5 mu mol/L) and to radiation (IC50 2-4Gy vs. >6 Gy). PARP-1 inhibition with short hairpin RNA(shRNA) or Ola sensitized Ewing sarcoma cells, but not non-Ewing sarcoma cells, to radiation therapy in both proliferation and colony formation assays. Using the Comet assay, radiation of Ewing sarcoma cells with Ola, compared to without Ola, resulted in more DNA damage at 1 hour (mean tail moment 36-54 vs. 26-28) and sustained DNA damage at 24 hours (24-29 vs. 6-8). This DNA damage led to a 2.9- to 4.0-fold increase in apoptosis and a 1.6- to 2.4-fold increase in cell death. The effect of PARP-1 inhibition and radiation therapy on Ewing sarcoma cells was lost when EWS-FLI1 was silenced by shRNA. A small dose of radiation therapy (4 Gy), when combined with PARP-1 inhibition, stopped the growth of SK-N-MC flank tumors xenografts. In conclusion, PARP-1 inhibition in Ewing sarcomas amplifies the level and duration of DNA damage caused by radiation therapy, leading to synergistic increases in apoptosis and cell death in a EWS-FLI1-dependent manner. Mol Cancer Ther; 12(11); 2591-600. (C) 2013 AACR. C1 [Lee, Hae-June; Schmidt, Benjamin; Zhang, Alexia Y.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lee, Hae-June; Schmidt, Benjamin; Zhang, Alexia Y.] Harvard Univ, Sch Med, Boston, MA USA. [Lee, Hae-June] Korea Inst Radiol & Med Sci, Div Radiat Effects, Seoul, South Korea. [Erkizan, Hayriye V.; Toretsky, Jeffrey A.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC USA. [Kirsch, David G.] Duke Univ, Med Ctr, Dept Pharmacol, Durham, NC 27710 USA. [Kirsch, David G.] Duke Univ, Med Ctr, Dept Canc Biol, Durham, NC 27710 USA. [Kirsch, David G.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC USA. [Yoon, Changhwan; Park, Do Joong; Kirsch, David G.; Yoon, Sam S.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. RP Yoon, SS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Surg, H-1209,1275 York Ave, New York, NY 10065 USA. EM yoons@mskcc.org FU NIH [1R01 CA158301-01] FX This work was supported by NIH grant 1R01 CA158301-01 (S. S. Yoon). NR 25 TC 17 Z9 17 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD NOV PY 2013 VL 12 IS 11 BP 2591 EP 2600 DI 10.1158/1535-7163.MCT-13-0338 PG 10 WC Oncology SC Oncology GA 250WB UT WOS:000326886000027 PM 23966622 ER PT J AU Whitney, N Kareus, S Cetas, JS Chung, K Brodsky, M AF Whitney, Nathaniel Kareus, Seth Cetas, Justin S. Chung, Kathryn Brodsky, Matthew TI Bilateral Deep Brain Stimulation Targeting Ventralis Intermedius Nucleus to Treat a Professional Musician's Task-Specific Tremor SO MOVEMENT DISORDERS LA English DT Letter ID PRIMARY WRITING TREMOR; DYSTONIA; WRITERS; CRAMP C1 [Whitney, Nathaniel; Cetas, Justin S.] Oregon Hlth & Sci Univ, Dept Neurol Surg, Portland, OR 97201 USA. [Kareus, Seth; Chung, Kathryn; Brodsky, Matthew] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Cetas, Justin S.; Chung, Kathryn; Brodsky, Matthew] Portland VA Med Ctr, Portland, OR USA. RP Brodsky, M (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. EM brodskym@ohsu.edu NR 7 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD NOV PY 2013 VL 28 IS 13 BP 1896 EP 1897 DI 10.1002/mds.25577 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 250NN UT WOS:000326859600030 PM 23893475 ER PT J AU MacDonald, SM Sethi, R Lavally, B Yeap, BY Marcus, KJ Caruso, P Pulsifer, M Huang, M Ebb, D Tarbell, NJ Yock, TI AF MacDonald, Shannon M. Sethi, Roshan Lavally, Beverly Yeap, Beow Y. Marcus, Karen J. Caruso, Paul Pulsifer, Margaret Huang, Mary Ebb, David Tarbell, Nancy J. Yock, Torunn I. TI Proton radiotherapy for pediatric central nervous system ependymoma: clinical outcomes for 70 patients SO NEURO-ONCOLOGY LA English DT Article DE central nervous system; pediatric ependymoma; proton; radiation ID CONFORMAL RADIATION-THERAPY; GROWTH-HORMONE-SECRETION; INTRACRANIAL EPENDYMOMA; LOCALIZED EPENDYMOMA; PROGNOSTIC-FACTORS; ANAPLASTIC EPENDYMOMA; CHILDHOOD EPENDYMOMA; BRAIN-TUMORS; PHASE-II; CHILDREN AB Ependymoma is treated with maximal surgical resection and localized radiotherapy. Minimizing unnecessary exposure to radiation is of paramount importance for young children. Proton radiotherapy (PRT) spares healthy tissues outside the target region, but reports of clinical outcomes are scarce. We report outcomes for 70 patients treated with PRT for intracranial ependymoma. Seventy patients with localized ependymoma treated with involved-field PRT at the Massachusetts General Hospital between October 2000 and February 2011 were included. Median age at diagnosis was 38 months (range, 3 mo20 y). Nineteen (27) patients had supratentorial ependymoma and 51(73) had infratentorial ependymoma. Forty-six (66) had gross total resection (GTR), and 24 (34) had subtotal resection (STR). At a median follow-up of 46 months, 3-year local control, progression-free survival, and overall survival were 83, 76, and 95, respectively. STR was significantly associated with worse progression-free survival (54 vs 88, P .001) and overall survival (90 vs 97 for GTR, P .001). In a subset of patients (n 14), mean intelligence was 108.5 at baseline and 111.3 after mean 2.05 years of follow-up. In a larger group of patients (n 28), overall adaptive skills were 100.1 at baseline and 100.8 after 2.21 years of follow-up. Few patients developed evidence of growth hormone deficiency, hypothyroidism, or hearing loss. Outcomes for children treated with PRT compare favorably with the literature. STR correlated with inferior outcome. The young age at diagnosis and the proximity of critical structures in patients with ependymoma make PRT an ideal radiation modality. C1 [MacDonald, Shannon M.; Sethi, Roshan; Tarbell, Nancy J.; Yock, Torunn I.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Lavally, Beverly; Huang, Mary; Ebb, David] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Yeap, Beow Y.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Pulsifer, Margaret] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Caruso, Paul] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Marcus, Karen J.] Childrens Hosp, Boston, MA 02115 USA. RP MacDonald, SM (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Yawkey 112,30 Fruit St, Boston, MA 02114 USA. EM smacdonald@partners.org FU Doris Duke Charitable Foundation; Massachusetts General Hospital, Proton Therapy Research and Treatment Center [C06 CA059267] FX R.V.S. was supported as a clinical research fellow by a grant from the Doris Duke Charitable Foundation to Harvard Medical School. B.Y.Y. and a portion of this research was supported by the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center. NR 30 TC 30 Z9 30 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2013 VL 15 IS 11 BP 1552 EP 1559 DI 10.1093/neuonc/not121 PG 8 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 249AH UT WOS:000326747900012 PM 24101739 ER PT J AU Prudente, S Copetti, M Morini, E Mendonca, C Andreozzi, F Chandalia, M Baratta, R Pellegrini, F Mercuri, L Bailetti, D Abate, N Frittitta, L Sesti, G Florez, JC Doria, A Trischitta, V AF Prudente, S. Copetti, M. Morini, E. Mendonca, C. Andreozzi, F. Chandalia, M. Baratta, R. Pellegrini, F. Mercuri, L. Bailetti, D. Abate, N. Frittitta, L. Sesti, G. Florez, J. C. Doria, A. Trischitta, V. CA DIAGRAM Consortium TI The SH2B1 obesity locus and abnormal glucose homeostasis: Lack of evidence for association from a meta-analysis in individuals of European ancestry SO NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES LA English DT Article DE SNP; Type 2 diabetes; Obesity; Glucose homeostasis; SH2B1 ID BODY-MASS INDEX; GENOME-WIDE ASSOCIATION; TYPE-2 DIABETES RISK; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; PRO12ALA POLYMORPHISM; ADULT OBESITY; VARIANTS; SENSITIVITY; SH2-B AB Background/Aims: The development of type 2 diabetes (T2D) is influenced both by environmental and by genetic determinants. Obesity is an important risk factor for T2D, mostly mediated by obesity-related insulin resistance. Obesity and insulin resistance are also modulated by the genetic milieu; thus, genes affecting risk of obesity and insulin resistance might also modulate risk of T2D. Recently, 32 loci have been associated with body mass index (BMI) by genome-wide studies, including one locus on chromosome 16p11 containing the SH2B1 gene. Animal studies have suggested that SH2B1 is a physiological enhancer of the insulin receptor and humans with rare deletions or mutations at SH2B1 are obese with a disproportionately high insulin resistance. Thus, the role of SH2B1 in both obesity and insulin resistance makes it a strong candidate for T2D. However, published data on the role of SH2B1 variability on the risk for T2D are conflicting, ranging from no effect at all to a robust association. Methods: The SH2B1 tag SNP rs4788102 (SNP, single nucleotide polymorphism) was genotyped in 6978 individuals from six studies for abnormal glucose homeostasis (AGH), including impaired fasting glucose, impaired glucose tolerance or T2D, from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) consortium. Data from these studies were then meta-analyzed, in a Bayesian fashion, with those from DIAGRAM+ (n = 47,117) and four other published studies (n = 39,448). Results: Variability at the SH2B1 obesity locus was not associated with AGH either in the GENIUS consortium (overall odds ratio (OR) = 0.96; 0.89-1.04) or in the meta-analysis (OR = 1.01; 0.98-1.05). Conclusion: Our data exclude a role for the SH2B1 obesity locus in the modulation of AGH. (C) 2013 Elsevier B. V. All rights reserved. C1 [Prudente, S.; Mercuri, L.; Bailetti, D.; Trischitta, V.] IRCSS Casa Sollievo Sofferenza, Mendel Lab, San Giovanni Rotondo, Italy. [Copetti, M.; Pellegrini, F.] IRCSS Casa Sollievo Sofferenza, Biostat Unit, San Giovanni Rotondo, Italy. [Morini, E.; Trischitta, V.] Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy. [Mendonca, C.; Doria, A.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Andreozzi, F.; Sesti, G.] Magna Graecia Univ Catanzaro, Dept Med & Surg Sci, Catanzaro, Italy. [Chandalia, M.; Abate, N.] Univ Texas SW Med Ctr Dallas, Dept Med, Div Endocrinol & Metab, Dallas, TX 75390 USA. [Chandalia, M.; Abate, N.] Univ Texas SW Med Ctr Dallas, Ctr Human Nutr, Dallas, TX 75390 USA. [Baratta, R.; Frittitta, L.] Univ Catania, Sch Med, Garibaldi Hosp, Endocrinol Unit,Dept Clin & Mol Biomed, Catania, Italy. [Pellegrini, F.] Consorzio Mario Negri Sud, Biostat Unit, Chieti, Italy. [Florez, J. C.; Doria, A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Florez, J. C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, J. C.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. [Florez, J. C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Doria, A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Trischitta, V.] IRCCS Casa Sollievo Sofferenza, Res Unit Diabet & Endocrine Dis, San Giovanni Rotondo, Italy. RP Prudente, S (reprint author), CSS Mendel Inst, Viale Regina Margherita 261, I-00198 Rome, Italy. EM s.prudente@css-mendel.it; vincenzo.trischitta@uniroma1.it RI Sesti, Giorgio/B-1509-2012; Altshuler, David/A-4476-2009; Hide, Winston Hide/C-7217-2009; Boehm, Bernhard/F-8750-2015; Meitinger, Thomas/O-1318-2015; Prudente, Sabrina/H-2886-2016; Rudan, Igor/I-1467-2012; Trischitta, Vincenzo/K-1487-2016; Copetti, Massimiliano/K-3186-2016; OI Zeggini, Eleftheria/0000-0003-4238-659X; Sesti, Giorgio/0000-0002-1618-7688; Jorgensen, Torben/0000-0001-9453-2830; Hattersley, Andrew/0000-0001-5620-473X; Altshuler, David/0000-0002-7250-4107; Hide, Winston Hide/0000-0002-8621-3271; Prudente, Sabrina/0000-0001-9220-8981; Rudan, Igor/0000-0001-6993-6884; Trischitta, Vincenzo/0000-0003-1174-127X; Copetti, Massimiliano/0000-0002-7960-5947; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Andreozzi, Francesco/0000-0001-9375-1513 FU Italian Ministry of Health; European Union [LSHM-CT-2004-512013] FX This work was partly supported by the Italian Ministry of Health (Ricerca Corrente 2011 and 2012 to S.P., F.P. and V.T.) and by the European Union (FP6 EUGENE2 no LSHM-CT-2004-512013 to G.S.). NR 43 TC 4 Z9 4 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0939-4753 EI 1590-3729 J9 NUTR METAB CARDIOVAS JI Nutr. Metab. Carbiovasc. Dis. PD NOV PY 2013 VL 23 IS 11 BP 1043 EP 1049 DI 10.1016/j.numecd.2013.05.001 PG 7 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism; Nutrition & Dietetics SC Cardiovascular System & Cardiology; Endocrinology & Metabolism; Nutrition & Dietetics GA 252EC UT WOS:000326986800002 PM 24103803 ER PT J AU Morse, LK AF Morse, Linda Knight TI The End of Your Life Book Club SO ONCOLOGY NURSING FORUM LA English DT Book Review C1 [Morse, Linda Knight] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Morse, LK (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 BP 611 EP 611 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 250IT UT WOS:000326847100016 ER PT J AU Osaki, TH de Castro, DK Yabumoto, C Mingkwansook, V Ting, E Nallasamy, N Curtin, H Fay, A AF Osaki, Tammy H. de Castro, Dawn K. Yabumoto, Cristina Mingkwansook, Varalee Ting, Eric Nallasamy, Nambi Curtin, Hugh Fay, Aaron TI Comparison of Methodologies in Volumetric Orbitometry SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID ORBITAL VOLUME; COMPUTED-TOMOGRAPHY; GROWTH; ENOPHTHALMOS; SOFTWARE AB Purpose: The rate at which the orbit matures is not well-documented. Limiting this pursuit are the difficulties inherent in measuring orbital volumes accurately. This study compared 3 common methods of determining orbital volume and sought to identify an accurate, practical manner for doing so. Methods: The volume of 1 orbit of 8 human cadaver heads was independently measured using 3 different methods: 1) CT was performed, and images were analyzed with 3-dimensional (3D) volumetric software; 2) The same orbits were then exenterated and a silicone cast was taken. The cast volumes were measured by water displacement; 3) The orbits were then filled with 1-mm glass beads that were transferred to a graduated cylinder where their volume was determined. The data were analyzed statistically. Results: Intraobserver agreements were good for both beads and casts. Interobserver agreements were good for both beads and CT (p > 0.05). Values obtained using the bead method were equal to values obtained using the cast method (p > 0.05). However, agreement between direct (orbital fillers and casts) and indirect measurements (radiographic techniques) was not satisfactory (p < 0.05). Conclusions: Independent of method, determining orbital volume is inherently difficult owing to the hyperbolic parabola that is the orbit entrance; all methods require estimation. Glass beads and casts yielded more reproducible values but can only be used in cadavers. CT measurement is prone to error due to the variability of methodologies used but allows access to enormous testing populations. Interstudy comparison is currently not possible. CT volumetric software with strict universal standards for estimating the anterior limit of the orbit appears to be the best method of studying human orbital volumes. C1 [Osaki, Tammy H.; de Castro, Dawn K.; Fay, Aaron] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Osaki, Tammy H.; de Castro, Dawn K.; Fay, Aaron] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Osaki, Tammy H.; Yabumoto, Cristina] Fed Univ Sao Paulo UNIFESP, Dept Ophthalmol, Ophthalm Plast Surg Div, Sao Paulo, Brazil. [Mingkwansook, Varalee; Ting, Eric; Curtin, Hugh] Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. [Ting, Eric] Natl Univ Hlth Syst, Dept Diagnost Imaging, Singapore, Singapore. [Nallasamy, Nambi] Harvard Univ, Sch Med, Boston, MA USA. RP Fay, A (reprint author), Mass Eye & Ear Infirm, 243 Charles St,10th Floor, Boston, MA 02114 USA. EM Aaron_fay@meei.harvard.edu RI Ting, Eric/F-5520-2014; Osaki, Tammy /G-1539-2016; Menezes, Isabel/D-9281-2012 OI Ting, Eric/0000-0002-6812-4945; FU CAPES Foundation; Pan American Ophthalmological Foundation; Retina Research Foundation FX Supported in part by CAPES Foundation and received the Gillingham Award from the Pan American Ophthalmological Foundation and Retina Research Foundation (T.H.O.). NR 35 TC 5 Z9 5 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0740-9303 EI 1537-2677 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD NOV-DEC PY 2013 VL 29 IS 6 BP 431 EP 436 DI 10.1097/IOP.0b013e31829d028a PG 6 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 253YK UT WOS:000327125700015 PM 24217474 ER PT J AU Gupta, M Shah, AS Vergilio, JA Chou, J Elliott, A AF Gupta, Meenakashi Shah, Ankoor S. Vergilio, Jo-Anne Chou, Janet Elliott, Alexandra TI Orbital Follicular Hyperplasia in Common Variable Immune Deficiency Syndrome SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID LYMPHOID INTERSTITIAL PNEUMONITIS; IMMUNODEFICIENCY SYNDROME; DISEASE; HYPOGAMMAGLOBULINEMIA; PATIENT AB Common variable immune deficiency (CVID) is characterized by reduced serum immune globulins and impaired or absent antibody responses. Patients become more susceptible to infections and to lymphoproliferation and granulomatous inflammation. Ophthalmic manifestations of CVID are rare. The authors describe a case of orbital follicular hyperplasia in a 15-year-old girl with CVID syndrome causing proptosis and exposure keratopathy. C1 [Gupta, Meenakashi] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Gupta, Meenakashi; Shah, Ankoor S.; Elliott, Alexandra] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Shah, Ankoor S.; Elliott, Alexandra] Boston Childrens Hosp, Dept Ophthalmol, Boston, MA 02115 USA. [Vergilio, Jo-Anne] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Vergilio, Jo-Anne] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Chou, Janet] Boston Childrens Hosp, Dept Allergy Immunol, Boston, MA 02115 USA. [Chou, Janet] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Shah, AS (reprint author), Boston Childrens Hosp, Dept Ophthalmol, Fegan 4,300 Longwood Ave, Boston, MA 02115 USA. EM ankoor.shah@childrens.harvard.edu FU Heed Ophthalmic Foundation, Cleveland, OH; Children's Hospital Ophthalmology Foundation, Boston, MA FX Supported by the Heed Ophthalmic Foundation, Cleveland, OH (A.S.S.) and, in part, by the Children's Hospital Ophthalmology Foundation, Boston, MA. NR 19 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0740-9303 EI 1537-2677 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD NOV-DEC PY 2013 VL 29 IS 6 BP E160 EP E162 DI 10.1097/IOP.0b013e3182873c61 PG 3 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 253YK UT WOS:000327125700010 PM 23446300 ER PT J AU Moschovis, PP Banajeh, S MacLeod, WB Saha, S Hayden, D Christiani, DC Mino, G Santosham, M Thea, DM Qazi, S Hibberd, PL AF Moschovis, Peter P. Banajeh, Salem MacLeod, William B. Saha, Samir Hayden, Douglas Christiani, David C. Mino, Greta Santosham, Mathuram Thea, Donald M. Qazi, Shamim Hibberd, Patricia L. TI Childhood Anemia at High Altitude: Risk Factors for Poor Outcomes in Severe Pneumonia SO PEDIATRICS LA English DT Article DE pneumonia; anemia; high altitude; international child health ID RESPIRATORY-TRACT INFECTIONS; NUTRITIONAL-STATUS; CHILDREN; SUPPLEMENTATION; EPIDEMIOLOGY; DEFINITION; HEMOGLOBIN; DEFICIENCY; COHORT AB BACKGROUND: Pneumonia is the leading cause of mortality in young children globally, and factors that affect tissue delivery of oxygen may affect outcomes of pneumonia. We studied whether altitude and anemia influence disease severity and outcomes in young children with World Health Organization-defined severe pneumonia. METHODS: We analyzed data from the SPEAR (Severe Pneumonia Evaluation Antimicrobial Research) study, a World Health Organization-and USAID-sponsored multinational randomized controlled trial of antibiotics for severe pneumonia among children aged 2 to 59 months in resource-poor settings. The trial enrolled 958 children in 8 sites at varying elevations, classified as high (>= 2000 m) or low (<2000 m) altitude. We compared illness severity and assessed the effect of anemia on treatment outcome at high and low altitudes, adjusting for potential confounders and study site. RESULTS: Children at high altitudes had significantly lower oxygen saturation on presentation, more cyanosis, lower systolic blood pressure, and higher hemoglobin. After adjusting for potential confounders, anemia predicted treatment failure in children living at high altitude (relative risk: 4.07; 95% confidence interval: 2.60-6.38) but not at low altitude (relative risk: 1.12; 95% confidence interval: 0.96-1.30). Children at high altitude took longer to reach normoxemia than did children at lower altitudes (5.25 vs 0.75 days; P <.0001). CONCLUSIONS: Children at high altitude present with more severe disease, and children with anemia at high altitude are at greater risk of poor outcome when being treated for severe pneumonia. Given the high global prevalence of anemia among young children, prevention and treatment of anemia should be a priority in children living at high altitude and could improve outcomes of pneumonia. C1 [Moschovis, Peter P.; Hayden, Douglas; Christiani, David C.; Hibberd, Patricia L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Banajeh, Salem] Sanaa Univ, Sanaa, Yemen. [MacLeod, William B.; Thea, Donald M.] Boston Univ, Ctr Global Hlth & Dev, Boston, MA 02215 USA. [MacLeod, William B.; Thea, Donald M.] Boston Univ, Sch Publ Hlth, Dept Int Hlth, Boston, MA USA. [Saha, Samir] Dhaka Shishu Hosp, Dhaka, Bangladesh. [Christiani, David C.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Mino, Greta] Childrens Hosp Dr Francisco de Ycaza Bustamante, Guayaquil, Ecuador. [Santosham, Mathuram] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. [Santosham, Mathuram] Johns Hopkins Univ, Dept Int Hlth, Baltimore, MD 21218 USA. [Qazi, Shamim] World Hlth Org, Dept Maternal Newborn Child & Adolescent Hlth, Geneva, Switzerland. RP Moschovis, PP (reprint author), Massachusetts Gen Hosp, Div Global Hlth, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM pmoschovis@partners.org FU NCATS NIH HHS [8UL1TR000170-05, UL1 TR000170]; NCCIH NIH HHS [K24 AT003683, K24AT003683]; NICHD NIH HHS [U01 HD058322] NR 31 TC 6 Z9 6 U1 0 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2013 VL 132 IS 5 BP E1156 EP E1162 DI 10.1542/peds.2013-0761 PG 7 WC Pediatrics SC Pediatrics GA 245PE UT WOS:000326475000006 PM 24101768 ER PT J AU Schroeder, AR Mansbach, JM Stevenson, M Macias, CG Fisher, ES Barcega, B Sullivan, AF Espinola, JA Piedra, PA Camargo, CA AF Schroeder, Alan R. Mansbach, Jonathan M. Stevenson, Michelle Macias, Charles G. Fisher, Erin Stucky Barcega, Besh Sullivan, Ashley F. Espinola, Janice A. Piedra, Pedro A. Camargo, Carlos A., Jr. TI Apnea in Children Hospitalized With Bronchiolitis SO PEDIATRICS LA English DT Article DE apnea; bronchiolitis; viral infections; infants; hospitalization ID RESPIRATORY SYNCYTIAL VIRUS; CLINICAL CHARACTERISTICS; TRACT INFECTION; YOUNG-CHILDREN; RISK-FACTORS; INFANTS; MANAGEMENT; MULTICENTER; DIAGNOSIS; SEVERITY AB OBJECTIVE: To identify risk factors for inpatient apnea among children hospitalized with bronchiolitis. METHODS: We enrolled 2207 children, aged <2 years, hospitalized with bronchiolitis at 16 sites during the winters of 2007 to 2010. Nasopharyngeal aspirates (NPAs) were obtained on all subjects, and real-time polymerase chain reaction was used to test NPA samples for 16 viruses. Inpatient apnea was ascertained by daily chart review, with outcome data in 2156 children (98%). Age was corrected for birth <37 weeks. Multivariable logistic regression was performed to identify independent risk factors for inpatient apnea. RESULTS: Inpatient apnea was identified in 108 children (5%, 95% confidence interval [CI] 4%-6%). Statistically significant, independent predictors of inpatient apnea included: corrected ages of <2 weeks (odds ratio [OR] 9.67) and 2 to 8 weeks (OR 4.72), compared with age >= 6 months; birth weight <2.3 kg (5 pounds; OR 2.15), compared with >= 3.2 kg (7 pounds); caretaker report of previous apnea during this bronchiolitis episode (OR 3.63); preadmission respiratory rates of <30 (OR 4.05), 30 to 39 (OR 2.35) and >70 (OR 2.26), compared with 40 to 49; and having a preadmission room air oxygen saturation <90% (OR 1.60). Apnea risk was similar across the major viral pathogens. CONCLUSIONS: In this prospective, multicenter study of children hospitalized with bronchiolitis, inpatient apnea was associated with younger corrected age, lower birth weight, history of apnea, and preadmission clinical factors including low or high respiratory rates and low room air oxygen saturation. Several bronchiolitis pathogens were associated with apnea, with similar apnea risk across the major viral pathogens. C1 [Schroeder, Alan R.] Santa Clara Valley Med Ctr, Dept Pediat, San Jose, CA 95128 USA. [Mansbach, Jonathan M.] Harvard Univ, Sch Med, Dept Med, Boston Childrens Hosp, Boston, MA USA. [Stevenson, Michelle] Univ Louisville, Dept Pediat, Louisville, KY 40292 USA. [Macias, Charles G.] Texas Childrens Hosp, Baylor Coll Med, Sect Emergency Med, Dept Pediat, Houston, TX 77030 USA. [Fisher, Erin Stucky] Univ Calif San Diego, Dept Pediat, Rady Childrens Hosp, San Diego, CA 92103 USA. [Barcega, Besh] Loma Linda Med Ctr, Dept Pediat, Loma Linda, CA USA. [Sullivan, Ashley F.; Espinola, Janice A.; Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. [Piedra, Pedro A.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Piedra, Pedro A.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. RP Schroeder, AR (reprint author), Santa Clara Valley Med Ctr, Dept Pediat, 751 S Bascom Ave, San Jose, CA 95128 USA. EM Alan.Schroeder@hhs.sccgov.org FU NCATS NIH HHS [UL1 TR000077]; NIAID NIH HHS [K23 AI077801, K23 AI-77801, U01 AI-67693, U01 AI067693] NR 27 TC 20 Z9 20 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2013 VL 132 IS 5 BP E1194 EP E1201 DI 10.1542/peds.2013-1501 PG 8 WC Pediatrics SC Pediatrics GA 245PE UT WOS:000326475000010 PM 24101759 ER PT J AU Rosansky, SJ Cancarini, G Clark, WF Eggers, P Germaine, M Glassock, R Goldfarb, DS Harris, D Hwang, SJ Imperial, EB Johansen, KL Kalantar-Zadeh, K Moist, LM Rayner, B Steiner, R Zuo, L AF Rosansky, Steven J. Cancarini, Giovanni Clark, William F. Eggers, Paul Germaine, Michael Glassock, Richard Goldfarb, David S. Harris, David Hwang, Shang-Jyh Imperial, Edwina Brown Johansen, Kirsten L. Kalantar-Zadeh, Kamyar Moist, Louise M. Rayner, Brian Steiner, Robert Zuo, Li TI Dialysis Initiation: What's the Rush? SO SEMINARS IN DIALYSIS LA English DT Article ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; QUALITY-OF-LIFE; NATIONAL COOPERATIVE DIALYSIS; HEMODIALYSIS-PATIENTS; PERITONEAL-DIALYSIS; MAINTENANCE HEMODIALYSIS; NUTRITIONAL PARAMETERS; STARTING DIALYSIS; MEMBRANE FLUX AB The recent trend to early initiation of dialysis (at eGFR >10ml/min/1.73m(2)) appears to have been based on conventional wisdoms that are not supported by evidence. Observational studies using administrative databases report worse comorbidity-adjusted dialysis survival with early dialysis initiation. Although some have concluded that the IDEAL randomized controlled trial of dialysis start provided evidence that patients become symptomatic with late dialysis start, there is no definitive support for this view. The potential harms of early start of dialysis, including the loss of residual renal function (RRF), have been well documented. The rate of RRF loss (renal function trajectory) is an important consideration for the timing of the dialysis initiation decision. Patients with low glomerular filtration rate (GFR) may have sufficient RRF to be maintained off dialysis for years. Delay of dialysis start until a working arterio-venous access is in place seems prudent in light of the lack of harm and possible benefit of late dialysis initiation. Prescribing frequent hemodialysis is not recommended when dialysis is initiated early. The benefits of early initiation of chronic dialysis after episodes of congestive heart failure or acute kidney injury require further study. There are no data to show that early start benefits diabetics or other patient groups. Preemptive start of dialysis in noncompliant patients may be necessary to avoid complications. The decision to initiate dialysis requires informed patient consent and a joint decision by the patient and dialysis provider. Possible talking points for obtaining informed consent are provided. C1 [Rosansky, Steven J.] Univ SC, Sch Publ Hlth, WJBDVA Hosp, Dorn Res Inst, Columbia, SC USA. [Cancarini, Giovanni] AO Spedali Civili, OU Nephrol, Brescia, Italy. [Cancarini, Giovanni] Univ Brescia, Brescia, Italy. [Clark, William F.] Western Univ Canada, London Hlth Sci Ctr, London, ON, Canada. [Eggers, Paul] NIDDK, Bethesda, MD 20892 USA. [Germaine, Michael] Tufts Univ, Sch Med, Baystate Med Ctr, Springfield, MA 01199 USA. [Glassock, Richard] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Goldfarb, David S.] New York Harbor VA Healthcare Syst, Langone Med Ctr, Nephrol Sect, New York, NY USA. [Goldfarb, David S.] NYU, New York, NY USA. [Harris, David] Univ Sydney, Westmead Millennium Inst, Sydney, Australia. [Hwang, Shang-Jyh] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Div Nephrol, Kaohsiung, Taiwan. [Imperial, Edwina Brown] Hammersmith Hosp, Renal & Transplant Ctr, London, England. [Johansen, Kirsten L.] Univ Calif San Francisco, San Francisco VA Med Ctr, Div Nephrol, San Francisco, CA 94143 USA. [Johansen, Kirsten L.] Nephrol Sect, San Francisco, CA USA. [Kalantar-Zadeh, Kamyar] Univ Calif Irvine, Sch Med, UC Irvine Med Ctr, Div Nephrol & Hypertens, Irvine, CA USA. [Moist, Louise M.] Univ Western Ontario, Schulich Sch Med & Dent, London Hlth Sci Ctr, Kidney Clin Res Unit, London, ON, Canada. [Rayner, Brian] Groote Schuur Hosp, Div Nephrol & Hypertens, ZA-7925 Cape Town, South Africa. [Rayner, Brian] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Steiner, Robert] Univ Calif San Diego, San Diego Med Ctr, San Diego, CA 92103 USA. [Zuo, Li] Peking Univ, Hosp 1, Inst Nephrol, Renal Div,Key Lab,Minist Hlth, Beijing, Peoples R China. RP Rosansky, SJ (reprint author), Dorn Res Inst, 526 N Trenholm Rd, Columbia, SC 29206 USA. EM sjrcra@yahoo.com OI Rayner, Brian/0000-0002-0167-9591; Kalantar-Zadeh, Kamyar/0000-0002-8666-0725; Goldfarb, David/0000-0002-9215-1273 NR 73 TC 15 Z9 15 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-0959 EI 1525-139X J9 SEMIN DIALYSIS JI Semin. Dial. PD NOV PY 2013 VL 26 IS 6 BP 650 EP 657 DI 10.1111/sdi.12134 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 252SK UT WOS:000327030200005 PM 24066675 ER PT J AU Treit, K Lam, D O'Hare, AM AF Treit, Kathryn Lam, Daniel O'Hare, Ann M. TI Timing of Dialysis Initiation in the Geriatric Population: Toward a Patient-centered Approach SO SEMINARS IN DIALYSIS LA English DT Article ID CHRONIC KIDNEY-DISEASE; SHARED DECISION-MAKING; STAGE RENAL-DISEASE; CONSERVATIVE MANAGEMENT; OF-LIFE; ELDERLY-PATIENTS; UNITED-STATES; OLDER-ADULTS; END; CARE AB Over the last 10-15years, the incidence of treated end-stage renal disease (ESRD) among older adults has increased and dialysis is being initiated at progressively higher levels of estimated glomerular filtration rate (eGFR). Average life expectancy after dialysis initiation among older adults is quite limited, and many experience an escalation of care and loss of independence after starting dialysis. Available data suggest that treatment decisions about dialysis initiation in older adults in the United States are guided more by system- than by patient-level factors. Stronger efforts are thus needed to ensure that treatment decisions for older adults with advanced kidney disease are optimally aligned with their goals and preferences. There is growing interest in more conservative approaches to the management of advanced kidney disease in older patients who prefer not to initiate dialysis and those for whom the harms of dialysis are expected to outweigh the benefits. A number of small single center studies, mostly from the United Kingdom report similar survival among the subset of older adults with a high burden of comorbidity treated with dialysis vs. those managed conservatively. However, the incidence of treated ESRD in older US adults is several-fold higher than in the United Kingdom, despite a similar prevalence of chronic kidney disease, suggesting large differences in the social, cultural, and economic context in which dialysis treatment decisions unfold. Thus, efforts may be needed to adapt conservative care models developed outside the United States to optimally meet the needs of US patients. More flexible approaches toward dialysis prescription and better integration of treatment decisions about conservative care with those related to modality selection will likely be helpful in meeting the needs of individual patients. Regardless of the chosen treatment strategy, time can often be a critical ally in centering care on what matters most to the patient, and a flexible and iterative approach of re-evaluation and redirection may often be needed to ensure that treatment strategies are fully aligned with patient priorities. C1 [Treit, Kathryn; Lam, Daniel; O'Hare, Ann M.] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [O'Hare, Ann M.] VA Puget Sound Healthcare Syst, Seattle, WA USA. RP O'Hare, AM (reprint author), 1660 South Columbian Way, Seattle, WA 98108 USA. EM Ann.OHare@va.gov NR 50 TC 17 Z9 17 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-0959 EI 1525-139X J9 SEMIN DIALYSIS JI Semin. Dial. PD NOV PY 2013 VL 26 IS 6 BP 682 EP 689 DI 10.1111/sdi.12131 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 252SK UT WOS:000327030200009 PM 24112631 ER PT J AU Johansen, KL Delgado, C Bao, YR Tamura, MK AF Johansen, Kirsten L. Delgado, Cynthia Bao, Yeran Tamura, Manjula Kurella TI Frailty and Dialysis Initiation SO SEMINARS IN DIALYSIS LA English DT Article ID GLOMERULAR-FILTRATION-RATE; SURVIVAL; MORTALITY; OLDER; START; HEMODIALYSIS; COMORBIDITY; PREDICTION; DISABILITY; DISEASE AB Frailty is a physiologic state of increased vulnerability to stressors that results from decreased physiologic reserves or dysregulation of multiple physiologic systems. The construct of frailty has been operationalized as a composite of poor physical function, exhaustion, low physical activity, and weight loss. Several studies have now examined the prevalence of frailty among chronic kidney disease (CKD) or end-stage renal disease (ESRD) patients and have found frailty to be more common among individuals with CKD than among those without. Furthermore, frailty is associated with adverse outcomes among incident dialysis patients, including higher risk of hospitalization and death. Recent evidence shows that frail patients are started on dialysis earlier (at a higher estimated glomerular filtration rate [eGFR]) on average than nonfrail patients, but it remains unclear whether these patients' frailty is a result of uremia or is independent of CKD. The survival disadvantage that has been associated with early initiation of dialysis in observational studies could be mediated in part through confounding on the basis of unmeasured frailty. However, available data do not suggest improvement in frailty upon initiation of dialysis; rather, the trajectory appears to be toward higher levels of dependence in activities of daily living (ADLs) after dialysis initiation. Overall, there are no data to suggest that frail patients derive any benefit from early initiation of dialysis either in the form of improved survival or functional status. C1 [Johansen, Kirsten L.; Delgado, Cynthia] Univ Calif San Francisco, Dept Med, Div Nephrol, San Francisco, CA USA. [Johansen, Kirsten L.; Delgado, Cynthia] San Francisco VA Med Ctr, Nephrol Sect, San Francisco, CA 94121 USA. [Bao, Yeran] John Muir Med Grp, Walnut Creek, CA USA. [Tamura, Manjula Kurella] Geriatr Res & Educ Clin Ctr, Palo Alto, CA USA. [Tamura, Manjula Kurella] Stanford Univ, Sch Med, Dept Med, VA Hlth Care Syst, Palo Alto, CA 94304 USA. [Tamura, Manjula Kurella] Stanford Univ, Sch Med, Dept Med, Div Nephrol, Palo Alto, CA 94304 USA. RP Johansen, KL (reprint author), San Francisco VA Med Ctr, Nephrol Sect, 4150 Clement St,111J, San Francisco, CA 94121 USA. EM kirsten.johansen@ucsf.edu RI Kurella Tamura, Manjula/C-8284-2014 OI Kurella Tamura, Manjula/0000-0001-5227-2479 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [1K24DK085153]; VA Career Development Award FX Dr. Johansen is supported by 1K24DK085153 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr. Delgado is supported by a VA Career Development Award. NR 36 TC 9 Z9 10 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-0959 EI 1525-139X J9 SEMIN DIALYSIS JI Semin. Dial. PD NOV PY 2013 VL 26 IS 6 BP 690 EP 696 DI 10.1111/sdi.12126 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 252SK UT WOS:000327030200010 PM 24004376 ER PT J AU Watnick, S AF Watnick, Suzanne TI Financial and Medico-Legal Implications of Late-Start Dialysis: Understanding the Present Policies through a Window of Past Performance SO SEMINARS IN DIALYSIS LA English DT Article ID STAGE RENAL-DISEASE; EARLY INITIATION; HEMODIALYSIS; COMORBIDITY; IMPROVEMENT; MORTALITY; SURVIVAL; FAILURE; PATIENT AB In the United States, multiple stakeholders have impacted the timing of dialysis initiation for patients with end-stage renal disease. The optimal policy to start dialysis for this vulnerable population remains unknown. Historically, patients initiated dialysis weeks after the appearance of uremic symptoms. This changed not only due to an evolution in medical providers' practice but also due to changes in the care delivery system, the political imperatives, and the economic driving forces surrounding the care of these patients. One large randomized control trial looked at patient outcomes with strategies of early versus late start. The trial included an economic analysis. Depending on the specific comparison, cost was either lower in the late-start group or was equivalent between groups. This result would tend to favor a late-start strategy, where patients had an additional 6months of dialysis-free time. However, the generalizability of this analysis has been questioned. Future care models that would include patients before and after dialysis initiation would be ideal to study cost and quality at the time of this transition of care. The recently implemented CMS Quality Incentive Program is one mechanism that could use such findings to implement a high-value strategy for patients starting chronic dialysis therapies. C1 [Watnick, Suzanne] Oregon Hlth & Sci Univ, Div Nephrol & Hypertens, Portland, OR 97201 USA. [Watnick, Suzanne] Portland VA Med Ctr, Portland, OR 97207 USA. [Watnick, Suzanne] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Watnick, S (reprint author), Portland VA Med Ctr, P3NEPH,3710 SW US Vet Hosp Rd, Portland, OR 97207 USA. EM Suzanne.Watnick@va.gov NR 41 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-0959 EI 1525-139X J9 SEMIN DIALYSIS JI Semin. Dial. PD NOV PY 2013 VL 26 IS 6 BP 702 EP 705 DI 10.1111/sdi.12135 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 252SK UT WOS:000327030200012 PM 24118409 ER PT J AU Tan, CS Jie, C Joe, J Irani, ZD Ganguli, S Kalva, SP Wicky, S Wu, S AF Tan, Chieh Suai Jie, Cui Joe, Jennifer Irani, Zubin D. Ganguli, Suvranu Kalva, Sanjeeva Prasad Wicky, Stephan Wu, Steven TI The Impact of Transvenous Cardiac Devices on Vascular Access Patency in Hemodialysis Patients SO SEMINARS IN DIALYSIS LA English DT Article ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; ELECTRONIC DEVICES; DIALYSIS PATIENTS; RHYTHM DEVICES; PACEMAKER; DISEASE; HEART; MULTICENTER; PLACEMENT; SURVIVAL AB Creating a vascular access in the presence of a cardiovascular implantable electronic device (CIED) in a patient with or approaching end-stage renal disease can be challenging. In this study, we aimed to evaluate the impact of a CIED on the outcomes of vascular access creation in hemodialysis patients and determine their effects on vascular access patency. This is a single-center retrospective review of hemodialysis patients who underwent vascular access creation after CIED placement. Outcomes of vascular access creation and need for endovascular interventions were compared between patients with vascular access created ipsilateral and contralateral to the site of CIED. Comparing patients with arteriovenous (AV) access created ipsilateral to CIED placement (n=19) versus the contralateral side (n=17), the primary failure rate was 78.9% versus 35.3% (p=0.02). For AV accesses that were matured, the median primary patency durations for AV accesses created ipsilateral to the CIED was 11.2months compared to 7.8months for AV accesses created contralateral to the CIED (p=1.00). AV accesses created ipsilateral to a CIED have a higher primary failure rate compared with the contralateral arm and should be avoided as much as possible. C1 [Tan, Chieh Suai; Irani, Zubin D.; Ganguli, Suvranu; Kalva, Sanjeeva Prasad; Wicky, Stephan; Wu, Steven] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vasc Imaging & Intervent Div, Boston, MA USA. [Jie, Cui; Joe, Jennifer; Wu, Steven] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol, Boston, MA USA. [Tan, Chieh Suai; Jie, Cui; Joe, Jennifer; Irani, Zubin D.; Ganguli, Suvranu; Kalva, Sanjeeva Prasad; Wicky, Stephan; Wu, Steven] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. RP Wu, S (reprint author), Massachusetts Gen Hosp, Dept Med, Hemodialysis Vasc Access Program, 55 Fruit St, Boston, MA 02114 USA. EM wu.steven@mgh.harvard.edu NR 25 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-0959 EI 1525-139X J9 SEMIN DIALYSIS JI Semin. Dial. PD NOV PY 2013 VL 26 IS 6 BP 728 EP 732 DI 10.1111/sdi.12073 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 252SK UT WOS:000327030200016 PM 23458207 ER PT J AU Schaefer, EAK Chung, RT AF Schaefer, Esperance A. K. Chung, Raymond T. TI HCV and Host Lipids: An Intimate Connection SO SEMINARS IN LIVER DISEASE LA English DT Review DE hepatitis C; lipid metabolism; host factors; hypocholesterolemia; lipoviral particle ID HEPATITIS-C VIRUS; FATTY-ACID SYNTHASE; B TYPE-I; TRIGLYCERIDE TRANSFER PROTEIN; DENSITY-LIPOPROTEIN RECEPTOR; SCAVENGER RECEPTOR; CORE PROTEIN; RNA REPLICATION; DIACYLGLYCEROL ACYLTRANSFERASE-1; CHOLESTEROL-SYNTHESIS AB The hepatitis C virus (HCV) requires elements of host lipid metabolism for every step in the viral life cycle. Clinically, it has long been observed that patients with chronic hepatitis C have lower nonhigh-density lipoprotein cholesterol, and these levels rise after successful treatment. The HCV itself circulates as a highly lipidated lipoviral particle, which closely resembles very low-density lipoprotein (VLDL). Several required coentry factors for the virus to gain access to the hepatocytes have been described, and several, including SRB1, LDL-R, and the NPC1L1 receptors, are important receptors for lipoprotein and cholesterol uptake. Inside the cell, the virus induces lipogenesis, and specifically induces the master regulator sterol response element binding protein. Viral replication then requires the concerted efforts of viral proteins combined with several host factors involved in cholesterol synthesis. The virus is then packaged alongside the cellular machinery for VLDL production. The complex interplay highlights pathways of hepatic steatosis and unveils drug targets for the treatment of HCV. C1 [Schaefer, Esperance A. K.; Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, GI Unit, Boston, MA 02114 USA. RP Schaefer, EAK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, GI Unit, 55 Fruit St, Boston, MA 02114 USA. EM eschaefer@partners.org NR 107 TC 21 Z9 22 U1 1 U2 12 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0272-8087 EI 1098-8971 J9 SEMIN LIVER DIS JI Semin. Liver Dis. PD NOV PY 2013 VL 33 IS 4 BP 358 EP 368 DI 10.1055/s-0033-1358524 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 251WP UT WOS:000326963900007 PM 24222093 ER PT J AU Benzer, JK Bauer, MS Chams, MP Topor, DR Dickey, CC AF Benzer, Justin K. Bauer, Mark S. Chams, Martin P. Topor, David R. Dickey, Chandlee C. TI Resident/Faculty Collaboration for Systems-Based Quality Improvement SO ACADEMIC PSYCHIATRY LA English DT Editorial Material C1 [Benzer, Justin K.; Chams, Martin P.] VA Boston Healthcare Syst Ctr Healthcare Org & Im, Boston, MA USA. [Benzer, Justin K.; Chams, Martin P.] Boston Univ, Boston, MA 02215 USA. [Bauer, Mark S.; Dickey, Chandlee C.] VA Boston Hlthcare Syst, Brockton, MA USA. [Topor, David R.] Harvard Univ, Sch Med, Dept Psychiat, VA Boston Healthcare Syst, Boston, MA 02115 USA. RP Benzer, JK (reprint author), VA Boston Healthcare Syst Ctr Healthcare Org & Im, Boston, MA USA. EM justin.benzer@va.gov OI Benzer, Justin/0000-0001-5151-2127 NR 5 TC 2 Z9 2 U1 0 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD NOV-DEC PY 2013 VL 37 IS 6 BP 433 EP 435 PG 3 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA 246TH UT WOS:000326561500016 PM 24185294 ER PT J AU Beach, SR Chen, DT Huffman, JC AF Beach, Scott Richard Chen, Donna T. Huffman, Jeff C. TI Attitudes and Beliefs of Trainees and Nurses Regarding Delirium in the Intensive Care Unit SO ACADEMIC PSYCHIATRY LA English DT Editorial Material ID CONFUSION ASSESSMENT METHOD; EDUCATION; PROFESSIONALS; KNOWLEDGE; ICU C1 [Beach, Scott Richard; Huffman, Jeff C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Chen, Donna T.] NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Beach, SR (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM sbeach1@partners.org NR 15 TC 1 Z9 1 U1 3 U2 11 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD NOV-DEC PY 2013 VL 37 IS 6 BP 436 EP 438 PG 3 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA 246TH UT WOS:000326561500017 PM 24185295 ER PT J AU Torlakovic, L Paster, BJ Ogaard, B Olsen, I AF Torlakovic, Lino Paster, Bruce J. Ogaard, Bjorn Olsen, Ingar TI Changes in the supragingival microbiota surrounding brackets of upper central incisors during orthodontic treatment SO ACTA ODONTOLOGICA SCANDINAVICA LA English DT Article DE fixed orthodontics; HOMIM; molecular microbiology; supragingival plaque ID WHITE-SPOT LESIONS; STREPTOCOCCUS-MUTANS; SUBGINGIVAL PLAQUE; CARIES; PERIODONTITIS; ADOLESCENTS; MICROARRAY; PROFILES; CHILDREN AB Objective. The aim of this study was to determine how fixed orthodontic appliances affect microbiota of supragingival plaque over 5 months. Materials and methods. Twenty individuals of Scandinavian origin, aged 10-16 years, were included. All subjects were fitted with fixed orthodontic appliances in both the maxillary and mandibular tooth arches. Pooled supragingival plaque samples from the labial surface of the two maxillary central incisors were collected before bonding (T1) and afterwards at 4 weeks (T2), 3 months (T3) and 5 months (T4). The plaque index (PI) was recorded for each sampling. The gingival status was documented at T1 and T4 by using clinical photographs. Plaque microbiota was identified using the Human Oral Microbe Identification Microarray (HOMIM). Results. Increased plaque levels were recorded after bonding, however the increase was not significant. The prevalence of gingivitis at the maxillary central incisors increased from 25% at T1 to 74% at T4. No significant changes of the plaque microbiota from the sample area were detected during the 5-month period. Trends toward a microbiota containing more periodontitis-and caries-associated bacteria were detected. Conclusions. Although trends toward a microbiota containing more periodontitis-and caries-associated bacteria were detected, the changes were not severe enough to be significant. Treatment with fixed orthodontics does not necessarily shift the microbiota to a more pathogenic composition. C1 [Torlakovic, Lino; Olsen, Ingar] Univ Oslo, Dept Oral Biol, NO-0316 Oslo, Norway. [Paster, Bruce J.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Paster, Bruce J.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Ogaard, Bjorn] Univ Oslo, Fac Dent, Inst Clin Dent, NO-0316 Oslo, Norway. RP Torlakovic, L (reprint author), Univ Oslo, Fac Dent, Dept Oral Biol, POB 1052, NO-0316 Oslo, Norway. EM linot@odont.uio.no FU University of Oslo, Faculty of Dentistry; University of Oslo, Oslo, Norway FX This work was financially supported by the University of Oslo, Faculty of Dentistry and by a grant from MSLUiO (Molecular Life Science at the University of Oslo). We would also like to thank Dr Jon-Olav Aabakken and his co-workers for allowing LT to collect samples from patients at his orthodontic clinic at Hamar, Norway.; Declaration of Interest: The authors report no conflicts of interest. The study was funded by the Faculty of Dentistry, University of Oslo, Oslo, Norway. NR 22 TC 3 Z9 3 U1 3 U2 12 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0001-6357 EI 1502-3850 J9 ACTA ODONTOL SCAND JI Acta Odontol. Scand. PD NOV PY 2013 VL 71 IS 6 BP 1547 EP 1554 DI 10.3109/00016357.2013.776107 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 248FC UT WOS:000326678700029 PM 24180590 ER PT J AU Kuller, LH Bracken, MB Ogino, S Prentice, RL Tracy, RP AF Kuller, Lewis H. Bracken, Michael B. Ogino, Shuji Prentice, Ross L. Tracy, Russell P. TI The Role of Epidemiology in the Era of Molecular Epidemiology and Genomics: Summary of the 2013 AJE-sponsored Society of Epidemiologic Research Symposium SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE immunology; pathology; study design AB On June 20, 2013, the American Journal of Epidemiology sponsored a symposium at the Society for Epidemiologic Researchs 46th Annual Meeting in Boston, Massachusetts, entitled, What Is the Role of Epidemiology in the Era of Molecular Biology and Genomics? The future of epidemiology depends on innovation in generating interesting and important testable hypotheses that are relevant to population health. These new strategies will depend on new technology, both in measurement of agents and environment and in the fields of pathophysiology and outcomes, such as cellular epidemiology and molecular pathology. The populations to be studied, sample sizes, and study designs should be selected based on the hypotheses to be tested and include case-control, cohort, and clinical trials. Developing large mega cohorts without attention to specific hypotheses is inefficient, will fail to address many associations with high-quality data, and may well produce spurious results. C1 [Kuller, Lewis H.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. [Bracken, Michael B.] Yale Univ, Sch Med, Ctr Perinatal Pediat & Environm Epidemiol, Sch Publ Hlth, New Haven, CT USA. [Ogino, Shuji] Harvard Univ, Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Prentice, Ross L.] Fred Hutchinson Canc Res Ctr, Publ Hlth Serv, Seattle, WA 98104 USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol, Colchester, VT USA. RP Kuller, LH (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, 130 North Bellefield Ave,Room 550, Pittsburgh, PA 15213 USA. EM kullerl@edc.pitt.edu FU NCI NIH HHS [P01 CA053996] NR 0 TC 16 Z9 17 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD NOV 1 PY 2013 VL 178 IS 9 BP 1350 EP 1354 DI 10.1093/aje/kwt239 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 247SZ UT WOS:000326642300001 PM 24105654 ER PT J AU Liu, QL Zhu, XL Xu, LS Fu, YC Garvey, WT AF Liu, Qinglan Zhu, Xiaolin Xu, Lusheng Fu, Yuchang Garvey, W. Timothy TI 6-Mercaptopurine augments glucose transport activity in skeletal muscle cells in part via a mechanism dependent upon orphan nuclear receptor NR4A3 SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE NR4A3; 6-mercaptopurine; glucose transport; gloucose transporter 4 translocation; Akt substrate of 160 kDa; insulin action; skeletal muscle ID ANTINEOPLASTIC AGENT 6-MERCAPTOPURINE; ACUTE LYMPHOBLASTIC-LEUKEMIA; LIGAND-BINDING DOMAIN; GENE-EXPRESSION; GLUT4 TRANSLOCATION; INSULIN-RESISTANCE; METABOLIC DISEASE; AS160; PHOSPHORYLATION; NOR-1 AB The purine anti-metabolite 6-mercaptopurine (6-MP) is widely used for the treatment of leukemia and inflammatory diseases. The cellular effects of 6-MP on metabolism remain unknown; however, 6-MP was recently found to activate the orphan nuclear receptor NR4A3 in skeletal muscle cell lines. We have reported previously that NR4A3 (also known as NOR-1, MINOR) is a positive regulator of insulin sensitivity in adipocytes. To further explore the role of NR4A3 activation in insulin action, we explored whether 6-MP activation of NR4A3 could modulate glucose transport system activity in L6 skeletal muscle cells. We found that 6-MP increased both NR4A3 expression and NR4A3 transcriptional activity and enhanced glucose transport activity via increasing GLUT4 translocation in both basal and insulin-stimulated L6 cells in an NR4A3-dependent manner. Furthermore, 6-MP increased levels of phospho-AS160, although this effect was not modulated by NR4A3 overexpression or knockdown. These primary findings provide a novel proof of principle that 6-MP, a small molecule NR4A3 agonist, can augment glucose uptake in insulin target cells, although this occurs via both NR4A3-dependent and -independent actions; the latter is related to an increase in phospho-AS160. These results establish a novel target for development of new treatments for insulin resistance. C1 [Liu, Qinglan] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Zhu, Xiaolin; Xu, Lusheng; Fu, Yuchang; Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Garvey, W. Timothy] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Liu, QL (reprint author), Univ Alabama Birmingham, Shelby Bldg 1231,1825 Univ Blvd, Birmingham, AL 35294 USA. EM chinglan@uab.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [DK-083562, DK-038764]; Merit Review Program of the Department of Veterans Affairs; Alabama Drug Discovery Alliance FX This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-083562 and DK-038764 to W. T. Garvey), the Merit Review Program of the Department of Veterans Affairs (W. T. Garvey), and the Alabama Drug Discovery Alliance (W. T. Garvey and Y. Fu). NR 44 TC 1 Z9 2 U1 1 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD NOV PY 2013 VL 305 IS 9 BP E1081 EP E1092 DI 10.1152/ajpendo.00169.2013 PG 12 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 246YU UT WOS:000326578600004 PM 24022864 ER PT J AU Attia, E Becker, AE Bryant-Waugh, R Hoek, HW Kreipe, RE Marcus, MD Mitchell, JE Striegel, RH Walsh, BT Wilson, GT Wolfe, BE Wonderlich, S AF Attia, Evelyn Becker, Anne E. Bryant-Waugh, Rachel Hoek, Hans W. Kreipe, Richard E. Marcus, Marsha D. Mitchell, James E. Striegel, Ruth H. Walsh, B. Timothy Wilson, G. Terence Wolfe, Barbara E. Wonderlich, Stephen TI Feeding and Eating Disorders in DSM-5 SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID CLINICAL UTILITY; ANOREXIA-NERVOSA; BULIMIA-NERVOSA; VALIDITY C1 [Walsh, B. Timothy] Columbia Univ, Dept Psychiat, New York, NY 10027 USA. Columbia Univ, Dept Epidemiol, New York, NY USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Weill Cornell Med Coll, New York, NY USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. Great Ormond St Hosp Sick Children, Dept Child & Adolescent Mental Hlth, London, England. Parnassia Psychiat Inst, The Hague, Netherlands. Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 AB Groningen, Netherlands. Univ Rochester, Dept Pediat, Rochester, NY 14627 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. Univ N Dakota, Sch Med & Hlth Sci, Neuropsychiat Res Inst, Dept Clin Neurosci, Fargo, ND USA. Wesleyan Univ, Dept Psychol, Middletown, CT USA. Rutgers State Univ, Grad Sch Appl & Profess Psychol, New Brunswick, NJ 08903 USA. Boston Coll, Sch Nursing, Chestnut Hill, MA 02167 USA. RP Walsh, BT (reprint author), Columbia Univ, Dept Psychiat, New York, NY 10027 USA. EM btw1@columbia.edu OI Hoek, Hans/0000-0001-6353-5465 NR 10 TC 27 Z9 27 U1 2 U2 23 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD NOV PY 2013 VL 170 IS 11 BP 1237 EP 1239 DI 10.1176/appi.ajp.2013.13030326 PG 3 WC Psychiatry SC Psychiatry GA 248SZ UT WOS:000326724300005 PM 24185238 ER PT J AU Pacchiarotti, I Bond, DJ Baldessarini, RJ Nolen, WA Grunze, H Licht, RW Post, RM Berk, M Goodwin, GM Sachs, GS Tondo, L Findling, RL Youngstrom, EA Tohen, M Undurraga, J Gonzalez-Pinto, A Goldberg, JF Yildiz, A Altshuler, LL Calabrese, JR Mitchell, PB Thase, ME Koukopoulos, A Colom, F Frye, MA Malhi, GS Fountoulakis, KN Vazquez, G Perlis, RH Ketter, TA Cassidy, F Akiskal, H Azorin, JM Valenti, M Mazzei, DH Lafer, B Kato, T Mazzarini, L Martinez-Aran, A Parker, G Souery, D Ozerdem, A McElroy, SL Girardi, P Bauer, M Yatham, LN Zarate, CA Nierenberg, AA Birmaher, B Kanba, S El-Mallakh, RS Serretti, A Rihmer, Z Young, AH Kotzalidis, GD MacQueen, GM Bowden, CL Ghaemi, SN Lopez-Jaramillo, C Rybakowski, J Ha, K Perugi, G Kasper, S Amsterdam, JD Hirschfeld, RM Kapczinski, F Vieta, E AF Pacchiarotti, Isabella Bond, David J. Baldessarini, Ross J. Nolen, Willem A. Grunze, Heinz Licht, Rasmus W. Post, Robert M. Berk, Michael Goodwin, Guy M. Sachs, Gary S. Tondo, Leonardo Findling, Robert L. Youngstrom, Eric A. Tohen, Mauricio Undurraga, Juan Gonzalez-Pinto, Ana Goldberg, Joseph F. Yildiz, Aysegul Altshuler, Lori L. Calabrese, Joseph R. Mitchell, Philip B. Thase, Michael E. Koukopoulos, Athanasios Colom, Francesc Frye, Mark A. Malhi, Gin S. Fountoulakis, Konstantinos N. Vazquez, Gustavo Perlis, Roy H. Ketter, Terence A. Cassidy, Frederick Akiskal, Hagop Azorin, Jean-Michel Valenti, Marc Mazzei, Diego Hidalgo Lafer, Beny Kato, Tadafumi Mazzarini, Lorenzo Martinez-Aran, Anabel Parker, Gordon Souery, Daniel Ozerdem, Aysegul McElroy, Susan L. Girardi, Paolo Bauer, Michael Yatham, Lakshmi N. Zarate, Carlos A. Nierenberg, Andrew A. Birmaher, Boris Kanba, Shigenobu El-Mallakh, Rif S. Serretti, Alessandro Rihmer, Zoltan Young, Allan H. Kotzalidis, Georgios D. MacQueen, Glenda M. Bowden, Charles L. Ghaemi, S. Nassir Lopez-Jaramillo, Carlos Rybakowski, Janusz Ha, Kyooseob Perugi, Giulio Kasper, Siegfried Amsterdam, Jay D. Hirschfeld, Robert M. Kapczinski, Flavio Vieta, Eduard TI The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID TREATMENT ENHANCEMENT PROGRAM; MAJOR DEPRESSIVE EPISODE; LONG-TERM FLUOXETINE; MOOD CONVERSION RATE; II DISORDER; STEP-BD; DOUBLE-BLIND; LONGITUDINAL-EVALUATION; LITHIUM MONOTHERAPY; CONTROLLED-TRIALS AB Objective: The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. Method: An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. Results: There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. Conclusions: Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to moodstabilizing medications. C1 [Vieta, Eduard] Univ Barcelona, CIBERSAM Ctr Biomed Res Network Mental Hlth, IDIBAPS Inst Biomed Res August Pi & Sunyer, Bipolar Disorders Program,Clin Inst Neurosci,Hosp, Barcelona, Spain. Univ British Columbia, Dept Psychiat, Mood Disorders Ctr, Vancouver, BC V5Z 1M9, Canada. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Aarhus Univ Hosp, Mood Disorders Res Unit, Risskov, Denmark. Bipolar Collaborat Network, Bethesda, MD USA. Deakin Univ, Sch Med, Geelong, Vic 3217, Australia. Warneford Hosp, Univ Dept Psychiat, Oxford OX3 7JX, England. Massachusetts Gen Hosp, Bipolar Clin, Boston, MA 02114 USA. Massachusetts Gen Hosp, Res Program, Boston, MA 02114 USA. Lucio Bini Mood Disorder Ctr, Cagliari, Italy. Case Western Reserve Univ, Sch Med, Div Child & Adolescent Psychiat, Cleveland, OH 44106 USA. Johns Hopkins Childrens Ctr, Baltimore, MD USA. Univ N Carolina, Dept Psychol, Chapel Hill, NC USA. Univ New Mexico, Sch Med, Dept Psychiat, Albuquerque, NM 87131 USA. Univ Basque Country, Santiago Apostol Hosp, Dept Psychiat, CIBERSAM, Vitoria, Spain. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. Dokuz Eylul Univ, Dept Psychiat, Izmir, Turkey. Dokuz Eylul Univ, Dept Neurosci, Izmir, Turkey. Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA. Univ New S Wales, Sch Psychiat, Randwick, NSW, Australia. Prince Wales Hosp, Black Dog Inst, Randwick, NSW 2031, Australia. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. Ctr Lucio Bini, Rome, Italy. Mayo Clin, Integrated Mood Grp, Dept Psychiat, Rochester, MN USA. Mayo Clin, Integrated Mood Grp, Dept Psychol, Rochester, MN USA. Univ Sydney, Discipline Psychiat, CADE Clin, Sydney, NSW 2006, Australia. Aristotle Univ Thessaloniki, Sch Med, Dept Psychiat 3, GR-54006 Thessaloniki, Greece. Univ Palermo, Dept Neurosci, Buenos Aires, DF, Argentina. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Calif San Diego, Int Mood Ctr, La Jolla, CA 92093 USA. Hop St Marguerite, Marseille, France. Univ Sao Paulo, Sch Med, Bipolar Res Program, Dept & Inst Psychiat, Sao Paulo, Brazil. RIKEN Brain Sci Inst, Lab Mol Dynam Mental Disorders, Saitama, Japan. Univ Roma La Sapienza, Sch Med & Psychol, NESMOS Dept, St Andrea Hosp, I-00185 Rome, Italy. Univ Libre Brussels, Lab Med Psychol, Brussels, Belgium. European Ctr Med Psychol, Brussels, Belgium. Univ Cincinnati, Coll Med, Cincinnati, OH USA. Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Psychiat & Psychotherapy, Dresden, Germany. NIMH, Bethesda, MD 20892 USA. Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA USA. Kyushu Univ, Grad Sch Med Sci, Dept Neuropsychiat, Fukuoka 812, Japan. Univ Louisville, Louisville, KY 40292 USA. Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy. Semmelweis Univ, Dept Clin & Theoret Mental Hlth, H-1085 Budapest, Hungary. Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. Univ Calgary, Dept Psychiat, Calgary, AB, Canada. Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX USA. Tufts Univ, Sch Med, Dept Psychiat, Mood Disorders Program,Tufts Med Ctr, Boston, MA 02111 USA. Univ Antioquia, Dept Psychiat, Fdn San Vicente de Paul, Mood Disorders Program, Medellin, Colombia. Poznan Univ Med Sci, Dept Adult Psychiat, Poznan, Poland. Seoul Natl Univ, Bundang Hosp, Dept Psychiat, Mood Disorders Clin, Bundang, South Korea. Seoul Natl Univ, Bundang Hosp, Dept Psychiat, Clin Affect Neurosci Lab, Bundang, South Korea. Univ Pisa, Dept Psychiat, Pisa, Italy. Med Univ Vienna, Dept Psychiat & Psychotherapy, Vienna, Austria. Univ Penn, Sch Med, Dept Psychiat, Depress Res Unit, Philadelphia, PA 19104 USA. Univ Texas Med Branch, Dept Psychiat & Behav Sci, Galveston, TX 77555 USA. Univ Fed Rio Grande do Sul, Hosp Clin Porto Alegre, Lab Mol Psychiat, Porto Alegre, RS, Brazil. RP Vieta, E (reprint author), Univ Barcelona, CIBERSAM Ctr Biomed Res Network Mental Hlth, IDIBAPS Inst Biomed Res August Pi & Sunyer, Bipolar Disorders Program,Clin Inst Neurosci,Hosp, Barcelona, Spain. EM evieta@clinic.ub.es RI Nolen, Willem/E-9006-2014; Kato, Tadafumi/J-3583-2014; Kapczinski, Flavio/J-5803-2014; Lafer, Beny/F-9390-2015; Undurraga, Juan/F-3438-2012; Lafer, Beny/C-1055-2012; OI Colom, Francesc/0000-0002-9516-9030; Vieta, Eduard/0000-0002-0548-0053; Parker, Gordon/0000-0003-3424-5519; Grunze, Heinz/0000-0003-4712-8979; Kato, Tadafumi/0000-0001-7856-3952; Lafer, Beny/0000-0002-6132-9999; Undurraga, Juan/0000-0001-6958-2369; Lafer, Beny/0000-0002-6132-9999; Martinez-Aran, Anabel/0000-0002-0623-6263; VALENTI, MARC/0000-0002-9783-6220; Mitchell, Philip/0000-0002-7954-5235; Lopez, Carlos/0000-0002-1875-1369; Berk, Michael/0000-0002-5554-6946 FU Canadian Institutes of Health Research; UBC Institute of Mental Health/Coast Capital Depression Research Fund; Pfizer; Netherlands Organization for Health Research and Development; European Union; Stanley Medical Research Institute; AstraZeneca; GlaxoSmithKline; Wyeth; Lundbeck; Bristol-Myers Squibb; Desitin; Eli Lilly; Gedeon-Richter; Hoffmann-La Roche; Janssen-Cilag; Merck; Otsuka; Sanofi-Aventis; Servier; Sepracor; UBC; Medical Research Council; National Institute for Health Research (U.K.); Cambridge University Press; Igaku-Shoin; Solal Ed.; Ars Medica; Giovani Fioriti Ed.; Medipage; La Esfera de Los Libros; Morales i Torres Ed; Panamericana; Mayo Ed. Columna; Mayo Foundation; Myriad; NARSAD; National Institute of Alcohol Abuse and Alcoholism; H; Journal of Affective Disorders; University of Lisbon; Aristotle University of Thesaloniki; Sanofi, Nevada Psychiatric Association; Medical Education Speakers Network; Sanofi; CAPES (Coordination for the Improvement of Higher Education Personnel); FAPESP (Sao Paulo Research Foundation); CNPq (National Council for Scientific and Technological Development); Janssen; Schering; Springer Healthcare; Abbott Laboratories; Agency for Healthcare Research and Quality; American Drug Utilization Review Society; American Society for Clinical Psychopharmacology; Basilea; Biomedical Development, Boston Center for the Arts; BrainCells; Brandeis University; Cederroth; Cephalon; Corcept; Cyberonics; East Asian Bipolar Forum; Elan; Forest; Genaissance; Harold Grinspoon Charitable Foundation; Health New England; Innapharma; International Society for Bipolar Disorder; Jazz Pharmaceuticals; Lichtwer Pharma; MGH Psychiatry Academy; Mid-Atlantic Permanente Research Institute; Mylan; NIMH; Novartis; PamLab; PGx Health; Ridge Diagnostics; Roche; Schering-Plough; Shire, Somerset; Stanley Foundation; Sunovion, Takeda; Targacept; Teva, University of Pisa; University of Wisconsin at Madison; University of Texas Southwestern Medical Center at Dallas; Wyeth-Ayerst; Zucker Hillside Hospital; Astellas; Dainippon Sumitomo; Eisai; Eli Lilly Japan; Kyowa Hakko Kirin; Meiji Seika Pharma; MSD; Ono; Shionogi; Taisho Toyama; Yoshitomiyakuhin; Janssen Cilag; NIH; University of Antioquia FX Dr. Bond has received honoraria from the Canadian Network for Mood and Anxiety Treatments, the Canadian Psychiatric Association, Pfizer, Sunovion, Bristol-Myers Squibb, Otsuka, AstraZeneca, and Janssen-Ortho; and has received research grants from the Canadian Institutes of Health Research, the UBC Institute of Mental Health/Coast Capital Depression Research Fund, and Pfizer. Dr. Nolen has received grants from the Netherlands Organization for Health Research and Development, the European Union, the Stanley Medical Research Institute, AstraZeneca, GlaxoSmithKline, and Wyeth and honoraria or speaking fees from AstraZeneca and Lundbeck. Dr. Grunze has received research support, consulting fees, or honoraria from AstraZeneca, Bristol-Myers Squibb, Desitin, Eli Lilly, Gedeon-Richter, Hoffmann-La Roche, Janssen-Cilag, Lundbeck, Merck, Otsuka, Sanofi-Aventis, Servier, Sepracor, and UBC. Dr. Licht has served on advisory boards for Bristol-Myers Squibb, AstraZeneca, and MSD and has received honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, and Pfizer. Dr. Post has served as a consultant or speaker for AstraZeneca, Sunovion, Teva, and Validas. Dr. Berk has received research support from or served as a consultant or speaker for AstraZeneca, Beyond Blue, Bristol-Myers Squibb, Cancer Council of Victoria, Cooperative Research Centre, Eli Lilly, Geelong Medical Research Foundation, GlaxoSmithKline, Janssen Cilag, Lundbeck, Mayne Pharma, MBF, Meat and Livestock Board, Merck, National Health and Medical Research Council (Australia), NIH, Novartis, Organon, Pfizer, Rotary Health, Sanofi Synthelabo, Servier, Simons Autism Foundation, Stanley Medical Research Foundation, Solvay, Woolworths, and Wyeth and is a co-inventor on two provisional patents regarding the use of N-acetylcysteine and related compounds for psychiatric indications. Dr. Goodwin has received grants from Bailly Thomas, Medical Research Council, National Institute for Health Research (U.K.), and Servier, has served as consultant, adviser, or CME speaker for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Cephalon/Teva Janssen-Cilag, Eli Lilly, Lundbeck, Otsuka, P1Vital, Roche, Servier, Schering-Plough, Shire, Sunovion, and Takeda, and holds shares in P1Vital. Dr. Sachs has served on advisory boards for Elan, Janssen, Merck, Otsuka, Roche, Sunovion, and Takeda. Dr. Findling has received research support or served as a consultant or speaker for Alexza Pharmaceuticals, American Psychiatric Publishing, AstraZeneca, Bracket, Bristol-Myers Squibb, Clinsys, Cognition Group, Forest, GlaxoSmithKline, Guilford Press, Johns Hopkins University Press, Johnson & Johnson, KemPharm, Lilly, Lundbeck, Merck, NIH, Novartis, Noven, Otsuka, Oxford University Press, Pfizer, Physicians Postgraduate Press, Rhodes Pharmaceuticals, Roche, Sage, Seaside Pharmaceuticals, Shire, Stanley Medical Research Institute, Sunovion, Supernus Pharmaceuticals, Transcept Pharmaceuticals, Validus, and WebMD. Dr. Youngstrom has served as a consultant for Lundbeck. Dr. Tohen has received honoraria from or served as a consultant for AstraZeneca, Bristol-Myers Squibb, Elan, Eli Lilly, Forest, GlaxoSmithKline, Johnson & Johnson, Lundbeck, Merck, Otsuka, PamLab, Roche, Sunovion, Teva, Wyeth, and Wiley Publishing; his spouse is an employee and stockholder at Eli Lilly. Dr.; Gonzalez-Pinto has received grants from or served as consultant, adviser, or CME speaker for Almirall, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Jazz, Johnson & Johnson, Lundbeck, Merck, Otsuka, Pfizer, Sanofi-Aventis, Servier, Schering-Plough, Solvay, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), the Basque Government, Stanley Medical Research Institute, and Wyeth. Dr. Goldberg has served as consultant or speaker for AstraZeneca, Grunenthal Group, Medscape, Merck, Mylan Pharmaceuticals, Novartis, Sunovion, and WebMD and receives royalties from American Psychiatric Publishing. Dr. Yildiz has received research grants from or served as a consultant or speaker for Abdi Ibrahim, Actavis, Ali Raif, AstraZeneca, Bristol-Myers Squibb, Janssen-Cilag, Lundbeck, Pfizer, Sanofi-Aventis, and Servier. Dr. Altshuler has served on advisory boards or as a consultant for Eli Lilly, Takeda Pharmaceuticals North America, Lundbeck, Sepracor, and Sunovion. Dr. Calabrese has received funding or research support from or served as a consultant or CME speaker or on advisory boards for Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Cleveland Foundation, Dainippon Sumitomo, Department of Defense, Eli Lilly, EPI-Q, Forest, France Foundation, GlaxoSmithKline, Health Resources Services Administration, Janssen, Johnson & Johnson, Lundbeck, Merck, NARSAD, Neurosearch, NIMH, Ortho-McNeil, Otsuka, Pfizer, Repligen, Sanofi-Aventis, Schering-Plough, Servier, Solvay, Stanley Medical Research Institute, Supernus, Synosia, Takeda, and Wyeth. Dr. Thase has received grant funding from or served as a consultant for Agency for Healthcare Research and Quality, Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb, Dey Pharma, Eli Lilly, Forest Laboratories, Forest Pharmaceuticals, Gerson Lehman Group, GlaxoSmithKline, Guidepoint Global, Lundbeck, MedAvante, Merck, NeoSync, Neuronetics, NIMH, Novartis, Otsuka, Ortho-McNeil Pharmaceuticals, PamLab, Pfizer (formerly Wyeth-Ayerst Laboratories), PharmaNeuroboost, Roche Laboratories, Shire US, Sunovion, Takeda, Teva, and Transcept; he receives royalties from American Psychiatric Foundation, Guilford Publications, Herald House, Oxford University Press, and W. W. Norton and has equity holdings in MedAvante; his wife is employed by Peloton Advantage, which does business with Pfizer. Dr. Colom has served as adviser or speaker for Adamed, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Lundbeck, MSD-Merck, Otsuka, Pfizer, Sanofi-Aventis, Shire, and Tecnifar and has received copyright fees from Cambridge University Press, Igaku-Shoin, Solal Ed., Ars Medica, Giovani Fioriti Ed., Medipage, La Esfera de Los Libros, Morales i Torres Ed, Panamericana, and Mayo Ed. & Columna. Dr. Frye has received grant support from the Mayo Foundation, Myriad, NARSAD, the National Institute of Alcohol Abuse and Alcoholism, NIMH, and Pfizer and travel support from Advanced Health Media, AstraZeneca, Bristol-Myers Squibb, Chilean Society of Neurology, Psychiatry, and Neurosurgery, Colombian Society of Neuropsychopharmacology, GlaxoSmithKline, Otsuka, and Sanofi-Aventis; he has served as an unpaid consultant for Allergan, Merck, Myriad, Sanofi-Aventis, Sunovion, Takeda Global Research, Teva Pharmaceuticals, and United Biosource Corporation. Dr. Malhi has received research support from or served as a speaker or consultant for AstraZeneca, Eli Lilly, Janssen-Cilag, Lundbeck, Organon, Pfizer, Ranbaxy, Servier, and Wyeth. Dr.; Fountoulakis has received research support or travel support from or served as a speaker or consultant for AstraZeneca, Bristol-Myers Squibb, Janssen-Cilag, Eli Lilly, Pfizer Foundation, and Wyeth. Dr. Vazquez has served as consultant or speaker for AstraZeneca, Gador, GlaxoSmithKline, Ivax, Eli Lilly, Lundbeck, Pfizer, Raffo, Servier, and Novartis. Dr. Perlis has served on advisory boards or as a consultant for Genomind, Healthrageous, PamLab, Pfizer, Proteus Biomedical, and RIDVentures. Dr. Ketter has received research support from or served as a consultant or speaker for Abbott, Allergan, AstraZeneca, Avanir, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen, Merck, Otsuka, Pfizer, Sunovion, and Teva; he receives royalties from American Psychiatric Publishing, and his spouse is an employee of and holds stock in Janssen Pharmaceuticals. Dr. Akiskal receives honoraria or fees from Journal of Affective Disorders, AstraZeneca, University of Lisbon, Aristotle University of Thesaloniki, Sanofi, Nevada Psychiatric Association, and Medical Education Speakers Network. Dr. Azorin has received grants from Eli Lilly and Sanofi and honoraria from AstraZeneca, Bristol-Myers Squibb, Lundbeck Servier, and Eli Lilly; he has served on advisory boards for Eli Lilly, Lundbeck, Bristol-Myers Squibb, and Roche and as an expert witness for Eli Lilly. Dr. Lafer has received grant or research support from Brazilian research agencies CAPES (Coordination for the Improvement of Higher Education Personnel), FAPESP (Sao Paulo Research Foundation), and CNPq (National Council for Scientific and Technological Development). Dr. Kato has received research support from Takeda and honoraria for lectures, manuscripts, or consultancy from Kyowa Hakko Kirin, Eli Lilly Japan, Otsuka, GlaxoSmithKline, Taisho Toyama Pharmaceutical, Dainippon Sumitomo, Meiji Seika Pharma, Pfizer Japan, Mochida Pharmaceutical, Shionogi, Janssen, and Astellas. Dr. Martinez-Aran has served as speaker or adviser for Bristol-Myers Squibb, Lundbeck, Otsuka, and Pfizer. Dr. Parker has served as a speaker or on advisory boards for or received travel or speaking fees from AstraZeneca, Eli Lilly, Lundbeck, Pfizer, and Servier. Dr. Souery has served on advisory boards for AstraZeneca and Lundbeck and has received unrestricted grants for clinical research and educational activities from AstraZeneca, GlaxoSmithKline, and Lundbeck. Dr. Ozerdem has received honoraria or travel support from Abdi Ibrahim, Adeka, AstraZeneca, Bristol-Myers Squibb, EGIS, GlaxoSmithKline, Lundbeck, Nobel, Pfizer, Schering-Plough, and Servier. Dr. McElroy has served as a consultant for or on scientific advisory boards for Alkermes, Bracket, Corcept, MedAvante, Shire, Sunovion, and Teva; she is a principal or co-investigator on studies sponsored by the Agency for Healthcare Research and Quality, Alkermes, AstraZeneca, Cephalon, Eli Lilly, Forest, Marriott Foundation, NIMH, Orexigen Therapeutics, Pfizer, Shire, Takeda, and Transcept; she is also an inventor on a patent for use of sulfamate derivatives for treating impulse control disorders. Dr. Girardi has received research support from, served on advisory boards for, and received honoraria from Eli Lilly, Janssen, Otsuka, Pfizer, Schering, and Springer Healthcare. Dr.; Bauer has received research support from or served as a consultant or speaker for Alkermes, American Foundation for Suicide Prevention, AstraZeneca, Bristol-Myers Squibb, Bundesministerium fur Bildung und Forschung, Deutsche Forschungsgemeinschaft, European Commission (FP7), Ferrer Internacional, GlaxoSmithKline, Janssen, Eli Lilly, Lundbeck, NARSAD, Otsuka, Pfizer, Servier, Stanley Medical Research Institute, and Takeda. Dr. Yatham has received research support from or served as a speaker or advisory board member for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, GlaxoSmithKline, Lundbeck, Novartis, Pfizer, Servier, and Sunovion. Dr. Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. Dr. Nierenberg has received research support from, served as a consultant for, or received honoraria from Abbott Laboratories, Agency for Healthcare Research and Quality, American Drug Utilization Review Society, American Society for Clinical Psychopharmacology, AstraZeneca, Basilea, Biomedical Development, Boston Center for the Arts, BrainCells, Brandeis University, Bristol-Myers Squibb, Cederroth, Cephalon, Corcept, Cyberonics, East Asian Bipolar Forum, Elan, Eli Lilly, Forest, Genaissance, GlaxoSmithKline, Harold Grinspoon Charitable Foundation, Health New England, Innapharma, International Society for Bipolar Disorder, Janssen, Jazz Pharmaceuticals, Lichtwer Pharma, Lundbeck, Merck, MGH Psychiatry Academy, Mid-Atlantic Permanente Research Institute, Mylan (formerly Dey Pharmaceuticals), NARSAD, NIMH, Novartis, PamLab, Pfizer, PGx Health, Ridge Diagnostics, Roche, Sepracor, Schering-Plough, Shire, Somerset, Stanley Foundation, Sunovion, Takeda, Targacept, Teva, University of Pisa, University of Wisconsin at Madison, University of Texas Southwestern Medical Center at Dallas, Wyeth-Ayerst, and Zucker Hillside Hospital; he receives other income from legal case reviews for CRICO, MBL Publishing for past services as editor-in-chief of CNS Spectrums, Slack Inc. for services as associate editor of Psychiatric Annals, and from Belvoir Publications for serving on the editorial board of Mind, Mood, and Memory; he has copyright joint ownership with MGH for the Structured Clinical Interview for MADRS and Clinical Positive Affect Scale and is a stakeholder in Appliance Computing (MindSite), Brain Cells, and InfoMed. Dr. Birmaher has received research support from NIMH and royalties from Random House, Lippincott Williams & Wilkins, and UpToDate. Dr. Kanba has received research support or honoraria from Astellas, Dainippon Sumitomo, Eisai, Eli Lilly Japan, GlaxoSmithKline, Janssen, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Ono, Otsuka, Pfizer, Shionogi, Taisho Toyama, Wyeth, and Yoshitomiyakuhin. Dr. El-Mallakh has received research support from Merck and has served as a speaker for AstraZeneca and Otsuka. Dr. Serretti has served as a consultant or speaker for Abbott, Angelini, AstraZeneca, Bristol-Myers Squibb, Boehringer, Clinical Data, Eli Lilly, GlaxoSmithKline, Italfarmaco, Janssen, Lundbeck, Pfizer, Sanofi, and Servier. Dr. MacQueen has received research support from AstraZeneca and served as a consultant or speaker for Bristol-Myers Squibb, Canadian Psychiatric Association, Eli Lilly, Lundbeck, Norlien Foundation, Pfizer, Sanofi, and Servier. Dr. Bowden has received grant support from Novartis. Dr. Ghaemi has received research support from Takeda and has served as a consultant for Sunovion. Dr.; Lopez-Jaramillo has received research support from Janssen Cilag, Lundbeck, NIH, Novartis, Pfizer, and University of Antioquia and honoraria from Abbott, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Sanofi, and Servier. Dr. Ha has received research support or honoraria from AstraZeneca, Eli Lilly, Pfizer, and Otsuka. Dr. Perugi has received research support from or served as a consultant, speaker, or advisory board member for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, and Sanofi-Aventis. Dr. Kasper has received research support from or served as a consultant, speaker, or advisory board member for Angelini, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, MSD, Neuraxpharm, Novartis, Organon, Pfizer, Pierre Fabre, Schwabe, Sepracor, and Servier. Dr. Hirschfeld has served as a consultant for or received honoraria from American College of Psychiatrists, Biostrategies, Brown University, CME Alliance, CME Outfitters, Equinox Group, Grey Healthcare, Letters & Sciences, Merck Manual Editorial Board, Nevada Psychiatric Association, and Physicians Post Graduate Press Health and Wellness Partners and receives royalties from Jones & Bartlett and Taylor & Francis. Dr. Kapczinski has received research support from or served as a consultant or speaker for AstraZeneca, CNPq, CAPES, Eli Lilly, Janssen, Janssen-Cilag, NARSAD, Stanley Medical Research Institute, and Servier. Dr. Vieta has received research support from or served as consultant, adviser, or speaker for Alexza, Almirall, AstraZeneca, Bristol-Myers Squibb, Elan, Eli Lilly, Ferrer, Forest Research Institute, 7th Framework Program of the European Union, Geodon Richter, GlaxoSmithKline, Janssen-Cilag, Jazz, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Solvay, Schering-Plough, Shire, Spanish Ministry of Science and Innovation, Stanley Medical Research Institute, Takeda, Teva, United Biosource Corporation, and Wyeth. The remaining authors report no competing interests. NR 102 TC 172 Z9 174 U1 4 U2 30 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD NOV PY 2013 VL 170 IS 11 BP 1249 EP 1262 DI 10.1176/appi.ajp.2013.13020185 PG 14 WC Psychiatry SC Psychiatry GA 248SZ UT WOS:000326724300008 PM 24030475 ER PT J AU Motzer, RJ Johnson, T Choueiri, TK Deen, KC Xue, Z Pandite, LN Carpenter, C Xu, CF AF Motzer, R. J. Johnson, T. Choueiri, T. K. Deen, K. C. Xue, Z. Pandite, L. N. Carpenter, C. Xu, C. F. TI Hyperbilirubinemia in pazopanib- or sunitinib-treated patients in COMPARZ is associated with UGT1A1 polymorphisms SO ANNALS OF ONCOLOGY LA English DT Letter ID GILBERTS-SYNDROME C1 [Motzer, R. J.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Johnson, T.; Xu, C. F.] GlaxoSmithKline Res & Dev Ltd, Genetics, Stevenage, Herts, England. [Choueiri, T. K.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Deen, K. C.; Carpenter, C.] GlaxoSmithKline Res & Dev Ltd, Oncology, Philadelphia, PA USA. [Xue, Z.] GlaxoSmithKline Res & Dev Ltd, Genetics, Res Triangle Pk, NC USA. [Pandite, L. N.] GlaxoSmithKline Res & Dev Ltd, Oncology, Res Triangle Pk, NC USA. RP Motzer, RJ (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. EM chun-fang.2.xu@gsk.com OI Johnson, Toby/0000-0002-5998-3270 NR 5 TC 8 Z9 8 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD NOV PY 2013 VL 24 IS 11 BP 2927 EP 2928 DI 10.1093/annonc/mdt394 PG 2 WC Oncology SC Oncology GA 247TF UT WOS:000326643200038 PM 24107802 ER PT J AU Namati, E Warger, WC Unglert, CI Eckert, JE Hostens, J Bouma, BE Tearney, GJ AF Namati, Eman Warger, William C., II Unglert, Carolin I. Eckert, Jocelyn E. Hostens, Jeroen Bouma, Brett E. Tearney, Guillermo J. TI Four-dimensional visualization of subpleural alveolar dynamics in vivo during uninterrupted mechanical ventilation of living swine SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; ACUTE LUNG INJURY; SURFACTANT DEACTIVATION; VASCULAR PERFUSION; RAT LUNG; VOLUME; PRESSURE; INFLATION; INSTABILITY; MICROSCOPY AB Pulmonary alveoli have been studied for many years, yet no unifying hypothesis exists for their dynamic mechanics during respiration due to their miniature size (100-300 mu m dimater in humans) and constant motion, which prevent standard imaging techniques from visualizing four-dimensional dynamics of individual alveoli in vivo. Here we report a new platform to image the first layer of air-filled subpleural alveoli through the use of a lightweight optical frequency domain imaging (OFDI) probe that can be placed upon the pleura to move with the lung over the complete range of respiratory motion. This device enables in-vivo acquisition of four-dimensional microscopic images of alveolar airspaces (alveoli and ducts), within the same field of view, during continuous ventilation without restricting the motion or modifying the structure of the alveoli. Results from an exploratory study including three live swine suggest that subpleural alveolar air spaces are best fit with a uniform expansion (r(2) = 0.98) over a recruitment model (r(2) = 0.72). Simultaneously, however, the percentage change in volume shows heterogeneous alveolar expansion within just a 1 mm x 1 mm field of view. These results signify the importance of four-dimensional imaging tools, such as the device presented here. Quantification of the dynamic response of the lung during ventilation may help create more accurate modeling techniques and move toward a more complete understanding of alveolar mechanics. (C) 2013 Optical Society of America C1 [Namati, Eman; Warger, William C., II; Unglert, Carolin I.; Eckert, Jocelyn E.; Bouma, Brett E.; Tearney, Guillermo J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Namati, Eman; Warger, William C., II; Unglert, Carolin I.; Eckert, Jocelyn E.; Bouma, Brett E.; Tearney, Guillermo J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Unglert, Carolin I.] Air Liquide Ctr Rech Claude Delorme, Med Gases Grp, Les Loges En Josas, France. [Bouma, Brett E.; Tearney, Guillermo J.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Tearney, Guillermo J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hostens, Jeroen] Bruker Corp, Kontich, Belgium. RP Namati, E (reprint author), Harvard Univ, Sch Med, 40 Blossom St,BAR 714, Boston, MA 02114 USA. EM gtearney@partners.org FU Air Liquide, Medical Gases, Les-Loges-en-Josas, France FX The authors thank Luis Guerrero for his help with the surgical procedures, Elk Halpern for his help with the statistical analysis, and Alex Chee, Lida Hariri, and Melissa Suter for discussions on lung physiology and pathology. This work has been supported by Air Liquide, Medical Gases, Les-Loges-en-Josas, France. NR 44 TC 5 Z9 5 U1 1 U2 13 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 NOV 1 PY 2013 VL 4 IS 11 BP 2492 EP 2506 DI 10.1364/BOE.4.002492 PG 15 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 246ZW UT WOS:000326582500017 PM 24298409 ER PT J AU Jammallo, LS Miller, CL Singer, M Horick, NK Skolny, MN Specht, MC O'Toole, J Taghian, AG AF Jammallo, Lauren S. Miller, Cynthia L. Singer, Marybeth Horick, Nora K. Skolny, Melissa N. Specht, Michelle C. O'Toole, Jean Taghian, Alphonse G. TI Impact of body mass index and weight fluctuation on lymphedema risk in patients treated for breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Lymphedema; Body mass index; Weight fluctuation; Breast cancer ID RECEIVING ADJUVANT CHEMOTHERAPY; ARM LYMPHEDEMA; AXILLARY DISSECTION; NODE BIOPSY; SURVIVORS; DIAGNOSIS; CARCINOMA; OBESITY; WOMEN; GAIN AB Identifying risk factors for lymphedema in patients treated for breast cancer has become increasingly important, given the current lack of standardization surrounding diagnosis and treatment. Reports on the association of body mass index (BMI) and weight change with lymphedema risk are conflicting. We sought to examine the impact of pre-operative BMI and post-treatment weight change on the incidence of lymphedema. From 2005 to 2011, 787 newly diagnosed breast cancer patients underwent prospective arm volume measurements with a Perometer pre- and post-operatively. BMI was calculated from same-day weight and height measurements. Lymphedema was defined as a relative volume change (RVC) of a parts per thousand yen10 %. Univariate and multivariate Cox proportional hazards models were used to evaluate the association between lymphedema risk and pre-operative BMI, weight change, and other demographic and treatment factors. By multivariate analysis, a pre-operative BMI a parts per thousand yen30 was significantly associated with an increased risk of lymphedema compared to a pre-operative BMI < 25 and 25- < 30 (p = 0.001 and p = 0.012, respectively). Patients with a pre-operative BMI 25- < 30 were not at an increased risk of lymphedema compared to patients with a pre-operative BMI < 25 (p = 0.409). Furthermore, a cumulative absolute weight fluctuation of 10 pounds gained/lost per month post-operatively significantly increased risk of lymphedema (HR: 1.97, p = < 0.0001). In conclusion, pre-operative BMI of a parts per thousand yen30 is an independent risk factor for lymphedema, whereas a BMI of 25- < 30 is not. Large post-operative weight fluctuations also increase risk of lymphedema. Patients with a pre-operative BMI a parts per thousand yen30 and those who experience large weight fluctuations during and after treatment for breast cancer should be considered at higher-risk for lymphedema. Close monitoring or early intervention to ensure optimal treatment of the condition may be appropriate for these patients. C1 [Jammallo, Lauren S.; Miller, Cynthia L.; Skolny, Melissa N.; Taghian, Alphonse G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Singer, Marybeth] Tufts Med Ctr, Ctr Canc, Boston, MA USA. [Horick, Nora K.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Specht, Michelle C.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [O'Toole, Jean] Massachusetts Gen Hosp, Dept Phys & Occupat Therapy, Boston, MA 02114 USA. RP Taghian, AG (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St, Boston, MA 02114 USA. EM ataghian@partners.org FU National Cancer Institute [R01CA139118, P50CA089393] FX The project described was supported by Award Number R01CA139118 (AGT), Award Number P50CA089393 (AGT) from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 43 TC 17 Z9 19 U1 0 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2013 VL 142 IS 1 BP 59 EP 67 DI 10.1007/s10549-013-2715-7 PG 9 WC Oncology SC Oncology GA 248HA UT WOS:000326687600006 PM 24122390 ER PT J AU Buist, DSM Bosco, JLF Silliman, RA Gold, HT Field, T Yood, MU Quinn, VP Prout, M Lash, TL AF Buist, Diana S. M. Bosco, Jaclyn L. F. Silliman, Rebecca A. Gold, Heather Taffet Field, Terry Yood, Marianne Ulcickas Quinn, Virginia P. Prout, Marianne Lash, Timothy L. CA Breast Canc Outcomes Older Women B TI Long-term surveillance mammography and mortality in older women with a history of early stage invasive breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Surveillance mammography; Breast carcinoma; Survivorship ID PERSONAL HISTORY; AMERICAN-SOCIETY; LASAGNA PLOTS; FOLLOW-UP; SURVIVORS; RECURRENCE; THERAPY; MANAGEMENT; RECEIPT; UPDATE AB Annual surveillance mammograms in older long-term breast cancer survivors are recommended, but this recommendation is based on little evidence and with no guidelines on when to stop. Surveillance mammograms should decrease breast cancer mortality by detecting second breast cancer events at an earlier stage. We examined the association between surveillance mammography beyond 5 years after diagnosis on breast cancer-specific mortality in a cohort of women aged a parts per thousand yen65 years diagnosed 1990-1994 with early stage breast cancer. Our cohort included women who survived disease free for a parts per thousand yen5 years (N = 1,235) and were followed from year 6 through death, disenrollment, or 15 years after diagnosis. Asymptomatic surveillance mammograms were ascertained through medical record review. We used Cox proportional hazards regression stratified by follow-up year to calculate the association between time-varying surveillance mammography and breast cancer-specific and other-than-breast mortality adjusting for site, stage, primary surgery type, age and time-varying Charlson Comorbidity Index. The majority (85 %) of the 1,235 5-year breast cancer survivors received a parts per thousand yen1 surveillance mammogram in years 5-9 (yearly proportions ranged from 48 to 58 %); 82 % of women received a parts per thousand yen1 surveillance mammogram in years 10-14. A total of 120 women died of breast cancer and 393 women died from other causes (average follow-up 7.3 years). Multivariable models and lasagna plots suggested a modest reduction in breast cancer-specific mortality with surveillance mammogram receipt in the preceding year (IRR 0.82, 95 % CI 0.56-1.19, p = 0.29); the association with other-cause mortality was 0.95 (95 % CI 0.78-1.17, p = 0.64). Among older breast cancer survivors, surveillance mammography may reduce breast cancer-specific mortality even after 5 years of disease-free survival. Continuing surveillance mammography in older breast cancer survivors likely requires physician-patient discussions similar to those recommended for screening, taking into account comorbid conditions and life-expectancy. C1 [Buist, Diana S. M.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Bosco, Jaclyn L. F.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Bosco, Jaclyn L. F.; Silliman, Rebecca A.; Prout, Marianne] Boston Univ, Sch Med, Boston, MA 02118 USA. [Silliman, Rebecca A.] Boston Med Ctr, Boston, MA 02118 USA. [Silliman, Rebecca A.; Yood, Marianne Ulcickas; Prout, Marianne] Boston Univ, Sch Publ Hlth, Boston, MA 02118 USA. [Gold, Heather Taffet] NYU, Sch Med, New York, NY 10016 USA. [Gold, Heather Taffet] NYU, Inst Canc, New York, NY 10016 USA. [Field, Terry] Meyers Primary Care Inst, Joint Endeavor Univ Massachusetts Med Sch Fallon, Worcester, MA 01605 USA. [Yood, Marianne Ulcickas] Henry Ford Hlth Syst, Detroit, MI 48202 USA. [Quinn, Virginia P.] Kaiser Permanente So Calif, Pasadena, CA 91101 USA. [Lash, Timothy L.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. RP Buist, DSM (reprint author), Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM buist.d@ghc.org FU National Cancer Institute [R01 CA093772] FX Supported by a grant from the National Cancer Institute (R01 CA093772 R. Silliman, PI). The CRN is a consortium of 14 integrated health care delivery systems with more than 10 million enrollees. The overall goal of the CRN is to assess and increase the effectiveness of preventive, curative and supportive interventions for major cancers through a program of collaborative research among diverse populations and health systems. We would like to thank site principal investigators Hans Petersen and Meaghan St. Charles from Lovelace Clinic Foundation and Pamala Pawloski from Heath Partners and Hongyuan Gao for her work developing the lasagna plots. We would also like to thank our site project managers, programmers, and medical record abstractors: Group Health-Linda Shultz, Kristin Delaney, Margaret Farrell-Ross, Mary Sunderland, Millie Magner, and Beth Kirlin; Meyers Primary Care Institute and Fallon Clinic-Jackie Fuller, Doris Hoyer, and Janet Guilbert; Henry Ford Health System-Sharon Hensley Alford, Karen Wells, Patricia Baker, and Rita Montague; HealthPartners-Maribet McCarty and Alex Kravchik; Kaiser Permanente Southern California-Julie Stern, Janis Yao, Michelle McGuire, and Erica Hnatek-Mitchell; and Lovelace Health Plan-Judith Hurley, Hans Petersen, and Melissa Roberts. NR 33 TC 7 Z9 7 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2013 VL 142 IS 1 BP 153 EP 163 DI 10.1007/s10549-013-2720-x PG 11 WC Oncology SC Oncology GA 248HA UT WOS:000326687600015 PM 24113745 ER PT J AU Warner, ET Colditz, GA Palmer, JR Partridge, AH Rosner, BA Tamimi, RM AF Warner, Erica T. Colditz, Graham A. Palmer, Julie R. Partridge, Ann H. Rosner, Bernard A. Tamimi, Rulla M. TI Reproductive factors and risk of premenopausal breast cancer by age at diagnosis: Are there differences before and after age 40? SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Age at diagnosis; Young women; Reproductive factors ID PROGESTERONE-RECEPTOR STATUS; AFRICAN-AMERICAN WOMEN; ORAL-CONTRACEPTIVE USE; YOUNG-WOMEN; HORMONE-RECEPTOR; NURSES HEALTH; UNITED-STATES; COMPETING RISKS; GENE-EXPRESSION; FAMILY-HISTORY AB We examined the relationship between reproductive factors and risk of premenopausal breast cancer among women less than age 40 compared with older premenopausal women. We documented 374 incident cases of breast cancer diagnosed before age 40, and 2,533 cases diagnosed at age 40 and older among premenopausal women in the Nurses' Health Study cohorts. Biennial questionnaires were used to determine age at menarche, age at first birth, parity, breastfeeding, and other reproductive factors. Multivariate relative risks (RR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards models within age at diagnosis groups. Tumors in younger women were significantly more likely to be higher grade, larger size, and hormone receptor negative than were tumors in older premenopausal women (p < 0.0001). There was no significant heterogeneity according to age in associations between reproductive factors and risk of premenopausal breast cancer. First birth at age 30 or older increased breast cancer risk in both age groups (age < 40: RR 1.10, 95 % CI 0.80-1.50; age a parts per thousand yen40: RR 1.16, 95 % CI 1.02-1.32; p-heterogeneity = 0.44). Risk of premenopausal breast cancer decreased with each additional year of age at menarche in both age groups (age < 40: RR 0.93, 95 % CI 0.87-0.99; p trend = 0.02; age a parts per thousand yen40: RR 0.94, 95 % CI 0.91-0.97; p trend = < 0.0001). Among premenopausal parous women, breastfeeding was protective regardless of age at diagnosis (age < 40: RR 0.84, 95 % CI 0.57-1.22; age a parts per thousand yen40: RR 0.85, 95 % CI 0.72-0.99; p-heterogeneity = 0.79). In the largest prospective examination of reproductive risk factors and risk of breast cancer before and after age 40, we found that younger women were more likely to develop tumors with less favorable prognostic characteristics. However, associations between reproductive factors and risk of breast cancer were similar regardless of age at diagnosis of premenopausal breast cancer. C1 [Warner, Erica T.; Colditz, Graham A.; Tamimi, Rulla M.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Warner, Erica T.; Rosner, Bernard A.; Tamimi, Rulla M.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Warner, Erica T.; Rosner, Bernard A.; Tamimi, Rulla M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Palmer, Julie R.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Partridge, Ann H.] Dana Farber Canc Inst, Breast Oncol Ctr, Boston, MA 02115 USA. [Rosner, Bernard A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Warner, ET (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. EM ewarner@hsph.harvard.edu RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU National Cancer Institute, the National Institutes of Health, Department of Health and Human Services [P01CA87969, UM1CA176726]; American Cancer Society; National Institute of General Medical Sciences Grant [2R25GM055353-13]; National Cancer Institute Grant [5T32CA009001-36] FX Financial supports were received under Grants P01CA87969, and UM1CA176726 from the National Cancer Institute, the National Institutes of Health, Department of Health and Human Services. Dr. Colditz was supported in part by an American Cancer Society Cissy Hornung Clinical Research Professorship. Dr. Warner was supported by the National Institute of General Medical Sciences Grant 2R25GM055353-13 and the National Cancer Institute Grant 5T32CA009001-36. The authors would like to thank the participants and the staff of Nurses' Health Study and Nurses' Health Study II for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. The authors assume full responsibility for analyses and interpretation of these data. NR 64 TC 13 Z9 13 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2013 VL 142 IS 1 BP 165 EP 175 DI 10.1007/s10549-013-2721-9 PG 11 WC Oncology SC Oncology GA 248HA UT WOS:000326687600016 PM 24136668 ER PT J AU Vaz-Luis, I Zeghibe, CA Frank, ES Sohl, J Washington, KE Silverman, SG Fonte, JM Mayer, EL Overmoyer, BA Richardson, AL Krop, IE Winer, EP Lin, NU AF Vaz-Luis, Ines Zeghibe, Catherine A. Frank, Elizabeth S. Sohl, Jessica Washington, Kimberly E. Silverman, Stuart G. Fonte, Joseph M. Mayer, Erica L. Overmoyer, Beth A. Richardson, Andrea L. Krop, Ian E. Winer, Eric P. Lin, Nancy U. TI Prospective clinical experience with research biopsies in breast cancer patients SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Research biopsies; Patients' preferences; Receptor discordance ID MANDATORY RESEARCH BIOPSIES; PHASE-I TRIALS; ANTICANCER AGENTS; TUMOR-BIOPSIES; PERCEPTIONS; ISSUES AB There are ethical concerns regarding the performance of biopsies in patients for research purposes. We examined our single-institution experience regarding acceptance, safety, and success rate with research biopsies in patients with breast cancer. Among patients with data from paired samples, receptor status agreement between primary and metastatic samples was examined, either on first recurrence or after progression on one or more lines of therapy. An IRB-approved prospective study at the Dana-Farber Cancer Institute collects research biopsies as additional passes at the time of a clinical biopsy (AB, additional biopsy) or as a separate procedure for banking purposes (RPOB, research purposes only biopsy). Biopsies are not linked to a specific therapeutic or correlative trial. Grade 2-5 adverse events are prospectively collected. 151 patients were included in the analytic cohort (total procedures = 161); 80.8 % underwent AB, 17.2 % underwent RPOB, and 2.0 % underwent both AB and RPOB. Most patients were white (88.7 %) with a performance status of 0-1 (94.0 %). 96.0 % of patients underwent a biopsy in the setting of known or suspected metastatic disease. Receptor status between primary cancer and recurrent research biopsies differed in 43.2 % of patients with available data (18.8 % among patients who underwent the research biopsy before any systemic treatment, 48.1 % after treatment). Tissue was successfully collected in 92.3 % of patients undergoing AB and 100 % patients undergoing RPOB. Only three (2.0 %) patients had adverse events a parts per thousand yengrade-2: one grade-2 pain; one grade-2 pneumothorax; and one grade-3 pain. Our experience suggests research biopsies can be performed safely with a high rate of successful tissue collection. Consistent with previous reports we found a high rate of discordance between primary and metastatic samples, which was even higher among treated patients. This supports continued efforts to study tissue samples at multiple points in a patient's disease course. C1 [Vaz-Luis, Ines; Zeghibe, Catherine A.; Frank, Elizabeth S.; Sohl, Jessica; Mayer, Erica L.; Overmoyer, Beth A.; Richardson, Andrea L.; Krop, Ian E.; Winer, Eric P.; Lin, Nancy U.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Vaz-Luis, Ines] Inst Mol Med, Lisbon, Portugal. [Washington, Kimberly E.; Fonte, Joseph M.] Faulkner Hosp, Boston, MA USA. [Silverman, Stuart G.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Lin, NU (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Nancy_Lin@dfci.harvard.edu FU National Cancer Institute Specialized Program of Research Excellence in Breast Cancer [NIH P50 CA089393]; Berry Junior Faculty Award; Karen Webster and David Evans Research Fund, Susan G. Komen for the Cure; Fundacao para a Ciencia e Tecnologia [HMSP-ICS/0004/2011] FX The study was supported by the National Cancer Institute Specialized Program of Research Excellence in Breast Cancer (NIH P50 CA089393), Berry Junior Faculty Award (to NUL), the Karen Webster and David Evans Research Fund, Susan G. Komen for the Cure (to EPW), and Fundacao para a Ciencia e Tecnologia (HMSP-ICS/0004/2011, Career Development Award to IVL). NR 19 TC 3 Z9 3 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2013 VL 142 IS 1 BP 203 EP 209 DI 10.1007/s10549-013-2717-5 PG 7 WC Oncology SC Oncology GA 248HA UT WOS:000326687600019 PM 24113744 ER PT J AU Chebib, I Rao, RA Wilbur, DC Tambouret, RH AF Chebib, Ivan Rao, Rema A. Wilbur, David C. Tambouret, Rosemary H. TI Using the ASC:SIL Ratio, Human Papillomavirus, and Interobserver Variability to Assess and Monitor Cytopathology Fellow Training Performance SO CANCER CYTOPATHOLOGY LA English DT Article DE cytopathology; fellow; interobserver variability; Papanicolaou test; human papillomavirus ID HIGH-RISK HPV; CYTOLOGY INTERPRETATIONS; RANDOMIZED-TRIAL; EXPERIENCE; MANAGEMENT; CELLS; ASCUS AB BACKGROUNDThe goal of this study was to assess objective measurements of cytopathology fellow performance during their training. METHODSThe authors examined cytopathology performance characteristics (the ratio of atypical squamous cells to squamous intraepithelial lesions [ASC:SIL], interobserver variability [IOV], high-risk human papillomavirus [hr-HPV]-positive atypical squamous cells of undetermined significance [ASC-US]) of cytopathology fellows and assessed whether they could be used as tools to further their education. RESULTSThe ASC:SIL ratio, the proportion of hr-HPV-positive ASC-US, and IOV were calculated for 5 consecutive cytopathology fellows. The average ASC:SIL ratio for the fellows was 1.15. The overall average Cohen -coefficient (-value) between fellow and cytopathologist interpretation was 0.75 (substantial agreement). The conditional -value for ASC-US only was higher for cases the fellows called ASC-US (0.70) than for cases the cytopathologist called ASC-US (0.60). Of the cases that were diagnosed as negative for intraepithelial lesion or malignancy (NILM) by the fellow and ASC-US by the pathologist, 33.2% were positive for hr-HPV. This was higher than the expected frequency of hr-HPV-positive results in the NILM population, suggesting that the fellows were over-interpreting NILM in hr-HPV-positive cases that had cytologic features sufficient for an ASC-US interpretation. CONCLUSIONSIn this study, agreement was compared between trainee and cytopathologist to determine where a fellow's interpretation differed. With the use of IOV, the ASC:SIL ratio, and the percentage of hr-HPV-positive results in the NILM, ASC-US, and low-grade SIL categories, the authors attempted to outline objective assessments and areas of improvement for fellows before they enter independent practice. Cancer (Cancer Cytopathol) 2013;121:638-43. (c) 2013 American Cancer Society. C1 [Chebib, Ivan] Massachusetts Gen Hosp, Div Cytopathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Chebib, I (reprint author), Massachusetts Gen Hosp, Div Cytopathol, James Homer Wright Pathol Labs, Warren 3,55 Fruit St, Boston, MA 02114 USA. EM ichebib@partners.org NR 15 TC 1 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1934-662X EI 1934-6638 J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD NOV PY 2013 VL 121 IS 11 BP 638 EP 643 DI 10.1002/cncy.21328 PG 6 WC Oncology; Pathology SC Oncology; Pathology GA 250IG UT WOS:000326845700007 PM 23861336 ER PT J AU Okemoto, K Kasai, K Wagner, B Haseley, A Meisen, H Bolyard, C Mo, XK Wehr, A Lehman, A Fernandez, S Kaur, B Chiocca, EA AF Okemoto, Kazuo Kasai, Kazue Wagner, Benjamin Haseley, Amy Meisen, Hans Bolyard, Chelsea Mo, Xiaokui Wehr, Allison Lehman, Amy Fernandez, Soledad Kaur, Balveen Chiocca, E. Antonio TI DNA Demethylating Agents Synergize with Oncolytic HSV1 against Malignant Gliomas SO CLINICAL CANCER RESEARCH LA English DT Article ID VALPROIC ACID; GENE-EXPRESSION; VIRUS; CELLS; TUMORS; TRICHOSTATIN; INHIBITION; INTERFERON; GENOME; BRAIN AB Purpose: Oncolytic viruses (OV) based on herpes simplex virus type 1 (HSV1) are being used in clinical trials for a variety of cancers. The OV, rQNestin34.5, uses a nestin promoter/enhancer to selectively drive robust viral replication in malignant glioma cells. We have discovered that this promoter becomes extensively methylated in infected glioma cells, reducing OV efficacy. Experimental Design: We used demethylating drugs [5-azacytidine (5-Aza)], decitabine, or valproic acid (VPA) in both in vitro and in vivo malignant glioma models to determine if they improved the efficacy of rQNestin34.5 therapy. Results: The use of demethylating agents, such as 5-Aza, improved OV replication and tumor cell lysis in vitro and, in fact, synergized pharmacologically on Chou-Talalay analysis. In vivo, the combination of the demethylating agents, 5-Aza or decitabine, with rQNestin34.5 significantly prolonged the survivorship of athymic mice harboring intracranial human glioma xenografts over single agent alone. Conclusion: These results, thus, provide further justification for the exploration of demethylating agents when combined with the OV, rQNestin34.5, in preclinical therapeutics and, possibly, clinical trials for malignant glioma. (C) 2013 AACR. C1 [Okemoto, Kazuo; Wagner, Benjamin; Haseley, Amy; Meisen, Hans; Bolyard, Chelsea; Mo, Xiaokui; Wehr, Allison; Kaur, Balveen; Chiocca, E. Antonio] James Canc Hosp, Solove Res Inst, Ctr Comprehens Canc, Dardinger Ctr Neurooncol & Neurosci,Dept Neurol S, Columbus, OH USA. [Okemoto, Kazuo; Wagner, Benjamin; Haseley, Amy; Meisen, Hans; Bolyard, Chelsea; Mo, Xiaokui; Wehr, Allison; Kaur, Balveen; Chiocca, E. Antonio] Wexner Med Ctr, Columbus, OH USA. [Lehman, Amy; Fernandez, Soledad] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Kasai, Kazue; Chiocca, E. Antonio] Brigham & Womens Faulkner Hosp, Dept Neurosurg, Inst Neurosci Brigham, Boston, MA 02116 USA. [Kasai, Kazue; Chiocca, E. Antonio] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02116 USA. RP Chiocca, EA (reprint author), Brigham & Womens Faulkner Hosp, Dept Neurosurg, Inst Neurosci Brigham, 75 Francis St, Boston, MA 02116 USA. EM eachiocca@partners.org RI kaur, Balveen/E-3355-2011 FU [7U01NS061811]; [CA069246]; [CA163205]; [CA150153]; [1NS064607]; [050NS045758] FX This work was financially supported by 7U01NS061811 and CA069246 (to E.A. Chiocca), CA163205 (to E.A. Chiocca and B. Kaur), and CA150153, 1NS064607, and 050NS045758 (to B. Kaur) NR 35 TC 7 Z9 7 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2013 VL 19 IS 21 BP 5952 EP 5959 DI 10.1158/1078-0432.CCR-12-3588 PG 8 WC Oncology SC Oncology GA 247AP UT WOS:000326585300016 PM 24056786 ER PT J AU Etemadmoghadam, D Au-Yeung, G Wall, M Mitchell, C Kansara, M Loehrer, E Batzios, C George, J Ftouni, S Weir, BA Carter, S Gresshoff, I Mileshkin, L Rischin, D Hahn, WC Waring, PM Getz, G Cullinane, C Campbell, LJ Bowtell, DD AF Etemadmoghadam, Dariush Au-Yeung, George Wall, Meaghan Mitchell, Chris Kansara, Maya Loehrer, Elizabeth Batzios, Crisoula George, Joshy Ftouni, Sarah Weir, Barbara A. Carter, Scott Gresshoff, Irma Mileshkin, Linda Rischin, Danny Hahn, William C. Waring, Paul M. Getz, Gad Cullinane, Carleen Campbell, Lynda J. Bowtell, David D. TI Resistance to CDK2 Inhibitors Is Associated with Selection of Polyploid Cells in CCNE1-Amplified Ovarian Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID DNA COPY NUMBER; CYCLIN-E; GENE AMPLIFICATION; THERAPEUTIC TARGET; SENSITIVITY; MECHANISMS; DISTINCT AB Purpose: Amplification of cyclin E1 (CCNE1) is associated with poor outcome in breast, lung, and other solid cancers, and is the most prominent structural variant associated with primary treatment failure in high-grade serous ovarian cancer (HGSC). We have previously shown that CCNE1-amplified tumors show amplicon-dependent sensitivity to CCNE1 suppression. Here, we explore targeting CDK2 as a novel therapeutic strategy in CCNE1-amplified cancers and mechanisms of resistance. Experimental Design: We examined the effect of CDK2 suppression using RNA interference and small-molecule inhibitors in SK-OV-3, OVCAR-4, and OVCAR-3 ovarian cancer cell lines. To identify mechanisms of resistance, we derived multiple, independent resistant sublines of OVCAR-3 to CDK2 inhibitors. Resistant cells were extensively characterized by gene expression and copy number analysis, fluorescence-activated cell sorting profiling and conventional karyotyping. In addition, we explored the relationship between CCNE1 amplification and polyploidy using data from primary tumors. Results: We validate CDK2 as a therapeutic target in CCNE1-amplified cells by showing selective sensitivity to suppression, either by gene knockdown or using small-molecule inhibitors. In addition, we identified two resistance mechanisms, one involving upregulation of CDK2 and another novel mechanism involving selection of polyploid cells from the pretreatment tumor population. Our analysis of genomic data shows that polyploidy is a feature of cancer genomes with CCNE1 amplification. Conclusions: These findings suggest that cyclinE1/CDK2 is an important therapeutic target in HGSC, but that resistance to CDK2 inhibitors may emerge due to upregulation of CDK2 target protein and through preexisting cellular polyploidy. (C) 2013 AACR. C1 [Etemadmoghadam, Dariush; Au-Yeung, George; Mitchell, Chris; Kansara, Maya; Loehrer, Elizabeth; George, Joshy; Ftouni, Sarah; Mileshkin, Linda; Rischin, Danny; Cullinane, Carleen; Bowtell, David D.] Peter MacCallum Canc Ctr, East Melbourne, Vic 8006, Australia. [Wall, Meaghan; Batzios, Crisoula; Campbell, Lynda J.] St Vincents Hosp, Victorian Canc Cytogenet Serv, Melbourne, Vic, Australia. [Etemadmoghadam, Dariush; Gresshoff, Irma; Waring, Paul M.; Bowtell, David D.] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. [Au-Yeung, George; George, Joshy; Bowtell, David D.] Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic 3052, Australia. [Mileshkin, Linda; Rischin, Danny] Univ Melbourne, Dept Med, Parkville, Vic 3052, Australia. [Gresshoff, Irma; Waring, Paul M.] Univ Melbourne, Ctr Translat Pathol, Parkville, Vic 3052, Australia. [Weir, Barbara A.; Hahn, William C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Weir, Barbara A.; Carter, Scott; Hahn, William C.; Getz, Gad] Broad Inst Harvard & MIT, Cambridge, MA USA. RP Bowtell, DD (reprint author), Peter MacCallum Canc Ctr, Locked Bag 1,A Beckett St, East Melbourne, Vic 8006, Australia. EM david.bowtell@petermac.org RI Bowtell, David/H-1007-2016; OI Bowtell, David/0000-0001-9089-7525; Loehrer, Elizabeth/0000-0003-1249-4442 FU National Health and Medical Research Council (NHMRC) [APP 1042358] FX This work was funded by a National Health and Medical Research Council (NHMRC) project grant (APP 1042358). NR 31 TC 25 Z9 25 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2013 VL 19 IS 21 BP 5960 EP 5971 DI 10.1158/1078-0432.CCR-13-1337 PG 12 WC Oncology SC Oncology GA 247AP UT WOS:000326585300017 PM 24004674 ER PT J AU Wagner, AJ Chugh, R Rosen, LS Morgan, JA George, S Gordon, M Dunbar, J Normant, E Grayzel, D Demetri, GD AF Wagner, Andrew J. Chugh, Rashmi Rosen, Lee S. Morgan, Jeffrey A. George, Suzanne Gordon, Michael Dunbar, Joi Normant, Emmanuel Grayzel, David Demetri, George D. TI A Phase I Study of the HSP90 Inhibitor Retaspimycin Hydrochloride (IPI-504) in Patients with Gastrointestinal Stromal Tumors or Soft-Tissue Sarcomas SO CLINICAL CANCER RESEARCH LA English DT Article ID SHOCK-PROTEIN 90; IMATINIB MESYLATE; KINASE INHIBITOR; ADJUVANT IMATINIB; CANCER CHAPERONE; TYROSINE KINASE; C-KIT; TRIAL; HEAT-SHOCK-PROTEIN-90; RESISTANCE AB Purpose: Heat shock protein 90 (HSP90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFR alpha) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase I study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective HSP90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS). Experimental Design: IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m(2) twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging. Results: Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m(2) twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26 of 37) of patients with GIST and 59% (10 of 17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11 of 29 (38%) patients with GIST. Conclusions: In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of antitumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy. C1 [Wagner, Andrew J.; Morgan, Jeffrey A.; George, Suzanne; Demetri, George D.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Wagner, Andrew J.; Morgan, Jeffrey A.; George, Suzanne; Demetri, George D.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Demetri, George D.] Harvard Canc Ctr, Ludwig Ctr Dana Farber, Boston, MA USA. [Chugh, Rashmi] Univ Michigan, Ann Arbor, MI 48109 USA. [Rosen, Lee S.] Univ Calif Los Angeles, Div Hematol Oncol, Santa Monica, CA USA. [Gordon, Michael] Pinnacle Oncol, Scottsdale, AZ USA. [Dunbar, Joi; Normant, Emmanuel; Grayzel, David] Infin Pharmaceut Inc, Cambridge, MA USA. RP Wagner, AJ (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM andrew_wagner@dfci.harvard.edu FU Infinity Pharmaceuticals, Inc. FX Dana-Farber/Harvard, University of Michigan, UCLA and Pinnacle Oncology received research funding from Infinity Pharmaceuticals, Inc. to support the conduct of this trial. NR 39 TC 23 Z9 23 U1 2 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD NOV 1 PY 2013 VL 19 IS 21 BP 6020 EP 6029 DI 10.1158/1078-0432.CCR-13-0953 PG 10 WC Oncology SC Oncology GA 247AP UT WOS:000326585300022 PM 24045182 ER PT J AU Martin, SS Blaha, MJ Toth, PP Joshi, PH McEvoy, JW Ahmed, HM Elshazly, MB Swiger, KJ Michos, ED Kwiterovich, PO Kulkarni, KR Chimera, J Cannon, CP Blumenthal, RS Jones, SR AF Martin, Seth S. Blaha, Michael J. Toth, Peter P. Joshi, Parag H. McEvoy, John W. Ahmed, Haitham M. Elshazly, Mohamed B. Swiger, Kristopher J. Michos, Erin D. Kwiterovich, Peter O. Kulkarni, Krishnaji R. Chimera, Joseph Cannon, Christopher P. Blumenthal, Roger S. Jones, Steven R. TI Very Large Database of Lipids: Rationale and Design SO CLINICAL CARDIOLOGY LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA; PLACEBO-CONTROLLED TRIAL; SUBTILISIN/KEXIN TYPE 9; LAPLACE-TIMI 57; CARDIOVASCULAR-DISEASE; MONOCLONAL-ANTIBODY; STATIN THERAPY; DOUBLE-BLIND; VITAMIN-D AB Blood lipids have major cardiovascular and public health implications. Lipid-lowering drugs are prescribed based in part on categorization of patients into normal or abnormal lipid metabolism, yet relatively little emphasis has been placed on: (1) the accuracy of current lipid measures used in clinical practice, (2) the reliability of current categorizations of dyslipidemia states, and (3) the relationship of advanced lipid characterization to other cardiovascular disease biomarkers. To these ends, we developed the Very Large Database of Lipids (NCT01698489), an ongoing database protocol that harnesses deidentified data from the daily operations of a commercial lipid laboratory. The database includes individuals who were referred for clinical purposes for a Vertical Auto Profile (Atherotech Inc., Birmingham, AL), which directly measures cholesterol concentrations of low-density lipoprotein, very low-density lipoprotein, intermediate-density lipoprotein, high-density lipoprotein, their subclasses, and lipoprotein(a). Individual Very Large Database of Lipids studies, ranging from studies of measurement accuracy, to dyslipidemia categorization, to biomarker associations, to characterization of rare lipid disorders, are investigator-initiated and utilize peer-reviewed statistical analysis plans to address a priori hypotheses/aims. In the first database harvest (Very Large Database of Lipids 1.0) from 2009 to 2011, there were 1340614 adult and 10294 pediatric patients; the adult sample had a median age of 59 years (interquartile range, 49-70 years) with even representation by sex. Lipid distributions closely matched those from the population-representative National Health and Nutrition Examination Survey. The second harvest of the database (Very Large Database of Lipids 2.0) is underway. Overall, the Very Large Database of Lipids database provides an opportunity for collaboration and new knowledge generation through careful examination of granular lipid data on a large scale. C1 [Martin, Seth S.; Blaha, Michael J.; Joshi, Parag H.; McEvoy, John W.; Ahmed, Haitham M.; Elshazly, Mohamed B.; Swiger, Kristopher J.; Michos, Erin D.; Kwiterovich, Peter O.; Blumenthal, Roger S.; Jones, Steven R.] Johns Hopkins Med, Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA. [Toth, Peter P.] CGH Med Ctr, Dept Prevent Cardiol, Sterling, IL USA. [Kulkarni, Krishnaji R.; Chimera, Joseph] Atherotech Diagnost Lab, Birmingham, AL USA. [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. RP Martin, SS (reprint author), Johns Hopkins Ciccarone Ctr Prevent Heart Dis, 600 North Wolfe St,Carnegie 565-G, Baltimore, MD 21287 USA. EM smart100@jhmi.edu OI McEvoy, John/0000-0001-6530-5479 FU Atherotech, Inc.; Pollin Fellowship in Preventive Cardiology; Marie-Josee and Henry R. Kravis endowed fellowship; Abbott Laboratories; Aegerion; Amgen; Amylin; AstraZeneca; GlaxoSmithKline; Kowa; Merck Co.; Pfizer; Ainylam, Bristol-Myers Squibb; Accumetrics; Essentialis; Merck; Regeneron; Sanofi; Takeda FX This work was supported by Atherotech, Inc.; the lab provided the investigators with deidentified data generated from commercial lipid analyses. Atherotech, Inc. did not provide payments to the investigators for the development of the database or writing of this article.; Drs. Martin, McEvoy, and Joshi are supported by the Pollin Fellowship in Preventive Cardiology. In addition, Dr. Martin is supported by the Marie-Josee and Henry R. Kravis endowed fellowship. Disclosures for Drs. Toth, Kwiterovich, Dr. Kulkarni, Dr. Chimera, Dr. Cannon, and Dr. Jones are as follows: Dr. Toth: medical advisory board for Atherotech, Inc.; compensation for consultancy and lecturers from Abbott Laboratories, Aegerion, Amgen, Amylin, AstraZeneca, GlaxoSmithKline, Kowa, and Merck & Co. Dr. Kwiterovich: compensation for consultancy from Merck & Co. and research grants from Pfizer. Dr. Kulkarni: Research Director, Atherotech, Inc.; receives royalty from the University of Alabama in Birmingham. Dr. Chimera: Executive Vice President of Scientific Development, Atherotech, Inc. Dr. Cannon: member of the advisory boards of and has received grant support from Ainylam, Bristol-Myers Squibb, and Pfizer; has received grant support from Accumetrics, AstraZeneca, Essentialis, GlaxoSmithKline, Merck, Regeneron, Sanofi, and Takeda; and is a clinical advisor to Automated Medical Systems. Dr. Jones: medical advisory board for Atherotech, Inc. NR 34 TC 15 Z9 15 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-9289 EI 1932-8737 J9 CLIN CARDIOL JI Clin. Cardiol. PD NOV PY 2013 VL 36 IS 11 BP 641 EP 648 DI 10.1002/clc.22214 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 248OU UT WOS:000326711800001 PM 24122913 ER PT J AU Harada, CN Love, MCN Triebel, KL AF Harada, Caroline N. Love, Marissa C. Natelson Triebel, Kristen L. TI Normal Cognitive Aging SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Mild cognitive impairment; Dementia; Aging; Cognition ID WHITE-MATTER INTEGRITY; OLDER-ADULTS; ALZHEIMERS-DISEASE; LEISURE ACTIVITIES; LIFE-STYLE; MENTAL FLEXIBILITY; BRAIN ACTIVITY; REDUCED RISK; AGE; MEMORY AB Even those who do not experience dementia or mild cognitive impairment may experience subtle cognitive changes associated with aging. Normal cognitive changes can affect an older adult's everyday function and quality of life, and a better understanding of this process may help clinicians distinguish normal from disease states. This article describes the neurocognitive changes observed in normal aging, followed by a description of the structural and functional alterations seen in aging brains. Practical implications of normal cognitive aging are then discussed, followed by a discussion of what is known about factors that may mitigate age-associated cognitive decline. C1 [Harada, Caroline N.] Univ Alabama Birmingham, Birmingham Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Div Gerontol Geriatr & Palliat Care, Birmingham, AL 35294 USA. [Love, Marissa C. Natelson] Univ Alabama Birmingham, Div Memory Disorders & Behav Neurol, Dept Neurol, Birmingham, AL 35233 USA. [Triebel, Kristen L.] Univ Alabama Birmingham, Dept Neurol, Sparks Ctr, Birmingham, AL 35294 USA. RP Harada, CN (reprint author), Univ Alabama Birmingham, Birmingham Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Div Gerontol Geriatr & Palliat Care, CH 19-201,1720 2nd Ave South, Birmingham, AL 35294 USA. EM charada@uabmc.edu FU Donald W. Reynolds Foundation; NIH [KL2TR000166] FX Dr Harada, Donald W. Reynolds Foundation; Dr Natelson Love, None; Dr Triebel, NIH KL2TR000166: Triebel, PI. NR 96 TC 41 Z9 45 U1 5 U2 28 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD NOV PY 2013 VL 29 IS 4 BP 737 EP + DI 10.1016/j.cger.2013.07.002 PG 17 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 247XX UT WOS:000326659400002 PM 24094294 ER PT J AU Courtney, DL AF Courtney, Donald L. TI Dealing with Mild Cognitive Impairment Help for Patients and Caregivers SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Mild cognitive impairment; Alzheimer disease; Activities of daily living; Dementia progression; Cognitive training ID RANDOMIZED CONTROLLED-TRIAL; OLDER-ADULTS; DRIVING CESSATION; NURSING-HOME; DEMENTIA; SPEED; INDIVIDUALS; EXERCISE; PEOPLE; HEALTH AB Mild cognitive impairment (MCI) is a unique entity in the spectrum of syndromes of cognitive loss. Many patients referred for evaluation of memory loss come with an assumption that they already have dementia. When patients are diagnosed with MCI, they and their caregivers have to deal with the challenge of uncertainties. Patient and family education must stress the uncertainty of whether the deficits will progress. This article aims to guide the clinician who has reached a diagnosis of MCI and is working with the patient and family on coping with the uncertainties of MCI. C1 Med Univ S Carolina, Sect Geriatr Med 11G, Div Gen & Geriatr Med, Dept Med,Ralph H Johnson VA Med Ctr, Charleston, SC 29401 USA. RP Courtney, DL (reprint author), Med Univ S Carolina, Sect Geriatr Med 11G, Div Gen & Geriatr Med, Dept Med,Ralph H Johnson VA Med Ctr, 109 Bee St, Charleston, SC 29401 USA. EM Donald.Courtney2@va.gov NR 25 TC 3 Z9 4 U1 1 U2 14 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD NOV PY 2013 VL 29 IS 4 BP 895 EP + DI 10.1016/j.cger.2013.07.010 PG 12 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 247XX UT WOS:000326659400010 PM 24094302 ER PT J AU O'Toole, J Jammallo, LS Skolny, MN Miller, CL Elliott, K Specht, MC Taghian, AG AF O'Toole, Jean Jammallo, Lauren S. Skolny, Melissa N. Miller, Cynthia L. Elliott, Krista Specht, Michelle C. Taghian, Alphonse G. TI Lymphedema following treatment for breast cancer: A new approach to an old problem SO CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY LA English DT Review DE Lymphedema; Screening; Perometer; Breast cancer ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; PROSPECTIVE SURVEILLANCE MODEL; UPPER-LIMB LYMPHEDEMA; ARM LYMPHEDEMA; AXILLARY DISSECTION; BIOELECTRICAL-IMPEDANCE; CLINICAL-TRIALS; SEPARATING FACT; RISK-FACTORS AB Lymphedema following treatment for breast cancer can be an irreversible condition with a profound negative impact on quality of life. The lack of consensus regarding standard definitions of clinically significant lymphedema and optimal methods of measurement and quantification are unresolved problems. Inconsistencies persist regarding the appropriate timing of intervention and what forms of treatment should be the standard of care. There are reports that early detection and intervention can prevent progression, however,the Level 1 evidence to support this hypothesis has yet to be generated. To assess these controversies, we propose the implementation of a screening program to detect early lymphedema in conjunction with a randomized, prospective trial designed to generate Level 1 evidence regarding the efficacy of early intervention and appropriate treatment strategies. Collaboration among institutions that manage breast cancer patients is essential to establish a standardized approach to lymphedema and to establish guidelines for best practice. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [O'Toole, Jean] Massachusetts Gen Hosp, Dept Phys & Occupat Therapy, Boston, MA 02114 USA. [Jammallo, Lauren S.; Skolny, Melissa N.; Miller, Cynthia L.; Taghian, Alphonse G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Elliott, Krista; Specht, Michelle C.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. RP Taghian, AG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, 100 Blossom St 55, Boston, MA 02114 USA. EM ataghian@partners.org FU National Cancer Institute [R01CA139118, P50CA089393] FX The project described was supported by Award Number R01CA139118 (AGT), Award Number P50CA089393 (AGT) from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 83 TC 11 Z9 11 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1040-8428 EI 1879-0461 J9 CRIT REV ONCOL HEMAT JI Crit. Rev. Oncol./Hematol. PD NOV PY 2013 VL 88 IS 2 BP 437 EP 446 DI 10.1016/j.critrevonc.2013.05.001 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 249KN UT WOS:000326776200017 PM 23777977 ER PT J AU Spronk, HMH Borissoff, JI ten Cate, H AF Spronk, Henri M. H. Borissoff, Julian I. ten Cate, Hugo TI New Insights into Modulation of Thrombin Formation SO CURRENT ATHEROSCLEROSIS REPORTS LA English DT Article DE Thrombin; Coagulation; Activated protein C; Atherosclerosis; Thrombosis; Atherothrombosis; Anticoagulant; Dabigatran; Vitamin K antagonist ID ACTIVATED PROTEIN-C; DISSEMINATED INTRAVASCULAR COAGULATION; E-DEFICIENT MICE; DEEP-VEIN THROMBOSIS; TISSUE FACTOR; CORONARY ATHEROSCLEROSIS; IN-VIVO; THROMBOMODULIN TRANSCRIPTION; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION AB Thrombin is a pleiotropic enzyme that regulates hemostasis and nonhemostatic functions, including an array of actions within and on the vasculature. Physiologically, thrombin generation serves mainly to protect against thrombosis, but also to maintain vascular endothelial integrity. This protective effect is mediated in part through generation of anticoagulant enzymes, including activated protein C, formed on the action of thrombin on the endothelial receptor thrombomodulin. Partly, thrombin's vascular effects are effectuated through interaction with protease-activated receptors on various cell types. Pathophysiologically, downregulation and shedding of anticoagulant-acting receptors such as thrombomodulin and endothelial protein C receptor may contribute to a shift in activities of thrombin towards thrombogenic and proinflammatory actions. This shift may typically occur in the process of atherosclerosis, leading to a proatherogenic direction of the effects of thrombin. Therapeutically, the long-terminhibition of thrombin may create new ways of reducing atherosclerosis burden, altering the plaque phenotype. C1 [Spronk, Henri M. H.; ten Cate, Hugo] Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Internal Med, Lab Clin Thrombosis & Haemostasis, NL-6200 MD Maastricht, Netherlands. [Borissoff, Julian I.] Harvard Univ, Sch Med, Program Cellular & Mol Med, Boston Childrens Hosp, Boston, MA USA. [Borissoff, Julian I.] Harvard Univ, Childrens Hosp, Immune Dis Inst, Sch Med, Boston, MA 02115 USA. RP ten Cate, H (reprint author), Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Internal Med, Lab Clin Thrombosis & Haemostasis, POB 616,UNS50 Box8, NL-6200 MD Maastricht, Netherlands. EM henri.spronk@maastrichtuniversity.nl; julian.borissoff@childrens.harvard.edu; h.tencate@maastrichtuniversity.nl OI ten Cate, Hugo/0000-0001-7796-4463 NR 90 TC 4 Z9 5 U1 0 U2 5 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1523-3804 EI 1534-6242 J9 CURR ATHEROSCLER REP JI Curr. Atheroscleros. Rep. PD NOV PY 2013 VL 15 IS 11 AR 363 DI 10.1007/s11883-013-0363-3 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 236RB UT WOS:000325815800002 PM 24026641 ER PT J AU Moe, SM Thadhani, R AF Moe, Sharon M. Thadhani, Ravi TI What have we learned about chronic kidney disease-mineral bone disorder from the EVOLVE and PRIMO trials? SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE cardiovascular disease; cinacalcet; chronic kidney disease; dialysis; heart; hyperparathyroidism; mortality; paricalcitol ID CARDIOVASCULAR EVENTS EVOLVE; LEFT-VENTRICULAR HYPERTROPHY; VITAMIN-D; CARDIAC-HYPERTROPHY; PHOSPHATE BINDERS; HEART-FAILURE; THERAPY; KLOTHO; RATS; HEMODIALYSIS AB Purpose of reviewThe treatment of chronic kidney disease-mineral bone disorder (CKD-MBD) has traditionally focused on improvement in biochemical parameters of the disease. However, studies evaluating hard clinical end points or surrogate end points are limited.Recent findingsTwo randomized controlled trials have recently been published. In the EVOLVE study (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events), cinacalcet was compared with placebo in 3883 haemodialysis patients with secondary hyperparathyroidism. The primary end point (death, myocardial infarction, unstable angina, heart failure or peripheral vascular disease) in an unadjusted intention-to-treat analysis was not significant [hazard ratio 0.93; 95% confidence interval (CI) 0.85-1.02, P=0.11]. However, the pre-specified secondary end points of an adjusted intention-to-treat analysis (hazard ratio 0.88; 95% CI 0.79-0.97, P=0.008) were significant. In the PRIMO (Paricalcitol Capsule Benefits in Renal Failure Induced Cardiac Morbidity) trial, 227 patients with CKD stage 3-4 and left ventricular hypertrophy by echocardiography were randomized to paricalcitol or placebo. The primary end point of change in left ventricular mass index by MRI after 12 months was not different between the two groups, but the prespecified end point of cardiovascular-related hospitalizations was reduced in the paricalcitol-treated group (P=0.04).SummaryThe results of these two randomized controlled trials have negative primary end points but significant secondary end points and thus require physicians to individualize therapies for the treatment of secondary hyperparathyroidism. C1 [Moe, Sharon M.] Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. [Moe, Sharon M.] Richard L Roudebush Vet Adm Med Ctr, Indianapolis, IN 46202 USA. [Thadhani, Ravi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Moe, SM (reprint author), Indiana Univ, Sch Med, Div Nephrol, 950 W Walnut St,R2-202, Indianapolis, IN 46202 USA. FU NIH [R01 AR058005, K24 DK 094872, R01 HL 11274602]; Veterans Administration; Genzyme-Sanofi; Novartis FX S.M.M. has research funding from the NIH (R01 AR058005), Veterans Administration, Genzyme-Sanofi, Novartis. R.T. has research funding from NIH (K24 DK 094872 and R01 HL 11274602) and Abbott Laboratories for the PRIMO Trial. NR 30 TC 6 Z9 6 U1 0 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 EI 1473-6543 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD NOV PY 2013 VL 22 IS 6 BP 651 EP 655 DI 10.1097/MNH.0b013e328365b3a3 PG 5 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 247CF UT WOS:000326591000009 PM 24100218 ER PT J AU Yeh, JE Toniolo, PA Frank, DA AF Yeh, Jennifer E. Toniolo, Patricia A. Frank, David A. TI Targeting transcription factors: promising new strategies for cancer therapy SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE cancer; therapy; transcription factor ID CHEMOTACTIC PROTEIN-1 SYNTHESIS; SUPPRESSOR-CELLS; DENDRITIC CELLS; TUMOR-GROWTH; IN-VIVO; STAT3; P53; INHIBITION; DIFFERENTIATION; MACROPHAGES AB Purpose of reviewA lack of effective treatments for advanced cancer remains a major challenge in oncology. Because cancer is a disease associated with aberrant gene expression patterns, transcription factors, which serve as the convergence points of oncogenic signaling and are functionally altered in many cancers, hold great therapeutic promise.Recent findingsMany human cancers are dependent on the inappropriate activity of oncogenic transcription factors. By contrast, normal cells can often tolerate disruption of these proteins with little toxicity. Direct inhibition of transcription factor expression (e.g., with RNA interference or microRNAs) and DNA binding (e.g., with oligodeoxynucleotide decoys or pyrrole-imidazole polyamides) has demonstrated antitumor responses with minimal side-effects. New strategies of targeting transcription factors include disrupting critical protein-protein interactions, and restricting binding at the epigenetic level by modulating chromatin accessibility. Moreover, targeting transcription factors in tumor-associated immune cells has the potential to overcome tumor immunoresistance.SummaryTranscription factors are an important target for cancer therapy, both through direct anticancer effects and immunomodulatory actions. Newly developed delivery systems that specifically target tumor cells also create opportunities for successes in targeting transcription in cancer. C1 [Yeh, Jennifer E.; Toniolo, Patricia A.; Frank, David A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Yeh, Jennifer E.; Toniolo, Patricia A.; Frank, David A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Yeh, Jennifer E.; Toniolo, Patricia A.; Frank, David A.] Harvard Univ, Sch Med, Boston, MA USA. [Toniolo, Patricia A.] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, Brazil. RP Frank, DA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Mayer 522B,450 Brookline Ave, Boston, MA 02215 USA. EM david_frank@dfci.harvard.edu FU NIH [R01-CA160979]; Lymphoma Research Foundation; DeGregorio Family Foundation FX David Frank is supported by grants from the NIH (R01-CA160979), the Lymphoma Research Foundation, and the DeGregorio Family Foundation. NR 51 TC 28 Z9 29 U1 2 U2 45 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 EI 1531-703X J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD NOV PY 2013 VL 25 IS 6 BP 652 EP 658 DI 10.1097/01.cco.0000432528.88101.1a PG 7 WC Oncology SC Oncology GA 247EK UT WOS:000326598100010 PM 24048019 ER PT J AU Platt, MY DeLelys, ME Preffer, FI Sohani, AR AF Platt, Mia Y. DeLelys, Michelle E. Preffer, Frederic I. Sohani, Aliyah R. TI Utility of Flow Cytometry for Immunophenotyping Double-Hit Lymphomas Response SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Letter ID B-CELL LYMPHOMAS RP Platt, MY (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,GRJ 235, Boston, MA 02114 USA. EM myplatt@partners.org NR 3 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4949 EI 1552-4957 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2013 VL 84 IS 6 BP 399 EP 399 DI 10.1002/cyto.b.21122 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 248KC UT WOS:000326697300006 PM 24038942 ER PT J AU Gros, DF Price, M Yuen, EK Acierno, R AF Gros, Daniel F. Price, Matthew Yuen, Erica K. Acierno, Ron TI PREDICTORS OF COMPLETION OF EXPOSURE THERAPY IN OEF/OIF VETERANS WITH POSTTRAUMATIC STRESS DISORDER SO DEPRESSION AND ANXIETY LA English DT Article DE Operation Enduring Freedom; Operation Iraqi Freedom; posttraumatic stress disorder; exposure therapy; dropout; social support; disability ID MENTAL-HEALTH PROBLEMS; RANDOMIZED CONTROLLED-TRIAL; IRAQI FREEDOM VETERANS; BEHAVIORAL ACTIVATION; AFGHANISTAN VETERANS; PTSD; DEPRESSION; DEPLOYMENT; SERVICES; CARE AB BackgroundDespite large-scale dissemination and implementation efforts of evidence-based psychotherapy to veterans from Operation Enduring/Iraqi Freedom (OEF/OIF), little is known regarding the factors that contribute to the successful completion of these treatments in this high-risk population. The present study investigated predictors of treatment completion during a standardized exposure-based psychotherapy for PTSD. MethodsNinety-two OEF/OIF combat veterans enrolled in a randomized controlled trial for an eight session exposure-based psychotherapy for PTSD. All participants completed structured clinical interviews and several background and symptom questionnaires. Of the initial 92 participants, 28% of the sample (n = 26) discontinued treatment prior to completion of the trial. ResultsPredictors of discontinuation of treatment were assessed with a hierarchical logistic regression. Disability status was positively associated with treatment discontinuation, and postdeployment social support was negatively associated with discontinuation. In contrast to previous findings, other factors, such as age and PTSD symptomatology, were not identified as significant predictors. ConclusionsThe present study suggested that disability status at the start of treatment increases the risk for treatment discontinuation whereas increased social support buffers against discontinuation. Together, these findings highlight the importance of increased assessment and early intervention when these factors are present to potentially reduce treatment discontinuation and improve treatment outcomes in OEF/OIF veterans with PTSD. C1 [Gros, Daniel F.; Acierno, Ron] Ralph H Johnson Vet Affairs Med Ctr, Mental Hlth Serv Line, Charleston, SC 29401 USA. [Gros, Daniel F.; Acierno, Ron] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Price, Matthew] Univ Vermont, Dept Psychol, Burlington, VT 05405 USA. [Yuen, Erica K.] Univ Tampa, Dept Psychol, Tampa, FL 33606 USA. RP Gros, DF (reprint author), Ralph H Johnson Vet Affairs Med Ctr, VAMC, Mental Hlth Serv 116, 109 Bee St, Charleston, SC 29401 USA. EM grosd@musc.edu FU Department of Defense [W81XWH-07-PTSD-IIRA] FX Contract grant sponsor: Department of Defense Grant; Contract grant number: W81XWH-07-PTSD-IIRA (PI: Acierno) NR 39 TC 12 Z9 12 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD NOV PY 2013 VL 30 IS 11 BP 1107 EP 1113 DI 10.1002/da.22207 PG 7 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 246AW UT WOS:000326509200007 PM 24151141 ER PT J AU Zalta, AK Dowd, S Rosenfield, D Smits, JAJ Otto, MW Simon, NM Meuret, AE Marques, L Hofmann, SG Pollack, MH AF Zalta, Alyson K. Dowd, Sheila Rosenfield, David Smits, Jasper A. J. Otto, Michael W. Simon, Naomi M. Meuret, Alicia E. Marques, Luana Hofmann, Stefan G. Pollack, Mark H. TI SLEEP QUALITY PREDICTS TREATMENT OUTCOME IN CBT FOR SOCIAL ANXIETY DISORDER SO DEPRESSION AND ANXIETY LA English DT Article DE sleep quality; cognitive behavioral therapy; psychotherapy; social anxiety disorder; social phobia; d-cycloserine ID COGNITIVE-BEHAVIORAL THERAPY; D-CYCLOSERINE; EXPOSURE THERAPY; CONDITIONED FEAR; AUGMENTATION STRATEGY; EXTINCTION; MEMORY; CONSOLIDATION; DEPRIVATION; EMOTION AB BackgroundSleep quality may be an important, yet relatively neglected, predictor of treatment outcome in cognitive-behavioral therapy (CBT) for anxiety disorders. Specifically, poor sleep quality may impair memory consolidation of in-session extinction learning. We therefore examined sleep quality as a predictor of treatment outcome in CBT for social anxiety disorder and the impact of d-cycloserine (DCS) on this relationship. MethodsOne hundred sixty-nine participants with a primary diagnosis of DSM-IV generalized social anxiety disorder were recruited across three sites. Participants were enrolled in 12 weeks of group CBT. Participants randomly received 50 mg of DCS (n = 87) or pill placebo (n = 82) 1 hr prior to sessions 3-7. Participants completed a baseline measure of self-reported sleep quality and daily diaries recording subjective feelings of being rested upon wakening. Outcome measures including social anxiety symptoms and global severity scores were assessed at each session. ResultsPoorer baseline sleep quality was associated with slower improvement and higher posttreatment social anxiety symptom and severity scores. Moreover, patients who felt more rested after sleeping the night following a treatment session had lower levels of symptoms and global severity at the next session, controlling for their symptoms and severity scores the previous session. Neither of these effects were moderated by DCS condition. ConclusionsOur findings suggest that poor sleep quality diminishes the effects of CBT for social anxiety disorder and this relation is not attenuated by DCS administration. Therapeutic attention to sleep quality prior to initiation of CBT and during the acute treatment phase may be clinically indicated. (C) 2013 Wiley Periodicals, Inc. C1 [Zalta, Alyson K.; Dowd, Sheila; Pollack, Mark H.] Rush Univ, Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. [Zalta, Alyson K.; Dowd, Sheila] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA. [Rosenfield, David; Meuret, Alicia E.] So Methodist Univ, Dept Psychol, Dallas, TX 75275 USA. [Smits, Jasper A. J.] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA. [Smits, Jasper A. J.] Univ Texas Austin, Mental Hlth Res Inst, Austin, TX 78712 USA. [Otto, Michael W.; Hofmann, Stefan G.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Simon, Naomi M.; Marques, Luana; Pollack, Mark H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Pollack, MH (reprint author), Rush Univ, Med Ctr, Dept Psychiat, 1645 West Jackson Blvd,Suite 600, Chicago, IL 60612 USA. EM Mark_Pollack@rush.edu RI Hofmann, Stefan/B-8769-2014; Smits, Jasper/A-4350-2008; OI Hofmann, Stefan/0000-0002-3548-9681; Smits, Jasper/0000-0001-7128-9807; Zalta, Alyson/0000-0002-5159-8431; Smits, Jasper/0000-0003-1633-9693 FU NIH [R01MH078308, R01MH075889] FX Contract grant sponsor: NIH; contract grant numbers: R01MH078308 (Hofmann) and R01MH075889 (Pollack). NR 31 TC 12 Z9 12 U1 2 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD NOV PY 2013 VL 30 IS 11 BP 1114 EP 1120 DI 10.1002/da.22170 PG 7 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 246AW UT WOS:000326509200008 PM 24038728 ER PT J AU Romeo, GR Pae, M Eberle, D Lee, J Shoelson, SE AF Romeo, Giulio R. Pae, Munkyong Eberle, Delphine Lee, Jongsoon Shoelson, Steven E. TI Profilin-1 Haploinsufficiency Protects Against Obesity-Associated Glucose Intolerance and Preserves Adipose Tissue Immune Homeostasis SO DIABETES LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; DIET-INDUCED OBESITY; INSULIN-RESISTANCE; T-CELLS; MESANGIAL CELLS; GROWTH-FACTOR; EXPRESSION; INFLAMMATION; ATHEROSCLEROSIS; MACROPHAGES AB Metabolic inflammation may contribute to the pathogenesis of obesity and its comorbidities, including type 2 diabetes and cardiovascular disease. Previously, we showed that the actin-binding protein profilin-1 (pfn) plays a role in atherogenesis because pfn heterozygote mice (PfnHet) exhibited a significant reduction in atherosclerotic lesion burden and vascular inflammation. In the current study, we tested whether pfn haploinsufficiency would also limit diet-induced adipose tissue inflammation and insulin resistance (IR). First, we found that a high-fat diet (HFD) upregulated pfn expression in epididymal and subcutaneous white adipose tissue (WAT) but not in the liver or muscle of C57BL/6 mice compared with normal chow. Pfn expression in WAT correlated with F4/80, an established marker for mature macrophages. Of note, HFD elevated pfn protein levels in both stromal vascular cells and adipocytes of WAT. We also found that PfnHet were significantly protected from HFD-induced glucose intolerance observed in pfn wild-type mice. With HFD, PfnHet displayed blunted expression of systemic and WAT proinflammatory cytokines and decreased accumulation of adipose tissue macrophages, which were also preferentially biased toward an M2-like phenotype; this correlated with preserved frequency of regulatory T cells. Taken together, the findings indicate that pfn haploinsufficiency protects against diet-induced IR and inflammation by modulating WAT immune homeostasis. C1 [Romeo, Giulio R.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Romeo, GR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. EM giulio.romeo@joslin.harvard.edu; steven.shoelson@joslin.harvard.edu FU JDRF Career Development Award [2-2004-609]; Pilot & Feasibility Program Joslin Diabetes Center; Pilot & Feasibility Program, Boston Obesity Nutrition Research Center; [R01-DK-51729]; [ADA 1-10-BS-97]; [P01-DK-036836] FX This work was supported by grants to G. R. R. (JDRF Career Development Award 2-2004-609, Pilot & Feasibility Program Joslin Diabetes Center, and Pilot & Feasibility Program, Boston Obesity Nutrition Research Center), S. E. S. (R01-DK-51729), J.L. (ADA 1-10-BS-97), and grant P01-DK-036836 to Joslin Diabetes Center. NR 41 TC 5 Z9 5 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD NOV PY 2013 VL 62 IS 11 BP 3718 EP 3726 DI 10.2337/db13-0050 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 243BF UT WOS:000326290700015 PM 23884883 ER PT J AU Hagopian, W Ferry, RJ Sherry, N Carlin, D Bonvini, E Johnson, S Stein, KE Koenig, S Daifotis, AG Herold, KC Ludvigsson, J AF Hagopian, William Ferry, Robert J., Jr. Sherry, Nicole Carlin, David Bonvini, Ezio Johnson, Syd Stein, Kathryn E. Koenig, Scott Daifotis, Anastasia G. Herold, Kevan C. Ludvigsson, Johnny CA Protege Trial Investigators TI Teplizumab Preserves C-Peptide in Recent-Onset Type 1 Diabetes SO DIABETES LA English DT Article ID BETA-CELL FUNCTION; ANTI-CD3 MONOCLONAL-ANTIBODY; INSULIN-SECRETION; IMMUNE THERAPY; SINGLE COURSE; AUTOIMMUNITY; MELLITUS; TRIAL; TOLERANCE; MICE AB Protege was a phase 3, randomized, double-blind, parallel, placebo-controlled 2-year study of three intravenous teplizumab dosing regimens, administered daily for 14 days at baseline and again after 26 weeks, in new-onset type 1 diabetes. We sought to determine efficacy and safety of teplizumab immunotherapy at 2 years and to identify characteristics associated with therapeutic response. Of 516 randomized patients, 513 were treated, and 462 completed 2 years of follow-up. Teplizumab (14-day full-dose) reduced the loss of C-peptide mean area under the curve (AUC), a prespecified secondary end point, at 2 years versus placebo. In analyses of prespecified and post hoc subsets at entry, U.S. residents, patients with C-peptide mean AUC >0.2 nmol/L, those randomized 6 weeks after diagnosis, HbA(1c) <7.5% (58 mmol/mol), insulin use <0.4 units/kg/day, and 8-17 years of age each had greater teplizumab-associated C-peptide preservation than their counterparts. Exogenous insulin needs tended to be reduced versus placebo. Antidrug antibodies developed in some patients, without apparent change in drug efficacy. No new safety or tolerability issues were observed during year 2. In summary, anti-CD3 therapy reduced C-peptide loss 2 years after diagnosis using a tolerable dose. C1 [Hagopian, William] Pacific Northwest Diabet Res Inst, Seattle, WA USA. [Ferry, Robert J., Jr.] Le Bonheur Childrens Hosp, Div Pediat Endocrinol & Metab, Memphis, TN USA. [Ferry, Robert J., Jr.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Sherry, Nicole] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Carlin, David; Bonvini, Ezio; Johnson, Syd; Stein, Kathryn E.; Koenig, Scott; Daifotis, Anastasia G.] MacroGenics, Rockville, MD USA. [Herold, Kevan C.] Yale Univ, Dept Immunobiol, New Haven, CT USA. [Herold, Kevan C.] Yale Univ, Dept Internal Med, New Haven, CT USA. [Ludvigsson, Johnny] Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Div Pediat, Linkoping, Sweden. RP Hagopian, W (reprint author), Pacific Northwest Diabet Res Inst, Seattle, WA USA. EM wah@uw.edu RI Ferry, Robert/O-6107-2016 FU MacroGenics, Inc (Rockville, MD); Johnson Johnson; Tolerx; MacroGenics; JDRF [2008-502]; Le Bonheur Foundation (Memphis, TN) FX This research was supported by MacroGenics, Inc. (Rockville, MD). D.C., E.B., S.J., S.K., and A.G.D. are full-time employees and K.E.S. is a part-time employee of MacroGenics, Inc. and have stock options as part of an employee-offering program. W.H., R.J.F., N.S., and J.L. received research support for this study from MacroGenics. J.L. has received advisory board support from Johnson & Johnson. R.J.F. has received research support within the past 3 years from Tolerx (to study otelixizumab for recent-onset type 1 diabetes), unrelated research support from the U.S. National Institutes of Health (grants R21-HD-059292, T35-DK007405, and U01-DK-085465), JDRF (grant 2011-597), Gabrielle's Angel Foundation, Eli Lilly, Diamyd, Pfizer, Bristol-Myers Squibb, Takeda, and Novo Nordisk, and unrestricted research support from Le Bonheur Foundation (Memphis, TN). W.H. chaired the data safety and monitoring board for the BHT-3021-01 insulin plasmid trial (Bayhill Pharmaceuticals) and received research support from Novo Nordisk. K.C.H. has received research support from MacroGenics and support from the JDRF (grant 2008-502) for laboratory studies on patients' samples from Protege. No other potential conflicts of interest relevant to this article were reported. NR 30 TC 48 Z9 49 U1 1 U2 12 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD NOV PY 2013 VL 62 IS 11 BP 3901 EP 3908 DI 10.2337/db13-0236 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 243BF UT WOS:000326290700033 PM 23801579 ER PT J AU Lazzari, AA Dussault, PM Thakore-James, M Gagnon, D Baker, E Davis, SA Houranieh, AM AF Lazzari, Antonio A. Dussault, Philip M. Thakore-James, Manisha Gagnon, David Baker, Errol Davis, Samuel A. Houranieh, Antoun M. TI Prevention of bone loss and vertebral fractures in patients with chronic epilepsy-Antiepileptic drug and osteoporosis prevention trial SO EPILEPSIA LA English DT Article DE Epilepsy; Anti-epileptic drugs; Osteoporosis; Bisphosphonates; Fractures ID MINERAL DENSITY; LUMBAR SPINE; RISK-FACTORS; THERAPY; MEN; WOMEN; ADULTS; CARBAMAZEPINE; OSTEOMALACIA; RISEDRONATE AB PurposeTo evaluate whether use of a bisphosphonate (risedronate) in addition to calcium and vitamin D in male veterans with epilepsy who were taking antiepileptic drugs (AEDs) long term can prevent the loss of bone mass (BMD, bone mineral density) associated with AED use compared to patients who were treated with a placebo plus calcium and vitamin D. As a secondary end point we studied the incidence of new morphometric vertebral and nonvertebral fractures. MethodsAntiepileptic drug and osteoporosis prevention trial (ADOPT) was designed as a prospective 2-year double-blind, randomized placebo controlled study involving 80 male veterans with epilepsy who were being treated with AEDs such as phenytoin, phenobarbital, sodium valproate, or carbamazepine for a minimum of 2years. All enrolled participants received calcium and vitamin D supplementation, and were randomized to risedronate or matching placebo. Total body, bilateral proximal femora, and anteroposterior (AP) lumbar spine BMDs in addition to morphometric lateral vertebral assessments (LVAs) were evaluated by a dual energy x-ray absorptiometry (DXA) instrument. Comparisons of BMDs were made between baseline, 1year, and after 2years of enrollment in the study. The incidence of new vertebral and nonvertebral fractures was secondary end point. Key FindingsOf the 80 patients initially enrolled in the study, 53 patients completed the study. Baseline characteristics of the two groups were similar. At the end of the study, in the placebo plus calcium and vitamin D group, we observed a significant improvement in BMD at any of the evaluated sites when compared to their baseline scans in 69% (18/26) of the participants. In the risedronate plus calcium and vitamin D group, we observed significant improvement of BMDs in 70% (19/27) of the participants. At the end of the study, the risedronate group experienced a significant increase of BMD at the lumbar spine L1-4 (1.267-1.332g/cm(2)), which was significantly larger than that seen in the placebo group) (1.229g/cm(2) vs. 1.245g/cm(2); p=0.0066).There were nonsignificant differences between the two groups regarding changes of total body BMD or at the proximal bilateral femora. Five new vertebral fractures and one nonvertebral fracture were observed only in the placebo group. SignificanceCalcium and vitamin D supplementation or calcium and vitamin D supplementation in addition to risedronate improved BMD in more than 69% of male veterans with epilepsy who were taking AEDs. In the group receiving risedronate plus calcium and vitamin D there was a significant improvement of BMD at the lumbar spine as compared to the placebo group, which also received calcium and vitamin D. The use of risedronate plus calcium and vitamin D prevented the incidence of new vertebral fractures and one nonvertebral fracture in this cohort. C1 [Lazzari, Antonio A.] Boston VA Healthcare Syst, Primary Care Serv, Boston, MA 02130 USA. [Lazzari, Antonio A.] Boston VA Healthcare Syst, Osteoporosis Clin, Boston, MA 02130 USA. [Lazzari, Antonio A.] Boston VA Healthcare Syst, Rheumatol Sect, Boston, MA 02130 USA. [Lazzari, Antonio A.] Boston VA Healthcare Syst, Dept Med, Boston, MA 02130 USA. [Lazzari, Antonio A.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Lazzari, Antonio A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Dussault, Philip M.] Boston VA Healthcare Syst, Osteoporosis Clin, Serv Pharm, Boston, MA 02130 USA. [Thakore-James, Manisha] Boston VA Healthcare Syst, Dept Neurol, Boston, MA 02130 USA. [Gagnon, David] Boston VA Healthcare Syst, MAVERIC, Boston, MA 02130 USA. [Gagnon, David] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Baker, Errol] Boston VA Healthcare Syst, Dept Res & Dev, Boston, MA 02130 USA. [Davis, Samuel A.] Boston VA Healthcare Syst, Dept Res & Dev, Osteoporosis Clin, Boston, MA 02130 USA. [Houranieh, Antoun M.] Boston VA Healthcare Syst, Serv Pharm, Boston, MA 02130 USA. RP Lazzari, AA (reprint author), Boston VA Healthcare Syst, 120 South Huntington Ave,Suite F2-29, Boston, MA 02130 USA. EM antonio.lazzari@va.gov FU Boston VA Research Institute FX We thank the following who have contributed to the design and statistical analysis or manuscript revision: Rachael Burns, RA; Roanna Bamford, RNP; Kent Creamer, MD; and Jack Bukowski, MD. We also thank the Boston VA Research Institute for their assistance and support and the VA Boston Healthcare System. NR 45 TC 23 Z9 25 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD NOV PY 2013 VL 54 IS 11 BP 1997 EP 2004 DI 10.1111/epi.12351 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 246PJ UT WOS:000326551300021 PM 24010637 ER PT J AU Singh, JP Abraham, WT Chung, ES Rogers, T Sambelashvili, A Coles, JA Martin, DO AF Singh, Jagmeet P. Abraham, William T. Chung, Eugene S. Rogers, Tyson Sambelashvili, Alex Coles, James A., Jr. Martin, David O. TI Clinical response with adaptive CRT algorithm compared with CRT with echocardiography-optimized atrioventricular delay: a retrospective analysis of multicentre trials SO EUROPACE LA English DT Article DE Cardiac resynchronization therapy; Pacing; Optimization ID CARDIAC-RESYNCHRONIZATION THERAPY; CHRONIC HEART-FAILURE; DEVICE ELECTROGRAMS; PROPENSITY SCORES; SYSTOLIC FUNCTION; FOLLOW-UP; CONDUCTION; RECOMMENDATIONS; HEMODYNAMICS; INTERVAL AB Adaptive cardiac resynchronization therapy (aCRT) is a novel algorithm for CRT pacing that provides automatic ambulatory selection between synchronized left ventricular (LV) or bi-ventricular (BiV) pacing and optimization of atrioventricular (AV) and inter-ventricular (VV) delays based on periodic measurement of intrinsic conduction. We aimed to compare the clinical response between aCRT and standard CRT in historical trials. The treatment arm of the aCRT trial was compared with a pooled historical control (HC) derived from the CRT arms of four clinical trials (MIRACLE, MIRACLE ICD, PROSPECT, and InSync III Marquis) with respect to the proportion of patients who had an improved clinical composite score (CCS) at the 6-month follow-up. Patients in the HC underwent echocardiography-guided AV optimization after the implant. A propensity score model was used to adjust for 22 potential baseline confounders of the effect of CRT. Patients were stratified into quintiles according to the propensity score and the adjusted absolute treatment effect was obtained by averaging estimates across these quintiles. The propensity score model included 751 patients (aCRT: 266, historical trials: 485). The adjusted absolute difference in percent improved in CCS between the aCRT and HC arms was 11.9 [95 confidence interval (CI): 2.719.2] favouring aCRT. The patients in the aCRT group were significantly more likely to have an improved CCS than the patients in the HC (odds ratio 1.65, 95 CI: 1.12.5). The aCRT algorithm may be associated with additional improvement in clinical response compared with historical CRT with echocardiographic AV optimization. C1 [Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Heart, Boston, MA 02114 USA. [Abraham, William T.] Ohio State Univ, Ctr Heart, Div Cardiovasc Med, Columbus, OH 43210 USA. [Chung, Eugene S.] Ohio Heart & Vasc Ctr, Lindner Clin Trial Ctr, Cincinnati, OH USA. [Chung, Eugene S.] Christ Hosp, Cincinnati, OH 45219 USA. [Rogers, Tyson; Sambelashvili, Alex; Coles, James A., Jr.] Medtronic Inc, Cardiac Rhythm Dis Management, Mounds View, MN USA. [Martin, David O.] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. RP Singh, JP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Heart, 55 Fruit St, Boston, MA 02114 USA. EM jsingh@partners.org FU Medtronic; St Jude Medical; Boston Scientific; Biotronik; Sorin FX J.P.S. received research grants from Medtronic, St Jude Medical, Boston Scientific, and Biotronik; received consulting and lecture fees from Boston Scientific, Medtronic, Sorin, and St Jude Medical. W. T. A. received consulting fees from Medtronic, St Jude Medical, and Biotronik. E. S. C. received consulting fees from Medtronic and Boston Scientific. T. R., A. S., and J.A.C. are employees of Medtronic. NR 36 TC 6 Z9 7 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1099-5129 EI 1532-2092 J9 EUROPACE JI Europace PD NOV PY 2013 VL 15 IS 11 BP 1622 EP 1628 DI 10.1093/europace/eut107 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 248DT UT WOS:000326674600017 PM 24014804 ER PT J AU Lesogor, A Cohn, JN Latini, R Tognoni, G Krum, H Massie, B Zalewski, A Kandra, A Hua, TA Gimpelewicz, C AF Lesogor, Anastasia Cohn, Jay N. Latini, Roberto Tognoni, Gianni Krum, Henry Massie, Barry Zalewski, Andrew Kandra, Albert Hua, Tsushung A. Gimpelewicz, Claudio TI Interaction between baseline and early worsening of renal function and efficacy of reninangiotensinaldosterone system blockade in patients with heart failure: insights from the Val-HeFT study SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Article DE Valsartan; Heart failure; Prognosis; eGFR; EWRF ID ANGIOTENSIN-RECEPTOR BLOCKER; GLOMERULAR-FILTRATION-RATE; MYOCARDIAL-INFARCTION; RANDOMIZED-TRIAL; TASK-FORCE; VALSARTAN; DYSFUNCTION; SURVIVAL; MORTALITY; ENALAPRIL AB We evaluated the effect of (dual) reninangiotensinaldosterone system (RAAS) blockade with valsartan and an ACE inhibitor [92.7 of patients were treated with an ACE inhibitor in the Valsartan in Heart Failure Trial (Val-HeFT)] in patients with NYHA class IIIV heart failure (HF) and reduced EF on cardiovascular (CV) death and HF hospitalization by subgroups and by presence of early worsening of renal function (EWRF) and according to baseline estimated glomerular filtration rate (eGFR). We analysed the data from 5010 patients enrolled in the Val-HeFT study. A total of 2346 (46.8) patients had baseline renal impairment (i.e. baseline eGFR 60 mL/min/1.73 m(2)). Further, 425 patients (8.6) had EWRF (i.e. eGFR decrease 20 within 1 month after randomization), whereas 4503 patients (91.4) had 20 decline in eGFR. Overall, the difference between valsartan and placebo on the composite endpoint of CV death and HF hospitalization was significant [P 0.0005; hazard ratio (HR) 0.83, 95 confidence interval (CI) 0.750.92)]. In patients with baseline renal impairment, the difference between the treatment groups was also significant (P 0.0002; HR 0.76, 95 CI 0.660.88). Patients with EWRF had higher risk of CV death and HF hospitalization vs. those without ERWF (P 0.0001; HR 1.44, 95 CI 1.211.71), and within the EWRF group a significant difference was also observed between valsartan and placebo (P 0.0086; HR 0.63, 95 CI 0.450.89). However, the interaction between treatment and eGFR at Month 1 was not significant (P 0.1160). Benefits were maintained in patients with renal dysfunction at baseline and those who experienced EWRF. C1 [Lesogor, Anastasia; Kandra, Albert; Gimpelewicz, Claudio] Novartis Pharma AG, Basel, Switzerland. [Cohn, Jay N.] Univ Minnesota, Sch Med, Dept Med, Div Cardiovasc, Minneapolis, MN 55455 USA. [Latini, Roberto] Ist Ric Farmacol Mario Negri, Milan, Italy. [Tognoni, Gianni] Consorzio Mario Negri Sud, Chieti, Italy. [Krum, Henry] Monash Univ, Alfred Hosp, Dept Epidemiol & Prevent Med, Monash Ctr Cardiovasc Res & Educ Therapeut, Melbourne, Vic 3181, Australia. [Massie, Barry] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Massie, Barry] San Francisco VA Med Ctr, Div Cardiol, San Francisco, CA USA. [Zalewski, Andrew; Hua, Tsushung A.] Novartis Pharmaceut, E Hanover, NJ USA. RP Cohn, JN (reprint author), Univ Minnesota, Sch Med, Dept Med, Div Cardiovasc, Minneapolis, MN 55455 USA. EM cohnx001@umn.edu FU Novartis Pharma AG, Basel, Switzerland FX Novartis Pharma AG, Basel, Switzerland. The Val-HeFT study was funded by Novartis Pharma AG, Basel, Switzerland. NR 31 TC 22 Z9 22 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1388-9842 EI 1879-0844 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD NOV PY 2013 VL 15 IS 11 BP 1236 EP 1244 DI 10.1093/eurjhf/hft089 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 248SR UT WOS:000326723200006 PM 23787721 ER PT J AU Tehrani, S Rozelle, C Solomon, A Steele, EA AF Tehrani, S. Rozelle, C. Solomon, A. Steele, E. A. TI Comment on 'Spontaneous haemorrhage in an eyelid hidrocystoma in a patient treated with clopidogrel' SO EYE LA English DT Letter C1 [Tehrani, S.; Steele, E. A.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Rozelle, C.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Solomon, A.] Oregon Hlth & Sci Univ, Dept Dermatol, Portland, OR 97201 USA. [Solomon, A.; Steele, E. A.] Portland VA Med Ctr, Portland, OR USA. RP Tehrani, S (reprint author), Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. EM steeleer@ohsu.edu OI Tehrani, Shandiz/0000-0001-6083-3336 NR 1 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-222X EI 1476-5454 J9 EYE JI Eye PD NOV PY 2013 VL 27 IS 11 BP 1326 EP 1327 DI 10.1038/eye.2013.170 PG 3 WC Ophthalmology SC Ophthalmology GA 251VA UT WOS:000326957700017 PM 23949492 ER PT J AU Mitchell, KS Aiello, AE Galea, S Uddin, M Wildman, D Koenen, KC AF Mitchell, Karen S. Aiello, Allison E. Galea, Sandro Uddin, Monica Wildman, Derek Koenen, Karestan C. TI PTSD and obesity in the Detroit neighborhood health study SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE PTSD; Obesity; Urban; African American ID POSTTRAUMATIC-STRESS-DISORDER; UNITED-STATES; ASSOCIATION; PREVALENCE; DISPARITIES; VIOLENCE AB Objective: Posttraumatic stress disorder (PTSD) has been associated with adverse health consequences, including overweight, obesity and cardiovascular disease. African Americans, particularly women, have among the highest rates of overweight and obesity in the U. S. compared to other racial groups. High rates of violence exposure in urban African Americans may lead to the development of PTSD and increase risk for overweight and obesity. The current study investigated the comorbidity of lifetime PTSD and overweight/obesity in a population-based African American, urban sample. Method: Data were from 463 African American male and female participants of the Detroit Neighborhood Health Study. Multivariable logistic regression models estimated the impact of lifetime PTSD on risk for overweight and obesity. Results: The prevalence of obesity was significantly higher among women (60.9%) than men (33.1%; P<.001). In sex-stratified models, after controlling for demographic variables, PTSD was associated obesity (odds ratio=4.4, 95% confidence interval: 1.3, 14.3) only among women. Conclusions: PTSD was associated with obesity, after controlling for confounding variables, among African American women. Results underscore the contribution of PTSD to obesity among African American women and the importance of addressing the physical health correlates of women with PTSD. Published by Elsevier Inc. C1 [Mitchell, Karen S.] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA 02130 USA. [Mitchell, Karen S.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Aiello, Allison E.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Galea, Sandro; Koenen, Karestan C.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Uddin, Monica; Wildman, Derek] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Uddin, Monica] Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI 48207 USA. RP Mitchell, KS (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA 02130 USA. EM ksmitche@bu.edu RI Koenen, Karestan/K-5402-2014 OI Koenen, Karestan/0000-0003-3293-4281 FU National Institute of Mental Health [K01MH093750]; [R01DA022720]; [R01DA022720-S1]; [MH093612] FX Karen S. Mitchell's contribution to this work was funded by a National Institute of Mental Health award K01MH093750. Allison E. Aiello's contribution to this work was funded by R01DA022720, R01DA022720-S1 and R01DA022720 (PhenX Supplement). Karestan C. Koenen's contribution to this work was funded by MH093612. NR 21 TC 11 Z9 11 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 EI 1873-7714 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD NOV-DEC PY 2013 VL 35 IS 6 BP 671 EP 673 DI 10.1016/j.genhosppsych.2013.07.015 PG 3 WC Psychiatry SC Psychiatry GA 247CV UT WOS:000326592800017 PM 24035634 ER PT J AU Cusin, C Franco, FB Fernandez-Robles, C DuBois, CM Welch, CA AF Cusin, Cristina Franco, Felipe Boschini Fernandez-Robles, Carlos DuBois, Christina M. Welch, Charles A. TI Rapid improvement of depression and psychotic symptoms in Huntington's disease: a retrospective chart review of seven patients treated with electroconvulsive therapy SO GENERAL HOSPITAL PSYCHIATRY LA English DT Editorial Material DE Huntington's disease; Psychiatry; Depression; Movement disorder; Electroconvulsive therapy ID ECT AB Many patients with Huntington's disease (HD) develop psychiatric symptoms such as depression and psychosis. For severe symptoms, electroconvulsive therapy (ECT) can be a valuable treatment. In this case series, we identified seven patients with HD who received ECT at Massachusetts General Hospital in the past 20 years. In all cases, ECT was well tolerated and produced improvement in psychiatric and behavioral symptoms. Our case series supports the hypothesis of a positive risk-benefit ratio for ECT in patients with HD and severe depression or psychosis. (C) 2013 Elsevier Inc. All rights reserved. C1 [Cusin, Cristina; Fernandez-Robles, Carlos; DuBois, Christina M.; Welch, Charles A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Franco, Felipe Boschini] Univ Sao Paulo, Sch Med, Sao Paulo, Brazil. RP Cusin, C (reprint author), Depress & Clin Res Program, 1 Bowdoin Sq,Suite 634, Boston, MA 02114 USA. EM ccusin@partners.org NR 19 TC 4 Z9 4 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 EI 1873-7714 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD NOV-DEC PY 2013 VL 35 IS 6 AR UNSP 678.e3 DI 10.1016/j.genhosppsych.2013.01.015 PG 3 WC Psychiatry SC Psychiatry GA 247CV UT WOS:000326592800023 PM 23541803 ER PT J AU Mogabgab, O Wiviott, SD Cannon, CP Sloan, S Sabatine, MS Antman, EM Braunwald, E Giugliano, RP AF Mogabgab, Owen Wiviott, Stephen D. Cannon, Christopher P. Sloan, Sarah Sabatine, Marc S. Antman, Elliott M. Braunwald, Eugene Giugliano, Robert P. TI Circadian Variation of Stent Thrombosis and the Effect of More Robust Platelet Inhibition: A Post Hoc Analysis of the TRITON-TIMI 38 Trial SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Article DE stent thrombosis; circadian variation; prasugrel; clopidogrel ID ELEVATION MYOCARDIAL-INFARCTION; ACUTE CORONARY SYNDROMES; DRUG-ELUTING STENTS; UPRIGHT POSTURE; OUTCOMES; CLOPIDOGREL; PREDICTORS; IMPLANTATION; PRASUGREL; ONSET AB Background: The well-described morning peak in the onset of acute coronary syndromes has been partly attributed to increased platelet activity upon arising. It has been suggested that stent thrombosis (ST) exhibits a similar pattern. We assessed whether a diurnal variation in ST occurs, and whether more robust antiplatelet therapy with prasugrel (vs clopidogrel) can attenuate a morning excess. Methods and Materials: Patients from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial (N = 13608) with adjudicated ST classified per the Academic Research Consortium definitions of definite (N = 135) and probable (N = 27) were grouped into prespecified 8-hour intervals by time of onset: early (6 am-2 pm), late-day (2 pm-10 pm), and overnight (10 pm-6 am). We compared the rates per 1000 patients of ST across time intervals and stratified by treatment and stent type. Results: A diurnal variation in definite/probable ST was observed with rates of 6.5, 3.7, and 2.1 for early, late-day, and overnight intervals, respectively (P < .001), per 1000 patients treated. A sensitivity analysis excluding periprocedural acute-ST (<24 hours after index percutaneous coronary intervention [PCI]) resulted in similar findings (5.2, 2.5, and 1.8 per 1000, P < .001). The circadian variation in ST was observed in patients on clopidogrel (9.7, 4.8, and 3.1 per 1000, P < .001) with the highest rate of ST early in the day. Patients on prasugrel also demonstrated a circadian variation with particularly low rates of overnight ST (3.4, 3.0, and 1.1 per 1000, P = .020). Conclusions: In TRITON-TIMI 38 trial, the timing of ST exhibited a significant diurnal variation similar to that seen with onset of other acute coronary syndromes. ST occurred less frequently among patients randomized to prasugrel compared to clopidogrel with the greatest absolute reduction (6.2 per 1000 patients) in events earlier in the day when platelet activity is known to be highest. C1 [Mogabgab, Owen] Univ Texas Southwestern Med Sch, Div Cardiol, Dallas, TX 75390 USA. [Wiviott, Stephen D.; Cannon, Christopher P.; Sloan, Sarah; Sabatine, Marc S.; Antman, Elliott M.; Braunwald, Eugene; Giugliano, Robert P.] Brigham & Womens Hosp, Div Cardiovasc Med, TIMI Study Grp, Boston, MA 02115 USA. [Wiviott, Stephen D.; Cannon, Christopher P.; Sloan, Sarah; Sabatine, Marc S.; Antman, Elliott M.; Braunwald, Eugene; Giugliano, Robert P.] Harvard Univ, Sch Med, Boston, MA USA. RP Mogabgab, O (reprint author), Univ Texas Southwestern Med Sch, Div Cardiol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM owen@mogabgab.com FU Daiichi-Sankyo; Lilly FX The author(s) declared the following conflicts of interest with respect to the research, authorship, and/or publication of this article: The TIMI Study Group (of which Dr. Mogabgab is a research fellow and remaining authors are current members) received research grant support for the TRITON-TIMI 38 trial from Daiichi-Sankyo and Lilly. Dr. Giugliano has received honorarium from Daiichi-Sankyo for consulting and CME lectures. Drs. Braunwald (CME lectures) and Sabatine (consulting and CME lectures) have received honoraria from Daiichi-Sankyo and Lilly. NR 24 TC 4 Z9 4 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1074-2484 EI 1940-4034 J9 J CARDIOVASC PHARM T JI J. Cardiovasc. Pharmacol. Ther. PD NOV PY 2013 VL 18 IS 6 BP 555 EP 559 DI 10.1177/1074248413497534 PG 5 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 248CR UT WOS:000326671800007 PM 24064010 ER PT J AU Lee, J Wu, WC Lesage, F Boas, DA AF Lee, Jonghwan Wu, Weicheng Lesage, Frederic Boas, David A. TI Multiple-capillary measurement of RBC speed, flux, and density with optical coherence tomography SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE capillaries; cerebral blood flow measurement; cranial windows; microscopy; optical imaging ID STIMULUS-INDUCED CHANGES; BLOOD-FLOW; INDIVIDUAL CAPILLARIES; RAT; CORTEX; FLUCTUATIONS; MICROSCOPY; PERFUSION; VELOCITY AB As capillaries exhibit heterogeneous and fluctuating dynamics even during baseline, a technique measuring red blood cell (RBC) speed and flux over many capillaries at the same time is needed. Here, we report that optical coherence tomography can capture individual RBC passage simultaneously over many capillaries located at different depths. Further, we demonstrate the ability to quantify RBC speed, flux, and linear density. This technique will provide a means to monitor microvascular flow dynamics over many capillaries at different depths at the same time. C1 [Lee, Jonghwan; Wu, Weicheng; Boas, David A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Lesage, Frederic] Polytech Montreal, Dept Elect Engn, Montreal, PQ, Canada. RP Lee, J (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, 149 13th St,Room 2280, Charlestown, MA 02129 USA. EM jonghwen@nmr.mgh.harvard.edu FU NIH [R01-NS057476, R01-EB000790, P01NS055104]; AFOSR [MFEL FA9550-07-1-0101] FX This study was supported by the NIH (R01-NS057476, R01-EB000790, P01NS055104) and the AFOSR (MFEL FA9550-07-1-0101). NR 13 TC 25 Z9 25 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD NOV PY 2013 VL 33 IS 11 BP 1707 EP 1710 DI 10.1038/jcbfm.2013.158 PG 4 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 246SL UT WOS:000326559300006 PM 24022621 ER PT J AU Lwin, T Zhao, XH Cheng, FD Zhang, XW Huang, A Shah, B Zhang, YZ Moscinski, LC Choi, YS Kozikowski, AP Bradner, JE Dalton, WS Sotomayor, E Tao, JG AF Lwin, Tint Zhao, Xiaohong Cheng, Fengdong Zhang, Xinwei Huang, Andy Shah, Bijal Zhang, Yizhuo Moscinski, Lynn C. Choi, Yong Sung Kozikowski, Alan P. Bradner, James E. Dalton, William S. Sotomayor, Eduardo Tao, Jianguo TI A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; FOLLICULAR DENDRITIC CELLS; MARROW STROMAL CELLS; MANTLE-CELL; DOWN-REGULATION; C-MYC; CHAPERONE FUNCTION; DRUG-RESISTANCE; HDAC6 INHIBITOR; UP-REGULATION AB A dynamic interaction occurs between the lymphoma cell and its microenvironxnent, with each profoundly influencing the behavior of the other. Here, using a clonogenic coculture growth system and a xenograft mouse model, we demonstrated that adhesion of mantle cell lymphoma (MCL) and other non-Hodgkin lymphoma cells to lymphoma stromal cells confers drug resistance, donogenicity, and induction of histone d.eacetylase 6 (HDAC6). Furthermore, stroma triggered a c-Myc/miR-548m feed-forward loop, linking sustained c-Myc activation, miR-548m downregulation, and subsequent HDAC6 upregulation and stroma-mediated cell survival and lymphoma progression in lymphoma cell lines, primary MCL and other B cell lymphoma canines. Treatment with an HDAC6-selective inhibitor alone or in synergy with a c-Myc inhibitor enhanced cell death, abolished cell adhesion-mediated drug resistance, and suppressed clonogenicity and lymphoma growth ex vivo and in vivo. Together, these data suggest that the lymphoma-stroma interaction in the lymphoma microenvironment directly impacts the biology of lymphoma through genetic and epigenetic regulation, with HDAC6 and c-Myc as potential therapeutic targets. C1 [Lwin, Tint; Zhao, Xiaohong; Huang, Andy; Moscinski, Lynn C.; Tao, Jianguo] Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Dept Hematopathol & Lab Med, Tampa, FL 33613 USA. [Lwin, Tint; Zhao, Xiaohong; Cheng, Fengdong; Huang, Andy; Shah, Bijal; Moscinski, Lynn C.; Dalton, William S.; Sotomayor, Eduardo; Tao, Jianguo] Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Expt Therapeut Program, Tampa, FL 33613 USA. [Cheng, Fengdong; Shah, Bijal; Dalton, William S.; Sotomayor, Eduardo] Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL 33613 USA. [Cheng, Fengdong; Shah, Bijal; Dalton, William S.; Sotomayor, Eduardo] Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL 33613 USA. [Zhang, Xinwei; Zhang, Yizhuo] Tianjin Canc Hosp, Dept Immunol & Hematol, Tianjin, Peoples R China. [Choi, Yong Sung] Alton Ochsner Med Fdn & Ochsner Clin, Lab Cellular Immunol, New Orleans, LA USA. [Kozikowski, Alan P.] Univ Illinois, Drug Discovery Program, Dept Med Chem & Pharmacognosy, Chicago, IL USA. [Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Tao, JG (reprint author), Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, MCC LAB 2071,12902 Magnolia Dr, Tampa, FL 33613 USA. EM Jianguo.Tao@moffitt.org FU National Cancer Institutes [R01CA137123]; Lymphoma Research Foundation; Maher Fund FX We are grateful to the Tissue Procurement, Molecular Core Laboratory, and Flow Cytometry Core Facilities at H. Lee Moffitt Cancer Center and Research Institute for providing specimens, molecular analysis, and cell apoptosis analysis. We thank Rasa Hamilton for editorial assistance. This work was supported by grants from the National Cancer Institutes (R01CA137123, to J. Tao), Lymphoma Research Foundation (to J. Tao), and Maher Fund (to J. Tao). NR 46 TC 25 Z9 28 U1 1 U2 7 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2013 VL 123 IS 11 BP 4612 EP 4626 DI 10.1172/JCI64210 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 247IU UT WOS:000326611900012 PM 24216476 ER PT J AU Kleinridders, A Lauritzen, HPMM Ussar, S Christensen, JH Mori, MA Bross, P Kahn, CR AF Kleinridders, Andre Lauritzen, Hans P. M. M. Ussar, Siegfried Christensen, Jane H. Mori, Marcelo A. Bross, Peter Kahn, C. Ronald TI Leptin regulation of Hsp60 impacts hypothalamic insulin signaling SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID RESPIRATORY-CHAIN DYSFUNCTION; HEPATIC GLUCOSE-PRODUCTION; RESISTANCE IN-VIVO; OXIDATIVE STRESS; MITOCHONDRIAL HSP60; BIDIRECTIONAL PROMOTER; TRANSCRIPTION FACTOR; EMBRYONIC LETHALITY; SKELETAL-MUSCLE; GENE-EXPRESSION AB Type 2 diabetes is characterized by insulin resistance and mitochondrial dysfunction in classical target tissues such as muscle, fat, and liver. Using a murine model of type 2 diabetes, we show that there is hypothalamic insulin resistance and mitochondrial dysfunction due to downregulation of the mitochondrial chaperone HSP60. HSP60 reduction in obese, diabetic mice was due to a lack of proper leptin signaling and was restored by leptin treatment. Knockdown of Hsp60 in a mouse hypothalamic cell line mimicked the mitochondrial dysfunction observed in diabetic mice and resulted in increased ROS production and insulin resistance, a phenotype that was reversed with antioxidant treatment. Mice with a heterozygous deletion of Hsp60 exhibited mitochondrial dysfunction and hypothalamic insulin resistance. Targeted acute downregulation of Hsp60 in the hypothalamus also induced insulin resistance, indicating that mitochondrial dysfunction can cause insulin resistance in the hypothalamus. Importantly, type 2 diabetic patients exhibited decreased expression of HSP60 in the brain, indicating that this mechanism is relevant to human disease. These data indicate that leptin plays an important role in mitochondrial function and insulin sensitivity in the hypothalamus by regulating HSP60. Moreover, leptin/insulin crosstalk in the hypothalamus impacts energy homeostasis in obesity and insulin-resistant states. C1 [Kleinridders, Andre; Lauritzen, Hans P. M. M.; Ussar, Siegfried; Mori, Marcelo A.; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Integrat Physiol & Metab, Boston, MA 02115 USA. [Christensen, Jane H.] Aarhus Univ, Dept Biomed, Aarhus C, Denmark. [Bross, Peter] Aarhus Univ Hosp, Res Unit Mol Med, DK-8000 Aarhus, Denmark. [Bross, Peter] Aarhus Univ, Aarhus, Denmark. RP Kahn, CR (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu RI Bross, Peter/B-7219-2013; OI Bross, Peter/0000-0001-9526-8525; Ussar, Siegfried/0000-0001-7575-0920 FU NIH [R01 DK33201, R01 DK31036, P30 DK036836]; German Research Foundation (DFG) [K12399-1/1]; HSFP long-term fellowship FX We thank M. Rourk and G. Smyth for animal care, J. LaVecchio and G. Buruzula (Joslin's DERC Flow Cytometry Core), G. Sankaranarayanan (Joslin's DERC Specialized Assay Core), and C. Cahill (Joslin's DERC Advanced Microscopy Core) for their technical assistance. We thank Megan Greenwald-Yarnell and Martin G. Myers for providing arcuate nucleus samples of leprS1138 mice. Furthermore, we thank J.J. Hansen for providing the HSP60 promoter luciferase vector and Jim Darnell for providing the STAT3 vector constructs. This work was supported by NIH grants R01 DK33201 and R01 DK31036 and a Mary K. Iacocca Professorship (to C.R. Kahn); by NIH grant P30 DK036836 (to Joslin DERC Core Facilities); and a German Research Foundation (DFG) project K12399-1/1 grant (to A. Kleinridders). S. Ussar was supported by an HSFP long-term fellowship. NR 73 TC 21 Z9 24 U1 0 U2 8 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2013 VL 123 IS 11 BP 4667 EP 4680 DI 10.1172/JCI67615 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 247IU UT WOS:000326611900016 PM 24084737 ER PT J AU Hahn, WC AF Hahn, William C. TI The perfect storm: challenges and opportunities for translational medicine SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID PRESIDENTIAL-ADDRESS C1 Dana Farber Canc Inst, Boston, MA 02215 USA. RP Hahn, WC (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 1538, Boston, MA 02215 USA. EM william_hahn@dfci.harvard.edu NR 4 TC 2 Z9 3 U1 0 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2013 VL 123 IS 11 BP 4963 EP 4966 DI 10.1172/JCI73221 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 247IU UT WOS:000326611900042 PM 24177467 ER PT J AU Hoffman, RM Penson, DF Zietman, AL Barry, MJ AF Hoffman, Richard M. Penson, David F. Zietman, Anthony L. Barry, Michael J. TI Comparative effectiveness research in localized prostate cancer treatment SO JOURNAL OF COMPARATIVE EFFECTIVENESS RESEARCH LA English DT Article DE cohort studies; comparative effectiveness research; decision-making; decision support techniques; prostatectomy; prostatic neoplasms; quality of life; radiotherapy ID QUALITY-OF-LIFE; ANDROGEN-DEPRIVATION THERAPY; PHASE-III TRIAL; RADICAL PROSTATECTOMY; RANDOMIZED-TRIAL; ACTIVE SURVEILLANCE; INITIAL TREATMENT; ELDERLY-MEN; MORTALITY OUTCOMES; RADIATION-THERAPY AB Prostate-specific antigen testing has dramatically increased the incidence of localized prostate cancer. Most men with localized cancer attempt curative therapy, usually with surgery or radiation. However, there is uncertainty about whether and how to best treat these cancers. No published controlled trials have directly compared surgery against radiation or either treatment against active surveillance. Given the indolent nature of prostate cancer and the substantial risks of treatment-related harms, the effects of cancer and treatment on quality of life are important patient-centered outcomes. Comparative effectiveness research, using observational cohorts, claims data and simulation models, enables comparisons of treatments that have not been studied in controlled trials and captures real-world outcomes data to better support informed decision-making. C1 [Hoffman, Richard M.] Univ New Mexico, Dept Med, Albuquerque, NM 87131 USA. [Hoffman, Richard M.] New Mexico VA Hlth Care Syst, Med Serv, Albuquerque, NM USA. [Penson, David F.] Vanderbilt Univ, Dept Urol Surg, Nashville, TN 37235 USA. [Penson, David F.] VA Tennessee Healthcare Syst, GRECC, Nashville, TN USA. [Zietman, Anthony L.; Barry, Michael J.] Harvard Univ, Sch Med, Boston, MA USA. [Zietman, Anthony L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barry, Michael J.] Informed Med Decis Fdn, Boston, MA USA. RP Hoffman, RM (reprint author), Univ New Mexico, Dept Med, Albuquerque, NM 87131 USA. EM rhoffman@unm.edu FU Informed Medical Decisions Foundation; Department of Veterans Affairs FX RM Hoffman receives partial salary support for editing a prostate cancer treatment decision aid from the Informed Medical Decisions Foundation, a not-for-profit (501 [c]3) private foundation. He is supported by the Department of Veterans Affairs. MJ Barry receives salary support as president of the Informed Medical Decisions Foundation. The Foundation develops content for patient education programs, including programs on prostate cancer screening and treatment. The Foundation has an arrangement with a for-profit company, Health Dialog, to coproduce these programs. The programs are used as part of the decision support and disease management services Health Dialog provides to consumers through healthcare organizations and employers. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 81 TC 3 Z9 3 U1 2 U2 7 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 2042-6305 EI 2042-6313 J9 J COMP EFFECT RES JI J. Comp. Eff. Res. PD NOV PY 2013 VL 2 IS 6 BP 583 EP 593 DI 10.2217/cer.13.66 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 248KZ UT WOS:000326699700015 PM 24236797 ER PT J AU Beach, SR Januzzi, JL Mastromauro, CA Healy, BC Beale, EE Celano, CM Huffman, JC AF Beach, Scott R. Januzzi, James L. Mastromauro, Carol A. Healy, Brian C. Beale, Eleanor E. Celano, Christopher M. Huffman, Jeff C. TI Patient Health Questionnaire-9 score and adverse cardiac outcomes in patients hospitalized for acute cardiac disease SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Article DE Cardiovascular disease; Depression; Patient Health Questionnaire-9 ID CORONARY-HEART-DISEASE; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CONTROLLED-TRIAL; ATRIAL-FIBRILLATION; COLLABORATIVE CARE; ARTERY-DISEASE; CARDIOVASCULAR EVENTS; MANAGEMENT PROGRAM; DEPRESSION; FAILURE AB Objective: The Patient Health Questionnaire-9 (PHQ-9) is increasingly used as a depression assessment tool in cardiac patients. However, in contrast to older depression instruments, there is little data linking PHQ-9 scores to adverse cardiac outcomes. Our goal was to evaluate whether higher PHQ-9 scores were predictive of subsequent cardiac readmissions among depressed patients hospitalized for an acute cardiac event. Methods: Patients diagnosed with depression during hospitalization for acute coronary syndrome, heart failure, or arrhythmia were enrolled in a randomized depression management trial. Participants were administered PHQ-9 at enrollment, and data was collected regarding cardiac readmissions and mortality over the next 6 months. To evaluate the independent association of PHQ-9 score with subsequent cardiac readmission, Cox regression analysis that included relevant sociodemographic and medical covariates was used. Survival analysis examining time to first event, stratified by quartile of initial PHQ-9 score, was performed using Kaplan-Meier curves and log-rank test for trend. Analyses were then repeated using a composite (cardiac readmission or mortality) outcome. Results: Among 172 subjects, 62 (36.0%) had a cardiac-related rehospitalization. Higher initial PHQ-9 score predicted cardiac-related rehospitalization, independent of multiple relevant covariates (hazard ratio 1.09 [95% confidence interval = 1.02-1.17]; p = 0.015). On survival analysis, log-rank test for trend revealed a significant rise in event rates across increasing PHQ-9 quartiles (chi(2) = 6.36; p = 0.012). Findings were similar (p < .05) for the composite outcome. Conclusion: In depressed cardiac patients, each additional point on the PHQ-9 was independently associated with a 9% greater risk of cardiac readmission over the subsequent 6 months. (C) 2013 Elsevier Inc. All rights reserved. C1 [Beach, Scott R.; Januzzi, James L.; Celano, Christopher M.; Huffman, Jeff C.] Harvard Univ, Sch Med, Boston, MA USA. [Beach, Scott R.; Mastromauro, Carol A.; Beale, Eleanor E.; Celano, Christopher M.; Huffman, Jeff C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA. [Healy, Brian C.] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. RP Huffman, JC (reprint author), Massachusetts Gen Hosp, 55 Fruit St Warren 1220D, Boston, MA 02114 USA. EM jhuffman@partners.org FU American Heart Association [0735530T] FX American Heart Association Scientist Development Grant 0735530T (Huffman). Clinical Trial Registration: Unique Identifier: NCT00847132. NR 49 TC 10 Z9 10 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 EI 1879-1360 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD NOV PY 2013 VL 75 IS 5 BP 409 EP 413 DI 10.1016/j.jpsychores.2013.08.001 PG 5 WC Psychiatry SC Psychiatry GA 248NZ UT WOS:000326709500002 PM 24182627 ER PT J AU Prager, LM AF Prager, Laura M. TI Appreciating "Normal" Development: How Did We Get Here? SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material ID CHILD C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Prager, LM (reprint author), Massachusetts Gen Hosp, Yawkey 6956,55 Fruit St, Boston, MA 02114 USA. EM lmprager@partners.org NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD NOV PY 2013 VL 52 IS 11 BP 1121 EP 1123 DI 10.1016/j.jaac.2013.08.021 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 245RF UT WOS:000326480800001 PM 24157384 ER PT J AU Jellinek, MS AF Jellinek, Michael S. TI Universal Mental Health Screening in Pediatrics: Toward Better Knowing, Treating, or Referring SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material C1 [Jellinek, Michael S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jellinek, Michael S.] Harvard Univ, Cambridge, MA 02138 USA. RP Jellinek, MS (reprint author), Partners HealthCare Syst Inc, Prudential Tower,Suite 1150,800 Boylston St, Boston, MA 02119 USA. EM mjellinek@partners.org NR 11 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD NOV PY 2013 VL 52 IS 11 BP 1131 EP 1133 DI 10.1016/j.jaac.2013.08.007 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 245RF UT WOS:000326480800004 PM 24157387 ER PT J AU Ruff, CT Bonaca, MP Kosowsky, JM Conrad, MJ Murphy, SA Jarolim, P Donahoe, SM O'Donoghue, ML Morrow, DA AF Ruff, Christian T. Bonaca, Marc P. Kosowsky, Joshua M. Conrad, Michael J. Murphy, Sabina A. Jarolim, Petr Donahoe, Sean M. O'Donoghue, Michelle L. Morrow, David A. TI Evaluation of the diagnostic performance of heart-type fatty acid binding protein in the BWH-TIMI ED chest pain study SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Chest pain; Emergency department; H-FABP; Myocardial infarction; Acute coronary syndromes ID ACUTE MYOCARDIAL-INFARCTION; ACUTE CORONARY SYNDROMES; TROPONIN-I ASSAY; CARDIAC TROPONIN; EMERGENCY-DEPARTMENT; PRACTICE GUIDELINES; MYOGLOBIN; SENSITIVITY; BIOMARKERS; ISCHEMIA AB Chest pain is one of the most common reasons for presentation to the Emergency Department and the ability to rapidly and correctly diagnose the minority of patients who have a myocardial infarction is of critical importance. We assessed the diagnostic performance of a multimarker strategy using heart-type fatty acid binding protein (H-FABP) in combination with a contemporary sensitive troponin (cTn) assay. We measured H-FABP (Randox) and a sensitive cTn (TnI-Ultra, Siemens) at baseline in 343 patients with chest pain enrolled in the prospective BWH-TIMI ED chest pain study. Final presenting diagnosis was adjudicated using all diagnostic data, including the local cTnI results, but reviewers were blinded to H-FABP and the sensitive cTn assays. The diagnostic accuracy of H-FABP and local cTn together (AUC 0.962) was superior to local cTn alone (AUC 0.910, p = 0.0009) with an especially marked improvement in early presenters (AUC 0.983 vs. 0.840, p = 0.0098). In contrast, when combined with the sensitive cTn assay, there was no significant difference in the AUC with H-FABP as compared with the sensitive cTn alone, either in the overall cohort (AUC 0.963 vs. 0.956, p = 0.23) or in early presenters (AUC 0.999 for both). In early presenters, the addition of H-FABP resulted in a NPV of 100 % when combined with either the local or sensitive cTn assay. In our study, the addition of H-FABP significantly enhanced the sensitivity and accuracy of diagnosis as compared to a prior-generation troponin assay alone, especially in patients who presented early. H-FABP but did improve overall diagnostic accuracy when added to a current-generation sensitive troponin assay; however, their combination offered the best NPV in early presenters. Further studies are needed to determine the utility a very rapid "rule out" of MI with a single blood draw of troponin and H-FABP at presentation. C1 [Ruff, Christian T.; Bonaca, Marc P.; Murphy, Sabina A.; O'Donoghue, Michelle L.; Morrow, David A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Cardiovasc Div,Dept Med,TIMI Study Grp, Boston, MA 02115 USA. [Kosowsky, Joshua M.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Conrad, Michael J.; Jarolim, Petr] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Ruff, CT (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Cardiovasc Div,Dept Med,TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM cruff@partners.org FU Abbott; Amgen; AstraZeneca; Beckman Coulter; BG Medicine; BRAHMS; Bristol-Myers Squibb; Buhlmann; Critical Diagnostics; CV Therapeutics; Daiichi Sankyo Co Ltd; Eli Lilly and Co; GlaxoSmithKline; Merck and Co; Nanosphere; Novartis Pharmaceuticals; Ortho-Clinical Diagnostics; Pfizer; Randox; Roche Diagnostics; Sanofi-Aventis; Siemens; Singulex FX The TIMI Study Group has received research Grant support from Abbott, Amgen, AstraZeneca, Beckman Coulter, BG Medicine, BRAHMS, Bristol-Myers Squibb, Buhlmann, Critical Diagnostics, CV Therapeutics, Daiichi Sankyo Co Ltd, Eli Lilly and Co, GlaxoSmithKline, Merck and Co, Nanosphere, Novartis Pharmaceuticals, Ortho-Clinical Diagnostics, Pfizer, Randox, Roche Diagnostics, Sanofi-Aventis, Siemens, and Singulex. NR 28 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 EI 1573-742X J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD NOV PY 2013 VL 36 IS 4 BP 361 EP 367 DI 10.1007/s11239-013-0870-7 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 249UH UT WOS:000326802500001 PM 23328883 ER PT J AU Zeglin-Sawczuk, M Jang, IK Kato, K Yonetsu, T Kim, S Choi, SY Kratlian, C Lee, H Dauerman, HL AF Zeglin-Sawczuk, Magdalena Jang, Ik-Kyung Kato, Koji Yonetsu, Taishi Kim, SooJoong Choi, So-Yeon Kratlian, Christina Lee, Hang Dauerman, Harold L. TI Lipid rich plaque, female gender and proximal coronary stent edge dissections SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Optical coherence tomography; Percutaneous coronary intervention; Edge dissection; Female gender ID OPTICAL COHERENCE TOMOGRAPHY; ACUTE MYOCARDIAL-INFARCTION; INTRAVASCULAR ULTRASOUND; CLINICAL-OUTCOMES; ARTERY-DISEASE; INTERVENTION; IMPLANTATION; WOMEN; COMPLICATIONS; ANGIOPLASTY AB We hypothesized that women are more prone to develop coronary dissections during PCI due to potential balloon-oversizing or gender specific plaque and vascular characteristics. To date, a gender related difference in edge dissection has not been systematically studied. The Massachusetts General Hospital Optical Coherence Tomography (MGH OCT) Registry is an international registry of patients undergoing OCT procedures. We identified 206 consecutive patients (159 men, 47 women) with stable or unstable coronary syndromes demonstrating adequate OCT images for gender specific comparison in areas of non-overlapping stents. Presence of proximal edge dissection, its characteristics, plaque composition at stent borders and luminal diameters were assessed. A multivariate logistic regression model was applied to determine if female gender was predictive of proximal coronary dissection after adjusting for clinical, procedural and plaque characteristics. Proximal coronary dissection was significantly more common in women as compared to men (30.6 vs 15.6 %, p = 0.02). No gender differences were observed in age, presentation, and stents per patient or plaque characteristics. The characteristics of edge dissections were different in women compared to men with a significant female predisposition to more complex proximal coronary dissection. In multivariable analysis, female gender was not a predictor of coronary dissection; on the other hand, stent oversizing and especially lipid rich plaque at proximal edge were independent predictors of proximal dissection. OCT confirms that female gender is associated with a greater than twofold increased risk of developing proximal coronary edge dissections as compared to men. But, the most potent independent predictor of proximal coronary edge dissection is the presence of a proximal lipid rich plaque. C1 [Zeglin-Sawczuk, Magdalena; Dauerman, Harold L.] Univ Vermont, Coll Med, Burlington, VT 05401 USA. [Zeglin-Sawczuk, Magdalena] Univ Vermont, Fletcher Allen Hlth Care, Div Cardiol, Burlington, VT 05401 USA. [Jang, Ik-Kyung; Kato, Koji; Yonetsu, Taishi; Kim, SooJoong; Kratlian, Christina; Lee, Hang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Choi, So-Yeon] Ajou Univ, Suwon 441749, South Korea. RP Zeglin-Sawczuk, M (reprint author), Univ Vermont, Fletcher Allen Hlth Care, Div Cardiol, McClure 1,111 Colchester Ave, Burlington, VT 05401 USA. EM magdalena.zeglin-sawczuk@vtmednet.org FU St. Jude Medical; Abbott Vascular; Medtronic; Cardiology Division, Massachusetts General Hospital FX Dr. Dauerman has research grants from Abbott Vascular and Medtronic and serves as a consultant to The Medicines Company and Medtronic. Dr. Jang has research grants from St. Jude Medical and serves as a consultant to St. Jude Medical. The other authors have no potential conflicts of interest. The MGH OCT Registry is funded by Cardiology Division, Massachusetts General Hospital and St. Jude Medical. NR 26 TC 4 Z9 4 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 EI 1573-742X J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD NOV PY 2013 VL 36 IS 4 BP 507 EP 513 DI 10.1007/s11239-013-0882-3 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 249UH UT WOS:000326802500021 PM 23378150 ER PT J AU Harvey, HB Prabhakar, AM Oklu, R AF Harvey, H. Benjamin Prabhakar, Anand M. Oklu, Rahmi TI Bringing Transparency to Physician-Industry Relationships: What the Physician Payment Sunshine Act Will Mean for Interventional Radiologists SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Editorial Material ID ACADEMIC MEDICAL-CENTERS; OF-INTEREST; DISCLOSURE C1 [Harvey, H. Benjamin; Prabhakar, Anand M.; Oklu, Rahmi] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Vasc Imaging & Intervent, Boston, MA 02114 USA. RP Oklu, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Vasc Imaging & Intervent, 55 Fruit St,290 Gray Bigelow, Boston, MA 02114 USA. EM roklu@partners.org NR 12 TC 5 Z9 5 U1 0 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD NOV PY 2013 VL 24 IS 11 BP 1589 EP 1592 DI 10.1016/j.jvir.2013.07.009 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 245QT UT WOS:000326479600001 PM 24160819 ER PT J AU Deatrick, KB Luke, CE Elfline, MA Sood, V Baldwin, J Upchurch, GR Jaffer, FA Wakefield, TW Henke, PK AF Deatrick, Kristopher B. Luke, Catherine E. Elfline, Megan A. Sood, Vikram Baldwin, Joseph Upchurch, Gilbert R., Jr. Jaffer, Farouc A. Wakefield, Thomas W. Henke, Peter K. TI The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID VENOUS THROMBOSIS RESOLUTION; MOLECULAR-WEIGHT HEPARIN; MUSCLE-CELL MIGRATION; P-SELECTIN PSI-697; MOUSE MODEL; TISSUE INHIBITORS; GELATINASE-A; COLLAGEN; INFLAMMATION; FIBROSIS AB Background: Vein wall fibrotic injury following deep venous thrombosis (VT) is associated with elevated matrix metalloproteinases (MMPs). Whether and by what mechanism MMP2 contributes to vein wall remodeling after VT is unknown. Methods: Stasis VT was produced by ligation of the inferior vena cava and tissue was harvested at 2, 8, and 21 days in MMP2 -/- and genetic wild type (WT) mice. Tissue analysis by immunohistochemistry, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and zymography was performed. Results: Thrombus resolution was less at 8 days in MMP2 -/- compared with WT, evidenced by a 51% increase in VT size (P < .01), and threefold fewer von Willebrand's factor positive channels (P < .05). In MMP2 -/- mice, the main phenotypic fibrotic differences occurred at 8 days post-VT, with significantly less vein wall collagen content (P = .013), fourfold lower procollagen III gene expression (P < .01), but no difference in procollagen I compared with WT. Decreased inflammation in MMP2 -/- vein walls was suggested by similar to threefold reduced TNF alpha and IL-1 beta at 2 days and 8 days post-VT (P < .05). A fourfold increase in vein wall monocytes (P = .03) with threefold decreased apoptosis (P < .05), but no difference in cellular proliferation at 8 days was found in MMP2 -/- compared with WT. As increased compensatory MMP9 activity was observed in the MMP2 -/- mice, MMP2/9 double null mice had thrombus induced with VT harvest at 8 days. Consistently, twofold larger VT, a threefold decrease in vein wall collagen, and a threefold increase in monocytes were found (all P < .05). Similar findings were observed in MMP9 -/- mice administered an exogenous MMP2 inhibitor. Conclusions: In stasis VT, deletion of MMP2 was associated with less midterm vein wall fibrosis and inflammation, despite an increase in monocytes. Consideration that VT resolution was impaired with MMP2 (and MMP2/9) deletion suggests direct inhibition will likely also require anticoagulant therapy. C1 [Deatrick, Kristopher B.; Luke, Catherine E.; Elfline, Megan A.; Sood, Vikram; Baldwin, Joseph; Upchurch, Gilbert R., Jr.; Wakefield, Thomas W.; Henke, Peter K.] Univ Michigan, Sch Med, Dept Surg, Vasc Surg Sect,Conrad Jobst Vasc Res Lab, Ann Arbor, MI USA. [Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. RP Henke, PK (reprint author), Univ Michigan Hlth Syst, 1500 E Med Ctr Dr,Cardiovasc Ctr 5463, Ann Arbor, MI 48109 USA. EM henke@umich.edu OI Jaffer, Farouc/0000-0001-7980-384X FU [HL083918]; [HL092129]; [T32HL092129] FX Supported by HL083918 and HL092129 (P. K. H.) and T32HL092129 (T.W.). NR 41 TC 15 Z9 18 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD NOV PY 2013 VL 58 IS 5 BP 1375 EP + DI 10.1016/j.jvs.2012.11.088 PG 12 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 247DE UT WOS:000326593900033 PM 23490298 ER PT J AU Paffett-Lugassy, N Singh, R Nevis, KR Guner-Ataman, B O'Loughlin, E Jahangiri, L Harvey, RP Burns, CG Burns, CE AF Paffett-Lugassy, Noelle Singh, Reena Nevis, Kathleen R. Guner-Ataman, Burcu O'Loughlin, Evan Jahangiri, Leila Harvey, Richard P. Burns, C. Geoffrey Burns, Caroline E. TI Heart field origin of great vessel precursors relies on nkx2.5-mediated vasculogenesis SO NATURE CELL BIOLOGY LA English DT Article ID CARDIOVASCULAR DEVELOPMENT; PROGENITOR SPECIFICATION; NEURAL CREST; ZEBRAFISH; EMBRYO; CELLS; PROTEIN; NKX2-5; GENE; ENDOCARDIUM AB The pharyngeal arch arteries (PAAs) are transient embryonic blood vessels that make indispensable contributions to the carotid arteries and great vessels of the heart, including the aorta and pulmonary arteries(1,2). During embryogenesis, the PAAs appear in a craniocaudal sequence to connect pre-existing segments of the primitive circulation after de novo vasculogenic assembly from angioblast precursors(3,4). Despite the unique spatiotemporal characteristics of PAA development, the embryonic origins of PM angioblasts and the genetic factors regulating their emergence remain unknown. Here, we identify the embryonic source of PAA endothelium as nlo(2.5(+) progenitors in lateral plate mesoderm long considered to adopt cell fates within the heart exclusively(5,6). Further, we report that PAA endothelial differentiation relies on Nkx2.5, a canonical cardiac transcription factor not previously implicated in blood vessel formation. Together, these studies reveal the heart field origin of PAA endothelium and attribute a new vasculogenic function to the cardiac transcription factor Nkx2.5 during great vessel precursor development. C1 [Paffett-Lugassy, Noelle; Nevis, Kathleen R.; Guner-Ataman, Burcu; O'Loughlin, Evan; Jahangiri, Leila; Burns, C. Geoffrey; Burns, Caroline E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Paffett-Lugassy, Noelle; Nevis, Kathleen R.; Guner-Ataman, Burcu; O'Loughlin, Evan; Jahangiri, Leila; Burns, C. Geoffrey; Burns, Caroline E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Paffett-Lugassy, Noelle; Burns, C. Geoffrey; Burns, Caroline E.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Singh, Reena; Harvey, Richard P.] Victor Chang Res Inst, Darlinghurst, NSW 2010, Australia. RP Burns, CG (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. EM gburns@cvrc.mgh.harvard.edu; cburns6@partners.org FU Harvard Stem Cell Institute Training Grant [5HL087735]; National Research Service Award [1F32HL 112579, 5F32HL110627]; National Heart, Lung and Blood Institute (NHLBI); American Heart Association (AHA) Post-Doctoral Fellowship [10P05T4170037]; American Heart Association [10GRNT4270021]; Harvard Stem Cell Institute (Seed Grant); March of Dimes Foundation [FY12-467]; Harvard Stem Cell Institute FX We are grateful to S. Paskaradevan and I. Scott (University of Toronto, USA) for their training in blastula transplantation. We thank C. Kinney for creating Supplementary Fig. 1; P. Obregon and T. Cashman for technical assistance in generating the Tg(nkx2.5:kaede) and Tg(nkx2.5:nZsYellow) transgenic lines, respectively; W. Goessling (Harvard Medical School, USA) for providing Tg(sox17:GFP) fish; T. North, and L. Zon (Harvard Medical School, USA) for providing Tg(kdrl:GFP) fish; I. Drummond (Massachusetts General Hospital, USA) for providing bon"425 fish; B. Barut (Harvard Medical School, USA) and L. Zon for providing bacterial artificial chromosomes; T. Evans (Weill Cornell Medical College, USA) for providing nkx2.5 plasmid for probe generation; G. Wilkinson (Medical College of Wisconsin, USA) and S. Sumanas (Cincinnati Children's Hospital Medical Center, USA) for providing etsrp71 plasmid for probe generation; and the MGH Nephrology Division for access to their confocal microscopy facilities. We thank A. Vasilyev for assistance with confocal microscopy. N.P.L was supported by the Harvard Stem Cell Institute Training Grant (5HL087735) and a National Research Service Award (1F32HL 112579) from the National Heart, Lung and Blood Institute (NHLBI). B.G-A. was financially supported by an American Heart Association (AHA) Post-Doctoral Fellowship (10P05T4170037). K.R.N. is financially supported by a National Research Service Award (5F32HL110627) from the National Heart, Lung and Blood Institute (NHLBI). R.P.H. is supported by grants from the National Health and Medical Research Council of Australia (NHMRC; 573732, 573703), Atlantic Philanthropies (19131) and National Heart Foundation of Australia (G0853718). R.P.H. holds an NHMRC Australia Fellowship (573705). This wo rk was financially supported 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. and the National Heart Lung and Blood Institute (5R01HL111179), the March of Dimes Foundation (FY12-467), and the Harvard Stem Cell Institute (Seed Grant and Young Investigator Award) to C.E.B. R.P.H. dedicates this work to Irene Myrtle Harvey, 1923-2013, from whom scholarship and inspiration were drawn. NR 44 TC 12 Z9 12 U1 2 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD NOV PY 2013 VL 15 IS 11 BP 1362 EP U225 DI 10.1038/ncb2862 PG 15 WC Cell Biology SC Cell Biology GA 248FN UT WOS:000326680700012 PM 24161929 ER PT J AU Cortazar, F Diaz-Wong, R Roth, D Isakova, T AF Cortazar, Frank Diaz-Wong, Roque Roth, David Isakova, Tamara TI Corticosteroid and calcineurin inhibitor sparing regimens in kidney transplantation SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Review DE belatacept; corticosteroids; mammalian target of rapamycin inhibitors ID RENAL-ALLOGRAFT RECIPIENTS; MYCOPHENOLATE-MOFETIL; PHASE-III; LONG-TERM; STEROID WITHDRAWAL; BENEFIT-EXT; BELATACEPT; SIROLIMUS; CYCLOSPORINE; IMMUNOSUPPRESSION AB Chronic kidney disease is a major public health problem that is associated with increased risks of kidney disease progression, cardiovascular disease and death. Kidney transplantation remains the renal replacement therapy of choice for patients with end-stage kidney disease. Despite impressive strides in short-term allograft survival, there has been little improvement in long-term kidney graft survival, and rates of death with a functioning allograft remain high. Long-term safety profiles of existing immunosuppressive regimens point to a need for continued search for alternative agents. This overview discusses emerging evidence on a few promising therapeutic approaches, juxtaposes conflicting findings and highlights remaining knowledge gaps. C1 [Cortazar, Frank] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Diaz-Wong, Roque; Roth, David; Isakova, Tamara] Univ Miami, Miller Sch Med, Dept Med, Div Nephrol & Hypertens, Miami, FL 33136 USA. RP Isakova, T (reprint author), Univ Miami, Miller Sch Med, Dept Med, Div Nephrol & Hypertens, Miami, FL 33136 USA. EM tisakova@med.miami.edu FU National Institutes of Health [K23DK087858] FX Dr. Isakova was supported by grant K23DK087858 from the National Institutes of Health. NR 35 TC 4 Z9 4 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD NOV PY 2013 VL 28 IS 11 BP 2708 EP 2716 DI 10.1093/ndt/gft231 PG 9 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 249AE UT WOS:000326747600012 PM 23825102 ER PT J AU Panizo, S Barrio-Vazquez, S Naves-Diaz, M Carrillo-Lopez, N Rodriguez, I Fernandez-Vazquez, A Valdivielso, JM Thadhani, R Cannata-Andia, JB AF Panizo, Sara Barrio-Vazquez, Sara Naves-Diaz, Manuel Carrillo-Lopez, Natalia Rodriguez, Isabel Fernandez-Vazquez, Amalia Valdivielso, Jose M. Thadhani, Ravi Cannata-Andia, Jorge B. TI Vitamin D receptor activation, left ventricular hypertrophy and myocardial fibrosis SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE CKD; LVH; myocardial fibrosis; VDRAs ID CHRONIC KIDNEY-DISEASE; SECONDARY HYPERPARATHYROIDISM; 1,25-DIHYDROXYVITAMIN D-3; VASCULAR CALCIFICATION; CARDIAC FIBROBLASTS; ERK CASCADE; UREMIC RATS; D THERAPY; HEART; CALCITRIOL AB Background. Left ventricular hypertrophy (LVH), a common complication in chronic kidney disease (CKD), is associated with high cardiovascular mortality. The aim of this experimental study was to analyze the effect of different vitamin D receptor activators (VDRAs) on both LVH and myocardial fibrosis in chronic renal failure (CRF). Methods. Male Wistar rats with CRF, carried out by 7/8 nephrectomy, were treated intraperitoneally with equivalent doses of VDRAs (calcitriol, paricalcitol and alfacalcidol, 5 days per week) during 4 weeks. A placebo group (CRF + vehicle) and a Sham group with normal renal function served as controls. Biochemical, morphological, functional and molecular parameters associated with LVH were evaluated, as well as cardiac fibrosis, collagen I, transforming growth factor beta 1 (TGF beta 1) and matrix metalloproteinase-1 (MMP1) expression. Results. All VDRAs treatment prevented LVH, with values of cardiomyocyte size, LV wall and septum thickness and heart-body weight ratio similar to those observed in the Sham group. At molecular levels, all VDRAs attenuated atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expression compared with CRF + vehicle. The phosphorylation of ERK1/2, a signal for activating growth, was stimulated in the CRF + vehicle group; VDRAs use prevented this activation. Paricalcitol was the only VDRA used that maintained in the normal range all parameters associated with myocardial fibrosis (total collagen, collagen I, TGF beta 1 and MMP1). Conclusions. Our findings demonstrated that the three VDRAs used induced similar changes in bone metabolic parameters and LVH. In addition, paricalcitol was the only VDRA which showed a relevant beneficial effect in the reduction of myocardial fibrosis, a key factor in the myocardial dysfunction in CKD patients. C1 [Panizo, Sara; Barrio-Vazquez, Sara; Naves-Diaz, Manuel; Carrillo-Lopez, Natalia; Rodriguez, Isabel; Cannata-Andia, Jorge B.] Univ Oviedo, Serv Metab Oseo & Min, Inst Reina Sofia Invest, REDinREN,ISCIII,Hosp Univ Cent Asturias, Oviedo, Spain. [Fernandez-Vazquez, Amalia] Ctr Med Asturias, Serv Anat Patol, Oviedo, Spain. [Valdivielso, Jose M.] Hosp Arnau Vilanova, Lab Nefrol Expt, IRB Lleida, Lleida, Spain. [Thadhani, Ravi] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. RP Cannata-Andia, JB (reprint author), Univ Oviedo, Serv Metab Oseo & Min, Inst Reina Sofia Invest, REDinREN,ISCIII,Hosp Univ Cent Asturias, Oviedo, Spain. EM cannata@hca.es RI Naves Diaz, Manuel/O-5100-2014; Cannata-Andia, Jorge/L-2260-2013; Valdivielso, Jose/B-5673-2009 OI Valdivielso, Jose/0000-0003-1343-0184 FU National Program of I+D+I; Instituto de Salud Carlos III (ISCIII)-Subdireccion General de Evaluacion y Fomento de la Investigacion,-Fondo de Investigacion Sanitaria [FIS 07/0893, FIS 10/0896]; Fondo Europeo de Desarrollo Regional (FEDER); Fundacion para el Fomento en Asturias de la Investigacion Cientifica Aplicada y la Tecnologia (FICYT); Instituto Reina Sofia de Investigacion; Fundacion Renal Inigo Alvarez de Toledo; REDinREN [16/06]; Abbott Pharmaceuticals [ACA-SPAI-08-22]; ISCIII [FIS 09/0415]; ISCIII-FICYT [CD11/00258]; FICYT [COF 11-02]; REDin REN [16/06]; ISCIII -FICYT [CA10/01327]; [ISCIII-Retic-RD06] FX The authors wish to thank Jose Luis Fernandez-Martin, Pablo Roman-Garcia, Ana Rodriguez-Rebollar, Socorro Braga and the Pathology Unit from Centro Medico de Asturias, particularly Ana Covadonga Suarez Merino, for their help. We also thank language consultant Marino Santirso. This study was supported by National Program of I+D+I 2008-2011 and Instituto de Salud Carlos III (ISCIII)-Subdireccion General de Evaluacion y Fomento de la Investigacion,-Fondo de Investigacion Sanitaria (FIS 07/0893 and FIS 10/0896), Fondo Europeo de Desarrollo Regional (FEDER), Fundacion para el Fomento en Asturias de la Investigacion Cientifica Aplicada y la Tecnologia (FICYT), Instituto Reina Sofia de Investigacion, Fundacion Renal Inigo Alvarez de Toledo, by ISCIII-Retic-RD06, REDinREN (16/06) and Abbott Pharmaceuticals (ACA-SPAI-08-22). Sara Panizo has been supported by ISCIII (FIS 09/0415) and ISCIII-FICYT (CD11/00258); Sara Barrio, by FICYT (COF 11-02); and Natalia Carrillo-Lopez, by ISCIII-Retic-RD06, REDin REN (16/06) and ISCIII -FICYT (CA10/01327). NR 52 TC 19 Z9 19 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD NOV PY 2013 VL 28 IS 11 BP 2735 EP 2744 DI 10.1093/ndt/gft268 PG 10 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 249AE UT WOS:000326747600019 PM 24013683 ER PT J AU Ramos, EM Latourelle, JC Gillis, T Mysore, JS Squitieri, F Di Pardo, A Di Donato, S Gellera, C Hayden, MR Morrison, PJ Nance, M Ross, CA Margolis, RL Gomez-Tortosa, E Ayuso, C Suchowersky, O Trent, RJ McCusker, E Novelletto, A Frontali, M Jones, R Ashizawa, T Frank, S Saint-Hilaire, MH Hersch, SM Rosas, HD Lucente, D Harrison, MB Zanko, A Abramson, RK Marder, K Gusella, JF Lee, JM Alonso, I Sequeiros, J Myers, RH MacDonald, ME AF Ramos, Eliana Marisa Latourelle, Jeanne C. Gillis, Tammy Mysore, Jayalakshmi S. Squitieri, Ferdinando Di Pardo, Alba Di Donato, Stefano Gellera, Cinzia Hayden, Michael R. Morrison, Patrick J. Nance, Martha Ross, Christopher A. Margolis, Russell L. Gomez-Tortosa, Estrella Ayuso, Carmen Suchowersky, Oksana Trent, Ronald J. McCusker, Elizabeth Novelletto, Andrea Frontali, Marina Jones, Randi Ashizawa, Tetsuo Frank, Samuel Saint-Hilaire, Marie-Helene Hersch, Steven M. Rosas, Herminia D. Lucente, Diane Harrison, Madaline B. Zanko, Andrea Abramson, Ruth K. Marder, Karen Gusella, James F. Lee, Jong-Min Alonso, Isabel Sequeiros, Jorge Myers, Richard H. MacDonald, Marcy E. TI Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington's disease motor onset SO NEUROGENETICS LA English DT Article DE Huntington's disease; Glutamate receptors; Dopamine pathway; Genetic modifiers ID AGE-OF-ONSET; RECEPTOR-MEDIATED EXCITOTOXICITY; VARIATIONS MODIFY AGE; TRINUCLEOTIDE REPEAT; MOUSE MODEL; VENEZUELAN KINDREDS; HEALTHY-VOLUNTEERS; A1 ALLELE; POLYMORPHISMS; AVAILABILITY AB Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3' UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations. C1 [Ramos, Eliana Marisa; Gillis, Tammy; Mysore, Jayalakshmi S.; Lucente, Diane; Gusella, James F.; Lee, Jong-Min; MacDonald, Marcy E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Ramos, Eliana Marisa; Alonso, Isabel; Sequeiros, Jorge] Univ Porto, IBMC Inst Mol & Cell Biol, UnIGENe, P-4100 Oporto, Portugal. [Latourelle, Jeanne C.; Frank, Samuel; Saint-Hilaire, Marie-Helene; Myers, Richard H.] Boston Univ Sch Med, Dept Neurol, Boston, MA 02118 USA. [Squitieri, Ferdinando; Di Pardo, Alba] IRCCS Neuromed, Ctr Neurogenet & Rare Dis, I-86077 Pozzilli, IS, Italy. [Di Donato, Stefano; Gellera, Cinzia] Fdn IRCCS Ist Neurol Carlo Besta, I-20133 Milan, Italy. [Hayden, Michael R.] Univ British Columbia, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 4H4, Canada. [Morrison, Patrick J.] Belfast HSC Trust, Reg Med Genet Ctr, Belfast BT9 7AB, Antrim, North Ireland. [Nance, Martha] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Ross, Christopher A.; Margolis, Russell L.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Gomez-Tortosa, Estrella] Fdn Jimenez Diaz, Dept Neurol, E-28040 Madrid, Spain. [Ayuso, Carmen] CIBERER, IIS Fdn Jimenez Diaz, Dept Genet, Madrid 28040, Spain. [Suchowersky, Oksana] Univ Alberta, Dept Med, Edmonton, AB T6G 2B7, Canada. [Trent, Ronald J.; McCusker, Elizabeth] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [McCusker, Elizabeth] Westmead Hosp, Dept Neurol, Sydney, NSW 2145, Australia. [Novelletto, Andrea] Univ Tor Vergata, Dept Biol, I-00133 Rome, Italy. [Frontali, Marina] CNR, Inst Translat Pharmacol, I-00133 Rome, Italy. [Jones, Randi] Emory Univ, Dept Neurol, Atlanta, GA 30329 USA. [Ashizawa, Tetsuo] Univ Florida, Dept Neurol, Gainesville, FL 32610 USA. [Hersch, Steven M.; Rosas, Herminia D.] Massachusetts Gen Hosp, MIND, Charlestown, MA 02129 USA. [Harrison, Madaline B.] Univ Virginia, Dept Neurol, Charlottesville, VA 22908 USA. [Zanko, Andrea] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Abramson, Ruth K.] Univ S Carolina Sch Med, Dept Neuropsychiat & Behav Sci, Columbia, SC 29208 USA. [Marder, Karen] Columbia Univ, Coll Phys & Surg, New York, NY 10032 USA. [Gusella, James F.; Lee, Jong-Min; MacDonald, Marcy E.] Broad Inst Harvard & Massachusetts Inst Technol, Harvard Med Sch & Program Med & Populat Genet, Cambridge, MA 02142 USA. [Alonso, Isabel; Sequeiros, Jorge] Univ Porto, CGPP, IBMC Inst Mol & Cell Biol, P-4100 Oporto, Portugal. [Alonso, Isabel; Sequeiros, Jorge] Univ Porto, ICBAS Inst Ciencias Biomed Abel Salazar, P-4100 Oporto, Portugal. [Morrison, Patrick J.] Univ Ulster, Coleraine BT52 15A, Londonderry, North Ireland. [Suchowersky, Oksana] Univ Alberta, Dept Med Genet, Edmonton, AB T6G 2B7, Canada. RP MacDonald, ME (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Simches Res Bldg,Room 5414,185 Cambridge St, Boston, MA 02114 USA. EM macdonam@helix.mgh.harvard.edu RI Alonso, Isabel/I-4307-2013; Hayden, Michael/D-8581-2011; GELLERA, CINZIA/J-7887-2016 OI Alonso, Isabel/0000-0001-8549-6903; Hayden, Michael/0000-0001-5159-1419; Squitieri, Ferdinando /0000-0002-7397-1727; Novelletto, Andrea/0000-0002-1146-7680; Ayuso, Carmen/0000-0002-9242-7065; Sequeiros, Jorge/0000-0002-9846-1037; GELLERA, CINZIA/0000-0002-3582-665X FU Fundacao para a Ciencia e a Tecnologia of Portugal [SFRH/BD/44335/2008]; NIH grants from the NINDS [NS16367, NS32765]; CHDI Foundation, Inc. FX The authors thank Drs. Ignacio Munoz-Sanjuan, Seung Kwak, and Jamshid Arjomand from CHDI Foundation, Inc., as well as the HD families, whose participation in genetic studies made this work possible; the COHORT co-investigators and contributors (see "Appendix"); contributors to the HD-MAPS study, Drs. Alexandra Durr, Adam Rosenblatt, Luigi Frati, Susan Perlman, P. Michael Conneally, Mary Lou Klimek, Melissa Diggin, Tiffany Hadzi, and Ayana Duckett; the Harvard Brain Tissue Resource Center at McLean Hospital; and the National Neurological Research Specimen Bank at the VA West Los Angeles Healthcare Center. EMR is the recipient of a scholarship from the Fundacao para a Ciencia e a Tecnologia of Portugal (SFRH/BD/44335/2008). Study funding was supported by NIH grants from the NINDS NS16367 (The Massachusetts HD Center Without Walls) and NS32765, and the CHDI Foundation, Inc. NR 39 TC 6 Z9 6 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1364-6745 EI 1364-6753 J9 NEUROGENETICS JI Neurogenetics PD NOV PY 2013 VL 14 IS 3-4 BP 173 EP 179 DI 10.1007/s10048-013-0364-y PG 7 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA 247SQ UT WOS:000326641000002 PM 23644918 ER PT J AU Sheth, SA Eskandar, EN Liker, MA AF Sheth, Sameer A. Eskandar, Emad N. Liker, Mark A. TI Evolving trends in movement disorder surgery Introduction SO NEUROSURGICAL FOCUS LA English DT Editorial Material C1 [Sheth, Sameer A.] Columbia Univ, NewYork Presbyterian Hosp, Dept Neurosurg, New York, NY 10027 USA. [Eskandar, Emad N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. [Liker, Mark A.] Univ So Calif, Keck Hosp, Dept Neurosurg, Los Angeles, CA USA. RP Sheth, SA (reprint author), Columbia Univ, NewYork Presbyterian Hosp, Dept Neurosurg, New York, NY 10027 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1092-0684 J9 NEUROSURG FOCUS JI Neurosurg. Focus PD NOV PY 2013 VL 35 IS 5 DI 10.3171/2013.9.FOCUS13392 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 247EB UT WOS:000326596900010 ER PT J AU Wang, CN Wilson, CM Moseley, CK Carlin, SM Hsu, S Arabasz, G Schroeder, FA Sander, CY Hooker, JM AF Wang, Changning Wilson, Colin M. Moseley, Christian K. Carlin, Stephen M. Hsu, Shirley Arabasz, Grae Schroeder, Frederick A. Sander, Christin Y. Hooker, Jacob M. TI Evaluation of potential PET imaging probes for the orexin 2 receptors SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Orexin; PET radiotracers; Imaging; Hypocretin; Carbon-11 ID ANTAGONIST SB-649868; RAT-BRAIN; SLEEP; INSOMNIA; SUVOREXANT; PROMOTION AB A wide range of central nervous system (CNS) disorders, particularly those related to sleep, are associated with the abnormal function of orexin (OX) receptors. Several orexin receptor antagonists have been reported in recent years, but currently there are no imaging tools to probe the density and function of orexin receptors in vivo. To date there are no published data on the pharmacokinetics (PK) and accumulation of some lead orexin receptor antagonists. Evaluation of CNS pharmacokinetics in the pursuit of positron emission tomography (PET) radiotracer development could be used to elucidate the association of orexin receptors with diseases and to facilitate the drug discovery and development. To this end, we designed and evaluated carbon-11 labeled compounds based on diazepane orexin receptor antagonists previously described. One of the synthesized compounds, [C-11]CW4, showed high brain uptake in rats and further evaluated in non-human primate (NHP) using PET-MR imaging. PET scans performed in a baboon showed appropriate early brain uptake for consideration as a radiotracer. However, [C-11]CW4 exhibited fast kinetics and high nonspecific binding, as determined after co-administration of [C-11]CW4 and unlabeled CW4. These properties indicate that [C-11]CW4 has excellent brain penetrance and could be used as a lead compound for developing new CNS-penetrant PET imaging probes of orexin receptors.(C) 2013 Elsevier Inc. All rights reserved. C1 [Wang, Changning; Wilson, Colin M.; Moseley, Christian K.; Carlin, Stephen M.; Hsu, Shirley; Arabasz, Grae; Schroeder, Frederick A.; Sander, Christin Y.; Hooker, Jacob M.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Schroeder, Frederick A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res,Dept Neurol, Boston, MA 02114 USA. [Schroeder, Frederick A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res,Dept Psychiat, Boston, MA 02114 USA. [Sander, Christin Y.] MIT, Cambridge, MA 02139 USA. RP Hooker, JM (reprint author), Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,13th St,Suite 2301, Charlestown, MA 02129 USA. EM hooker@nmr.mgh.harvard.edu OI Hooker, Jacob/0000-0002-9394-7708 FU National Institute of Biomedical Imaging and Bioengineering (NIBIB) National Institutes of Health [P41EB015896]; NIH [S10RR017208, S10RR026666, S10RR022976, S10RR019933, S10RR029495] FX This research was carried out at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Regional Resource supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. This work also involved the use of instrumentation supported by the NIH Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program; specifically, grant numbers: S10RR017208, S10RR026666, S10RR022976, S10RR019933, S10RR029495. We would like fo thank members of the Hooker laboratory for helpful discussions and thanks to Dr. Ramesh Neelamegam for revising the paper. The authors are grateful to Joseph Mandeville and Helen Deng for assistance during NHP imaging. NR 17 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 0969-8051 EI 1872-9614 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD NOV PY 2013 VL 40 IS 8 BP 1000 EP 1005 DI 10.1016/j.nucmedbio.2013.07.001 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 247IO UT WOS:000326611300009 PM 23953751 ER PT J AU Edderkaoui, M Lugea, A Hui, HX Eibl, G Lu, QY Moro, A Lu, XY Li, G Go, VL Pandol, SJ AF Edderkaoui, Mouad Lugea, Aurelia Hui, Hongxiang Eibl, Guido Lu, Qing-Yi Moro, Aune Lu, Xuyang Li, Gang Go, Vay-Liang Pandol, Stephen J. TI Ellagic Acid and Embelin Affect Key Cellular Components of Pancreatic Adenocarcinoma, Cancer, and Stellate Cells SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID FACTOR-KAPPA-B; APOPTOSIS; MICROENVIRONMENT; PROLIFERATION; SUPPRESSION; XENOGRAFTS; INHIBITION; EXPRESSION; CARCINOMA; SURVIVAL AB Ellagic acid is a polyphenolic phytochemical present in many fruits and nuts with anticancer properties demonstrated in experimental tumor studies. Embelin is a benzoquinone phytochemical isolated from the Japanese herb Ardisiae Japonicae and has been shown to induce apoptosis in cancer cells. We found that ellagic acid and embelin each dose-dependently increased apoptosis and inhibited proliferation in human pancreatic cancer cells, MIA PaCa-2 and HPAF-II cells, and in pancreatic stellate cells, which are progenitors of pancreatic cancer desmoplasia. In each of these cell types, combinations of ellagic acid and embelin at low micromolar concentrations (0.5-3M) induced synergistic increases in apoptosis and decreases in proliferation. Ellagic acid decreased NF-B transcriptional activity, whereas embelin decreased STAT-3 phosphorylation and protein expression of its downstream target survivin in cancer cells. In vivo dietary ellagic acid alone or in combination with embelin decreased tumor size and tumor cellularity in a subcutaneous xenograft mouse model of pancreatic cancer. These results show that ellagic acid and embelin interact with divergent intracellular signaling pathways resulting in augmentation of apoptosis and inhibition of proliferation at low micromolar concentrations for the key cellular components of pancreatic adenocarcinoma. C1 [Edderkaoui, Mouad; Lugea, Aurelia; Hui, Hongxiang; Pandol, Stephen J.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Edderkaoui, Mouad; Lugea, Aurelia; Hui, Hongxiang; Eibl, Guido; Lu, Qing-Yi; Moro, Aune; Lu, Xuyang; Li, Gang; Go, Vay-Liang; Pandol, Stephen J.] Univ Calif Los Angeles, Ctr Excellence Pancreat Dis, Los Angeles, CA USA. [Edderkaoui, Mouad; Pandol, Stephen J.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Pandol, SJ (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,Bldg 258, Los Angeles, CA 90073 USA. EM stephen.pandol@cshs.org FU UCLA Center for Excellence in Pancreatic Diseases [NCCAM: 1 P01 AT003960]; Department of Veterans Affairs; NIAAA [K01 AA019996, R01 AA019954] FX We acknowledge the support of the Animal and Morphology Cores of the UCLA Center for Excellence in Pancreatic Diseases (P01AT003960) for their assistance with the xenograft model of pancreatic cancer. This work was supported by the UCLA Center for Excellence in Pancreatic Diseases (NCCAM: 1 P01 AT003960), the Department of Veterans Affairs, and two NIAAA awards (K01 AA019996 to Mouad Edderkaoui and R01 AA019954 to Aurelia Lugea). Mouad Edderkaoui and Aurelia Lugea contributed equally to this work. NR 36 TC 9 Z9 15 U1 0 U2 6 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0163-5581 EI 1532-7914 J9 NUTR CANCER JI Nutr. Cancer PD NOV 1 PY 2013 VL 65 IS 8 BP 1232 EP 1244 DI 10.1080/01635581.2013.832779 PG 13 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 251HL UT WOS:000326918300015 PM 24127740 ER PT J AU Goldman, RL Canterberry, M Borckardt, JJ Madan, A Byrne, TK George, MS O'Neil, PM Hanlon, CA AF Goldman, Rachel L. Canterberry, Melanie Borckardt, Jeffrey J. Madan, Alok Byrne, T. Karl George, Mark S. O'Neil, Patrick M. Hanlon, Colleen A. TI Executive Control Circuitry Differentiates Degree of Success in Weight Loss Following Gastric-Bypass Surgery SO OBESITY LA English DT Article ID BARIATRIC SURGERY; PREFRONTAL CORTEX; DRUG-ADDICTION; BRAIN ACTIVITY; CALORIE FOODS; OBESITY; MODULATION; ACTIVATION; IMPACT; ADULTS AB Objective: While overall success rates of bariatric surgery are high, approximately 20% of patients either regain or never lose the expected amount of weight. The purpose of this study was to determine whether, after gastric-bypass surgery, the degree of weight loss can be differentiated based on the neural response to food cues. Design and Methods: In this functional MRI study, 31 post-surgical patients viewed food and neutral images in two counterbalanced runs during which they were either instructed to "crave" or to "resist" craving. The neural response to food cues was assessed within and between runs for all participants, and further analyzed between more successful (n = 24) and less successful (n = 7) groups. More successful was defined by meeting 50% excess weight loss. Results: Overall, instructions to "crave" elicited significant activity in the dorsomedial prefrontal cortex (PFC) whereas "resist" elicited significant activity in the dorsolateral PFC (DLPFC). Between groups there was no brain difference when instructed to "crave." The more successful participants however had significantly more activity in the DLPFC when instructed to "resist." Conclusions: These findings suggest that the ability to mobilize neural circuits involved in executive control post-gastric-bypass surgery may be a unique component of successful outcome post-surgery. C1 [Goldman, Rachel L.; Canterberry, Melanie; Borckardt, Jeffrey J.; Madan, Alok; George, Mark S.; O'Neil, Patrick M.; Hanlon, Colleen A.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Borckardt, Jeffrey J.] Dept Anesthesiol & Perioperat Med, Charleston, SC USA. [Byrne, T. Karl; George, Mark S.] Med Univ S Carolina, Dept Surg, Dept Neurol & Radiol, Charleston, SC 29425 USA. [George, Mark S.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Goldman, RL (reprint author), Med Univ S Carolina, Dept Psychiat & Behav Sci, 171 Ashley Ave, Charleston, SC 29425 USA. EM Rachel.goldman2@nyumc.org OI Goldman, Rachel/0000-0001-6147-3934 FU Covidien through Obesity Society; [K01DA027756]; [T32DA02788] FX This study was supported by Covidien through a grant from the Obesity Society. The following grants enabled Drs. Canterberry and Hanlon to contribute to this study: K01DA027756 (to C. H.) and T32DA02788 (to M.C.). NR 36 TC 11 Z9 11 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD NOV PY 2013 VL 21 IS 11 BP 2189 EP 2196 DI 10.1002/oby.20575 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 247RO UT WOS:000326637400005 PM 24136926 ER PT J AU Berry, D Sanda, M Chang, P Hayes, J Halpenny, B AF Berry, Donna Sanda, Martin Chang, Peter Hayes, Julia Halpenny, Barbara TI IMPROVING A TREATMENT DECISION SUPPORT SYSTEM FOR MINORITY MEN WITH LOCALIZED PROSTATE CANCER SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Berry, Donna; Hayes, Julia; Halpenny, Barbara] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sanda, Martin] Emory Univ, Atlanta, GA 30322 USA. [Chang, Peter] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RI Sanda, Martin/B-2023-2015 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E433 EP E433 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400055 ER PT J AU Boucher, J Underhill, M Habin, K Lundquist, D Woodford, M Guillaume, D AF Boucher, Jean Underhill, Meghan Habin, Karleen Lundquist, Debra Woodford, Marylou Guillaume, Donna TI NAVIGATING THE SYSTEM OF CANCER GENETIC TESTING: CLINICAL GENETIC COUNSELORS PERSPECTIVES OF PATIENT ACCESS, RESOURCES, AND FOLLOW-UP CARE SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Boucher, Jean; Guillaume, Donna] Univ Massachusetts, Worcester, MA 01605 USA. [Underhill, Meghan] Dana Farber Canc Inst, Boston, MA 02115 USA. [Habin, Karleen; Lundquist, Debra; Woodford, Marylou] Canc Resource Fdn, Marlborough, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E443 EP E444 PG 2 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400081 ER PT J AU Boucher, J McDermott, K Boyajian, R Walsh, M Underhill, M Roper, K Berry, D AF Boucher, Jean McDermott, Kathleen Boyajian, Richard Walsh, Michele Underhill, Meghan Roper, Kristin Berry, Donna TI A PILOT STUDY EVALUATING THE FEASIBILITY OF A HOME-BASED ACTIVITY PROGRAM TO REDUCE CANCER-RELATED FATIGUE SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Boucher, Jean; McDermott, Kathleen; Boyajian, Richard; Walsh, Michele; Underhill, Meghan; Roper, Kristin; Berry, Donna] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E421 EP E421 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400025 ER PT J AU Burke, M Hoffner, B Rubin, K AF Burke, Matthew Hoffner, Brianna Rubin, Krista TI MANAGEMENT OF SELECTED TOXICITIES ASSOCIATED WITH THE USE OF IMMUNE CHECKPOINT MODULATORS SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Burke, Matthew] Smilow Canc Hosp Yale New Haven, New Haven, CT USA. [Hoffner, Brianna] Angeles Clin & Res Inst, Los Angeles, CA USA. [Rubin, Krista] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E419 EP E420 PG 2 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400021 ER PT J AU Cooley, M Abrahm, J Braun, I Rabin, M Nayak, M Melendez, M Berry, D AF Cooley, Mary Abrahm, Janet Braun, Ilana Rabin, Michael Nayak, Manan Melendez, Maribel Berry, Donna TI PATIENT AND CAREGIVER PERSPECTIVES OF SYMPTOM AND QUALITY OF LIFE EXPERIENCES DURING CANCER THERAPIES: IMPLICATIONS FOR E-HEALTH SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Cooley, Mary; Abrahm, Janet; Braun, Ilana; Rabin, Michael; Nayak, Manan; Melendez, Maribel; Berry, Donna] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E457 EP E457 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400112 ER PT J AU Drapek, L Doherty, C Fitton, L Viscosi, E Mannix, C AF Drapek, Lorraine Doherty, Carol Fitton, Lindsay Viscosi, Elene Mannix, Catherine TI IV HYDRATION IN RADIATION ONCOLOGY FOR PATIENTS RECEIVING CHEMORADIATION SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Drapek, Lorraine; Doherty, Carol; Fitton, Lindsay; Viscosi, Elene; Mannix, Catherine] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E426 EP E426 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400038 ER PT J AU Grenon, N AF Grenon, Nina TI EARLY INTEGRATION OF PALLIATIVE CARE IN PATIENTS WITH PANCREATIC CANCER: A RETROSPECTIVE STUDY FOR QUALITY IMPROVEMENT SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Grenon, Nina] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E453 EP E453 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400103 ER PT J AU Harrington, S Houston, S AF Harrington, Shannon Houston, Sharon TI A FAITH-BASED CANCER OUTREACH AND EDUCATION PROGRAM SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Harrington, Shannon] UMass Boston, Dana Farber Canc Inst, Boston, MA USA. [Houston, Sharon] Gethsemane Community Fellowship Baptist Church, Norfolk, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E430 EP E430 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400047 ER PT J AU Jeffries, K Hodgman, E Blakeney, BA Cashavelley, B Wold, MC Driscoll, M Brezina, M AF Jeffries, Kellyann Hodgman, Elizabeth Blakeney, Barbara A. Cashavelley, Barbara Wold, Mali C. Driscoll, Margaret Brezina, Martha TI INPATIENT ONCOLOGY DISCHARGES: INTERDISCIPLINARY APPROACH TO IMPROVING QUALITY, COMMUNICATION, AND EFFICIENCY SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Jeffries, Kellyann; Hodgman, Elizabeth; Blakeney, Barbara A.; Cashavelley, Barbara; Wold, Mali C.; Driscoll, Margaret; Brezina, Martha] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E415 EP E416 PG 2 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400014 ER PT J AU Roper, K Calarese, P Hilton, N Siefert, ML Berry, D AF Roper, Kristin Calarese, Pamela Hilton, Nancy Siefert, Mary Lou Berry, Donna TI SCREENING AND ASSESSMENT OF ANOREXIA IN NEWLY DIAGNOSED LUNG CANCER PATIENTS SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Roper, Kristin; Calarese, Pamela; Hilton, Nancy; Siefert, Mary Lou; Berry, Donna] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E416 EP E417 PG 2 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400015 ER PT J AU Sheldon, LK Hilaire, D Hong, FX Blonquist, T Berry, DL AF Sheldon, Lisa Kennedy Hilaire, Dany Hong, Fangxin Blonquist, Traci Berry, Donna L. TI PREDICTORS OF ASSESSMENT OF CANCER PATIENT PSYCHOSOCIAL CONCERNS SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Sheldon, Lisa Kennedy; Hilaire, Dany] Univ Massachusetts, Boston, MA 02125 USA. [Hong, Fangxin; Blonquist, Traci] Dana Farber Canc Inst, Boston, MA 02115 USA. [Berry, Donna L.] Dana Farber Canc Inst, Cantor Ctr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E432 EP E432 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400053 ER PT J AU Siefert, ML Blonquist, T Hong, FX Berry, DL AF Siefert, Mary Lou Blonquist, Traci Hong, Fangxin Berry, Donna L. TI FACTORS ASSOCIATED WITH SYMPTOM RELATED EMERGENCY DEPARTMENT VISITS AND HOSPITAL ADMISSIONS DURING AMBULATORY CANCER TREATMENT SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Siefert, Mary Lou; Blonquist, Traci; Hong, Fangxin; Berry, Donna L.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E439 EP E440 PG 2 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400071 ER PT J AU Somayaji, D Nayak, M Hayman, L Sorrentino, E Fox, E Green, A Cooley, M AF Somayaji, Darryl Nayak, Manan Hayman, Laura Sorrentino, Erica Fox, Erica Green, Amanda Cooley, Mary TI APPLIED PATIENT TRACER METHODOLOGY: A USEFUL STRATEGY TO EXPLORE RECRUITMENT CHALLENGES IN BIOBEHAVIORAL RESEARCH SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Somayaji, Darryl; Nayak, Manan; Sorrentino, Erica; Fox, Erica; Cooley, Mary] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hayman, Laura; Green, Amanda] Univ Massachusetts, Boston, MA 02125 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E412 EP E412 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400007 ER PT J AU Underhill, M Brown, E Grealish, R Shienda, J Syngal, S Berry, D AF Underhill, Meghan Brown, Emily Grealish, Rhonda Shienda, Jaclyn Syngal, Sapna Berry, Donna TI NOT ALL HEREDITARY CANCER SYNDROMES ARE CREATED EQUAL: PATIENT EXPERIENCES LIVING WITH HEREDITARY PANCREATIC CANCER RISK SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Underhill, Meghan; Brown, Emily; Grealish, Rhonda; Shienda, Jaclyn; Syngal, Sapna; Berry, Donna] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E447 EP E448 PG 2 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400091 ER PT J AU Underhill, M Kennedy-Sheldon, L Halpenny, B Berry, D AF Underhill, Meghan Kennedy-Sheldon, Lisa Halpenny, Barbara Berry, Donna TI CLINICIAN PERCEPTIONS OF COMMUNICATION ABOUT SYMPTOMS AND QUALITY OF LIFE ISSUES IN PATIENTS WITH CANCER SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Underhill, Meghan] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kennedy-Sheldon, Lisa] U Mass Boston, Boston, MA USA. [Halpenny, Barbara; Berry, Donna] DFCI, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E432 EP E432 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400052 ER PT J AU Awh, CC Lane, AM Hawken, S Zanke, B Kim, IK AF Awh, Carl C. Lane, Anne-Marie Hawken, Steven Zanke, Brent Kim, Ivana K. TI CFH and ARMS2 Genetic Polymorphisms Predict Response to Antioxidants and Zinc in Patients with Age-related Macular Degeneration SO OPHTHALMOLOGY LA English DT Article ID COMPLEMENT FACTOR-H; OXIDATIVE STRESS; BETA-CAROTENE; VITAMIN-C; DISEASE; ASSOCIATION; TRIAL AB Objective: The Age-Related Eye Disease Study (AREDS) demonstrated that antioxidant and zinc supplementation decreases progression to advanced age-related macular degeneration (AMD) in patients with moderate to severe disease. We evaluated the interaction of genetics and type of nutritional supplement on progression from moderate to advanced AMD. Design: Genetic analysis of a randomized, prospective clinical trial. Participants: White patients with AREDS category 3 AMD in 1 eye and AREDS categories 1 through 4 AMD in the fellow eye enrolled in the AREDS with available peripheral blood-derived DNA (995). Methods: Subjects were evaluated for known AMD genetic risk markers and treatment category. The progression rate to advanced AMD was analyzed by genotypes and AREDS treatment group using Cox regression. Main Outcome Measures: The effect of inherited gene polymorphisms on treatment groupespecific rate of progression to advanced AMD. Results: Over an average of 10.1 years, individuals with 1 or 2 complement factor H (CFH) risk alleles derived maximum benefit from antioxidants alone. In these patients, the addition of zinc negated the benefits of antioxidants. Treatment with zinc and antioxidants was associated with a risk ratio (RR) of 1.83 with 2 CFH risk alleles (P=1.03E-02), compared with outcomes for patients without CFH risk alleles. Patients with age-related maculopathy sensitivity 2 (ARMS2) risk alleles derived maximum benefit from zinc-containing regimens, with a deleterious response to antioxidants in the presence of ARMS2 risk alleles. Treatment with antioxidants was associated with an RR of 2.58 for those with 1 ARMS2 risk allele and 3.96 for those with 2 ARMS2 risk alleles (P 1.04E-6), compared with patients with no ARMS2 risk alleles. Individuals homozygous for CFH and ARMS2 risk alleles derived no benefit from any category of AREDS treatment. Conclusions: Individuals with moderate AMD could benefit from pharmacogenomic selection of nutritional supplements. In this analysis, patients with no CFH risk alleles and with 1 or 2 ARMS2 risk alleles derived maximum benefit from zinc-only supplementation. Patients with one or two CFH risk alleles and no ARMS2 risk alleles derived maximum benefit from antioxidant-only supplementation; treatment with zinc was associated with increased progression to advanced AMD. These recommendations could lead to improved outcomes through genotype-directed therapy. (C) 2013 by the American Academy of Ophthalmology. C1 [Awh, Carl C.] Tennessee Retina PC, Nashville, TN USA. [Lane, Anne-Marie; Kim, Ivana K.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Dept Ophthalmol, Boston, MA USA. [Hawken, Steven] Ottawa Hosp, Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. [Zanke, Brent] Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Zanke, Brent] Univ Ottawa, Dept Med, Div Hematol, Ottawa, ON, Canada. [Zanke, Brent] Arctic Grp Co, Toronto, ON, Canada. RP Zanke, B (reprint author), Arctic Diagnost Inc, 101 Coll St,Suite 335, Toronto, ON M5G 1L7, Canada. EM Brent.zanke@arcticdx.com FU ArcticDx, Inc., Toronto, Canada FX Supported by funding from ArcticDx, Inc., Toronto, Canada. NR 27 TC 39 Z9 39 U1 0 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2013 VL 120 IS 11 BP 2317 EP 2323 DI 10.1016/j.ophtha.2013.07.039 PG 7 WC Ophthalmology SC Ophthalmology GA 248FT UT WOS:000326681700030 PM 23972322 ER PT J AU Dietz, MJ Chase, S Burke, DW Kwon, YM AF Dietz, Matthew J. Chase, Samantha Burke, Dennis W. Kwon, Young-Min TI Novel Technique for Removal of a Broken Intracortical Screw During THA SO ORTHOPEDICS LA English DT Editorial Material ID INTERTROCHANTERIC VALGUS OSTEOTOMY; HIP; OSTEOARTHRITIS; HARDWARE AB Most reports regarding hardware removal involve the violation of the cortex to allow a specialized to tool to extract a retained fragment. This leaves large, unfilled screw holes that act as stress risers for months postoperatively. This article describes a novel technique to remove a retained intracortical screw fragment during total hip arthroplasty. Conversion of an intertrochanteric osteotomy to a total hip arthroplasty can be made more difficult by anatomical changes to the femur and retained hardware. Direct access to the intramedullary canal during total hip arthroplasty allowed for the safe removal of a retained intracortical screw using this technique. C1 [Dietz, Matthew J.] W Virginia Univ, Ruby Mem Hosp, Dept Orthopaed, Morgantown, WV 26506 USA. [Chase, Samantha; Burke, Dennis W.; Kwon, Young-Min] Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Ctr Outpatient Care, Boston, MA 02114 USA. RP Dietz, MJ (reprint author), W Virginia Univ, Ruby Mem Hosp, Dept Orthopaed, POB 9196, Morgantown, WV 26506 USA. EM mdietz@hsc.wvu.edu NR 18 TC 0 Z9 0 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0147-7447 EI 1938-2367 J9 ORTHOPEDICS JI Orthopedics PD NOV PY 2013 VL 36 IS 11 BP 846 EP 849 DI 10.3928/01477447-20131021-03 PG 4 WC Orthopedics SC Orthopedics GA 248ZY UT WOS:000326746900029 PM 24200426 ER PT J AU Ku, WL Girvan, M Yuan, GC Sorrentino, F Ott, E AF Ku, Wai Lim Girvan, Michelle Yuan, Guo-Cheng Sorrentino, Francesco Ott, Edward TI Modeling the Dynamics of Bivalent Histone Modifications SO PLOS ONE LA English DT Article ID EMBRYONIC STEM-CELLS; GENOME; MEMORY; DIFFERENTIATION; DEMETHYLASES; PLURIPOTENT; PROPAGATION; METHYLATION; INHERITANCE; ACTIVATION AB Epigenetic modifications to histones may promote either activation or repression of the transcription of nearby genes. Recent experimental studies show that the promoters of many lineage-control genes in stem cells have "bivalent domains" in which the nucleosomes contain both active (H3K4me3) and repressive (H3K27me3) marks. It is generally agreed that bivalent domains play an important role in stem cell differentiation, but the underlying mechanisms remain unclear. Here we formulate a mathematical model to investigate the dynamic properties of histone modification patterns. We then illustrate that our modeling framework can be used to capture key features of experimentally observed combinatorial chromatin states. C1 [Ku, Wai Lim; Girvan, Michelle; Ott, Edward] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Ku, Wai Lim; Girvan, Michelle; Ott, Edward] Univ Maryland, Inst Res Elect & Appl Phys, College Pk, MD 20742 USA. [Girvan, Michelle] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. [Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Sorrentino, Francesco] Univ New Mexico, Dept Mech Engn, Albuquerque, NM 87131 USA. [Ott, Edward] Univ Maryland, Dept Elect & Comp Engn, College Pk, MD 20742 USA. RP Ku, WL (reprint author), Univ Maryland, Dept Phys, College Pk, MD 20742 USA. EM wlku@umd.edu RI O, E/F-1630-2015; Ku, Wai Lim/R-7170-2016 OI Ku, Wai Lim/0000-0002-8859-6771 FU Office of Naval Research [N000140710734]; United States National Institutes of Health [HG005085] FX This work was supported by Office of Naval Research grant N000140710734 and United States National Institutes of Health grant HG005085. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 5 Z9 5 U1 0 U2 12 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 NOV 1 PY 2013 VL 8 IS 11 AR e77944 DI 10.1371/journal.pone.0077944 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 245XZ UT WOS:000326499300016 PM 24223747 ER PT J AU Surman, OS AF Surman, O. S. TI Informed Consent: What the Patient Heard SO TRANSPLANTATION PROCEEDINGS LA English DT Review ID ORGAN-TRANSPLANTATION; DEPRESSION; LIVER AB Transplant Psychiatrist: "Why is it important to take (routine) medications after transplantation?" Transplant candidate: "To protect the liver." Doctor: "How?" Patient: "I don't know." Doctor: "Think about it for a moment." Patient: "To prevent rejection and infection." Doctor: "Which one: rejection or infection?" Patient: "Both." This article reports significant conceptual limitations in patient medical knowledge. In the course of customary comprehensive psychiatric evaluation, patients with end-stage renal and/or hepatic disease were asked about knowledge of benefits and side effects of required post-transplant medication. Liver transplant candidates were asked about their understanding of primary organ function and instructed in reference to components of Model for End-stage Liver Disease status on the deceased donor transplant list. Candidates for renal transplantation were selectively asked about risks regarding medical dietary compliance, including dangers of hyperkalemia. Patients had less than expected understanding of required immunosuppression. Liver transplant candidates, with infrequent exception, described the organ as a filter. Those with medical compliance problems related to end-stage renal disease had limited understanding of the kidney's role in homeostasis and impact of hyperkalemia on neurologic function. Additional teaching centered on narrative and analogy specific to individual life experience and skills. Historical reference to Sir Peter Medawar's Nobel Prize winning work on skin allograft failure for treatment of World War II burn victims effectively illustrated the primacy of immunosuppression for successful organ transplantation. Patients were receptive to this teaching approach. Many expressed gratitude for improved understanding. Clinical awareness of patient skills and life experience can enrich understanding of transplantation objectives and importance of medical compliance. C1 [Surman, O. S.] Massachusetts Gen Hosp, Kidney Liver & Pancreas Transplantat Program, Boston, MA 02114 USA. [Surman, O. S.] Harvard Univ, Sch Med, Boston, MA USA. RP Surman, OS (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Wang Ambulatory Care Ctr, Suite 812,15 Parkman St, Boston, MA 02114 USA. EM ossurman@yahoo.com NR 11 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0041-1345 EI 1873-2623 J9 TRANSPL P JI Transplant. Proc. PD NOV PY 2013 VL 45 IS 9 BP 3155 EP 3156 DI 10.1016/j.transproceed.2013.03.053 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 248NY UT WOS:000326709400001 PM 24182776 ER PT J AU Lowalekar, SK Lu, XG Thatte, HS AF Lowalekar, S. K. Lu, X. G. Thatte, H. S. TI Further Evaluation of Somah: Long-Term Preservation, Temperature Effect, and Prevention of Ischemia-Reperfusion Injury in Rat Hearts Harvested After Cardiocirculatory Death SO TRANSPLANTATION PROCEEDINGS LA English DT Article ID ORGAN-TRANSPLANTATION; SAPHENOUS-VEIN; COLD-STORAGE; HYPOTHERMIA; HEPATOCYTES; MEMBRANE; DONORS; DAMAGE AB Objective. To identify and evaluate the ideal temperature for long-term storage of hearts from donation after cardiocirculatory death, in the novel organ preservation solution Somah. Methods. DCD hearts from Sprague-Dawley rats were harvested after 30 minutes of euthanasia, preserved in Somah at 4 degrees C, 10 degrees C, 21 degrees C, or 37 degrees C for 24 hours and then reperfused with blood:Somah (3:1) perfusate at 37 degrees C for 30 minutes. Myocardial biopsies were taken during storage and before and after reperfusion to assess the structural and functional viability of tissue using multiphoton imaging, biochemistry, and immunofluorescence. Results. Myocyte viability, determined by Live-Dead and esterase assays, was similar at 4 degrees C, 10 degrees C, and 21 degrees C (193, 198 and 217 normalized fluorescence counts [NFC]) with a significant decrease at 37 degrees C (131 NFC). Upon reperfusion, esterase activity was enhanced in DCD hearts stored in Somah at 21 degrees C but noticeably decreased at all other temperatures. High-energy adenosine triphosphate/creatine phosphate (ATP/CP) syntheses and the expression of structural/contractile proteins was well preserved at 21 degrees C, both after 24-hour storage and upon reperfusion. In contrast, hearts stored at all other temperatures demonstrated variable degenerative changes, loss of protein expression, and/or deranged ATP/CP synthesis after 24 hours of storage and/or upon reperfusion. Conclusion. The robust maintenance of structural/functional integrity of cardiac tissue and the preservation of protein expression and cellular energy metabolism in DCD hearts after long-term preservation at subnormothermic temperature suggests that 21 degrees C is ideal for long-term storage of DCD hearts in Somah solution. C1 [Lowalekar, S. K.; Lu, X. G.; Thatte, H. S.] VA Boston Healthcare Syst, Dept Surg, Div Cardiothorac Surg, Boston, MA USA. [Lowalekar, S. K.; Lu, X. G.; Thatte, H. S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Lowalekar, S. K.; Lu, X. G.; Thatte, H. S.] Harvard Univ, Sch Med, Boston, MA USA. RP Thatte, HS (reprint author), VA Boston Healthcare Syst, Dept Surg 112, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM hemant_thatte@hms.harvard.edu FU DoD/ONR (Department of Defense/Office of Naval Research); Merit Grant, Department of Veterans Affairs FX Supported by the DoD/ONR (Department of Defense/Office of Naval Research) and the Merit Grant, Department of Veterans Affairs (HST). NR 23 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0041-1345 EI 1873-2623 J9 TRANSPL P JI Transplant. Proc. PD NOV PY 2013 VL 45 IS 9 BP 3192 EP 3197 DI 10.1016/j.transproceed.2013.06.006 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 248NY UT WOS:000326709400009 PM 24182783 ER PT J AU Liu, Q Berendsen, T Izamis, ML Uygun, B Yarmush, ML Uygun, K AF Liu, Q. Berendsen, T. Izamis, M. -L. Uygun, B. Yarmush, M. L. Uygun, K. TI Perfusion Defatting at Subnormothermic Temperatures in Steatotic Rat Livers SO TRANSPLANTATION PROCEEDINGS LA English DT Article ID MACHINE PERFUSION; NORMOTHERMIC PERFUSION; ORGAN-PRESERVATION; HEPATIC STEATOSIS; UNITED-STATES; EX-VIVO; TRANSPLANTATION; INJURY AB Hepatic steatosis is a major risk factor in liver transplantation. Use of machine perfusion to reduce steatosis has been reported previously at normothermic (37 C) temperatures, with minimal media as well as specialized defatting cocktails. In this work, we tested if subnormothermic (room temperature) machine perfusion, a more practical version of machine perfusion approach that does not require temperature control or oxygen carriers, could also be used to reduce fat content in steatotic livers. Steatotic livers recovered from obese Zucker rats were perfused for 6 hours. A significant increase of very low density lipoprotein (VLDL) and triglyceride (TG) content in perfusate, with or without a defatting cocktail, was observed although the changes in histology were minimal and changes in intracellular TG content were not statistically significant. The oxygen uptake rate, VLDL secretion, TG secretion, and venous resistance were similar in both groups. This study confirms lipid export during subnormothermic machine perfusion; however, the duration of perfusion necessary appears much higher than required in normothermic perfusion. C1 [Liu, Q.; Berendsen, T.; Izamis, M. -L.; Uygun, B.; Yarmush, M. L.; Uygun, K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. Shriners Burns Hosp, Boston, MA USA. [Yarmush, M. L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ USA. RP Yarmush, ML (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org; uygun.korkut@mgh.harvard.edu RI Liu, Qiang/M-5922-2013; Uygun, Basak/I-1792-2012 OI Uygun, Basak/0000-0002-2600-7900 FU National Institutes of Health [R01DK096075, R01EB008678, R00DK080942, K99DK088962]; Shriners Hospitals for Children FX Supported by funding from the National Institutes of Health (R01DK096075, R01EB008678, R00DK080942, K99DK088962), and the Shriners Hospitals for Children. NR 20 TC 6 Z9 7 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0041-1345 EI 1873-2623 J9 TRANSPL P JI Transplant. Proc. PD NOV PY 2013 VL 45 IS 9 BP 3209 EP 3213 DI 10.1016/j.transproceed.2013.05.005 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 248NY UT WOS:000326709400012 PM 24182786 ER PT J AU Shaw, T Addae, L Bridger, C Pepin, D AF Shaw, T. Addae, L. Bridger, C. Pepin, D. TI CHARACTERIZATION OF POSTOVULATORY WOUND REPAIR SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Shaw, T.; Addae, L.; Bridger, C.] Univ London, London, England. [Pepin, D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1067-1927 EI 1524-475X J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD NOV PY 2013 VL 21 IS 6 BP A83 EP A83 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 243OU UT WOS:000326327100122 ER PT J AU Evans, ME Kralovic, SM Simbartl, LA Freyberg, RW Obrosky, DS Roselle, GA Jain, R AF Evans, Martin E. Kralovic, Stephen M. Simbartl, Loretta A. Freyberg, Ron W. Obrosky, D. Scott Roselle, Gary A. Jain, Rajiv TI Veterans Affairs methicillin-resistant Staphylococcus aureus prevention initiative associated with a sustained reduction in transmissions and health care-associated infections SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE Veterans health care; MDRO; Methicillin-resistant organism; Infection prevention ID BLOOD AB Implementation of a methicillin-resistant Staphylococcus aureus (MRSA) Prevention Initiative was associated with significant declines in MRSA transmission and MRSA health care-associated infection rates in Veterans Affairs acute care facilities nationwide in the 33-month period from October 2007 through June 2010. Here, we show continuing declines in MRSA transmissions (P=.004 for trend, Poisson regression) and MRSA health care-associated infections (P<.001) from July 2010 through June 2012. The Veterans Affairs Initiative was associated with these effects, sustained over 57 months, in a large national health care system. Published by Elsevier Inc. on behalf of the Association for Professionals in Infection Control and Epidemiology, Inc. C1 [Evans, Martin E.] VA Cent Off, Patient Care Serv, Natl Infect Dis Serv, VHA MRSA MDRO Program Off, Lexington, KY USA. [Evans, Martin E.] Lexington VA Med Ctr, Lexington, KY USA. [Evans, Martin E.] Univ Kentucky, Sch Med, Dept Internal Med, Lexington, KY 40536 USA. [Kralovic, Stephen M.; Simbartl, Loretta A.; Roselle, Gary A.] VA Cent Off, Patient Care Serv, Natl Infect Dis Serv, Cincinnati, OH USA. [Kralovic, Stephen M.; Simbartl, Loretta A.; Roselle, Gary A.] Cincinnati VA Med Ctr, Cincinnati, OH USA. [Kralovic, Stephen M.; Roselle, Gary A.] Univ Cincinnati, Coll Med, Dept Internal Med, Cincinnati, OH USA. [Freyberg, Ron W.] VA Off Informat & Analyt, Cincinnati, OH USA. [Obrosky, D. Scott] VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Jain, Rajiv] VA Cent Off, Patient Care Serv, Washington, DC USA. RP Evans, ME (reprint author), 1101 Vet Dr, Lexington, KY USA. EM Martin.Evans@va.gov NR 7 TC 11 Z9 11 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-6553 EI 1527-3296 J9 AM J INFECT CONTROL JI Am. J. Infect. Control PD NOV PY 2013 VL 41 IS 11 BP 1093 EP 1095 DI 10.1016/j.ajic.2013.04.015 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 242KY UT WOS:000326241700030 PM 24176769 ER PT J AU Magill, SS Klompas, M Balk, R Burns, SM Deutschman, CS Diekema, D Fridkin, S Greene, L Guh, A Gutterman, D Hammer, B Henderson, D Hess, DR Hill, NS Horan, T Kollef, M Levy, M Septimus, E VanAntwerpen, C Wright, D Lipsett, P AF Magill, Shelley S. Klompas, Michael Balk, Robert Burns, Suzanne M. Deutschman, Clifford S. Diekema, Daniel Fridkin, Scott Greene, Linda Guh, Alice Gutterman, David Hammer, Beth Henderson, David Hess, Dean R. Hill, Nicholas S. Horan, Teresa Kollef, Marin Levy, Mitchell Septimus, Edward VanAntwerpen, Carole Wright, Don Lipsett, Pamela TI Developing a new national approach to surveillance for ventilator-associated events: Executive summary SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE Ventilator-associated pneumonia; Intensive care unit; Epidemiology; Public health; Critical care; Mechanical ventilation AB In September 2011, the Centers for Disease Control and Prevention (CDC) convened a Ventilator-Associated Pneumonia (VAP) Surveillance Definition Working Group to organize a formal process for leaders and experts of key stakeholder organizations to discuss the challenges of VAP surveillance definitions and to propose new approaches to VAP surveillance in adult patients (Table 1). The charges to the Working Group were to (1) critically review a draft, streamlined VAP surveillance definition developed for use in adult patients; (2) suggest modifications to enhance the reliability and credibility of the surveillance definition within the critical care and infection prevention communities; and (3) propose a final adult surveillance definition algorithm to be implemented in the CDC's National Healthcare Safety Network (NHSN), taking into consideration the potential future use of the definition algorithm in public reporting, interfacility comparisons, and pay-for-reporting and pay-for-performance programs. Published by Elsevier Inc. on behalf of the Association for Professionals in Infection Control and Epidemiology, Inc. C1 [Magill, Shelley S.; Fridkin, Scott; Guh, Alice; Horan, Teresa] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA 30329 USA. [Klompas, Michael] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Klompas, Michael] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Klompas, Michael] Brigham & Womens Hosp, Infect Control Dept, Boston, MA 02115 USA. [Klompas, Michael] Soc Healthcare Epidemiol Amer, Arlington, VA USA. [Balk, Robert] Rush Univ, Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60612 USA. [Burns, Suzanne M.] Univ Virginia, Sch Nursing Crit & Acute Care, Charlottesville, VA USA. [Deutschman, Clifford S.] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Diekema, Daniel] Univ Iowa, Div Infect Dis, Carver Coll Med, Iowa City, IA USA. [Diekema, Daniel] Healthcare Infect Control Practices Advisory Comm, Surveillance Working Grp, Atlanta, GA USA. [Greene, Linda] Rochester Gen Hlth Syst, Infect Prevent & Control Dept, Rochester, NY USA. [Greene, Linda] Assoc Profess Infect Control & Epidemiol, Washington, DC USA. [Gutterman, David] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Hammer, Beth] Zablocki VA Med Ctr, Dept Cardiol, Milwaukee, WI USA. [Henderson, David] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Hess, Dean R.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Hess, Dean R.] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. [Hess, Dean R.] Amer Assoc Resp Care, Irving, TX USA. [Hill, Nicholas S.] Tufts Med Ctr, Div Pulm & Crit Care Med, Boston, MA USA. [Kollef, Marin] Washington Univ, Div Pulm & Crit Care Med, St Louis, MO USA. [Levy, Mitchell] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Pulm Crit Care & Sleep, Providence, RI 02903 USA. [Septimus, Edward] Texas A&M Hlth Sci Ctr, Dept Internal Med, College Stn, TX USA. [Septimus, Edward] Infect Dis Soc Amer, Arlington, VA USA. [VanAntwerpen, Carole] New York State Dept Hlth, Bur Healthcare Associated Infect, Albany, NY USA. [VanAntwerpen, Carole] Council State & Territorial Epidemiologists, Atlanta, GA USA. [Wright, Don] US Dept HHS, Off Dis Prevent & Hlth Promot, Washington, DC 20201 USA. [Lipsett, Pamela] Johns Hopkins Univ, Sch Med, Dept Surg Anesthesiol & Crit Care Med, Baltimore, MD USA. RP Magill, SS (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, 1600 Clifton Rd,MS A-24, Atlanta, GA 30329 USA. EM smagill@cdc.gov OI Diekema, Daniel/0000-0003-1273-0724 FU Centers for Disease Control and Prevention (CDC) FX Supported by the Centers for Disease Control and Prevention (CDC). NR 2 TC 3 Z9 4 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-6553 EI 1527-3296 J9 AM J INFECT CONTROL JI Am. J. Infect. Control PD NOV PY 2013 VL 41 IS 11 BP 1096 EP 1099 DI 10.1016/j.ajic.2013.07.001 PG 4 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 242KY UT WOS:000326241700031 PM 24176770 ER PT J AU Bateman, BT Huybrechts, KF Hernandez-Diaz, S Liu, J Ecker, JL Avorn, J AF Bateman, Brian T. Huybrechts, Krista F. Hernandez-Diaz, Sonia Liu, Jun Ecker, Jeffrey L. Avorn, Jerry TI Methylergonovine maleate and the risk of myocardial ischemia and infarction SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE methylergonovine; myocardial infarction; postpartum hemorrhage; uterine atony ID POSITIVE PREDICTIVE-VALUE; MAJOR NONCARDIAC SURGERY; CORONARY-ARTERY SPASM; POSTPARTUM HEMORRHAGE; MORTALITY; THERAPY; DELIVERIES; PREGNANCY AB OBJECTIVE: The purpose of this study was to examine the risks of acute coronary syndrome (ACS) and acute myocardial infarction (AMI) that are associated with methylergonovine maleate (Methergine; Novartis Pharmaceuticals Corporation, Plantation, FL) use in a large database of inpatient delivery admissions in the United States. STUDY DESIGN: We conducted a retrospective cohort study using data from the Premier Perspective Database and identified 2,233,630 women who were hospitalized for delivery between 2007 and 2011 (approximately one-seventh of all US deliveries during this period). Exposure was defined by a charge code for methylergonovine during the delivery hospitalization. Study outcomes included ACS and AMI. Propensity score matching was used to address potential confounding. RESULTS: Methylergonovine was administered to 139,617 patients (6.3%). Overall, 6 patients (0.004%) who were exposed to methylergonovine and 52 patients (0.002%) who were not exposed to methylergonovine had an ACS. Four patients (0.003%) who were exposed to methylergonovine and 44 patients (0.002%) in the notexposed group had an AMI. After propensity score matching, the relative risk for ACS that was associated with methylergonovine exposure was 1.67 (95% confidence interval [CI], 0.40-6.97), and the risk difference was 1.44 per 100,000 patients (95% CI, -2.56 to 5.45); the relative risk for AMI that was associated with methylergonovine exposure was 1.00 (95% CI, 0.20-4.95), and the risk difference was 0.00 per 100,000 patients (95% CI, -3.47 to 3.47). CONCLUSION: Despite studying a very large proportion of US deliveries, we did not find a significant increase in the risk of ACS or AMI in women who received methylergonovine compared with those who did not; estimates were increased only modestly or not at all. The upper limit of the 95% CI of our analysis suggests that treatment with methylergonovine would result in no more than 5 additional cases of ACS and 3 additional cases of AMI per 100,000 exposed patients. C1 [Bateman, Brian T.; Huybrechts, Krista F.; Liu, Jun; Avorn, Jerry] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. [Bateman, Brian T.] Massachusetts Gen Hosp, Dept Anesthesiol, Boston, MA 02114 USA. [Bateman, Brian T.] Massachusetts Gen Hosp, Dept Crit Care, Boston, MA 02114 USA. [Bateman, Brian T.] Massachusetts Gen Hosp, Dept Pain Med, Boston, MA 02114 USA. [Ecker, Jeffrey L.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Hernandez-Diaz, Sonia] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bateman, Brian T.; Huybrechts, Krista F.; Ecker, Jeffrey L.; Avorn, Jerry] Harvard Univ, Sch Med, Boston, MA USA. RP Bateman, BT (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. FU [GM007592] FX Supported by the T32 Training Grant (GM007592; B.T.B.). NR 30 TC 2 Z9 2 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD NOV PY 2013 VL 209 IS 5 AR 459.e1 DI 10.1016/j.ajog.2013.07.001 PG 13 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 242LP UT WOS:000326243700022 PM 23850529 ER PT J AU Rauh-Hain, JA Clemmer, J Clark, RM Bradford, LS Growdon, WB Goodman, A Boruta, DM Schorge, JO del Carmen, MG AF Rauh-Hain, J. Alejandro Clemmer, Joel Clark, Rachel M. Bradford, Leslie S. Growdon, Whitfield B. Goodman, Annekathryn Boruta, David M., II Schorge, John O. del Carmen, Marcela G. TI Racial disparities and changes in clinical characteristics and survival for vulvar cancer over time SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE African-American; disparities; race; vulvar cancer ID INVASIVE CERVICAL-CANCER; SQUAMOUS-CELL CARCINOMA; END RESULTS DATA; MARITAL-STATUS; UNITED-STATES; OVARIAN-CANCER; BREAST-CANCER; SEER DATA; IN-SITU; WOMEN AB OBJECTIVE: The purpose of this study was to examine changes over time in survival for African-American (AA) and white women diagnosed with squamous cell carcinoma of the vulva. STUDY DESIGN: The Surveillance, Epidemiology, and End Results (SEER) Program for 1973-2009 was used for this analysis. We evaluated racial differences in survival between AA and white women. Kaplan-Meier and Cox proportional hazards survival methods were used to assess differences in survival by race by decade of diagnosis. RESULTS: The study sample included 5867 women, including 5379 whites (91.6%) and 488 AA (8.3%). AA women were younger (57 vs 67 years; P < .001) and had a higher rate of distant metastasis (6.1% vs 3.7%; P < .001). AA women had surgery less frequently (84.2% vs 87.6%; P = .03) and more frequently radiotherapy (24.2% vs 20.6%; P < .001). AA women had a hazard ratio (HR) of 0.84 (95% confidence interval [CI], 0.74-0.95) of all-cause mortality and 0.66 (95% CI, 0.53-0.82) of vulvar cancer mortality compared with whites. Adjusting for SEER Registry, marital status, stage, age, surgery, radiotherapy, grade, lymph node status, and decade, AA women had an HR of 0.67 (95% CI, 0.53-0.84) of vulvar cancer-related mortality compared with whites. After adjusting for the same variables, there was a significant difference in survival between AA and whites in the periods of 1990-1999 (HR, 0.62; 95% CI, 0.41-0.95) and 2000-2009 (HR, 0.46; 95% CI, 0.30-0.72) but not earlier. CONCLUSION: AA presented at a significantly younger age compared with white women and had better survival compared with whites. C1 [Rauh-Hain, J. Alejandro; Clemmer, Joel; Clark, Rachel M.; Bradford, Leslie S.; Growdon, Whitfield B.; Goodman, Annekathryn; Boruta, David M., II; Schorge, John O.; del Carmen, Marcela G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol,Div Gynecol Oncol, Boston, MA USA. RP del Carmen, MG (reprint author), Massachusetts Gen Hosp, Div Gynecol Oncol, Vincent Obstet & Gynecol, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM mdelcarmen@partners.org NR 28 TC 0 Z9 0 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD NOV PY 2013 VL 209 IS 5 AR 468.e1 DI 10.1016/j.ajog.2013.07.021 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 242LP UT WOS:000326243700025 PM 23891626 ER PT J AU Yang, J Wheeler, SE Velikoff, M Kleaveland, KR LaFemina, MJ Frank, JA Chapman, HA Christensen, PJ Kim, KK AF Yang, Jibing Wheeler, Sarah E. Velikoff, Miranda Kleaveland, Kathryn R. LaFemina, Michael J. Frank, James A. Chapman, Harold A. Christensen, Paul J. Kim, Kevin K. TI Activated Alveolar Epithelial Cells Initiate Fibrosis through Secretion of Mesenchymal Proteins SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID IDIOPATHIC PULMONARY-FIBROSIS; USUAL INTERSTITIAL PNEUMONIA; TISSUE GROWTH-FACTOR; LIVER FIBROSIS; LUNG FIBROSIS; FIBROBLASTS DERIVE; PROPEPTIDE LEVELS; TRANSGENIC MICE; BETA RECEPTOR; TRANSITION AB Fibrosis is characterized by accumulation of activated fibroblasts and pathological deposition of fibrillar collagens. Activated fibroblasts overexpress matrix proteins and release factors that promote further recruitment of activated fibroblasts, leading to progressive fibrosis. The contribution of epithelial cells to this process remains unknown. Epithelium-directed injury may lead to activation of epithelial cells with phenotypes and functions similar to activated fibroblasts. Prior reports that used a reporter gene fate-mapping strategy are limited in their ability to investigate the functional significance of epithelial cell-derived mesenchymal proteins during fibrogenesis. We found that lung epithelial cell-derived collagen I activates fibroblast collagen receptor discoidin domain receptor-2, contributes significantly to fibrogenesis, and promotes resolution of lung inflammation. Alveolar epithelial cells undergoing transforming growth factor-beta-mediated mesenchymal transition express several other secreted profibrotic factors and are capable of activating lung fibroblasts. These studies provide direct evidence that activated epithelial cells produce mesenchymal proteins that initiate a cycle of fibrogenic effector cell activation, leading to progressive fibrosis. Therapy targeted at epithelial cell production of type I collagen offers a novel pathway for abrogating this progressive cycle and for Limiting tissue fibrosis but may lead to sustained Lung injury/inflammation. C1 [Yang, Jibing; Velikoff, Miranda; Kleaveland, Kathryn R.; Christensen, Paul J.; Kim, Kevin K.] Univ Michigan, Dept Internal Med, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. [Wheeler, Sarah E.; Chapman, Harold A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Wheeler, Sarah E.; Chapman, Harold A.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [LaFemina, Michael J.; Frank, James A.] Univ Calif San Francisco, Dept Med, San Francisco VA Med Ctr, San Francisco, CA USA. RP Kim, KK (reprint author), 109 Zina Pitcher Pl,BSRB 4061, Ann Arbor, MI 48109 USA. EM kevkim@med.umich.edu FU NIH [R01 HL108904, K08 HL085290, RO1 HL44712] FX Supported by NIH grants R01 HL108904 (K.K.K.), K08 HL085290 (K.K.K.), and RO1 HL44712 (H.A.C.). NR 66 TC 17 Z9 17 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD NOV PY 2013 VL 183 IS 5 BP 1559 EP 1570 DI 10.1016/j.ajpath.2013.07.016 PG 12 WC Pathology SC Pathology GA 246QE UT WOS:000326553400022 PM 24012677 ER PT J AU Phitayakorn, R Morales-Garcia, D Wanderer, J Lubitz, CC Gaz, RD Stephen, AE Ehrenfeld, JM Daniels, GH Hodin, RA Parangi, S AF Phitayakorn, Roy Morales-Garcia, Dieter Wanderer, Jonathan Lubitz, Carrie C. Gaz, Randall D. Stephen, Antonia E. Ehrenfeld, Jesse M. Daniels, Gilbert H. Hodin, Richard A. Parangi, Sareh TI Surgery for Graves' disease: a 25-year perspective SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Graves' disease; Surgical therapy; Incidental malignancy ID NONCARDIAC SURGERY; TOTAL THYROIDECTOMY; SUBTOTAL THYROIDECTOMY; RADIOIODINE THERAPY; SURGICAL-TREATMENT; CARDIAC EVENTS; HYPERTHYROIDISM; MANAGEMENT; OPTION; TRIAL AB BACKGROUND: Optimal treatment of Graves' disease (GD) remains controversial. The authors retrospectively reviewed the surgical cases of GD at a single academic tertiary center. METHODS: Demographic, clinical, and surgical data were analyzed for all patients with GD undergoing thyroidectomy over 25 years, in 3 periods: 1985 to 1993 (n = 32), 1994 to 2002 (n = 91), and 2003 to 2010 (n 5 177). RESULTS: There were 300 patients with GD (85.7% women; mean age, 39.3 years; median length of follow-up, 24.6 months). Overall, perioperative morbidity occurred in 36 patients (12.0%), and there was no mortality. Thyroidectomy-specific morbidity was very low, and the incidental malignancy rate was 10.3%. CONCLUSIONS: Surgical treatment of GD has a very high safety profile, with low perioperative and thyroidectomy-specific morbidity, even in patients with overt hyperthyroidism. Incidental malignancy in patients with GD is not uncommon. (C) 2013 Elsevier Inc. All rights reserved. C1 [Phitayakorn, Roy; Morales-Garcia, Dieter; Lubitz, Carrie C.; Gaz, Randall D.; Stephen, Antonia E.; Daniels, Gilbert H.; Hodin, Richard A.; Parangi, Sareh] Harvard Univ, Sch Med, Thyroid Canc Res Lab, Endocrine Surg Unit,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Wanderer, Jonathan; Ehrenfeld, Jesse M.] Vanderbilt Univ, Med Ctr, Dept Anesthesiol, Nashville, TN USA. RP Parangi, S (reprint author), Harvard Univ, Sch Med, Thyroid Canc Res Lab, Endocrine Surg Unit,Massachusetts Gen Hosp, 15 Parkman St,Wang ACC 460, Boston, MA 02115 USA. EM sparangi@partners.org OI Ehrenfeld, Jesse/0000-0003-3427-0140; Phitayakorn, Roy/0000-0002-8327-1484 NR 23 TC 3 Z9 3 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 EI 1879-1883 J9 AM J SURG JI Am. J. Surg. PD NOV PY 2013 VL 206 IS 5 BP 669 EP 673 DI 10.1016/j.amjsurg.2013.07.005 PG 5 WC Surgery SC Surgery GA 246BG UT WOS:000326510600008 PM 24011567 ER PT J AU Magee, MJ Wright, CD McDonald, D Fernandez, FG Kozower, BD AF Magee, Mitchell J. Wright, Cameron D. McDonald, Donna Fernandez, Felix G. Kozower, Benjamin D. TI External Validation of The Society of Thoracic Surgeons General Thoracic Surgery Database SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT Late-Breaking Clinical Trial Abstract Session at the 49th Annual Meeting of the Society-of-Thoracic-Surgeons CY JAN 26-30, 2013 CL Los Angeles, CA SP Soc Thorac Surg ID RISK-ADJUSTMENT MODEL; ADMINISTRATIVE DATA; MAJOR MORBIDITY; LUNG-CANCER; PREDICTORS; MORTALITY; OUTCOMES AB Background. The Society of Thoracic Surgeons (STS) General Thoracic Surgery Database (GTSD) reports outstanding results for lung and esophageal cancer resection. However, a major weakness of the GTSD has been the lack of validation of this voluntary registry. The purpose of this study was to perform an external, independent audit to assess the accuracy of the data collection process and the quality of the database. Methods. An independent firm was contracted to audit 5% of sites randomly selected from the GTDB in 2011. Audits were performed remotely to maximize the number of audits performed and reduce cost. Auditors compared lobectomy cases submitted to the GTSD with the hospital operative logs to evaluate completeness of the data. In addition, 20 lobectomy records from each site were audited in detail. Agreement rates were calculated for 32 individual data elements, 7 data categories pertaining to patient status or care delivery, and an overall agreement rate for each site. Six process variables were also evaluated to assess best practice for data collection and submission. Results. Ten sites were audited from the 222 participants. Comparison of the 559 submitted lobectomy cases with operative logs from each site identified 28 omissions, a 94.6% agreement rate (discrepancies/site range, 2 to 27). Importantly, cases not submitted had no mortality or major morbidity, indicating a lack of purposeful omission. The aggregate agreement rates for all categories were greater than 90%. The overall data accuracy was 94.9%. Conclusions. External audits of the GTSD validate the accuracy and completeness of the data. Careful examination of unreported cases demonstrated no purposeful omission or gaming. Although these preliminary results are quite good, it is imperative that the audit process is refined and continues to expand along with the GTSD to insure reliability of the database. The audit results are currently being incorporated into educational and quality improvement processes to add further value. (C) 2013 by The Society of Thoracic Surgeons C1 [Magee, Mitchell J.] Med City Dallas Hosp, Dallas, TX 75230 USA. Emory Univ, Sch Med, Atlanta, GA USA. Univ Virginia, Charlottesville, VA USA. Soc Thorac Surg, Chicago, IL USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Magee, MJ (reprint author), Med City Dallas Hosp, 7777 Forest Ln, Dallas, TX 75230 USA. EM mitchell.magee@hcahealthcare.com NR 8 TC 13 Z9 13 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD NOV PY 2013 VL 96 IS 5 BP 1734 EP 1739 DI 10.1016/j.athoracsur.2013.04.124 PG 6 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 244GP UT WOS:000326375700038 PM 23998406 ER PT J AU Yukawa, S Takeuchi, M Nakazono, A Sakamoto, K Araya, K Eto, M Nishimura, Y Harada, M Levine, RA Otsuji, Y AF Yukawa, Sawami Takeuchi, Masaaki Nakazono, Akemi Sakamoto, Kyoko Araya, Kiyoshi Eto, Masataka Nishimura, Yosuke Harada, Masaru Levine, Robert A. Otsuji, Yutaka TI Mitral Stenosis Reversed by Medical Treatment for Heart Failure SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material AB It is reported that functional mitral stenosis frequently develops after ring annuloplasty for ischemic mitral regurgitation. The mechanism is a combination of annular size reduction by surgery and diastolic mitral valve tethering, restricting the anterior leaflet opening due to posteriorly displaced papillary muscles with left ventricular dilatation. We report the case of a 57-year-old man who had a history of successful mitral valve plasty for degenerative mitral regurgitation. Four years later he developed heart failure, severe hypertension, mild mitral regurgitation, and significant mitral stenosis, which were reversed by aggressive medical treatment for heart failure. (C) 2013 by The Society of Thoracic Surgeons C1 Univ Occupat & Environm Hlth, Dept Surg Pathol Lab & Transfus Med, Kitakyushu, Fukuoka 8078555, Japan. Univ Occupat & Environm Hlth, Dept Internal Med 2, Kitakyushu, Fukuoka 8078555, Japan. Univ Occupat & Environm Hlth, Dept Cardiovasc Surg, Kitakyushu, Fukuoka 8078555, Japan. Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. RP Takeuchi, M (reprint author), Univ Occupat & Environm Hlth, Dept Internal Med 2, Sch Med, Yahatanishi Ku, 1-1 Iseigaoka, Kitakyushu, Fukuoka 8078555, Japan. EM takeuchi@med.uoeh-u.ac.jp FU NHLBI NIH HHS [R01 HL072265, R01 HL109506] NR 2 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD NOV PY 2013 VL 96 IS 5 BP E115 EP E117 DI 10.1016/j.athoracsur.2013.04.132 PG 3 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 244GP UT WOS:000326375700003 PM 24182508 ER PT J AU Yamakoshi, Y Simmer, JP Bartlett, JD Karakida, T Oida, S AF Yamakoshi, Yasuo Simmer, James P. Bartlett, John D. Karakida, Takeo Oida, Shinichiro TI MMP20 and KLK4 activation and inactivation interactions in vitro SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE Enamel; MMP20; KLK4; Proteases; Tooth ID ENAMEL FORMATION; MATRIX METALLOPROTEINASES; AMELOGENIN; MMP-20; AMELOBLASTIN; CLEAVAGE; TOOTH; MATURATION; MODULATION; PROTEINS AB Objective: Enamelysin (MMP20) and kallikrein 4 (KLK4) are believed to be necessary to clear proteins from the enamel matrix of developing teeth. MMP20 is expressed by secretory stage ameloblasts, while KLK4 is expressed from the transition stage throughout the maturation stage. The aim of this study is to investigate the activation of KLK4 by MMP20 and the inactivation of MMP20 by KLK4. Design: Native pig MMP20 (pMMP20) and KLK4 (pKLK4) were isolated directly from enamel scrapings from developing molars. Recombinant human proKLK4 (rh-proKLK4) was activated by incubation with pMMP20 or recombinant human MMP20 (rhMMP20), and the resulting KLK4 activity was detected by zymography. Reaction products were isolated by reverse-phase high performance liquid chromatography (RP-HPLC), and their N-termini characterized by Edman degradation. The pMMP20 was incubated with pKLK4 under mildly acidic or under physiologic conditions, and enzyme activity was analyzed by zymography. The catalytic domain of rhMMP20 was incubated with pKLK4 or recombinant human KLK4 (rhKLK4) and the digestion products were characterized by zymography and Edman degradation. Results: Both pMMP20 and rhMMP20 activated rh-proKLK4 by cleaving at the propeptide-enzyme junction used in vivo. The pMMP20 was inactivated by pKLK4 under physiologic conditions, but not under mildly acidic conditions. Both pKLK4 and rhKLK4 cleaved MMP20 principally at two sites in the catalytic domain of MMP20. Conclusions: MMP20 activates proKLK4 and KLK4 inactivates MMP20 in vitro, and these actions are likely to occur during enamel formation in vivo. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Yamakoshi, Yasuo; Karakida, Takeo; Oida, Shinichiro] Tsurumi Univ, Sch Dent Med, Dept Biochem & Mol Biol, Tsurumi Ku, Yokohama, Kanagawa 2308501, Japan. [Simmer, James P.] Univ Michigan, Dept Biol & Mat Sci, Sch Dent, Ann Arbor, MI 48108 USA. [Bartlett, John D.] Harvard Univ, Sch Dent Med, Forsyth Inst, Dept Mineralized Tissue Biol, Cambridge, MA 02142 USA. [Bartlett, John D.] Harvard Univ, Sch Dent Med, Dept Dev Biol, Cambridge, MA 02142 USA. RP Yamakoshi, Y (reprint author), Tsurumi Univ, Sch Dent Med, Dept Biochem & Mol Biol, Tsurumi Ku, 2-1-3 Tsurumi, Yokohama, Kanagawa 2308501, Japan. EM yamakoshi-y@tsurumi-u.ac.jp; jsimmer@umich.edu; jbartlett@forsyth.org; karakida-t@tsurumi-u.ac.jp; oida-s@tsurumi-u.ac.jp FU JSPS [24890265]; National Institutes of Health from NIDCR [DE 019775] FX This study was supported by JSPS Grant-in-Aid for Research Activity Start-up Number 24890265, and National Institutes of Health Grant DE 019775 from NIDCR. NR 37 TC 6 Z9 7 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 EI 1879-1506 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD NOV PY 2013 VL 58 IS 11 BP 1569 EP 1577 DI 10.1016/j.archoralbio.2013.08.005 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 244BW UT WOS:000326363100001 PM 24112721 ER PT J AU Thadhani, RI Manson, JE AF Thadhani, Ravi I. Manson, JoAnn E. TI Vitamin D Too Soon to Turn Out the Lights? SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Editorial Material DE atherosclerosis; cardiovascular outcomes; parathyroid hormone; risk factors; vitamin D ID INTIMA-MEDIA THICKNESS; BONE-MINERAL DENSITY; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; RISK; METAANALYSIS C1 [Thadhani, Ravi I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol, Boston, MA 02115 USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. RP Manson, JE (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, 900 Commonwealth Ave,3rd Floor, Boston, MA 02115 USA. EM jmanson@rics.bwh.harvard.edu FU NCI NIH HHS [CA138962]; NHLBI NIH HHS [R01 HL112746, HL34594, HL112746]; NIDDK NIH HHS [DK094872, DK094486] NR 24 TC 1 Z9 1 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2013 VL 33 IS 11 BP 2467 EP 2469 DI 10.1161/ATVBAHA.113.302089 PG 3 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 244VQ UT WOS:000326418700006 PM 24132745 ER PT J AU Arce, G Bak, K Bain, G Calvo, E Ejnisman, B Di Giacomo, G Gutierrez, V Guttmann, D Itoi, E Ben Kibler, W Ludvigsen, T Mazzocca, A Pochini, AD Savoie, F Sugaya, H Uribe, J Vergara, F Willems, J Yoo, YS McNeil, JW Provencher, MT AF Arce, Guillermo Bak, Klaus Bain, Gregory Calvo, Emilio Ejnisman, Benno Di Giacomo, Giovanni Gutierrez, Vicente Guttmann, Dan Itoi, Eiji Ben Kibler, W. Ludvigsen, Tom Mazzocca, Augustus de Castro Pochini, Alberto Savoie, Felix, III Sugaya, Hiroyuki Uribe, John Vergara, Francisco Willems, Jaap Yoo, Yon Sik McNeil, John W., II Provencher, Matthew T. TI Management of Disorders of the Rotator,Cuff: Proceedings of the ISAKOS Upper Extremity Committee Consensus Meeting SO ARTHROSCOPY-THE JOURNAL OF ARTHROSCOPIC AND RELATED SURGERY LA English DT Article ID REVERSE SHOULDER ARTHROPLASTY; CUFF REPAIR; TENDON REPAIR; SINGLE-ROW; SUBACROMIAL IMPINGEMENT; SUPRASPINATUS TENDON; SUPRASCAPULAR NERVE; GLENOHUMERAL JOINT; LATISSIMUS-DORSI; BICEPS TENODESIS AB The goal of this article is to consolidate the International Society of Arthroscopy, Knee Surgery & Orthopaedic Sports Medicine (ISAKOS) Upper Extremity Committee's (UEC's) current knowledge on rotator cuff disease and management, as well as highlight key unresolved issues. The rotator cuff is an anatomically complex structure important for providing glenohumeral function and stability as part of a closed chain system. Current consensus suggests rotator cuff injuries are most accurately diagnosed, at levels similar to diagnosis by magnetic resonance imaging, with a combination of cuff- and impingement-specific clinical tests. Updates in the understanding of acromion morphology, the insertional anatomy of the rotator cuff, and the role of suprascapular nerve release may require changes to current classification systems and surgical strategies. Although initial management focuses on nonoperative protocols, discussion continues on whether surgery for isolated impingement is clinically more beneficial than rehabilitation. However, clear indications have yet to be established for the use of single- versus double-row repair because evidence confirms neither is clinically efficacious than the other. Biceps tenodesis, however, in non-isolated cuff tears has proven more successful in addressing the etiology of shoulder pain and yields improved outcomes over tenotomy. Data reviewing the benefits of tendon transfers, shoulder prostheses, and mechanical scaffolds, as well as new research on the potential benefit of platelet-rich plasma, pluripotential stem cells, and gene therapies, will also be presented. C1 Massachusetts Gen Hosp, Sports Med Serv, Dept Surg & Orthopaed, Boston, MA 02114 USA. RP Provencher, MT (reprint author), Massachusetts Gen Hosp, Sports Med Serv, Dept Surg & Orthopaed, 175 Cambridge St,Ste 400, Boston, MA 02114 USA. EM mtprovencher@partners.org NR 67 TC 14 Z9 15 U1 0 U2 32 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-8063 EI 1526-3231 J9 ARTHROSCOPY JI Arthroscopy PD NOV PY 2013 VL 29 IS 11 BP 1840 EP 1850 DI 10.1016/j.arthro.2013.07.265 PG 11 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 240YN UT WOS:000326133700022 PM 24041864 ER PT J AU Baek, JH Bernstein, EE Nierenberg, AA AF Baek, Ji Hyun Bernstein, Emily E. Nierenberg, Andrew A. TI One-carbon metabolism and bipolar disorder SO AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY LA English DT Review DE Bipolar disorder; mood disorder; folate; nutraceuticals ID MAJOR DEPRESSIVE DISORDER; 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE GENE; WEEKLY SYMPTOMATIC STATUS; PLACEBO-CONTROLLED TRIAL; FOLIC-ACID; DOUBLE-BLIND; FOLATE-DEFICIENCY; SODIUM VALPROATE; SERUM FOLATE; PSYCHIATRIC-DISORDERS AB Objective: Folate is one of the most widely used nutraceuticals for the treatment of mood disorders. In this article, we review folate metabolism, its relationship with bipolar disorder, and its therapeutic potential. Methods: We searched PubMed and the Cochrane Library for relevant articles up to and including the year 2012. Background information, proposed mechanisms of action, and results from clinical trials were reviewed. Results: Folate is an essential cofactor involved in methylation reactions, which are critical for monoamine synthesis and homocysteine regulation. Folate level is thought to be associated with mood disorders and limited response to antidepressants. Functional deficiency, due to a common genetic variant of the methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR) gene, could also affect the presentation of bipolar disorder. Sodium valproate and lamotrigine, commonly used mood stabilizers for the treatment of bipolar disorder, can potentially interfere with folate and homocysteine metabolism. Previous studies consistently support the efficacy of folate in the treatment of depression; one study showed efficacy in the treatment of mania. Biologically active forms of folate formulations, which do not require biochemical conversion, could be beneficial in the treatment of bipolar disorder. Conclusions: Folate augmentation could be effective for the treatment of bipolar disorder. A common genetic variant of the MTHFR gene might impact the treatment effect of folate augmentation. The biologically active form of folate could potentially correct mood stabilizer-associated functional folate deficiency, help normalize monoamine synthesis, and improve outcomes. C1 [Baek, Ji Hyun; Bernstein, Emily E.; Nierenberg, Andrew A.] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. [Nierenberg, Andrew A.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Nierenberg, AA (reprint author), Massachusetts Gen Hosp, Bipolar Clin & Res Program, 50 Staniford St,Suite 580, Boston, MA 02114 USA. EM anierenberg@partners.org OI Bernstein, Emily/0000-0001-8609-3153 FU Pamlab, LCC (Covington, Louisiana, USA) FX Dr Nierenberg served as a consultant and received a research grant from Pamlab, LCC (Covington, Louisiana, USA). Dr Baek and Ms Bernstein report no relevant funding or support that may represent a conflict of interest on this article. NR 68 TC 6 Z9 6 U1 2 U2 12 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0004-8674 EI 1440-1614 J9 AUST NZ J PSYCHIAT JI Aust. N. Z. J. Psych. PD NOV PY 2013 VL 47 IS 11 BP 1013 EP 1018 DI 10.1177/0004867413502091 PG 6 WC Psychiatry SC Psychiatry GA 246TK UT WOS:000326561800009 PM 23969624 ER PT J AU Ivers, NM Schwalm, JD Jackevicius, CA Guo, H Tu, JV Natarajan, M AF Ivers, Noah M. Schwalm, J. -D. Jackevicius, Cynthia A. Guo, Helen Tu, Jack V. Natarajan, Madhu TI Length of Initial Prescription at Hospital Discharge and Long-term Medication Adherence for Elderly Patients With Coronary Artery Disease: A Population-Level Study SO CANADIAN JOURNAL OF CARDIOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; PRIMARY-CARE; STATIN THERAPY; SECONDARY PREVENTION; ADMINISTRATIVE DATA; AFTER-DISCHARGE; ASSOCIATION; DISCONTINUATION; PHYSICIANS; MORTALITY AB Background: Patient adherence to cardiac secondary prevention medications declines over time. We examined whether the length of the initial prescription at hospital discharge after coronary angiography would be associated with long-term adherence. Methods: We conducted a population-level cohort study to examine adherence to cardiac medications for 18 months after coronary angiography in elderly patients with coronary artery disease (CAD). We identified patients with clinical indications for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACE-I/ARB), beta-blockers (BB), and/or statins. In each medication class cohort, we defined high adherence as proportion of days covered (PDC) > 80%. The length of the initial prescription was defined as 0-30 days, 31-60 days, and more than 60 days. We controlled for patient sociodemographic factors, previous adherence, and comorbidities. Results: The ACE-I/ARB cohort included 13,305 patients, the BB cohort included 5,792 patients, and the statin cohort included 16,134 patients. Using < 30 days as the reference, initial prescriptions covering at least 60 days were more likely to result in high long-term adherence for ACE-I/ARB (adjusted odds ratio [aOR], 4.1; 95% confidence interval [CI], 3.6-4.7); BB (aOR, 2.4; 95% CI, 1.9-3.1), and statins (aOR, 3.0; 95% CI, 2.6-3.4). More than 80% of patients had outpatient follow-up with a primary care provider within 30 days, and this did not vary based on length of initial prescription. Conclusions: Giving patients longer prescriptions for cardiac secondary prevention medications at hospital discharge seems to increase the likelihood of high long-term adherence in elderly patients. C1 [Ivers, Noah M.] Womens Coll Hosp, Family Practice Hlth Ctr, Toronto, ON M5S1B3, Canada. [Ivers, Noah M.] Univ Toronto, Dept Family & Community Med, Toronto, ON M5S 1A1, Canada. [Schwalm, J. -D.; Natarajan, Madhu] Hamilton Gen Hosp, Heart Invest Unit, Hamilton, ON, Canada. [Schwalm, J. -D.; Natarajan, Madhu] McMaster Univ, Populat Hlth Res Unit, Hamilton, ON, Canada. [Jackevicius, Cynthia A.] Western Univ Hlth Sci, Coll Pharm, Pomona, CA USA. [Jackevicius, Cynthia A.] Vet Affairs Greater Los Angeles Hlth Care Syst, Dept Pharm, Los Angeles, CA USA. [Jackevicius, Cynthia A.] Univ Hlth Network, Dept Pharm, Toronto, ON, Canada. [Jackevicius, Cynthia A.] Univ Toronto, Inst Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Jackevicius, Cynthia A.; Guo, Helen; Tu, Jack V.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Tu, Jack V.] Univ Toronto, Sunnybrook Schulich Heart Ctr, Toronto, ON, Canada. [Natarajan, Madhu] Cardiac Care Network Ontario, Toronto, ON, Canada. RP Ivers, NM (reprint author), Womens Coll Hosp, Dept Family & Community Med, 77 Grenville St, Toronto, ON M5S1B3, Canada. EM noah.ivers@utoronto.ca FU Canadian Institutes for Health Research (CIHR); Department of Family and Community Medicine, University of Toronto; McMaster University; Canada Research Chair in Health Services Research; HSFO; Cardiac Care Network of Ontario (CCN); CIHR; Ontario Ministry of Health and Long-Term Care (MOHLTC) FX Dr Ivers is supported by Fellowship awards from the Canadian Institutes for Health Research (CIHR) and the Department of Family and Community Medicine, University of Toronto. Dr Schwalm is supported by a New Investigator award from McMaster University. Dr Tu is supported by a Canada Research Chair in Health Services Research and a Career Investigator Award from the HSFO.; This study was funded by the Cardiac Care Network of Ontario (CCN) and CIHR. Institute for Clinical Evaluative Sciences (ICES) and CCN are funded by the Ontario Ministry of Health and Long-Term Care (MOHLTC). CCN serves as system support to the MOHLTC, Local Health Integration Networks, and service providers and is dedicated to improving quality, efficiency, access, and equity in the delivery of the continuum of adult cardiac services in Ontario. The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by CCN, ICES, or the Ontario MOHLTC is intended or should be inferred. NR 40 TC 8 Z9 8 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0828-282X EI 1916-7075 J9 CAN J CARDIOL JI Can. J. Cardiol. PD NOV PY 2013 VL 29 IS 11 BP 1408 EP 1414 DI 10.1016/j.cjca.2013.04.009 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 242VG UT WOS:000326270800012 PM 23816280 ER PT J AU Mroz, P Vatansever, F Muchowicz, A Hamblin, MR AF Mroz, Pawel Vatansever, Fatma Muchowicz, Angelika Hamblin, Michael R. TI Photodynamic Therapy of Murine Mastocytoma Induces Specific Immune Responses against the Cancer/Testis Antigen P1A SO CANCER RESEARCH LA English DT Article ID CYTOLYTIC T-LYMPHOCYTES; TUMOR-INFILTRATING LYMPHOCYTES; MOUSE GENE P1A; SOLID TUMORS; COMPLEMENT ACTIVATION; HLA-A2 MELANOMAS; CANCER; INDUCTION; CELLS; REJECTION AB Photodynamic therapy (PDT) involves the intravenous administration of photosensitizers followed by illumination of the tumor with visible light, leading to local production of reactive oxygen species that cause vascular shutdown and tumor cell death. Antitumor immunity is stimulated after PDT because of the acute inflammatory response that involves activation of the innate immune system, leading to stimulation of adaptive immunity. We carried out PDT using benzoporphyrin derivative and 690-nm light after 15 minutes, in DBA/2 mice bearing either the mastocytoma, P815, which expresses the naturally occurring cancer/testis antigen P1A, or the corresponding tumor P1.204 that lacks P1A expression. Tumor cures, significantly higher survival, and rejection of tumor rechallenge were obtained with P815, which were not seen with P1.204 or seen with P815 growing in nude mice. Both CD4 and CD8 T cells had higher levels of intracellular cytokines when isolated from mice receiving PDT of P815 tumors than P1.204 tumors and CD8 T cells from P815-cured mice recognized the peptide epitope of the P1A antigen (LPYLGWLVF) using pentamer staining. Taken together, these findings show that PDT can induce a potent antigen- and epitope-specific immune response against a naturally occurring mouse tumor antigen. (C)2013 AACR. C1 [Mroz, Pawel; Vatansever, Fatma; Muchowicz, Angelika; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Mroz, Pawel; Vatansever, Fatma; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Muchowicz, Angelika] Med Univ Warsaw, Dept Immunol, Warsaw, Poland. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, BAR414,40 Blossom St, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu OI Hamblin, Michael/0000-0001-6431-4605 FU U.S. NIH [RO1CA/AI838801, R01AI050875]; Genzyme-Partners Translational Research Grant; NIH Dermatology Training Grant; Foundation for Polish Science; International Union Against Cancer; European Structural Fund "Mazowieckie Stypendium Doktoranckie" FX The study was supported by the U.S. NIH (grants RO1CA/AI838801 and R01AI050875; M.R. Hamblin). P. Mroz was partly supported by Genzyme-Partners Translational Research Grant and NIH Dermatology Training Grant. A. Muchowicz was supported by the Foundation for Polish Science, International Union Against Cancer, and European Structural Fund "Mazowieckie Stypendium Doktoranckie". NR 51 TC 14 Z9 14 U1 1 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD NOV 1 PY 2013 VL 73 IS 21 BP 6462 EP 6470 DI 10.1158/0008-5472.CAN-11-2572 PG 9 WC Oncology SC Oncology GA 247AN UT WOS:000326585100010 PM 24072749 ER PT J AU Ogiwara, H Ui, A Shiotani, B Zou, L Yasui, A Kohno, T AF Ogiwara, Hideaki Ui, Ayako Shiotani, Bunsyo Zou, Lee Yasui, Akira Kohno, Takashi TI Curcumin suppresses multiple DNA damage response pathways and has potency as a sensitizer to PARP inhibitor SO CARCINOGENESIS LA English DT Article ID STRAND BREAK REPAIR; REPLICATION PROTEIN-A; ADP-RIBOSE POLYMERASE; HOMOLOGOUS RECOMBINATION REPAIR; CELL-CYCLE; POLY(ADP-RIBOSE) POLYMERASE; CANCER-CELLS; MITOTIC CATASTROPHE; OVARIAN-CANCER; RAD51 GENE AB Inhibitors of poly(ADP-ribose) polymerase (PARP) are promising anticancer drugs, particularly for the treatment of tumors deficient in the DNA damage response (DDR). However, it is challenging to design effective therapeutic strategies for use of these compounds against cancers without DDR deficiencies. In this context, combination therapies in which PARP inhibitors are used alongside DDR inhibitors have elicited a great deal of interest. Curcumin, a component of turmeric (Curcuma longa), has been tested in clinical studies for its chemosensitizing potential; however, the mechanisms of chemosensitization by curcumin have not been fully elucidated. This study demonstrates that curcumin suppresses three major DDR pathways: non-homologous end joining (NHEJ), homologous recombination (HR) and the DNA damage checkpoint. Curcumin suppresses the histone acetylation at DNA double-strand break (DSB) sites by inhibiting histone acetyltransferase activity, thereby reducing recruitment of the key NHEJ factor KU70/KU80 to DSB sites. Curcumin also suppresses HR by reducing expression of the BRCA1 gene, which regulates HR, by impairing histone acetylation at the BRCA1 promoter. Curcumin also inhibits ataxia telangiectasia and Rad3-related protein (ATR) kinase (IC50 in vitro 493nM), resulting in impaired activation of ATR-CHK1 signaling, which is necessary for HR and the DNA damage checkpoint pathway. Thus, curcumin suppresses three DDR pathways by inhibiting histone acetyltransferases and ATR. Concordantly, curcumin sensitizes cancer cells to PARP inhibitors by enhancing apoptosis and mitotic catastrophe via inhibition of both the DNA damage checkpoint and DSB repair. Our results indicate that curcumin is a promising sensitizer for PARP inhibitor-based therapy. C1 [Ogiwara, Hideaki; Kohno, Takashi] Natl Canc Ctr, Res Inst, Div Genome Biol, Tokyo 1040045, Japan. [Ui, Ayako; Yasui, Akira] Tohoku Univ, Div Dynam Proteome Aging & Canc, Inst Dev, Dept Mol Genet, Sendai, Miyagi 9808575, Japan. [Shiotani, Bunsyo; Zou, Lee] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP Kohno, T (reprint author), Natl Canc Ctr, Res Inst, Div Genome Biol, Chuo Ku, 5-1-1 Tsukiji, Tokyo 1040045, Japan. EM tkkohno@ncc.go.jp FU Ministry of Education, Culture, Sports, Science, and Technology of Japan [22131006]; Japan Society for the Promotion of Science [23701110]; Institute of Development, Aging, and Cancer of Tohoku University FX Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan for Scientific Research on Innovative Areas (22131006); Grant-in-Aid from the Japan Society for the Promotion of Science for Young Scientists (B) KAKENHI (23701110); Management Expenses Grants from the Government to the National Cancer Center; Cooperative Research Project Program of the Institute of Development, Aging, and Cancer of Tohoku University. NR 67 TC 16 Z9 16 U1 1 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD NOV PY 2013 VL 34 IS 11 BP 2486 EP 2497 DI 10.1093/carcin/bgt240 PG 12 WC Oncology SC Oncology GA 247WV UT WOS:000326655200006 PM 23825154 ER PT J AU Cohen, E Spiegel, B AF Cohen, Erica Spiegel, Brennan TI Limited Evidence for the Existence of Postdiverticulitis Irritable Bowel Syndrome Reply SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Letter ID DIVERTICULAR-DISEASE C1 [Cohen, Erica; Spiegel, Brennan] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. RP Cohen, E (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. NR 5 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD NOV PY 2013 VL 11 IS 11 BP 1521 EP 1522 DI 10.1016/j.cgh.2013.08.005 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 235YS UT WOS:000325759900030 PM 23954651 ER PT J AU Magill, SS Klompas, M Balk, R Burns, SM Deutschman, CS Diekema, D Fridkin, S Greene, L Guh, A Gutterman, D Hammer, B Henderson, D Hess, D Hill, NS Horan, T Kollef, M Levy, M Septimus, E VanAntwerpen, C Wright, D Lipsett, P AF Magill, Shelley S. Klompas, Michael Balk, Robert Burns, Suzanne M. Deutschman, Clifford S. Diekema, Daniel Fridkin, Scott Greene, Linda Guh, Alice Gutterman, David Hammer, Beth Henderson, David Hess, Dean Hill, Nicholas S. Horan, Teresa Kollef, Marin Levy, Mitchell Septimus, Edward VanAntwerpen, Carole Wright, Don Lipsett, Pamela TI Developing a New, National Approach to Surveillance for Ventilator-Associated Events SO CRITICAL CARE MEDICINE LA English DT Article DE ventilator-associated pneumonia; intensive care unit; epidemiology; public health; critical care; mechanical ventilation ID DIAGNOSTIC-TECHNIQUES; RANDOMIZED-TRIAL; PNEUMONIA RATES; INFECTIONS; VALIDATION; CRITERIA; DEFINITIONS AB Objective: To develop and implement an objective, reliable approach to surveillance for ventilator-associated events in adult patients. Design: The Centers for Disease Control and Prevention (CDC) convened a Ventilator-Associated Pneumonia (VAP) Surveillance Definition Working Group in September 2011. Working Group members included representatives of stakeholder societies and organizations and federal partners. Main results: The Working Group finalized a three-tier, adult surveillance definition algorithm for ventilator-associated events. The algorithm uses objective, readily available data elements and can identify a broad range of conditions and complications occurring in mechanically ventilated adult patients, including but not limited to VAP. The first tier definition, ventilator-associated condition (VAC), identifies patients with a period of sustained respiratory deterioration following a sustained period of stability or improvement on the ventilator, defined by changes in the daily minimum fraction of inspired oxygen or positive end-expiratory pressure. The second tier definition, infection-related ventilator-associated complication (IVAC), requires that patients with VAC also have an abnormal temperature or white blood cell count, and be started on a new antimicrobial agent. The third tier definitions, possible and probable VAP, require that patients with IVAC also have laboratory and/or microbiological evidence of respiratory infection. Conclusions: Ventilator-associated events surveillance was implemented in January 2013 in the CDC's National Healthcare Safety Network. Modifications to improve surveillance may be made as additional data become available and users gain experience with the new definitions. C1 [Magill, Shelley S.; Fridkin, Scott; Guh, Alice; Horan, Teresa] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA 30333 USA. [Klompas, Michael] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Klompas, Michael] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Klompas, Michael] Brigham & Womens Hosp, Infect Control Dept, Boston, MA 02115 USA. [Klompas, Michael] Soc Healthcare Epidemiol Amer, Arlington, VA USA. [Balk, Robert] Rush Univ, Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60612 USA. [Balk, Robert; Burns, Suzanne M.; Deutschman, Clifford S.; Gutterman, David; Hammer, Beth; Hill, Nicholas S.; Kollef, Marin; Levy, Mitchell; Lipsett, Pamela] Amer Thorac Soc, Amer Coll Chest Phys, Soc Crit Care Med, Crit Care Soc Collaborat Amer Assoc Crit Care Nur, New York, NY USA. [Burns, Suzanne M.] Univ Virginia, Sch Nursing Crit & Acute Care, Charlottesville, VA USA. [Deutschman, Clifford S.] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Diekema, Daniel] Univ Iowa, Carver Coll Med, Div Infect Dis, Iowa City, IA USA. [Diekema, Daniel] Healthcare Infect Control Practices Advisory Comm, Atlanta, GA USA. [Greene, Linda] Rochester Gen Hlth Syst, Infect Prevent & Control Dept, Rochester, NY USA. [Greene, Linda] Assoc Profess Infect Control & Epidemi, Washington, DC USA. [Gutterman, David] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Hammer, Beth] Med Coll Wisconsin, Zablocki Vet Adm Med Ctr, Dept Cardiol, Milwaukee, WI 53226 USA. [Henderson, David] NIH, Hosp Epidemiol & Qual Improvement, Ctr Clin, Bethesda, MD 20892 USA. [Hess, Dean] Massachusetts Gen Hosp, Dept Res Care, Boston, MA 02114 USA. [Hess, Dean] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Hess, Dean] Amer Assoc Resp Care, Irving, TX USA. [Hill, Nicholas S.] Tufts Med Ctr, Div Pulm & Crit Care Med, Boston, MA USA. [Kollef, Marin] Washington Univ, Div Pulm & Crit Care Med, St Louis, MO USA. [Levy, Mitchell] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Divis Pulm Crit Care & Sleep, Providence, RI 02903 USA. [Septimus, Edward] Texas A&M Univ, Ctr Sci, Dept Internal Med, College Stn, TX USA. [Septimus, Edward] Infect Dis Soc Amer, Arlington, VA USA. [VanAntwerpen, Carole] New York State Dept Hlth, Bur Healthcare Associated Infect, Albany, NY USA. [VanAntwerpen, Carole] Council State & Terr Epidemiologists, Atlanta, GA USA. [Wright, Don] US Dept HHS, Off Dis Prevent & Hlth Promot, Washington, DC 20201 USA. [Lipsett, Pamela] Johns Hopkins Univ, Sch Med, Dept Surg Anesthesiol & Crit Care Med, Baltimore, MD USA. RP Magill, SS (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA 30333 USA. EM smagill@cdc.gov OI Diekema, Daniel/0000-0003-1273-0724 FU Centers for Disease Control and Prevention (CDC); Centers for Disease Control (CDC); U.S. Food and Drug Administration; Office of the National Co-ordinator for Health IT; CDC; bioMerieux; National Institute of General Medical Sciences; Merck; Cerexa; bioMeriuex; PurThread Technologies; Pfizer; Society of Critical Care Medicine FX The work described herein was supported by the Centers for Disease Control and Prevention (CDC).; Dr. Klompas received grant support from the Centers for Disease Control (CDC), U.S. Food and Drug Administration, and the Office of the National Co-ordinator for Health IT. Dr. Balk received grant support from the CDC and bioMerieux for participation in the EPIC CAP study (CDC) and the Procalcitonin in ICU antibiotic stewardship study (CDC and bioMerieux). Dr. Deutschman received grant support from the National Institute of General Medical Sciences. Dr. Diekema received grant support from Merck, Cerexa, bioMeriuex, PurThread Technologies, and Pfizer.; Ms. Greene is employed by the Rochester General Hospital. Dr. Lipsett has board membership with the Society of Critical Care Medicine. Dr. Deutschman received a stipend for his Presidency with the Society of Critical Care Medicine. NR 37 TC 71 Z9 71 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD NOV PY 2013 VL 41 IS 11 BP 2467 EP 2475 DI 10.1097/CCM.0b013e3182a262db PG 9 WC Critical Care Medicine SC General & Internal Medicine GA 243BO UT WOS:000326291600032 PM 24162674 ER PT J AU Baron, DM Beloiartsev, A Nakagawa, A Martyn, T Stowell, CP Malhotra, R Mayeur, C Bloch, KD Zapol, WM AF Baron, David M. Beloiartsev, Arkadi Nakagawa, Akito Martyn, Trejeeve Stowell, Christopher P. Malhotra, Rajeev Mayeur, Claire Bloch, Kenneth D. Zapol, Warren M. TI Adverse Effects of Hemorrhagic Shock Resuscitation With Stored Blood Are Ameliorated by Inhaled Nitric Oxide in Lambs SO CRITICAL CARE MEDICINE LA English DT Article DE blood transfusion; hemorrhagic shock; inflammation; nitric oxide; pulmonary hypertension; resuscitation ID ACUTE LUNG INJURY; ISCHEMIA-REPERFUSION INJURY; CELL-FREE HEMOGLOBIN; ENDOTHELIAL DYSFUNCTION; TRAUMA PATIENTS; PULMONARY-HYPERTENSION; PLATELET ACTIVATION; TRANSFUSED BLOOD; STORAGE LESION; SHEEP AB Objectives: Transfusion of stored RBCs is associated with increased morbidity and mortality in trauma patients. Plasma hemoglobin scavenges nitric oxide, which can cause vasoconstriction, induce inflammation, and activate platelets. We hypothesized that transfusion of RBCs stored for prolonged periods would induce adverse effects (pulmonary vasoconstriction, tissue injury, inflammation, and platelet activation) in lambs subjected to severe hemorrhagic shock and that concurrent inhalation of nitric oxide would prevent these adverse effects. Design: Animal study. Setting: Research laboratory at the Massachusetts General Hospital, Boston, MA. Subjects: Seventeen awake Polypay-breed lambs. Interventions: Lambs were subjected to 2 hours of hemorrhagic shock by acutely withdrawing 50% of their blood volume. Lambs were resuscitated with autologous RBCs stored for 2 hours or less (fresh) or 39 2 (mean sd) days (stored). Stored RBCs were administered with or without breathing nitric oxide (80 ppm) during resuscitation and for 21 hours thereafter. Measurements and Main Results: We measured hemodynamic and oxygenation variables, markers of tissue injury and inflammation, plasma hemoglobin concentrations, and platelet activation. Peak pulmonary arterial pressure was higher after resuscitation with stored than with fresh RBCs (24 +/- 4 vs 14 +/- 2 mm Hg, p < 0.001) and correlated with peak plasma hemoglobin concentrations (R-2 = 0.56, p = 0.003). At 21 hours after resuscitation, pulmonary myeloperoxidase activity was higher in lambs resuscitated with stored than with fresh RBCs (11 +/- 2 vs 4 +/- 1 U/g, p = 0.007). Furthermore, transfusion of stored RBCs increased plasma markers of tissue injury and sensitized platelets to adenosine diphosphate activation. Breathing nitric oxide prevented the pulmonary hypertension and attenuated the pulmonary myeloperoxidase activity, as well as tissue injury and sensitization of platelets to adenosine diphosphate. Conclusions: Our data suggest that resuscitation of lambs from hemorrhagic shock with autologous stored RBCs induces pulmonary hypertension and inflammation, which can be ameliorated by breathing nitric oxide. C1 [Baron, David M.; Beloiartsev, Arkadi; Nakagawa, Akito; Martyn, Trejeeve; Mayeur, Claire; Bloch, Kenneth D.; Zapol, Warren M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Baron, David M.] Med Univ Vienna, Dept Anesthesia Gen Intens Care & Pain Management, Vienna, Austria. [Stowell, Christopher P.] Massachusetts Gen Hosp, Dept Pathol, Blood Transfus Serv, Boston, MA 02114 USA. [Stowell, Christopher P.; Malhotra, Rajeev] Harvard Univ, Sch Med, Boston, MA USA. [Malhotra, Rajeev] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Zapol, WM (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. EM wzapol@partners.org OI Malhotra, Rajeev/0000-0003-0120-4630 FU Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA; American Heart Association (Dallas, TX) [11FTF7290032]; National Institutes of Health (NIHLBI); National Institute of Health (Bethesda, MD) [HL074352]; Ikaria, Clinton, NJ; NIHLBI FX Supported, in part, by the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA.; Dr. Malhotra and his institution were supported by the Fellow-to-Faculty Transition Award 11FTF7290032 from the American Heart Association (Dallas, TX) and the National Institutes of Health (NIHLBI). Dr. Bloch was supported by the National Institute of Health R01 grant HL074352 (Bethesda, MD) and has received grants from Ikaria, Clinton, NJ, to study inhaled nitric oxide. Dr. Stowell consulted for Haemonetics. Dr. Stowell and his institution received grant support from NIHLBI. He also received travel reimbursement from the Australian New Zealand Society of Hematology. Dr. Zapol and his institution receive royalties from patents on inhaled nitric oxide licensed by Massachusetts General Hospital to Linde Corporation, Munich, Germany, and Ikaria, and he has applied for a U.S. patent entitled, "Attenuation of artificial oxygen carrier-induced vasoconstriction," Provisional Patent Application 60/864,734. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 47 TC 14 Z9 14 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD NOV PY 2013 VL 41 IS 11 BP 2492 EP 2501 DI 10.1097/CCM.0b013e31828cf456 PG 10 WC Critical Care Medicine SC General & Internal Medicine GA 243BO UT WOS:000326291600035 PM 23887236 ER PT J AU Bajwa, EK Volk, JA Christiani, DC Harris, RS Matthay, MA Thompson, BT Januzzi, JL AF Bajwa, Ednan K. Volk, Jessica A. Christiani, David C. Harris, R. Scott Matthay, Michael A. Thompson, B. Taylor Januzzi, James L. CA Natl Heart Lung & Blood Inst Acute TI Prognostic and Diagnostic Value of Plasma Soluble Suppression of Tumorigenicity-2 Concentrations in Acute Respiratory Distress Syndrome SO CRITICAL CARE MEDICINE LA English DT Article DE acute respiratory distress syndrome; biomarkers; fluid therapy ID ACUTE LUNG INJURY; ACUTE KIDNEY INJURY; ST2 PROTEIN; NATRIURETIC PEPTIDE; HEART-FAILURE; MYOCARDIAL-INFARCTION; ACUTE EXACERBATION; CRITICALLY-ILL; CYTOKINE; OUTCOMES AB Objectives: Soluble suppression of tumorigenicity-2 is a biomarker of myocardial strain and inflammation. The characteristics of acute respiratory distress syndrome include inflammation and cardiovascular dysfunction. We sought to determine whether plasma soluble suppression of tumorigenicity-2 concentration is associated with outcome and response to conservative fluid management and whether soluble suppression of tumorigenicity-2 concentration discriminates acute respiratory distress syndrome from decompensated heart failure. Design: A retrospective analysis of the Fluid and Catheter Treatment Trial, a multi-center randomized controlled trial of conservative fluid management in the acute respiratory distress syndrome, as well as of a cohort of patients with decompensated heart failure. Setting: Twenty acute care hospitals. Patients: Eight hundred twenty-six patients with acute respiratory distress syndrome and 209 patients with acutely decompensated heart failure. Measurements and Main Results: Nonsurvivors had higher day 0 (p < 0.0001) and day 3 (p < 0.0001) soluble suppression of tumorigenicity-2 concentrations. After adjustment for severity of illness, higher soluble suppression of tumorigenicity-2 concentration was associated with mortality, with odds ratio(adj) 1.47 (95% CI, 0.99-2.20; p = 0.06) at day 0, 2.94 (95% CI, 2.00-4.33; p < 0.0001) at day 3, and 3.63 (95% CI, 2.38-5.53; p < 0.0001) if soluble suppression of tumorigenicity-2 increased between days. Cumulative fluid balance was more positive among patients with higher day 0 (median, 5,212 mL [interquartile range, 200-12,284 mL] vs median, 2,020 mL [interquartile range, -2,034 to 7,091 mL]; p < 0.0001) and day 3 soluble suppression of tumorigenicity-2 (median, 7,678 mL [interquartile range, 2,217-14,278 mL] vs median, 1,492 mL [interquartile range, -2,384 to 6,239 mL]; p < 0.0001). Soluble suppression of tumorigenicity-2 showed excellent discriminative ability between the Fluid and Catheter Treatment Trial and heart failure populations (area under receiver-operating characteristic curve = 0.98; p < 0.0001). Conclusions: Higher soluble suppression of tumorigenicity-2 concentrations are associated with worse outcome in acute respiratory distress syndrome and may have value for discriminating acute respiratory distress syndrome from heart failure. C1 [Bajwa, Ednan K.; Harris, R. Scott; Thompson, B. Taylor] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Volk, Jessica A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Matthay, Michael A.] Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA 94143 USA. [Januzzi, James L.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Bajwa, EK (reprint author), Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. EM ebajwa@partners.org FU National Heart, Lung and Blood Institute (NHLBI) [HL60710, HL67197, HL084060, HL086667]; NHLBI [NO1-HR 46046-64, NO1-HR-16146-54]; American Physician Institute; NIH; NIHLBI; Critical Diagnostics FX Supported, in part, by grants HL60710, HL67197, HL084060, and HL086667 from National Heart, Lung and Blood Institute (NHLBI). Soluble ST2 assays were donated by Critical Diagnostics. The Fluid and Catheter Treatment Trial study was supported, in part, by contracts (NO1-HR 46046-64 and NO1-HR-16146-54) with the NHLBI.; Dr. Harris is a board member at Altor Biosciences, has given expert testimony for MedQuest, received payment for the development of educational presentations from the American Physician Institute, and received grant support from NIH. Dr. Matthay has consulted for GSK, Biogen, and Roche Genentech; received grant support from NIHLBI, and received support for article research from NIH. Dr. Januzzi is a board member and has consulted for and received grant support from Critical Diagnostics. Dr. Thompson received grant support from NIHLBI. Dr. Bajwa received grant support from NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 33 TC 11 Z9 11 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD NOV PY 2013 VL 41 IS 11 BP 2521 EP 2531 DI 10.1097/CCM.0b013e3182978f91 PG 11 WC Critical Care Medicine SC General & Internal Medicine GA 243BO UT WOS:000326291600038 PM 23939353 ER PT J AU Begun, J Xavier, RJ AF Begun, Jakob Xavier, Ramnik J. TI Autophagy at the crossroads of metabolism and cellular defense SO CURRENT OPINION IN GASTROENTEROLOGY LA English DT Review DE autophagy; bacteria; inflammatory bowel disease; metabolism; mTOR ID INFLAMMATORY-BOWEL-DISEASE; CROHNS-DISEASE; VACUOLATING CYTOTOXIN; IMPAIRED AUTOPHAGY; LIPID-METABOLISM; MTOR INHIBITOR; GENE ATG16L1; RAG GTPASES; AMINO-ACIDS; ER STRESS AB Purpose of reviewFrom its initial description as a homeostatic process required for starvation response, autophagy has emerged as a ubiquitous cellular process involved in a broad range of cellular activities from metabolic adaptation to cellular defense against invading pathogens. This review provides an overview of autophagy and highlights the recent developments in deciphering its role in metabolic adaptation and its importance in antibacterial defense with attention to regulatory pathways.Recent findingsWithin the last 2 years, there has been significant progress in deciphering the mechanisms by which autophagy is regulated, including subcellular localization, posttranslational modifications, and transcriptional control. In addition, the cell type-specific role of autophagy in maintaining cellular homeostasis has been defined, including its role in handling intracellular pathogens and its contribution to inflammatory bowel disease.SummaryAutophagy is a critical pathway that integrates numerous regulatory inputs to maintain cellular homeostasis and defend against intracellular pathogens. C1 [Begun, Jakob; Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Ctr Study Inflammatory Bowel Dis, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Broad Inst Harvard Univ & Massachusetts Inst Tech, Cambridge, MA USA. RP Begun, J (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Ctr Study Inflammatory Bowel Dis, Richard B Simches Res Ctr, 185 Cambridge St, Boston, MA 02114 USA. EM xavier@molbio.mgh.harvard.edu RI Begun, Jakob/J-6793-2014 OI Begun, Jakob/0000-0001-5256-7672 FU Crohn's and Colitis Foundation of America; Leona M. and Harry B. Helmsley Charitable Trust; NIH [DK043351, DK097485] FX This work was supported by funding from the Crohn's and Colitis Foundation of America, the Leona M. and Harry B. Helmsley Charitable Trust, and NIH grants DK043351 and DK097485 (to R.J.X.). J.B. is supported by funding from the Crohn's and Colitis Foundation of America. NR 77 TC 6 Z9 6 U1 1 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0267-1379 EI 1531-7056 J9 CURR OPIN GASTROEN JI Curr. Opin. Gastroenterol. PD NOV PY 2013 VL 29 IS 6 BP 588 EP 596 DI 10.1097/MOG.0b013e328365d34d PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 247AH UT WOS:000326583900002 PM 24100719 ER PT J AU Devkota, S Chang, EB AF Devkota, Suzanne Chang, Eugene B. TI Nutrition, microbiomes, and intestinal inflammation SO CURRENT OPINION IN GASTROENTEROLOGY LA English DT Review DE diet; inflammation; microbiome; nutrition; pathobiont ID GUT MICROBIOTA; METABOLISM; DIET; PATHOBIONT AB Purpose of reviewTo present and evaluate the recent findings that contribute to our understanding of the functional impact of diet on the enteric microbiome and outcomes of disease.Recent findingsNutrients in excess and in deficiency have significant impact on gut microbial communities in both rodents and humans, acting directly on the microbiota or indirectly via altering host physiology. Furthermore, the effects of diet on the microbiome in determining health or disease can differ substantially depending on the age and environment of the individual.SummaryDietary compounds can have profound short-term and long-term effects on the assemblage of the gut microbiome, which in turn affects the host-microbe interactions critically important for intestinal, metabolic, and immune homeostasis. Until recently, the mechanisms underlying these effects were poorly understood. However, new insights have now been gained, made possible through the application of advanced technologies and bioinformatics, novel experimental models, and human research. As a result, our conceptual framework for understanding the impact of diet on the gut microbiome, health, and disease has advanced considerably, bringing the promise of better tools of risk assessment, diagnostics, and therapeutic intervention in an age of personalized medicine. C1 [Devkota, Suzanne] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Chang, Eugene B.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. RP Devkota, S (reprint author), Univ Chicago, 900 East 57th St, Chicago, IL 60637 USA. EM echang@medicine.bsd.uchicago.edu FU National Institutes of Health FX Funding sources: This study was funded by the National Institutes of Health. NR 14 TC 16 Z9 17 U1 2 U2 53 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0267-1379 EI 1531-7056 J9 CURR OPIN GASTROEN JI Curr. Opin. Gastroenterol. PD NOV PY 2013 VL 29 IS 6 BP 603 EP 607 DI 10.1097/MOG.0b013e328365d38f PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 247AH UT WOS:000326583900004 PM 24100722 ER PT J AU Kemmerly, T Kaunitz, JD AF Kemmerly, Thomas Kaunitz, Jonathan D. TI Gastroduodenal mucosal defense SO CURRENT OPINION IN GASTROENTEROLOGY LA English DT Review DE apoptosis; gastrointestinal defense; Helicobacter pylori; mucins; oxidative stress ID INDUCED GASTRIC-ULCER; HELICOBACTER-PYLORI; CYCLOOXYGENASE INHIBITORS; ANTIINFLAMMATORY DRUGS; OXIDATIVE STRESS; RATS; INDOMETHACIN; DAMAGE; CYSTEAMINE; EXPRESSION AB Purpose of reviewTo review recent developments in the field of gastroduodenal mucosal defense.Recent findingsResearch in the field of gastroduodenal mucosal defense has focused on continued elucidation of molecular mechanisms that protect the mucosa and influence healing at the cellular level. Review of literature over the past year reveals focus on familiar processes such as superoxide dismutase, nitric oxide, heme oxygenase-1, neutrophil infiltration, cysteamine, mucin, hydrogen sulfide, ghrelin, adiponectin and the influence of Helicobacter pylori, but also brings into light new processes such as the balance between apoptosis and cellular proliferation, as well as the influence of other organ systems such as the bone marrow and central nervous system on the gastrointestinal tract.SummaryThese new published findings contribute to our overall understanding of gastroduodenal defense and suggest innovative avenues of future research and possible novel therapeutic targets. C1 [Kemmerly, Thomas] Cedars Sinai Med Residency Program, Los Angeles, CA USA. [Kaunitz, Jonathan D.] Greater Angeles Veteran Affairs Healthcare Syst, WLAVA Med Ctr, Los Angeles, CA USA. [Kaunitz, Jonathan D.] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Kaunitz, Jonathan D.] Univ Calif Los Angeles, Sch Med, Dept Surg, Los Angeles, CA 90024 USA. [Kaunitz, Jonathan D.] CURE, Digest Dis Res Ctr, Dept Med, Los Angeles, CA USA. [Kaunitz, Jonathan D.] Brentwood Biomed Res Inst, Los Angeles, CA USA. RP Kaunitz, JD (reprint author), W Los Angeles Vet Affairs Med Ctr, Bldg 114,Room 217E, Los Angeles, CA 90073 USA. EM jake@ucla.edu FU BLRD VA [I01 BX001245] NR 33 TC 6 Z9 9 U1 0 U2 22 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0267-1379 EI 1531-7056 J9 CURR OPIN GASTROEN JI Curr. Opin. Gastroenterol. PD NOV PY 2013 VL 29 IS 6 BP 642 EP 649 DI 10.1097/MOG.0b013e328365d42e PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 247AH UT WOS:000326583900011 PM 24100725 ER PT J AU Abraham, NS Castillo, DL AF Abraham, Neena S. Castillo, Diana L. TI Novel anticoagulants: bleeding risk and management strategies SO CURRENT OPINION IN GASTROENTEROLOGY LA English DT Review DE acute gastrointestinal hemorrhage; apixaban; dabigatran; endoscopy ID ACUTE CORONARY SYNDROME; NONVALVULAR ATRIAL-FIBRILLATION; FACTOR XA INHIBITOR; ORAL ANTICOAGULANTS; ANTIPLATELET THERAPY; NATIONWIDE COHORT; PREDICTING STROKE; TASK-FORCE; DABIGATRAN; APIXABAN AB Purpose of reviewTo quantify the novel oral anticoagulant (NOAC)-related gastrointestinal bleeding, summarize the management strategies and highlight the knowledge gaps.Recent findingsDabigatran, rivaroxaban and apixaban differ from warfarin with their fixed oral dose and no requirement for routine monitoring. Patients at highest risk of thromboembolism benefit most from NOACs; however, there is a clinically significant risk for NOAC-related gastrointestinal bleeding. The management of NOACs in the acute and elective setting differs from that used with warfarin.SummaryThe magnitude of gastrointestinal risk is still unclear because of paucity of literature. Current risk-stratification models are incomplete and cannot be used solely to predict future risk. The periendoscopic management requires an understanding of drug half-life, metabolism and patient's ability to excrete the agent. Acute bleeding management relies on fluid resuscitation to promote renal excretion of active metabolite, withholding the doses and timely management of endoscopic stigmata. The administration of coagulation factors (fresh frozen plasma, prothrombin complex concentrates or recombinant activated FVII) is more successful in reversing the activity of the upstream inhibitors of coagulation (rivaroxaban and apixaban) than dabigatran which is a direct thrombin inhibitor. C1 [Abraham, Neena S.] Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, Scottsdale, AZ 85259 USA. [Castillo, Diana L.] Houston Hlth Serv Res & Dev Ctr Excellence, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. RP Abraham, NS (reprint author), Mayo Clin, 13400 East Shea Blvd, Scottsdale, AZ 85259 USA. EM abraham.neena@mayo.edu NR 27 TC 11 Z9 11 U1 0 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0267-1379 EI 1531-7056 J9 CURR OPIN GASTROEN JI Curr. Opin. Gastroenterol. PD NOV PY 2013 VL 29 IS 6 BP 676 EP 683 DI 10.1097/MOG.0b013e328365d415 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 247AH UT WOS:000326583900015 PM 24100724 ER PT J AU Korman, JB Jalian, HR Avram, MM AF Korman, John B. Jalian, H. Ray Avram, Mathew M. TI Analysis of Botulinum Toxin Products and Litigation in the United States SO DERMATOLOGIC SURGERY LA English DT Article ID COMPLEXING PROTEINS; GLABELLAR LINES; SAFETY; INJECTIONS; EFFICACY AB BackgroundBotulinum neurotoxin (BoNT) has diverse cosmetic and therapeutic applications, spanning multiple medical specialties. Recent lawsuits alleging complications from its clinical use have raised significant questions about medicolegal risk. ObjectiveTo identify and assess legal cases related to clinical complications of BoNT products. Methods and MaterialsUsing the LexisNexis Academic online database, a search of U.S. federal and state cases between 1985 and 2012 was performed. A second search of U.S. newspapers and wires was also completed. In all but one case, the plaintiffs' legal complaints were obtained for review. ResultsTwenty-four relevant legal cases were found, mostly in state courts. All cases alleged adverse effects from onabotulinumtoxinA, and each named its manufacturer, Allergan, Inc., as a defendant. Most lawsuits against Allergan, Inc. were dismissed or settled. In three cases, physicians were codefendants, including one dermatologist. In two cases, jury verdicts resulted in multimillion-dollar judgments in favor of the plaintiffs. None of the lawsuits named a dermatologist when the complication arose from on-label indications and cosmetic use. ConclusionLawsuits related to complications from BoNT products are uncommon, are more likely to result from therapeutic than cosmetic applications, and typically involve product liability claims against the manufacturer. C1 [Korman, John B.; Jalian, H. Ray; Avram, Mathew M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02114 USA. [Jalian, H. Ray; Avram, Mathew M.] Massachusetts Gen Hosp, Dermatol Laser & Cosmet Ctr, Boston, MA 02114 USA. [Jalian, H. Ray; Avram, Mathew M.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Korman, JB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. EM jkorman@partners.org NR 16 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1076-0512 EI 1524-4725 J9 DERMATOL SURG JI Dermatol. Surg. PD NOV PY 2013 VL 39 IS 11 BP 1587 EP 1591 DI 10.1111/dsu.12188 PG 5 WC Dermatology; Surgery SC Dermatology; Surgery GA 246PK UT WOS:000326551400003 PM 23464535 ER PT J AU Sturmer, T Marquis, MA Zhou, HB Meigs, JB Lim, S Blonde, L MacDonald, E Wang, R LaVange, LM Pate, V Buse, JB AF Stuermer, Til Marquis, M. Alison Zhou, Haibo Meigs, James B. Lim, Soo Blonde, Lawrence MacDonald, Eileen Wang, Ray LaVange, Lisa M. Pate, Virginia Buse, John B. TI Cancer Incidence Among Those Initiating Insulin Therapy With Glargine Versus Human NPH Insulin SO DIABETES CARE LA English DT Article ID SHORT-TERM INCIDENCE; POPULATION-BASED OBSERVATION; PROPENSITY SCORES; RISK; MALIGNANCIES; COHORT; DATABASES; ANALOGS; BREAST AB OBJECTIVETo add to the evidence on comparative long-term effects of insulin analog glargine versus human NPH insulin on the risk for cancer.RESEARCH DESIGN AND METHODSWe identified cohorts of initiators of glargine and human NPH without an insulin prescription during the prior 19 months among patients covered by the Inovalon Medical Outcomes Research for Effectiveness and Economics Registry (MORE2 Registry) between January 2003 and December 2010. Patients were required to have a second prescription of the same insulin within 180 days and to be free of cancer. We balanced cohorts on risk factors for cancer outcomes based on comorbidities, comedication, and health care use during the prior 12 months using inverse probability of treatment weighting. Incident cancer was defined as having two claims for cancer (any cancer) or the same cancer (breast, prostate, colon) within 2 months. We estimated adjusted hazard ratios (HRs) and their 95% CI using weighted Cox models censoring for stopping, switching, or augmenting insulin treatment, end of enrollment, and mortality.RESULTSMore patients initiated glargine (43,306) than NPH (9,147). Initiators of glargine (NPH) were followed for 1.2 (1.1) years and 50,548 (10,011) person-years; 993 (178) developed cancer. The overall HR was 1.12 (95% CI 0.95-1.32). Results were consistent for breast cancer, prostate cancer, and colon cancer; various durations of treatment; and sensitivity analyses.CONCLUSIONSPatients initiating insulin glargine rather than NPH do not seem to be at an increased risk for cancer. While our study contributes significantly to our evidence base for long-term effects, this evidence is very limited mainly based on actual dynamics in insulin prescribing. C1 [Stuermer, Til; Pate, Virginia] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Marquis, M. Alison; LaVange, Lisa M.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Zhou, Haibo] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Meigs, James B.; Lim, Soo] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.; Lim, Soo] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Lim, Soo] Seoul Natl Univ, Coll Med, Dept Internal Med, Songnam, South Korea. [Lim, Soo] Seoul Natl Univ, Bundang Hosp, Songnam, South Korea. [Blonde, Lawrence] Ochsner Med Ctr, Dept Endocrinol, New Orleans, LA USA. [MacDonald, Eileen; Wang, Ray] Inovalon Inc, Bowie, MD USA. [Buse, John B.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27515 USA. RP Buse, JB (reprint author), Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27515 USA. EM jbuse@med.unc.edu FU National Center for Research Resources [UL1RR025747]; National Center for Advancing Translational Sciences [UL1TR000083]; Sanofi (Paris, France); Agency for Healthcare Research and Quality; Patient-Centered Outcomes Research Institute; Center for Pharmacoepidemiology; GlaxoSmithKline; Merck; Sanofi; Pfizer; Eli Lilly and Co.; Novo Nordisk; Amgen; Amylin Pharmaceuticals, Inc.; Andromeda; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Catabasis; Cebix; Diartis; Elcelyx; Exsulin; GI Dynamics; Halozyme; Hoffman-La Roche; Johnson Johnson; LipoScience; Medtronic MiniMed; Metabolic Solutions Development Company; Metabolon; Novan; Novo Nordisk Pharmaceuticals; Novartis; Osiris Therapeutics; Orexigen; Takeda; Tolerex; Transition Therapeutics; TransPharma; Veritas; Verva Pharmaceuticals FX Assistance was received from the NC Translational and Clinical Sciences Institute, funded by National Center for Research Resources (UL1RR025747), now the National Center for Advancing Translational Sciences (UL1TR000083). Assistance was also received from the National Institute for Diabetes and Digestive and Kidney Diseases (K24DK080140) (to J.B.M.) and the National Institute on Aging (R01AG023178) (to T.S.).; Funding for this project was provided by Sanofi (Paris, France). Sanofi provided input on the design of the study and reviewed the manuscript prior to submission. T. S. receives research funding as principal investigator of the UNC DEcIDE center from the Agency for Healthcare Research and Quality and from the Patient-Centered Outcomes Research Institute. He does not accept personal compensation of any kind from any pharmaceutical company, though he receives salary support from the Center for Pharmacoepidemiology, currently funded by GlaxoSmithKline, and from unrestricted research grants from pharmaceutical companies (Merck and Sanofi) to the University of North Carolina. M. A. M. previously received salary support from a research grant from Pfizer. Eli Lilly and Co., Novo Nordisk, and Sanofi have provided grant/research support to L.B.'s institution for his role as investigator. L. B. is also a speaker or consultant for the following companies: Amylin Pharmaceuticals, Inc.; Bristol-Myers Squibb/AstraZeneca; Janssen; Merck; Johnson & Johnson Diabetes Institute; Novo Nordisk; Pfizer; Sanofi; and Santarus; and L.B.'s late wife's estate contains Pfizer stock. V. P. receives salary support from investigator-initiated grants from Merck and Amgen. J.B.B. is an investigator or consultant without any direct financial benefit to him under contracts between his employer and the following companies: Amylin Pharmaceuticals, Inc.; Andromeda; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Catabasis; Cebix; Diartis; Elcelyx; Eli Lilly and Co.; Exsulin; GI Dynamics; GlaxoSmithKline; Halozyme; Hoffman-La Roche; Johnson & Johnson; LipoScience; Medtronic MiniMed; Merck; Metabolic Solutions Development Company; Metabolon; Novan; Novo Nordisk Pharmaceuticals; Novartis; Osiris Therapeutics; Orexigen; Pfizer; Sanofi; Takeda; Tolerex; Transition Therapeutics; TransPharma; Veritas; and Verva Pharmaceuticals. L. M. L. participated in this research effort while on the faculty at UNC; she is currently Director of the Office of Biostatistics at the Center for Drug Evaluation and Research, U. S. Food and Drug Administration. No other potential conflicts of interest relevant to this article were reported. NR 34 TC 9 Z9 10 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD NOV PY 2013 VL 36 IS 11 BP 3517 EP 3525 DI 10.2337/dc13-0263 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 242VZ UT WOS:000326274100029 PM 23877991 ER PT J AU Esposito, E Mandeville, ET Hayakawa, K Singhal, AB Lo, EH AF Esposito, Elga Mandeville, Emiri T. Hayakawa, Kazuhide Singhal, Aneesh B. Lo, Eng H. TI Effects of normobaric oxygen on the progression of focal cerebral ischemia in rats SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Normobaric oxygen therapy; Stroke; Neuroprotection ID BLOOD-FLOW; GLIAL SCAR; STROKE; HYPEROXIA; BRAIN; THERAPY; MODEL; NEUROPROTECTION; REGENERATION; REPERFUSION AB Normobaric oxygen (NBO) reduces infarction at 24-48 h in experimental models of focal cerebral ischemia. However, to be clinically relevant, longer term safety and efficacy must be explored. Here, we assessed the effects of NBO on glial activation, neurovascular recovery, and behavioral outcomes at 2 weeks after transient focal ischemia in rats. 100 min transient focal ischemia was induced by intraluminal occlusion of the middle cerebral artery in adult male Sprague-Dawley rats. Animals were randomized into sham, controls or 85'NBO started 15 min after ischemic onset. Infarct volumes and behavioral outcomes were blindly quantified. Immunohistochemistry was used to examine the effects of NBO on glial activation and neurovascular responses. After 2 weeks of reperfusion the infarct volume was marked reduced in animals subjected to NBO. They also had better outcomes in forelimb placement test and in body-swing test and weight loss reduction. After 14 days, NBO decreased expression of Iba1, a marker of activated microglia, and GFAP, a marker of activated astrocytes. NBO treatment had no detectable effect on angiogenesis. These results suggest that protective effects of NBO may persist for up to 2 weeks post-stroke. (C) 2013 Elsevier Inc. All rights reserved. C1 [Esposito, Elga] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Esposito, E (reprint author), Otfried Muller Str 27, D-72076 Tubingen, Germany. EM elga.esposito@gmail.com; asinghal@partners.org FU National Institutes of Health FX This work was supported in part by grants from the National Institutes of Health. NR 28 TC 14 Z9 14 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 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD NOV PY 2013 VL 249 BP 33 EP 38 DI 10.1016/j.expneurol.2013.08.005 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 240ZE UT WOS:000326135400004 PM 23958492 ER PT J AU Imudia, AN Wang, N Tanaka, Y White, YAR Woods, DC Tilly, JL AF Imudia, Anthony N. Wang, Ning Tanaka, Yoshihiro White, Yvonne A. R. Woods, Dori C. Tilly, Jonathan L. TI Comparative gene expression profiling of adult mouse ovary-derived oogonial stem cells supports a distinct cellular identity SO FERTILITY AND STERILITY LA English DT Article DE Oogenesis; oocyte; germ cell; oogonial stem cell; Stra8 ID ACTIVE GERM-CELLS; MAMMALIAN OVARIES; PURIFICATION; GENERATION; DIFFERENTIATION; OOGENESIS; HOMOLOG; OOCYTES; PROTEIN; GONADS AB Objective: Perform gene expression profiling of adult mouse ovary-derived oogonial stem cells (OSCs). Design: Experimental animal study. Setting: Research laboratory. Animal(s): Adult C57BL/6 female mice. Intervention(s): None. Main Outcome Measure(s): Gene expression profiles were compared between freshly isolated and cultured OSCs, as well as between OSCs and embryonic stem cells (ESCs), fetal primordial germ cells (PGCs), and spermatogonial stem cells (SSCs); OSC yield from ovaries versus meiotic gene activation during the estrous cycle was determined. Result(s): Freshly isolated OSCs, PGCs, and SSCs exhibited distinct gene expression profiles. Cultured OSCs maintained their germline gene expression pattern but gained expression of pluripotency markers found in PGCs and ESCs. Cultured OSCs also expressed the meiotic marker, stimulated by retinoic acid gene 8 (Stra8). In vivo, OSC yield was higher from luteal versus follicular phase ovaries, and this was inversely related to Stra8 expression. Conclusion(s): Freshly isolated OSCs exhibit a germline gene expression profile that overlaps with, but is distinct from, that of PGCs and SSCs. After in vitro expansion, OSCs activate expression of pluripotency genes found in freshly isolated PGCs. In vivo, OSC numbers in the ovaries fluctuate during the estrous cycle, with the highest numbers noted during the luteal phase. This is followed by activation of Stra8 expression during the follicular phase, which may signify a wave of neo-oogenesis to partially offset follicular loss through atresia and ovulation in the prior cycle. (C)2013 by American Society for Reproductive Medicine. C1 Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. RP Tilly, JL (reprint author), Northeastern Univ, Dept Biol, 134 Mugar Hall,360 Huntington Ave, Boston, MA 02115 USA. EM j.tilly@neu.edu FU Method to Extend Research in Time (MERIT) award from the National Institute on Aging [NIH R37-AG012279]; Ruth L. Kirschstein National Research Service Award [NIH F32-AG034809]; Glenn Foundation Award for Research in the Biological Mechanisms of Aging FX Supported by a Method to Extend Research in Time (MERIT) award from the National Institute on Aging (NIH R37-AG012279 to J.L.T.), a Ruth L. Kirschstein National Research Service Award (NIH F32-AG034809 to D.C.W.), and a Glenn Foundation Award for Research in the Biological Mechanisms of Aging (J.L.T.). NR 38 TC 13 Z9 14 U1 0 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD NOV PY 2013 VL 100 IS 5 BP 1451 EP + DI 10.1016/j.fertnstert.2013.06.036 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 242IU UT WOS:000326233700049 PM 23876535 ER PT J AU Park, ES Woods, DC Tilly, JL AF Park, Eun-Sil Woods, Dori C. Tilly, Jonathan L. TI Bone morphogenetic protein 4 promotes mammalian oogonial stem cell differentiation via Smad1/5/8 signaling SO FERTILITY AND STERILITY LA English DT Article DE BMP4; oogenesis; oocyte; germ cells; stem cells ID PRIMORDIAL GERM-CELLS; MEIOTIC INITIATION; MOUSE EPIBLAST; RETINOIC ACID; HUMAN OVARIES; ADULT-MOUSE; GENERATION; CULTURE; MICE; PURIFICATION AB Objective: To test whether bone morphogenetic protein 4 (BMP4) directly regulates differentiation of adult mouse ovary-derived oogonial stem cells (OSCs) in vitro. Design: Animal study. Setting: Research laboratory. Animal(s): Adult C57BL/6 female mice. Intervention(s): After purification from adult ovaries by fluorescence-activated cell sorting, OSCs were cultured without or with BMP4 in the absence or presence of the BMP4 antagonist, Noggin. Main Outcome Measure(s): Rates of in vitro-derived (IVD) oocyte formation and changes in gene expression were assessed. Result(s): Cultured OSCs expressed BMP receptor (BMPR) 1A (BMPR1A), BMPR1B, and BMPR2, suggesting that BMP signaling can directly affect OSC function. In agreement with this, BMP4 significantly increased the number of IVD oocytes formed by cultured OSCs in a dose-dependent manner, and this response was inhibited in a dose-dependent fashion by cotreatment with Noggin. Exposure of OSCs to BMP4 was associated with rapid phosphorylation of BMPR-regulated Smad1/5/8 proteins, and this response was followed by increased expression of the meiosis initiation factors, stimulated by retinoic acid gene 8 (Stra8), muscle-segment homeobox 1 (Msx1), and Msx2. In keeping with the IVD oocyte formation data, the ability of BMP4 to activate Smad1/5/8 signaling and meiotic gene expression in OSCs was abolished by cotreatment with Noggin. Conclusion(s): Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in vitro drives differentiation of these cells into IVD oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes. (C)2013 by American Society for Reproductive Medicine. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. RP Tilly, JL (reprint author), Northeastern Univ, Dept Biol, 134 Mugar Hall,360 Huntington Ave, Boston, MA 02115 USA. EM j.tilly@neu.edu FU National Institute on Aging (National Institutes of Health [NIH] [R37-AG012279]; National Research Service Award (NIH) [F32-AG034809]; Glenn Foundation Award for Research in the Biological Mechanisms of Aging FX This work was supported by a Method to Extend Research in Time (MERIT) Award from the National Institute on Aging (National Institutes of Health [NIH] grant no. R37-AG012279 to J.L.T.), a Ruth L. Kirschstein National Research Service Award (NIH grant no. F32-AG034809 to D.C.W.), and a Glenn Foundation Award for Research in the Biological Mechanisms of Aging (J.L.T.). NR 41 TC 16 Z9 18 U1 6 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD NOV PY 2013 VL 100 IS 5 BP 1468 EP + DI 10.1016/j.fertnstert.2013.07.1978 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 242IU UT WOS:000326233700051 PM 23993924 ER PT J AU Liu, JF Kindelberger, D Doyle, C Lowe, A Barry, WT Matulonis, UA AF Liu, Joyce F. Kindelberger, David Doyle, Courtney Lowe, Alarice Barry, William T. Matulonis, Ursula A. TI Predictive value of circulating tumor cells (CTCs) in newly-diagnosed and recurrent ovarian cancer patients SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian cancer; Circulating tumor cells ID PROGRESSION-FREE SURVIVAL; PROGNOSTIC-SIGNIFICANCE; PERIPHERAL-BLOOD AB Objective. To determine whether circulating tumor cells (CTCs), as detected and enumerated by the Veridex CellSearch (TM) system, could predict for clinical outcomes in women with newly diagnosed or recurrent epithelial ovarian cancer. Methods. Serial measurements of CTC s and paired serum CM125 were collected in a series of 78 women with newly diagnosed or recurrent ovarian cancer seen at our institution over a period of 15 months. Clinical data were abstracted from patient medical records. CTCs were detected and enumerated by the CellSearch (TM) protocol, and patients were divided into CTC negative (<2 CTCs) or positive (>= 2 CTCs) groups. CTC groups were correlated with clinical characteristics and outcomes. A longitudinal analysis of CTC change and CA125 trends was also performed. Results. At least one CTC was isolated from the peripheral blood of over 80% of the women participating in this study, with a range from 0 to 8. No correlations were observed between CTC numbers and clinical characteristics or outcomes. Although both serum CA125 and CTC number exhibited an overall significant decreasing trend over time, there was no correlation observed between change in CFCs and CA125. Conclusion. Using the FDA-approved CellSearch (TM) system, CTCs can be isolated from women with newly diagnosed or recurrent ovarian cancer. However, CTC numbers do not significantly correlate with clinical characteristics or patient outcomes. Future studies should focus on phenotypic characterization of CTCs and whether different isolation protocols yield a higher number of CTCs or add prognostic value. (C) 2013 Elsevier Inc. All rights reserved. C1 [Liu, Joyce F.; Doyle, Courtney; Matulonis, Ursula A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kindelberger, David; Lowe, Alarice] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Barry, William T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. RP Liu, JF (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM joyce_liu@dfci.harvard.edu NR 15 TC 15 Z9 17 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD NOV PY 2013 VL 131 IS 2 BP 352 EP 356 DI 10.1016/j.ygyno.2013.08.006 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 244ZE UT WOS:000326427900014 PM 23954902 ER PT J AU Rauh-Hain, JA Davis, M Clemmer, J Clark, RM Growdon, WB Goodman, AK Boruta, DM Schorge, JO del Carmen, MG AF Rauh-Hain, J. Alejandro Davis, Michelle Clemmer, Joel Clark, Rachel M. Growdon, Whitfield B. Goodman, A. K. Boruta, David M., II Schorge, John O. del Carmen, Marcela G. TI Prognostic determinants in patients with uterine and ovarian clear cell carcinoma: A SEER analysis SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Uterine clear cell carcinoma; Ovarian clear cell carcinoma ID ONCOLOGY-GROUP EXPERIENCE; CLINICAL CHARACTERISTICS; ENDOMETRIAL CANCER; ADJUVANT THERAPY; ADENOCARCINOMA; MANAGEMENT; SUBTYPES AB Introduction. The purpose of this study is to analyze and compare the demographics, treatment, and survival rates in patients with uterine clear cell carcinoma (UCCC) and ovarian clear cell carcinoma (OCCC). Methods. The Surveillance, Epidemiology and End Results (SEER) program data for all 18 registries from 1988 to 2010 was reviewed to identify women with OCCC and UCCC. Demographic and clinical data were compared, and the impact of tumor site on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. Results. The final study group consisted of 5421 women with clear cell histopathology. 3631 (67%) had OCCC and 1790 (33%) had UCCC. The mean age at diagnosis was 56 (+/- 12) years for women with OCCC and 67.7 (+/- 12.0) years for UCCC (P < 0.001). Patients with OCCC had a higher rate of late stage disease (38.9% vs. 21.2%; P < 0.001). Over the entire study period, after adjusting for known variables, there was no significant difference in cancer specific mortality between UCCC and OCCC, HR 1.05 (0.92-1.19). In the subset analysis by staging, in women with localized disease there was an improved survival in UCCC compared to OCCC. In contrast, in women with distant disease there was an increased mortality in women with UCCC. Conclusion. In the entire population, there was no significant difference in cancer related mortality between the groups. However, in women with localized disease, UCCC had improved survival, but increased mortality in distant disease compared to OCCC. (C) 2013 Elsevier Inc. All rights reserved. C1 [Rauh-Hain, J. Alejandro; Davis, Michelle; Clemmer, Joel; Clark, Rachel M.; Growdon, Whitfield B.; Goodman, A. K.; Boruta, David M., II; Schorge, John O.; del Carmen, Marcela G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gynecol Oncol,Vincent Obstet & Gynecol, Boston, MA USA. RP del Carmen, MG (reprint author), Massachusetts Gen Hosp, Div Gynecol Oncol, Vincent Obstet & Gynecol, 55 Fruit St,Yawkey 9 E, Boston, MA 02114 USA. EM mdelcarmen@partners.org NR 22 TC 8 Z9 9 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD NOV PY 2013 VL 131 IS 2 BP 404 EP 409 DI 10.1016/j.ygyno.2013.08.029 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 244ZE UT WOS:000326427900024 PM 24004647 ER PT J AU Dizon, DS AF Dizon, Don S. CA Dana Farber Harvard Comprehensive TI Pushing the bar in treatment of cervical cancer: What can comprehensive cancer centers do on their own? SO GYNECOLOGIC ONCOLOGY LA English DT Editorial Material ID RADICAL TRACHELECTOMY; BRACHYTHERAPY; CARCINOMA; RADIATION; SURVIVAL; IMPACT C1 [Dizon, Don S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dizon, DS (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM ddizon@partners.org NR 14 TC 2 Z9 2 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD NOV PY 2013 VL 131 IS 2 BP 464 EP 466 DI 10.1016/j.ygyno.2013.08.002 PG 3 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 244ZE UT WOS:000326427900033 PM 23938373 ER PT J AU Recht, M Liel, MS Turner, RT Klein, RF Taylor, JA AF Recht, M. Liel, M. S. Turner, R. T. Klein, R. F. Taylor, J. A. TI The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption SO HAEMOPHILIA LA English DT Article DE factor VIII deficiency; osteopenia; osteoporosis ID SEVERE HEMOPHILIA; OSTEOCLAST DIFFERENTIATION; ACTIVATED RECEPTOR-1; CYTOKINE EXPRESSION; MINERAL DENSITY; OSTEOPOROSIS; THROMBIN; OSTEOPROTEGERIN; OSTEOBLASTS; INVOLVEMENT AB Osteopenia and osteoporosis have increasingly become a recognized morbidity of factor VIII (FVIII) deficiency. Recently, we demonstrated that FVIII knockout (KO) mice had significantly decreased bone mass and bone strength despite the fact that they did not have haemarthroses. The aim of this study was to explore the mechanism of bone disease associated with FVIII deficiency. We compared biochemical markers of bone formation and osteoclastogenesis, inflammatory cytokines, as well as static and dynamic histomorphometry of genetically engineered FVIII KO male mice to those of wild-type (WT) controls. At 20weeks of age, FVIII KO mice, as well as WT controls, were sacrificed. Serum and bones were obtained at the time of sacrifice to study biochemical markers of bone formation (osteocalcin) and osteoclastogenesis (receptor activator of nuclear factor kappa- and osteoprotegerin), levels of inflammatory cytokines (interleukin-1 and interferon-) and to perform static and dynamic histomorphometry of tibia cancellous bone. There was no difference in the biochemical markers of bone formation or osteoclastogenesis. However, there were differences in the two bone-associated cytokines studied. In addition, histomorphometric examination revealed cancellous osteopenia in FVIII KO mice as evidenced by decreased bone area and trabecular number and increased trabecular separation. Bone formation parameters were normal in FVIII KO mice. In contrast, osteoclast-lined bone perimeter was increased. These data demonstrate that bone disease in FVIII KO mice is due to an increased rate of bone resorption. C1 [Recht, M.; Liel, M. S.; Taylor, J. A.] Oregon Hlth & Sci Univ, Hemophilia Ctr, Portland, OR 97239 USA. [Liel, M. S.; Taylor, J. A.] Portland VA Med Ctr, Portland, OR USA. [Turner, R. T.] Oregon State Univ, Coll Publ Hlth & Human Sci, Corvallis, OR 97331 USA. [Klein, R. F.] Oregon Hlth & Sci Univ, Div Endocrinol, Bone & Mineral Res Unit, Portland, OR 97239 USA. RP Recht, M (reprint author), Oregon Hlth & Sci Univ, Hemophilia Ctr, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM rechtm@ohsu.edu FU CSL Behring Foundation; The Hemophilia Center at OHSU FX We thank Emily Larson and Sigrid Holmgren for their technical assistance. This research was funded by a pilot grant from the CSL Behring Foundation and The Hemophilia Center at OHSU. NR 28 TC 9 Z9 9 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-8216 EI 1365-2516 J9 HAEMOPHILIA JI Haemophilia PD NOV PY 2013 VL 19 IS 6 BP 908 EP 912 DI 10.1111/hae.12195 PG 5 WC Hematology SC Hematology GA 240NZ UT WOS:000326105100039 PM 23731369 ER PT J AU Mukherjee, G Geliebter, A Babad, J Santamaria, P Serreze, DV Freeman, GJ Tarbell, KV Sharpe, A DiLorenzo, TP AF Mukherjee, Gayatri Geliebter, Ari Babad, Jeffrey Santamaria, Pere Serreze, David V. Freeman, Gordon J. Tarbell, Kristin V. Sharpe, Arlene DiLorenzo, Teresa P. TI DEC-205-mediated antigen targeting to steady-state dendritic cells induces deletion of diabetogenic CD8 T cells independently of PD-1 and PD-L1 SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE Autoimmunity; diabetes; NOD mice ID NONOBESE DIABETIC MICE; IN-VIVO; NOD MICE; MONOCLONAL-ANTIBODY; RECEPTOR DEC-205; ISLET ANTIGENS; EXPRESSION; TOLERANCE; RESPONSES; SUBSETS AB Targeting antigen to steady state DCs causes deletion of endogenous islet-specific T cells.CD8 T cells specific for islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) have been implicated in type 1 diabetes in both humans and non-obese diabetic (NOD) mice, in which T cells specific for IGRP(206214) are highly prevalent. We sought to manipulate these pathogenic T cells by exploiting the ability of steady-state dendritic cells (DCs) to present antigens in a tolerogenic manner. The endocytic receptor DEC-205 was utilized to deliver an IGRP(206214) mimotope to DCs in NOD mice, and the impact of this delivery on a polyclonal population of endogenous islet-reactive cognate T cells was determined. Assessment of islet-infiltrating CD8 T cells showed a decrease in the percentage, and the absolute number, of endogenous IGRP(206214)-specific T cells when the mimotope was delivered to DCs, compared with delivery of a specificity control. Employing an adoptive transfer system, deletion of CD8 T cells as a result of DEC-205-mediated antigen targeting was found to occur independently of programmed death-1 (PD-1) and its ligand (PD-L1), both often implicated in the regulation of peripheral T-cell tolerance. Given its promise for the manipulation of self-reactive polyclonal T cells demonstrated here, the distinctive characteristics of this antigen delivery system will be important to appreciate as its potential as an intervention for autoimmune diseases continues to be investigated. C1 [Mukherjee, Gayatri; Geliebter, Ari; Babad, Jeffrey; DiLorenzo, Teresa P.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. [Santamaria, Pere] Univ Calgary, Julia McFarlane Diabet Res Ctr, Calgary, AB T2N 4N1, Canada. [Santamaria, Pere] Univ Calgary, Fac Med, Dept Microbiol Immunol & Infect Dis, Calgary, AB T2N 4N1, Canada. [Santamaria, Pere] Inst Invest Biomed August Pi & Sunyer, Barcelona 08036, Spain. [Serreze, David V.] Jackson Lab, Bar Harbor, ME 04609 USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Tarbell, Kristin V.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Diabet Endocrinol & Obes Branch, Immune Tolerance Sect, Bethesda, MD 20892 USA. [Sharpe, Arlene] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA 02215 USA. [Sharpe, Arlene] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. [DiLorenzo, Teresa P.] Albert Einstein Coll Med, Dept Med, Div Endocrinol, Bronx, NY 10461 USA. RP DiLorenzo, TP (reprint author), Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. EM teresa.dilorenzo@einstein.yu.edu OI Tarbell, Kristin/0000-0003-3738-379X FU National Institutes of Health [R01 DK094327, R01 DK064315, R01 DK046266, U01 DK072473, P01 AI056299, P60 DK020541]; Juvenile Diabetes Research Foundation; American Diabetes Association; Irma T. Hirschl/Monique Weill-Caulier Trust; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Canadian Institutes of Health Research; Canadian Diabetes Association; National Institutes of Health Cancer Center [P30 CA013330] FX National Institutes of Health [R01 DK094327 and R01 DK064315 to T.P.D., R01 DK046266 and U01 DK072473 (Beta Cell Biology Consortium) to D.V.S., P01 AI056299 to A.S., P60 DK020541 (Albert Einstein College of Medicine's Diabetes Research Center)]; the Juvenile Diabetes Research Foundation to D. V. S. and T. P. D.; the American Diabetes Association to D. V. S. and T. P. D.; the Irma T. Hirschl/Monique Weill-Caulier Trust to T. P. D.; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases to K. V. T.; Canadian Institutes of Health Research to P. S.; Canadian Diabetes Association to Julia McFarlane Diabetes Research Centre; National Institutes of Health Cancer Center (P30 CA013330 for flow cytometry facility at Albert Einstein College of Medicine). P.S. is scientific founder of Parvus Therapeutics, Inc. and a scientist of Alberta Innovates-Health Solutions. T.P.D. is the Diane Belfer, Cypres & Endelson Families Faculty Scholar in Diabetes Research. NR 49 TC 7 Z9 7 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 EI 1460-2377 J9 INT IMMUNOL JI Int. Immunol. PD NOV PY 2013 VL 25 IS 11 BP 651 EP 660 DI 10.1093/intimm/dxt031 PG 10 WC Immunology SC Immunology GA 244GR UT WOS:000326375900005 PM 24021877 ER PT J AU Shingleton, RM Eddy, KT Keshaviah, A Franko, DL Swanson, SA Yu, JS Krishna, M Nock, MK Herzog, DB AF Shingleton, Rebecca M. Eddy, Kamryn T. Keshaviah, Aparna Franko, Debra L. Swanson, Sonja A. Yu, Jessica S. Krishna, Meera Nock, Matthew K. Herzog, David B. TI Binge/Purge Thoughts in Nonsuicidal Self-Injurious Adolescents: An Ecological Momentary Analysis SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE eating disorders; adolescents; non-suicidal self-injury; ecological momentary assessment ID NATURAL-ENVIRONMENT; EATING-DISORDERS; BODY-IMAGE; BEHAVIORS; DISSATISFACTION; MAINTENANCE; RELIABILITY; PATHOLOGY; CHILDREN; VALIDITY AB ObjectiveAdolescents who self-injure often engage in bingeing/purging (BP). Ecological momentary assessment (EMA) has potential to offer insight into the relationship between self-injury and BP. The aims of this study were to examine the frequency and context of BP using EMA in a sample of nonsuicidal self-injurious (NSSI) adolescents. MethodThirty adolescents with a history of NSSI responded to questions regarding self-destructive thoughts/behaviors using a palm-pilot device. Descriptive analyses compared thought/behavior contexts during reports of BP and NSSI thoughts/behaviors (occurring together vs. individually). ResultsBP thoughts were present in 22 (73%) participants, occurring on 32% of the person-days recorded; 59% of these participants actually engaged in BP behavior. Seventy-nine percent of BP thoughts co-occurred with other self-destructive thoughts. Adolescents were more often with friends/peers than alone or with family when having BP thoughts. Worry and pressure precipitated both BP and NSSI thoughts, but perceived criticism and feelings of rejection/hurt were associated more often with BP thoughts than with NSSI thoughts. DiscussionBP thoughts and behaviors were common in this sample, often occurring with other self-destructive thoughts. Future EMA research is needed to address the function of BP symptoms, the contextual variables that increase risk for BP thoughts, and the factors that predict the transition of thoughts into behaviors in adolescents with and without self-injury. (c) 2013 Wiley Periodicals, Inc. (Int J Eat Disord 2013; 46:684-689) C1 [Shingleton, Rebecca M.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Eddy, Kamryn T.; Keshaviah, Aparna; Krishna, Meera] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Eddy, Kamryn T.; Herzog, David B.] Harvard Univ, Sch Med, Boston, MA USA. [Franko, Debra L.] Northeastern Univ, Dept Counseling & Appl Educ Psychol, Boston, MA 02115 USA. [Swanson, Sonja A.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Yu, Jessica S.] Rutgers State Univ, Dept Psychol, Newark, NJ 07102 USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. RP Shingleton, RM (reprint author), Boston Univ, Dept Psychol Boston, Boston, MA 02215 USA. EM rshingleton@gmail.com FU American Foundation for Suicide Prevention; Matina Horner Fellowship; Harris Center for Education and Advocacy in Eating Disorders at Massachusetts General Hospital; [F31MH097308] FX This research was supported by the American Foundation for Suicide Prevention (MKN). Manuscript preparation was supported by the Matina Horner Fellowship, Harris Center for Education and Advocacy in Eating Disorders at Massachusetts General Hospital (RMS, JY), and F31MH097308 (RMS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 33 TC 7 Z9 8 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 EI 1098-108X J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD NOV PY 2013 VL 46 IS 7 BP 684 EP 689 DI 10.1002/eat.22142 PG 6 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA 241OG UT WOS:000326175900006 PM 23729243 ER PT J AU Schiavina, R Borghesi, M Fiorentino, M Brunocilla, E Manferrari, F Vagnoni, V Martorana, G AF Schiavina, Riccardo Borghesi, Marco Fiorentino, Michelangelo Brunocilla, Eugenio Manferrari, Fabio Vagnoni, Valerio Martorana, Giuseppe TI Identification of prostate cancer risk categories according to surgical margins status, pathological stage and Gleason score SO INTERNATIONAL JOURNAL OF UROLOGY LA English DT Article DE biochemical relapse; Gleason score; positive surgical margins; prostate cancer; radical prostatectomy ID RADICAL RETROPUBIC PROSTATECTOMY; RANDOMIZED CLINICAL-TRIAL; ADJUVANT RADIOTHERAPY; PROGNOSTIC-SIGNIFICANCE; CAPSULAR INCISION; POSTOPERATIVE RADIOTHERAPY; EXTRACAPSULAR EXTENSION; RADIATION-THERAPY; SPECIMENS; NOMOGRAM AB ObjectivesOne-third of patients with positive surgical margins after radical prostatectomy develop recurrent disease. The distinction between pT2 with positive margins and pT3a can be difficult. Aim of the present study was to assess the impact of positive surgical margins on biochemical relapse after radical prostatectomy, adjusted for pathological stage and Gleason score. MethodsWe retrospectively evaluated 837 consecutive patients who underwent radical prostatectomy for organ-confined or locally-advanced prostate cancer. Exclusion criteria were: presence of node or distant metastases, neo-adjuvant or adjuvant therapy, and unavailability of full data regarding pathological stage and margin status. A single dedicated genitourinary pathologist evaluated all the specimens. The Kaplan-Meier method and univariable and multivariable Cox regressions were applied for survival analyses. ResultsThe median follow up was 54.035.0 months. Margin status, prostate-specific antigen and Gleason score significantly predicted biochemical relapse in the pT2 group at multivariable analysis, whereas only pathological stage and pathological Gleason score were significant predictors of recurrence in pT3a patients. There were no significant differences in biochemical disease-free survival among pT2 with positive margins patients and pT3a patients (with or without positive surgical margins). Pathological Gleason score was the only significant predictor of biochemical relapse in patients with negative and positive margins, regardless of the pathological stage. ConclusionspT2 patients with positive surgical margins and pT3a (with or without positive margins) seem to have similar biochemical disease-free survival. Positive margins and pathological stage might be insufficient clinical predictors. Gleason score remains the most reliable prognostic factor. C1 [Schiavina, Riccardo; Borghesi, Marco; Brunocilla, Eugenio; Manferrari, Fabio; Vagnoni, Valerio; Martorana, Giuseppe] Univ Bologna, S Orsola Malpighi Hosp, Dept Urol, I-40134 Bologna, Italy. [Fiorentino, Michelangelo] Univ Bologna, S Orsola Malpighi Hosp, Dept Pathol & Mol Oncol, I-40134 Bologna, Italy. [Fiorentino, Michelangelo] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Schiavina, R (reprint author), Univ Bologna, S Orsola Malpighi Hosp, Dept Urol, Palagi 9, I-40134 Bologna, Italy. EM rschiavina@yahoo.it OI Borghesi, Marco/0000-0001-6021-6805 NR 30 TC 6 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0919-8172 EI 1442-2042 J9 INT J UROL JI Int. J. Urol. PD NOV PY 2013 VL 20 IS 11 BP 1097 EP 1103 DI 10.1111/iju.12124 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 242DS UT WOS:000326218200010 PM 23521710 ER PT J AU Buehring, B Viswanathan, R Binkley, N Busse, W AF Buehring, Bjoern Viswanathan, Ravi Binkley, Neil Busse, William TI Glucocorticoid-induced osteoporosis: An update on effects and management SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Glucocorticoid; inhaled and oral corticosteroid; asthma; growth; osteoporosis; bisphosphonates ID BONE-MINERAL DENSITY; INHALED BECLOMETHASONE DIPROPIONATE; LONG-TERM TREATMENT; ADULT HEIGHT; FLUTICASONE PROPIONATE; ASTHMATIC-CHILDREN; OFFICIAL POSITIONS; CORTICOSTEROID USE; CHILDHOOD ASTHMA; SECONDARY OSTEOPOROSIS AB Glucocorticoids remain a cornerstone of guideline-based management of persistent asthma and allergic diseases. Glucocorticoid-induced osteoporosis (GIO) is the most common iatrogenic cause of secondary osteoporosis and an issue of concern for physicians treating patients with inhaled or oral glucocorticoids either continuously or intermittently. Patients with GIO experience fragility fractures at better dual-energy x-ray absorptiometry T-scores than those with postmenopausal or age-related osteoporosis. This might be explained, at least in part, by the effects of glucocorticoids not only on osteoclasts but also on osteoblasts and osteocytes. Effective options to detect and manage GIO exist, and a management algorithm has been published by the American College of Rheumatology to provide treatment guidance for clinicians. This review will summarize GIO epidemiology and pathophysiology and assess the role of inhaled and oral glucocorticoids in asthmatic adults and children, with particular emphasis on the effect of such therapies on bone health. Lastly, we will review the American College of Rheumatology GIO guidelines and discuss diagnostic and therapeutic strategies to mitigate the risk of GIO and fragility fractures. C1 [Buehring, Bjoern; Binkley, Neil] Univ Wisconsin, Sch Med & Publ Hlth, Osteoporosis Res Program, Div Geriatr & Gerontol, Madison, WI 53705 USA. [Buehring, Bjoern; Binkley, Neil] William S Middleton Mem Vet Adm Med Ctr, GRECC, Madison, WI USA. [Viswanathan, Ravi; Busse, William] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Sect Allergy Pulm & Crit Care, Madison, WI 53705 USA. RP Buehring, B (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Osteoporosis Res Program, Sect Geriatr & Gerontol,Dept Med, 2870 Univ Ave,Suite 100, Madison, WI 53705 USA. EM bbuehring@medicine.wisc.edu; rviswanathan@medicine.wisc.edu RI Buehring, Bjoern/L-5581-2013 OI Buehring, Bjoern/0000-0003-3841-624X FU Merck; Lilly; Amgen; Novartis; GlaxoSmithKline; MedImmune; Genentech; Boston Scientific; ICON; National Institutes of Health (NIH)/National Institutes of Allergy and Infectious Diseases; NIH/National Heart, Lung, and Blood Institute FX N. Binkley has consultant arrangements with Merck and Lilly and has received grants from Merck, Lilly, and Amgen. W. Busse is on the Merck Board; has received consultancy fees from Amgen, Novartis, GlaxoSmithKline, MedImmune, Genentech, Boston Scientific, and ICON; has received research support from the National Institutes of Health (NIH)/National Institutes of Allergy and Infectious Diseases and the NIH/National Heart, Lung, and Blood Institute; and has received royalties from Elsevier. The rest of the authors declare they have no relevant conflicts of interest. NR 92 TC 35 Z9 37 U1 0 U2 17 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2013 VL 132 IS 5 BP 1019 EP 1030 DI 10.1016/j.jaci.2013.08.040 PG 12 WC Allergy; Immunology SC Allergy; Immunology GA 242JH UT WOS:000326235600001 PM 24176682 ER PT J AU Leung, J Hundal, NV Katz, AJ Shreffler, WG Yuan, Q Butterworth, CA Hesterberg, PE AF Leung, John Hundal, Navneet Virk Katz, Aubrey J. Shreffler, Wayne G. Yuan, Qian Butterworth, Carolyn A. Hesterberg, Paul E. TI Tolerance of baked milk in patients with cow's milk-mediated eosinophilic esophagitis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID ELIMINATION DIET; CHILDREN; ALLERGY C1 [Leung, John; Shreffler, Wayne G.; Hesterberg, Paul E.] Massachusetts Gen Hosp, Dept Allergy & Immunol, Boston, MA 02114 USA. [Hundal, Navneet Virk; Katz, Aubrey J.; Yuan, Qian; Butterworth, Carolyn A.] Massachusetts Gen Hosp, Dept Pediat Gastroenterol & Nutr, Boston, MA 02114 USA. RP Leung, J (reprint author), Massachusetts Gen Hosp, Dept Allergy & Immunol, Boston, MA 02114 USA. EM phesterberg@partners.org FU NIAID NIH HHS [U19 AI095261]; NIDDK NIH HHS [P30 DK040561] NR 9 TC 17 Z9 17 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD NOV PY 2013 VL 132 IS 5 BP 1215 EP 1216 DI 10.1016/j.jaci.2013.08.017 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 242JH UT WOS:000326235600024 PM 24084076 ER PT J AU Henwood, PC Peak, DA Gonen, L Nadel, ES Brown, DFM AF Henwood, Patricia C. Peak, David A. Gonen, Liza Nadel, Eric S. Brown, David F. M. TI SHOCK ONE WEEK AFTER ABDOMINAL SURGERY SO JOURNAL OF EMERGENCY MEDICINE LA English DT Editorial Material ID COMPARTMENT SYNDROME; INTRAABDOMINAL HYPERTENSION; INTERNATIONAL-CONFERENCE; MANAGEMENT; EXPERTS C1 [Henwood, Patricia C.; Peak, David A.; Gonen, Liza; Nadel, Eric S.; Brown, David F. M.] Harvard Univ, Sch Med, Div Emergency Med, Boston, MA USA. [Henwood, Patricia C.; Peak, David A.; Gonen, Liza; Nadel, Eric S.; Brown, David F. M.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Henwood, Patricia C.; Gonen, Liza; Nadel, Eric S.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. RP Brown, DFM (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Founders 114,Fruit St, Boston, MA 02114 USA. NR 13 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 0736-4679 EI 1090-1280 J9 J EMERG MED JI J. Emerg. Med. PD NOV PY 2013 VL 45 IS 5 BP 702 EP 705 PG 4 WC Emergency Medicine SC Emergency Medicine GA 242VP UT WOS:000326272300024 PM 23988142 ER PT J AU Modi, P Munyaneza, RBM Goldberg, E Choy, G Shailam, R Sagar, P Westra, SJ Nyakubyara, S Gakwerere, M Wolfman, V Vinograd, A Moore, M Levine, AC AF Modi, Payal Munyaneza, Richard B. Mark Goldberg, Elizabeth Choy, Garry Shailam, Randheer Sagar, Pallavi Westra, Sjirk J. Nyakubyara, Solange Gakwerere, Mathias Wolfman, Vanessa Vinograd, Alexandra Moore, Molly Levine, Adam C. TI OXYGEN SATURATION CAN PREDICT PEDIATRIC PNEUMONIA IN A RESOURCE-LIMITED SETTING SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article DE pediatric; pneumonia; developing countries; international; child; diagnosis ID RESPIRATORY-TRACT INFECTION; CHILDHOOD ILLNESS STRATEGY; INTEGRATED MANAGEMENT; CLINICAL PREDICTORS; CHILDREN; HYPOXEMIA; DIAGNOSIS; MORTALITY; ETIOLOGY; SIGNS AB Background: The World Health Organization (WHO) recommends using age-specific respiratory rates for diagnosing pneumonia in children. Past studies have evaluated the WHO criteria with mixed results. Objective: We examined the accuracy of clinical and laboratory factors for diagnosing pediatric pneumonia in resource-limited settings. Methods: We conducted a retrospective chart review of children under 5 years of age presenting with respiratory complaints to three rural hospitals in Rwanda who had received a chest radiograph. Data were collected on the presence or absence of 31 historical, clinical, and laboratory signs. Chest radiographs were interpreted by pediatric radiologists as the gold standard for diagnosing pneumonia. Overall correlation and test characteristics were calculated for each categorical variable as compared to the gold standard. For continuous variables, we created receiver operating characteristic (ROC) curves to determine their accuracy for predicting pneumonia. Results: Between May 2011 and April 2012, data were collected from 147 charts of children with respiratory complaints. Approximately 58% of our sample had radiologist-diagnosed pneumonia. Of the categorical variables, a negative blood smear for malaria ( chi(2) = 6.21, p = 0.013) and the absence of history of asthma (chi(2) = 4.48, p = 0.034) were statistically associated with pneumonia. Of the continuous variables, only oxygen saturation had a statistically significant area under the ROC curve (AUC) of 0.675 (95% confidence interval [CI] 0.581-0.769 and p = 0.001). Respiratory rate had an AUC of 0.528 (95% CI 0.428-0.627 and p = 0.588). Conclusion: Oxygen saturation was the best clinical predictor for pediatric pneumonia and should be further studied in a prospective sample of children with respiratory symptoms in a resource-limited setting. (C) 2013 Elsevier Inc. C1 [Modi, Payal; Goldberg, Elizabeth; Levine, Adam C.] Brown Univ, Sch Med, Dept Emergency Med, Providence, RI 02903 USA. [Munyaneza, Richard B. Mark] Rwanda Minist Hlth, Dept Community Hlth, Kigali, Rwanda. [Choy, Garry; Shailam, Randheer; Sagar, Pallavi; Westra, Sjirk J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Nyakubyara, Solange; Gakwerere, Mathias] Rwanda Minist Hlth, Butaro Hosp, Burera Dist, Rwanda. [Wolfman, Vanessa; Vinograd, Alexandra; Moore, Molly] Partners Hlth Inshuti Mu Buzima, Rwinkwavu, Rwanda. [Wolfman, Vanessa; Moore, Molly] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Gen Pediat, Boston, MA USA. RP Modi, P (reprint author), Brown Univ, Sch Med, Dept Emergency Med, 593 Eddy St,Claverick 274, Providence, RI 02903 USA. OI Goldberg, Elizabeth M./0000-0003-1817-0705; Levine, Adam/0000-0003-3982-3824 FU Rwanda Ministry of Health FX We would like to thank the Rwanda Ministry of Health and Partners in Health/Inshuti Mu Buzima for their support of this project. NR 25 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0736-4679 EI 1090-1280 J9 J EMERG MED JI J. Emerg. Med. PD NOV PY 2013 VL 45 IS 5 BP 752 EP 760 DI 10.1016/j.jemermed.2013.04.041 PG 9 WC Emergency Medicine SC Emergency Medicine GA 242VP UT WOS:000326272300035 PM 23937809 ER PT J AU Fogerty, RL Schoenfeld, A Al-Damluji, MS Horwitz, LI AF Fogerty, Robert L. Schoenfeld, Amy Al-Damluji, Mohammed Salim Horwitz, Leora I. TI Effectiveness of Written Hospitalist Sign-outs in Answering Overnight Inquiries SO JOURNAL OF HOSPITAL MEDICINE LA English DT Article ID PHYSICIAN HANDOFFS; UNITED-STATES; PATIENT-CARE; HOUSE STAFF; TASK-FORCE; MEDICINE; COMMUNICATION; IMPROVEMENT; CONTINUITY; EFFICIENCY AB BACKGROUNDHospitalists are key providers of care to medical inpatients, and sign-out is an integral part of providing safe, high-quality inpatient care. There is little known about hospitalist-to-hospitalist sign-out. OBJECTIVETo evaluate the quality of hospitalist/physician-extender sign-outs by assessing how well the sign-out prepares the night team for overnight events and to determine attributes of effective sign-out. DESIGNAnalysis of a written-only sign-out protocol on a nonteaching hospitalist service using prospective data collected by an attending physician survey during overnight shifts. SETTINGYale-New Haven Hospital, a 966-bed, urban, academic medical center in New Haven, Connecticut with approximately 13,700 hospitalist discharges annually. RESULTSWe recorded 124 inquiries about 96 patients during 6 days of data collection in 2012. Hospitalists referenced the sign-out for 89 (74%) inquiries, and the sign-out was considered sufficient in isolation to respond to 27 (30%) of these inquiries. Hospitalists physically saw the patient for 14 (12%) of inquiries. Nurses were the originator for most inquiries (102 [82%]). The most common inquiry topics were medications (55 [45%]), plan of care (26 [21%]), and clinical changes (26 [21%]). Ninety-five (77%) inquiries were considered to be somewhat or very clinically important by the hospitalist. CONCLUSIONSOverall, we found that attending hospitalists rely heavily on written sign-out to address overnight inquiries, but that those sign-outs are not reliably effective. Future work to better understand the roles of written and verbal components in sign-out is needed to help improve the safety of overnight care. Journal of Hospital Medicine 2013;8:609-614. (c) 2013 Society of Hospital Medicine C1 [Fogerty, Robert L.; Horwitz, Leora I.] Yale Univ, Sch Med, Sect Gen Internal Med, New Haven, CT 06520 USA. [Fogerty, Robert L.] Yale New Haven Med Ctr, Yale New Haven Hosp Hospitalist Serv, New Haven, CT 06504 USA. [Schoenfeld, Amy] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Al-Damluji, Mohammed Salim] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. [Horwitz, Leora I.] Yale New Haven Hlth Syst, Ctr Outcomes Res & Evaluat, New Haven, CT USA. RP Fogerty, RL (reprint author), Yale Univ, Sch Med, POB 208093, New Haven, CT 06520 USA. EM robert.fogerty@yale.edu OI Horwitz, Leora/0000-0003-1800-6040 FU National Institute on Aging [K08 AG038336]; American Federation for Aging Research through the Paul B. Beeson Career Development Award Program; Claude D. Pepper Older Americans Independence Center at Yale University School of Medicine [P30AG021342 NIH/NIA] FX Dr. Horwitz is supported by the National Institute on Aging (K08 AG038336) and by the American Federation for Aging Research through the Paul B. Beeson Career Development Award Program. Dr. Horwitz is also a Pepper Scholar with support from the Claude D. Pepper Older Americans Independence Center at Yale University School of Medicine (#P30AG021342 NIH/NIA). Dr. Fogerty 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. The authors do not have conflicts of interest to report. Dr. Schoenfeld was a medical student at the Yale University School of Medicine, New Haven, Connecticut at the time of the study. She is now a resident at Massachusetts General Hospital in Boston, Massachusetts. NR 30 TC 6 Z9 6 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1553-5592 EI 1553-5606 J9 J HOSP MED JI J. Hosp. Med. PD NOV PY 2013 VL 8 IS 11 BP 609 EP 614 DI 10.1002/jhm.2090 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 245HU UT WOS:000326455200002 PM 24132945 ER PT J AU Hatano, H Strain, MC Scherzer, R Bacchetti, P Wentworth, D Hoh, R Martin, JN McCune, JM Neaton, JD Tracy, RP Hsue, PY Richman, DD Deeks, SG AF Hatano, Hiroyu Strain, Matthew C. Scherzer, Rebecca Bacchetti, Peter Wentworth, Deborah Hoh, Rebecca Martin, Jeffrey N. McCune, Joseph M. Neaton, James D. Tracy, Russell P. Hsue, Priscilla Y. Richman, Douglas D. Deeks, Steven G. TI Increase in 2-Long Terminal Repeat Circles and Decrease in D-dimer After Raltegravir Intensification in Patients With Treated HIV Infection: A Randomized, Placebo-Controlled Trial SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; raltegravir intensification; 2-LTR circles; ongoing viral replication; D-dimer ID T-CELL-ACTIVATION; ANTIRETROVIRAL THERAPY; DISEASE PROGRESSION; IMMUNE ACTIVATION; COAGULATION; ADULTS; AIDS; REPLICATION; SUPPRESSION; MARKERS AB Background. The degree to which human immunodeficiency virus (HIV) continues to replicate during antiretroviral therapy (ART) is controversial. We conducted a randomized, double-blind, placebo-controlled study to assess whether raltegravir intensification reduces low-level viral replication, as defined by an increase in the level of 2-long terminal repeat (2-LTR) circles. Methods. Thirty-one subjects with an ART-suppressed plasma HIV RNA level of <40 copies/mL and a CD4(+) T-cell count of >= 350 cells/mm(3) for >= 1 year were randomly assigned to receive raltegravir 400 mg twice daily or placebo for 24 weeks. 2-LTR circles were analyzed by droplet digital polymerase chain reaction at weeks 0, 1, 2, and 8. Results. The median duration of ART suppression was 3.8 years. The raltegravir group had a significant increase in the level of 2-LTR circles, compared to the placebo group. The week 1 to 0 ratio was 8.8-fold higher (P = .0025) and the week 2 to 0 ratio was 5.7-fold higher (P = .023) in the raltegravir vs. placebo group. Intensification also led to a statistically significant decrease in the D-dimer level, compared to placebo (P = .045). Conclusions. Raltegravir intensification resulted in a rapid increase in the level of 2-LTR circles in a proportion of subjects, indicating that low-level viral replication persists in some individuals even after long-term ART. Intensification also reduced the D-dimer level, a coagulation biomarker that is predictive of morbidity and mortality among patients receiving treatment for HIV infection. C1 [Hatano, Hiroyu; Scherzer, Rebecca; Hoh, Rebecca; McCune, Joseph M.; Hsue, Priscilla Y.; Deeks, Steven G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Bacchetti, Peter; Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Scherzer, Rebecca] San Francisco VA Med Ctr, Dept Med, San Diego, CA USA. [Strain, Matthew C.; Richman, Douglas D.] Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. [Strain, Matthew C.; Richman, Douglas D.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Wentworth, Deborah; Neaton, James D.] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol, Colchester, Essex, England. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Colchester, Essex, England. RP Hatano, H (reprint author), San Francisco Gen Hosp, Bldg 80,Ward 84,995 Potrero Ave, San Francisco, CA 94110 USA. EM hhatano@php.ucsf.edu FU National Institute of Allergy and Infectious Diseases [R01 AI087145, K24 AI069994, AI080193, AI69432, AI047745, AI74621]; Delaney AIDS Research Enterprise [U19 AI0961090]; Collaboratory for AIDS Research on Eradication [U19 AI096113]; National Heart Lung and Blood Institute [R01 HL095130]; American Foundation for AIDS Research [106710-40-RGRL]; UCSF/Gladstone Institute of Virology & Immunology Center for AIDS Research (CFAR) [P30 AI027763]; University of California, San Diego, CFAR [AI306214]; University of California, San Francisco, Clinical and Translational Research Institute Clinical Research Center [UL1 RR024131]; Center for AIDS Prevention Studies [P30 MH62246]; CFAR Network of Integrated Systems [R24 AI067039]; Department of Veterans Affairs FX This work was supported by the National Institute of Allergy and Infectious Diseases (grants R01 AI087145, K24 AI069994, AI080193, AI69432, AI047745, and AI74621); the Delaney AIDS Research Enterprise (grant U19 AI0961090); the Collaboratory for AIDS Research on Eradication (grant U19 AI096113); the National Heart Lung and Blood Institute (grant R01 HL095130); the American Foundation for AIDS Research (grant 106710-40-RGRL); the UCSF/Gladstone Institute of Virology & Immunology Center for AIDS Research (CFAR; grant P30 AI027763); the University of California, San Diego, CFAR (grant AI306214); the University of California, San Francisco, Clinical and Translational Research Institute Clinical Research Center (grant UL1 RR024131); the Center for AIDS Prevention Studies (grant P30 MH62246); the CFAR Network of Integrated Systems (grant R24 AI067039); and the Department of Veterans Affairs. NR 36 TC 69 Z9 69 U1 1 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2013 VL 208 IS 9 BP 1436 EP 1442 DI 10.1093/infdis/jit453 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 244HD UT WOS:000326377500013 PM 23975885 ER PT J AU Cheng, SJ Clancy, CJ Xu, WJ Schneider, F Hao, BH Mitchell, AP Nguyen, MH AF Cheng, Shaoji Clancy, Cornelius J. Xu, Wenjie Schneider, Frank Hao, Binghua Mitchell, Aaron P. Hong Nguyen, M. TI Profiling of Candida albicans Gene Expression During Intra-abdominal Candidiasis Identifies Biologic Processes Involved in Pathogenesis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Candida albicans; intra-abdominal candidiasis; in vivo gene expression; nanoString; RIM101; SAP5 ID SECRETED ASPARTYL PROTEINASES; ABSCESS FORMATION; SURGICAL PATIENTS; VIRULENCE GENE; INFECTION; PERITONITIS; PH; INVASION; MODEL; DEGRADATION AB Background. The pathogenesis of intra-abdominal candidiasis is poorly understood. Methods. Mice were intraperitoneally infected with Candida albicans (1 x 106 colony-forming units) and sterile stool. nanoString assays were used to quantitate messenger RNA for 145 C. albicans genes within the peritoneal cavity at 48 hours. Results. Within 6 hours after infection, mice developed peritonitis, characterized by high yeast burdens, neutrophil influx, and a pH of 7.9 within peritoneal fluid. Organ invasion by hyphae and early abscess formation were evident 6 and 24 hours after infection, respectively; abscesses resolved by day 14. nanoString assays revealed adhesion and responses to alkaline pH, osmolarity, and stress as biologic processes activated in the peritoneal cavity. Disruption of the highly-expressed gene RIM101, which encodes an alkaline-regulated transcription factor, did not impact cellular morphology but reduced both C. albicans burden during early peritonitis and C. albicans persistence within abscesses. RIM101 influenced expression of 49 genes during intra-abdominal candidiasis, including previously unidentified Rim101 targets. Overexpression of the RIM101-dependent gene SAP5, which encodes a secreted protease, restored the ability of a rim101 mutant to persist within abscesses. Conclusions. A mouse model of intra-abdominal candidiasis is valuable for studying pathogenesis and C. albicans gene expression. RIM101 contributes to persistence within intra-abdominal abscesses, at least in part through activation of SAP5. C1 [Cheng, Shaoji; Clancy, Cornelius J.; Hao, Binghua; Hong Nguyen, M.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15203 USA. [Schneider, Frank] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15203 USA. [Clancy, Cornelius J.] VA Pittsburgh Hlth Syst, Med Serv, Pittsburgh, PA USA. [Xu, Wenjie; Mitchell, Aaron P.] Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. RP Clancy, CJ (reprint author), Univ Pittsburgh, Scaife Hall,Ste 871, Pittsburgh, PA 15203 USA. EM cjc76@pitt.edu OI Mitchell, Aaron/0000-0002-0868-4000 FU Department of Medicine, University of Pittsburgh; National Institutes of Health [R01 AI070272] FX This work was supported by the Department of Medicine, University of Pittsburgh (to C. J. C. and M. H. N.) and the National Institutes of Health (grant R01 AI070272 to A. P. M.). NR 43 TC 20 Z9 20 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2013 VL 208 IS 9 BP 1529 EP 1537 DI 10.1093/infdis/jit335 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 244HD UT WOS:000326377500025 PM 24006479 ER PT J AU Church, D Funke, B Hegde, M Chao, C Trow, J Slotta, D Halavi, M Meric, PA Ananiev, V Frishberg, D Rubinstein, W da Silva, C Gowrisankar, S Ajay, S Chapman, B Compton, J Dames, S Das, S Feng, Y Hambuch, T Kulkarni, S Mao, R O'Fallon, BD Shrivastava, S Toji, L Zhang, V Zook, J Kalman, L AF Church, D. Funke, B. Hegde, M. Chao, C. Trow, J. Slotta, D. Halavi, M. Meric, P. A. Ananiev, V. Frishberg, D. Rubinstein, W. da Silva, C. Gowrisankar, S. Ajay, S. Chapman, B. Compton, J. Dames, S. Das, S. Feng, Y. Hambuch, T. Kulkarni, S. Mao, R. O'Fallon, B. D. Shrivastava, S. Toji, L. Zhang, V. Zook, J. Kalman, L. TI Development of Consensus Reference Material Tools for Clinical Next-Generation Sequencing Tests SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Church, D.] NIH, Bethesda, MD 20892 USA. [Funke, B.] Massachusetts Gen Hosp, Cambridge, MA USA. [Funke, B.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Hegde, M.; da Silva, C.] Emory Univ, Sch Med, Atlanta, GA USA. [Chao, C.; Trow, J.; Slotta, D.; Halavi, M.; Meric, P. A.; Ananiev, V.; Frishberg, D.; Rubinstein, W.] NIH, Bethesda, MD 20892 USA. [Gowrisankar, S.] Partners Healthcare Ctr Personalized Genet Med, Cambridge, MA USA. [Ajay, S.; Hambuch, T.] Illumina, San Diego, CA USA. [Chapman, B.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Compton, J.] GeneDx Inc, Gaithersburg, MD USA. [Dames, S.; Mao, R.; O'Fallon, B. D.] ARUP Labs, Salt Lake City, UT USA. [Das, S.] Univ Chicago, Chicago, IL 60637 USA. [Feng, Y.; Zhang, V.] Baylor Coll Med, Houston, TX 77030 USA. [Kulkarni, S.; Shrivastava, S.] Washington Univ, Sch Med, St Louis, MO USA. [Toji, L.] Coriell Inst Med Res, Camden, NJ USA. [Zook, J.] NIST, Gaithersburg, MD 20899 USA. [Kalman, L.] Ctr Dis Control & Prevent, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 847 EP 847 PG 1 WC Pathology SC Pathology GA 248BF UT WOS:000326668000032 ER PT J AU Murphy, DM Bejar, R Stevenson, K Neuberg, D Shi, Y Cubrich, C Richardson, K Eastlake, P Garcia-Manero, G Kantarjian, HM Ebert, BL Makrigiorgos, GM AF Murphy, D. M. Bejar, R. Stevenson, K. Neuberg, D. Shi, Y. Cubrich, C. Richardson, K. Eastlake, P. Garcia-Manero, G. Kantarjian, H. M. Ebert, B. L. Makrigiorgos, G. M. TI COLD/ICE-COLD-PCR Reanalysis of Myelodysplastic Syndrome Samples Reveals Low-Level Point Mutations with Independent Prognostic Significance in the NRAS Oncogene SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Murphy, D. M.; Neuberg, D.; Ebert, B. L.; Makrigiorgos, G. M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bejar, R.] Univ Calif San Diego, San Diego, CA 92103 USA. [Stevenson, K.] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Shi, Y.; Cubrich, C.; Richardson, K.; Eastlake, P.] Transgenomic, Omaha, NE USA. [Garcia-Manero, G.; Kantarjian, H. M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 857 EP 857 PG 1 WC Pathology SC Pathology GA 248BF UT WOS:000326668000070 ER PT J AU Kluk, MJ Oh, DJ Klitgaard, JL Fernandes, SM Aster, JC Brown, JR Lindeman, NI AF Kluk, M. J. Oh, D. J. Klitgaard, J. L. Fernandes, S. M. Aster, J. C. Brown, J. R. Lindeman, N. I. TI Validation and Implementation of a Pyrosequencing Assay to Detect the NOTCH1 c.7541_7542deICT Mutation in Chronic Lymphocytic Leukemia SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Kluk, M. J.; Oh, D. J.; Aster, J. C.; Lindeman, N. I.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Klitgaard, J. L.; Fernandes, S. M.; Brown, J. R.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 864 EP 864 PG 1 WC Pathology SC Pathology GA 248BF UT WOS:000326668000093 ER PT J AU Garcia, EP Kuo, FC Jia, Y Zepf, D Crosby, L Joshi, R Manning, AL Byrne, MN Conneely, J Wade, JE Shivdasani, PR Chung, LP Gong, X Pugh, TJ Leslin, CM Ducar, MD Van Hummelen, P Sholl, LM Rollins, BJ Lindeman, NI MacConaill, LE AF Garcia, E. P. Kuo, F. C. Jia, Y. Zepf, D. Crosby, L. Joshi, R. Manning, A. L. Byrne, M. N. Conneely, J. Wade, J. E. Shivdasani, P. R. Chung, L. P. Gong, X. Pugh, T. J. Leslin, C. M. Ducar, M. D. Van Hummelen, P. Sholl, L. M. Rollins, B. J. Lindeman, N. I. MacConaill, L. E. TI Development and Clinical Validation of a Targeted Next-Generation Sequencing Platform for the Detection of Somatic Mutations, Indels, Rearrangements, and Copy-Number Alterations in Human Tumors SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Garcia, E. P.; Kuo, F. C.; Jia, Y.; Zepf, D.; Crosby, L.; Joshi, R.; Manning, A. L.; Byrne, M. N.; Conneely, J.; Wade, J. E.; Shivdasani, P. R.; Chung, L. P.; Gong, X.; Pugh, T. J.; Leslin, C. M.; Sholl, L. M.; Lindeman, N. I.; MacConaill, L. E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ducar, M. D.; Van Hummelen, P.; Rollins, B. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 872 EP 872 PG 1 WC Pathology SC Pathology GA 248BF UT WOS:000326668000122 ER PT J AU Harrington, AT Peltier, C Hwang, S Clarridge, JE AF Harrington, A. T. Peltier, C. Hwang, S. Clarridge, J. E. TI Comparison of Two Sample-to-Result Nucleic Acid Detection Methods for the Detection of Toxigenic Clostridium difficile in Clinical Stool Specimens SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Harrington, A. T.; Peltier, C.; Hwang, S.; Clarridge, J. E.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 900 EP 900 PG 1 WC Pathology SC Pathology GA 248BF UT WOS:000326668000229 ER PT J AU Sholl, LM Van Allen, E Oliver, N Fostel, J Perrin, DL Friedrich, DC Fisher, SA Gabriel, S Church, A Rojas-Rudilla, V Garcia, EP Gray, S Garber, J Lindeman, NI Janne, P Joffe, S Wagle, N Garraway, L AF Sholl, L. M. Van Allen, E. Oliver, N. Fostel, J. Perrin, D. L. Friedrich, D. C. Fisher, S. A. Gabriel, S. Church, A. Rojas-Rudilla, V. Garcia, E. P. Gray, S. Garber, J. Lindeman, N. I. Janne, P. Joffe, S. Wagle, N. Garraway, L. TI Prospective Whole Exome Sequencing for Clinical Management of Patients with Advanced Lung and Colon Adenocarcinoma SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Sholl, L. M.; Church, A.; Rojas-Rudilla, V.; Garcia, E. P.; Lindeman, N. I.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Van Allen, E.; Oliver, N.; Gray, S.; Garber, J.; Janne, P.; Joffe, S.; Wagle, N.; Garraway, L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Fostel, J.; Perrin, D. L.; Friedrich, D. C.; Fisher, S. A.; Gabriel, S.] Broad Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 918 EP 918 PG 1 WC Pathology SC Pathology GA 248BF UT WOS:000326668000295 ER PT J AU Garcia, EP Kuo, FC Jia, Y Zepf, D Crosby, L Byrne, MN Wade, JE Joshi, R Conneely, J Manning, AL Shivdasani, PR Chung, LP Gong, X Hatton, C Ducar, MD Van Hummelen, P Sholl, LM Rollins, BJ Lindeman, NI MacConaill, LE AF Garcia, E. P. Kuo, F. C. Jia, Y. Zepf, D. Crosby, L. Byrne, M. N. Wade, J. E. Joshi, R. Conneely, J. Manning, A. L. Shivdasani, P. R. Chung, L. P. Gong, X. Hatton, C. Ducar, M. D. Van Hummelen, P. Sholl, L. M. Rollins, B. J. Lindeman, N. I. MacConaill, L. E. TI Profile: A Comprehensive Multiplexed Analysis of Critical Cancer Gene Mutations in Clinical Specimens from Every Patient in a Cancer Center SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Garcia, E. P.; Kuo, F. C.; Jia, Y.; Zepf, D.; Crosby, L.; Byrne, M. N.; Wade, J. E.; Joshi, R.; Conneely, J.; Manning, A. L.; Shivdasani, P. R.; Chung, L. P.; Gong, X.; Rollins, B. J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Hatton, C.; Ducar, M. D.; Van Hummelen, P.; Rollins, B. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 924 EP 924 PG 1 WC Pathology SC Pathology GA 248BF UT WOS:000326668000318 ER PT J AU Leon, A Dias-Santagata, D Marino, JM Moreno, KD Obrera, R Kemel, Y Borger, DR Lee, LP Iafrate, AJ Weisberger, J AF Leon, A. Dias-Santagata, D. Marino, J. M. Moreno, K. D. Obrera, R. Kemel, Y. Borger, D. R. Lee, L. P. Iafrate, A. J. Weisberger, J. TI Tumor Profiling: A Clinical Approach for Personalized Medicine SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Leon, A.; Marino, J. M.; Moreno, K. D.; Obrera, R.; Kemel, Y.; Weisberger, J.] GenPath Diagnost, BioReference Labs, Elmwood Pk, NJ USA. [Dias-Santagata, D.; Borger, D. R.; Lee, L. P.; Iafrate, A. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dias-Santagata, D.; Borger, D. R.; Lee, L. P.; Iafrate, A. J.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 924 EP 925 PG 2 WC Pathology SC Pathology GA 248BF UT WOS:000326668000320 ER PT J AU Castellanos-Rizaldos, E Makrigiorgos, G AF Castellanos-Rizaldos, E. Makrigiorgos, G. TI Single-Tube Enrichment of Mutations in Cancer Gene Panels Using COLD-PCR Prior to Targeted Amplicon Resequencing SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Castellanos-Rizaldos, E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Makrigiorgos, G.] HMS, Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 929 EP 929 PG 1 WC Pathology SC Pathology GA 248BF UT WOS:000326668000335 ER PT J AU Nham, P Moatamed, F Phan, RT AF Nham, P. Moatamed, F. Phan, R. T. TI A Low-Cost High-Throughput Multiple SNPs Simultaneous Genotyping (MSSG) Assay for Thrombophilia Risk Factors SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Nham, P.; Moatamed, F.; Phan, R. T.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 934 EP 934 PG 1 WC Pathology SC Pathology GA 248BF UT WOS:000326668000355 ER PT J AU Lakin, JR Smith, AK AF Lakin, Joshua R. Smith, Alexander K. TI Opening It Up For More Questions: Racial Disparities in Hospice Use SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Editorial Material C1 [Lakin, Joshua R.] Univ Calif San Francisco, Palliat Care Program, San Francisco, CA 94143 USA. [Lakin, Joshua R.] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. [Smith, Alexander K.] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA 94143 USA. [Smith, Alexander K.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Smith, AK (reprint author), Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA 94143 USA. EM aksmith@ucsf.edu FU NIA NIH HHS [P30 AG044281, K23 AG040772] NR 2 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 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD NOV PY 2013 VL 46 IS 5 BP 617 EP 617 DI 10.1016/j.jpainsymman.2013.06.001 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 242JQ UT WOS:000326236900004 PM 23953597 ER PT J AU Sethi, RV Marino, R Niemierko, A Tarbell, NJ Yock, TI MacDonald, SM AF Sethi, Roshan V. Marino, Rose Niemierko, Andrzej Tarbell, Nancy J. Yock, Torunn I. MacDonald, Shannon M. TI Delayed Diagnosis in Children with Intracranial Germ Cell Tumors SO JOURNAL OF PEDIATRICS LA English DT Article ID PEDIATRIC BRAIN-TUMORS; RADIATION-THERAPY; CHILDHOOD-CANCER; SYMPTOM ONSET; IRRADIATION; EXPERIENCE; GERMINOMA; GROWTH; PINEAL AB Objective To review symptoms and provider history in a large cohort of patients with germ cell tumors (GCTs) to highlight the variety of manifestations and assess the effect of delayed diagnosis on outcomes. Study design Patients treated for intracranial pure germinoma and nongerminomatous GCTs at Massachusetts General Hospital between 1998 and 2012 were included (n = 70). The primary outcome was time from onset of symptoms to diagnostic imaging. Delay was defined as an interval of >= 6 months. Results The median duration of symptoms before diagnostic magnetic resonance imaging was 6 months (range, 2 days to 72 months). Thirty-eight of the 70 patients (54%) had a delayed diagnosis. Patients with suprasellar tumors presented with symptoms related to endocrinopathies, and patients with pineal region tumors presented with symptoms related to hydrocephalus. Most of the patients were evaluated by a general pediatrician (49%) and/or pediatric subspecialists (66%) before diagnosis. Patients with delayed diagnosis saw a greater number of physicians before diagnosis (P =.006). The majority of patients (63%) with delayed diagnosis were seen by 2 or more physicians, and many (40%) were seen by 2 or more subspecialists. Progression-free survival was similar in the patients with delayed diagnosis and those without delayed diagnosis (P = .90), but the former were more likely to present with disseminated disease at diagnosis (34% vs 6%; P =.007). Conclusion A significant proportion of patients with GCT experience a delay in time to diagnosis, in some cases despite evaluation by general pediatricians and specialists. This delay increases the risk of disseminated disease. C1 [Sethi, Roshan V.] Harvard Univ, Sch Med, Boston, MA USA. [Marino, Rose] Massachusetts Gen Hosp, Dept Pediat Endocrinol, Boston, MA 02114 USA. [Niemierko, Andrzej; Tarbell, Nancy J.; Yock, Torunn I.; MacDonald, Shannon M.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP MacDonald, SM (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St,Yawkey 112, Boston, MA 02114 USA. EM smacdonald@partners.org FU Doris Duke Clinical Research Fellowship FX R.S. is supported by the Doris Duke Clinical Research Fellowship. N.T. was on the medical advisory board of ProCure until 2008, and N.T.'s spouse continues to serve on medical advisory board of ProCure. The other authors declare no conflicts of interest. NR 27 TC 21 Z9 23 U1 0 U2 10 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD NOV PY 2013 VL 163 IS 5 BP 1448 EP 1453 DI 10.1016/j.jpeds.2013.06.024 PG 6 WC Pediatrics SC Pediatrics GA 242WD UT WOS:000326274600046 PM 23896184 ER PT J AU Morris, BJ Krieger, JN AF Morris, Brian J. Krieger, John N. TI Does Male Circumcision Affect Sexual Function, Sensitivity, or Satisfaction?-A Systematic Review SO JOURNAL OF SEXUAL MEDICINE LA English DT Review DE Circumcision; Erectile Function; Sexual Satisfaction; Premature Ejaculation; Ejaculatory Latency; Penile Sensitivity; Penile Sensation; Male Sexual Function and Pleasure ID DECREASES PENILE SENSITIVITY; LIFELONG PREMATURE EJACULATION; TOUCH PRESSURE THRESHOLDS; MUCOSAL CUFF LENGTH; LARGE COHORT; LATENCY TIME; ADULT PENIS; MEN; PREVALENCE; HEALTH AB IntroductionCircumcision of males is commonly carried out worldwide for reasons of health, medical need, esthetics, tradition, or religion. Whether circumcision impairs or improves male sexual function or pleasure is controversial. AimsThe study aims to conduct a systematic review of the scientific literature. MethodsA systematic review of published articles retrieved using keyword searches of the PubMed, EMBASE, and Cochrane databases was performed. Main Outcome MeasuresThe main outcome measure is the assessment of findings in publications reporting original data relevant to the search terms and rating of quality of each study based on established criteria. ResultsSearches identified 2,675 publications describing the effects of male circumcision on aspects of male sexual function, sensitivity, sensation, or satisfaction. Of these, 36 met our inclusion criteria of containing original data. Those studies reported a total of 40,473 men, including 19,542 uncircumcised and 20,931 circumcised. Rated by the Scottish Intercollegiate Guidelines Network grading system, 2 were 1++ (high quality randomized controlled trials) and 34 were case-control or cohort studies (11 high quality: 2++; 10 well-conducted: 2+; 13 low quality: 2-). The 1++, 2++, and 2+ studies uniformly found that circumcision had no overall adverse effect on penile sensitivity, sexual arousal, sexual sensation, erectile function, premature ejaculation, ejaculatory latency, orgasm difficulties, sexual satisfaction, pleasure, or pain during penetration. Support for these conclusions was provided by a meta-analysis. Impairment in one or more parameters was reported in 10 of the 13 studies rated as 2-. These lower-quality studies contained flaws in study design (11), selection of cases and/or controls (5), statistical analysis (4), and/or data interpretation (6); five had multiple problems. ConclusionThe highest-quality studies suggest that medical male circumcision has no adverse effect on sexual function, sensitivity, sexual sensation, or satisfaction. Morris BJ and Krieger JN. Does male circumcision affect sexual function, sensitivity, or satisfaction?A systematic review. J Sex Med 2013;10:2644-2657. C1 [Morris, Brian J.] Univ Sydney, Sch Med Sci, Sydney, NSW 2006, Australia. [Krieger, John N.] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Krieger, John N.] VA Puget Sound Hlth Care Syst, Urol Sect, Seattle, WA USA. RP Morris, BJ (reprint author), Univ Sydney, Sch Med Sci, Bldg F13, Sydney, NSW 2006, Australia. EM brian.morris@sydney.edu.au NR 59 TC 37 Z9 38 U1 3 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-6095 EI 1743-6109 J9 J SEX MED JI J. Sex. Med. PD NOV PY 2013 VL 10 IS 11 BP 2644 EP 2657 DI 10.1111/jsm.12293 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA 245LT UT WOS:000326465900005 PM 23937309 ER PT J AU Singh, S Khawaja, RDA Pourjabbar, S Padole, A Lira, D Kalra, MK AF Singh, Sarabjeet Khawaja, Ranish Deedar Ali Pourjabbar, Sarvenaz Padole, Atul Lira, Diego Kalra, Mannudeep K. TI Iterative Image Reconstruction and Its Role in Cardiothoracic Computed Tomography SO JOURNAL OF THORACIC IMAGING LA English DT Review DE radiation dose reduction; iterative reconstruction algorithm; low-dose chest computed tomography; cardiac computed tomography radiation dose optimization ID RADIATION-DOSE REDUCTION; FILTERED BACK-PROJECTION; CORONARY CT ANGIOGRAPHY; DUAL-SOURCE CT; TUBE-CURRENT MODULATION; HIGH-RESOLUTION CT; CHEST CT; PULMONARY-EMBOLISM; PEDIATRIC CT; CARDIAC CT AB Revolutionary developments in multidetector-row computed tomography (CT) scanner technology offer several advantages for imaging of cardiothoracic disorders. As a result, expanding applications of CT now account for >85 million CT examinations annually in the United States alone. Given the large number of CT examinations performed, concerns over increase in population-based risk for radiation-induced carcinogenesis have made CT radiation dose a top safety concern in health care. In response to this concern, several technologies have been developed to reduce the dose with more efficient use of scan parameters and the use of newer image reconstruction techniques. Although iterative image reconstruction algorithms were first introduced in the 1970s, filtered back projection was chosen as the conventional image reconstruction technique because of its simplicity and faster reconstruction times. With subsequent advances in computational speed and power, iterative reconstruction techniques have reemerged and have shown the potential of radiation dose optimization without adversely influencing diagnostic image quality. In this article, we review the basic principles of different iterative reconstruction algorithms and their implementation for various clinical applications in cardiothoracic CT examinations for reducing radiation dose. C1 [Singh, Sarabjeet; Khawaja, Ranish Deedar Ali; Pourjabbar, Sarvenaz; Padole, Atul; Lira, Diego; Kalra, Mannudeep K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Thorac & Cardiac Imaging,MGH Imaging, Boston, MA 02114 USA. RP Singh, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Thorac & Cardiac Imaging,MGH Imaging, 55 Fruit St,Founders 202, Boston, MA 02114 USA. EM ssingh6@partners.org NR 66 TC 11 Z9 11 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0883-5993 EI 1536-0237 J9 J THORAC IMAG JI J. Thorac. Imaging PD NOV PY 2013 VL 28 IS 6 BP 355 EP 367 DI 10.1097/RTI.0000000000000054 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 246AN UT WOS:000326507900009 PM 24149861 ER PT J AU Dai, Y Gu, LY Yuan, WJ Yu, Q Ni, ZH Ross, MJ Kaufman, L Xiong, HB Salant, DJ He, JC Chuang, PY AF Dai, Yan Gu, Leyi Yuan, Weijie Yu, Qing Ni, Zhaohui Ross, Michael J. Kaufman, Lewis Xiong, Huabao Salant, David J. He, John C. Chuang, Peter Y. TI Podocyte-specific deletion of signal transducer and activator of transcription 3 attenuates nephrotoxic serum-induced glomerulonephritis SO KIDNEY INTERNATIONAL LA English DT Article DE glomerulonephritis; glomerulus; podocyte; proliferation; signaling ID PROGRESSIVE CRESCENTIC GLOMERULONEPHRITIS; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; COLLAPSING GLOMERULOPATHY; EXPRESSION; INJURY; MOUSE; STAT3; MICE; NEPHROPATHY; PROLIFERATION AB Activation of signal transducer and activator of transcription (STAT) 3 correlates with proliferation of extracapillary glomerular epithelial cells and the extent of renal injury in glomerulonephritis. To delineate the role of STAT3 in glomerular epithelial cell proliferation, we examined the development of nephrotoxic serum-induced glomerulonephritis in mice with and without podocyte-restricted STAT3 deletion. Mice with STAT3 deletion in podocytes developed less crescents and loss of renal function compared with those without STAT3 deletion. Proliferation of glomerular cells, loss of podocyte markers, and recruitment of parietal epithelial cells were found in nephritic mice without STAT3 deletion, but mitigated in nephritic mice with podocyte STAT3 deletion. Glomerular expression of pro-inflammatory STAT3 target genes was significantly reduced in nephritic mice with, compared with those without, podocyte STAT3 deletion. However, the extent of glomerular immune complex deposition was not different. Podocytes with STAT3 deletion were resistant to interleukin-6-induced STAT3 phosphorylation and pro-inflammatory STAT3 target gene expression. Thus, podocyte STAT3 activation is critical for the development of crescentic glomerulonephritis. C1 [Dai, Yan; Ross, Michael J.; Kaufman, Lewis; He, John C.; Chuang, Peter Y.] Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY 10029 USA. [Dai, Yan; Yuan, Weijie; Yu, Qing] Shanghai Jiao Tong Univ, Sch Med, Div Nephrol, Shanghai Peoples Hosp 1, Shanghai 200030, Peoples R China. [Gu, Leyi; Ni, Zhaohui] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Div Renal, Shanghai 200030, Peoples R China. [Gu, Leyi; Ni, Zhaohui] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Mol Cell Lab Kidney Dis, Shanghai 200030, Peoples R China. [Xiong, Huabao] Mt Sinai Sch Med, Immunobiol Ctr, New York, NY 10029 USA. [Salant, David J.] Boston Univ, Renal Sect, Boston, MA 02215 USA. [He, John C.] James J Peters Vet Affairs Med Ctr, Renal Sect, Bronx, NY USA. RP Chuang, PY (reprint author), Mt Sinai Sch Med, Dept Med, Div Nephrol, 1 Gustave L Levy Pl,Box 1243, New York, NY 10029 USA. EM peter.chuang@mssm.edu FU NIH [1R01DK078897, 1R01DK088541-01A1, 5K08DK082760]; Veterans Affairs Merit Review Award [1I01BX000345]; Chinese 973 Fund [2012CB517601] FX We thank Pete Mundel (Massachusetts General Hospital, Boston) for sharing cultured conditionally immortalized podocytes. JCH is supported by NIH 1R01DK078897 and 1R01DK088541-01A1 and a Veterans Affairs Merit Review Award 1I01BX000345; PYC is supported by NIH 5K08DK082760. LG, ZN, and JCH are supported by Chinese 973 Fund 2012CB517601. NR 42 TC 14 Z9 14 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD NOV PY 2013 VL 84 IS 5 BP 950 EP 961 DI 10.1038/ki.2013.197 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 245YG UT WOS:000326500400016 PM 23842188 ER PT J AU Mehrotra, R Peralta, CA Chen, SC Li, SY Sachs, M Shah, A Norris, K Saab, G Whaley-Connell, A Kestenbaum, B McCullough, PA AF Mehrotra, Rajnish Peralta, Carmen A. Chen, Shu-Cheng Li, Suying Sachs, Michael Shah, Anuja Norris, Keith Saab, Georges Whaley-Connell, Adam Kestenbaum, Bryan McCullough, Peter A. CA Kidney Early Evaluation Program TI No independent association of serum phosphorus with risk for death or progression to end-stage renal disease in a large screen for chronic kidney disease SO KIDNEY INTERNATIONAL LA English DT Article DE barrier to care; cardiovascular disease; chronic kidney disease; end-stage renal disease; mortality; phosphorus ID CORONARY-ARTERY CALCIFICATION; VASCULAR CALCIFICATION; PHOSPHATE CONCENTRATIONS; SOCIOECONOMIC-STATUS; MINERAL METABOLISM; MORTALITY; CALCIUM; DIALYSIS; ATHEROSCLEROSIS; RESTRICTION AB Whether higher serum phosphorus levels are associated with a higher risk for death and/or progression of chronic kidney disease (CKD) is not well established, and whether the association is confounded by access and barriers to care is unknown. To answer these questions, data of 10,672 individuals identified to have CKD (estimated glomerular filtration rate <60 ml/min per 1.73 m(2)) from those participating in a community-based screening program were analyzed. Over a median follow-up of 2.3 years, there was no association between quartiles of serum phosphorus and all-cause mortality (adjusted hazards ratio for serum phosphorus over 3.3 to 3.7, over 3.7 to 4.1, and over 4.1 mg/dl, respectively: 1.22 (0.95-1.56), 1.00 (0.76-1.32), and 1.00 (0.75-1.33); reference, serum phosphorus of 3.3 mg/dl and below). Individuals in the highest quartile for serum phosphorus had a significantly higher risk for progression to end-stage renal disease (ESRD) (unadjusted hazards ratio, 6.72 (4.16-10.85)); however, the risk became nonsignificant on adjustment for potential confounders. There was no appreciable change in hazards ratio with inclusion of variables related to access and barriers to care. Additional analyses in subgroups based on 12 different variables yielded similar negative associations. Thus, in the largest cohort of individuals with early-stage CKD to date, we could not validate an independent association of serum phosphorus with risk for death or progression to ESRD. C1 [Mehrotra, Rajnish; Sachs, Michael; Kestenbaum, Bryan] Univ Washington, Kidney Res Inst, Seattle, WA 98104 USA. [Mehrotra, Rajnish; Sachs, Michael; Kestenbaum, Bryan] Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. [Peralta, Carmen A.] Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Chen, Shu-Cheng; Li, Suying] Chron Dis Res Grp, Minneapolis, MN USA. [Shah, Anuja] Harbor UCLA, Los Angeles Biomed Res Inst, Torrance, CA USA. [Norris, Keith] Charles Drew Univ, Los Angeles, CA USA. [Saab, Georges] Metro Hlth Med Ctr, Cleveland, OH USA. [Whaley-Connell, Adam] Harry S Truman Mem Vet Hosp, Columbia, MO 65201 USA. [Whaley-Connell, Adam] Univ Missouri, Columbia Sch Med, Columbia, MO USA. [McCullough, Peter A.] St John Providence Hlth Syst, Providence Hosp & Med Ctr, Southfield, MI USA. [McCullough, Peter A.] St John Providence Hlth Syst, Providence Hosp & Med Ctr, Novi, MI USA. RP Mehrotra, R (reprint author), Univ Washington, Div Nephrol, 325 9th Ave,Box 359606, Seattle, WA 98104 USA. EM rmehrotr@uw.edu OI Whaley-Connell, Adam/0000-0001-8955-5560 FU NIH [U54MD007598, UL1TR000124, P30AG021684, P20MD000182]; [RO1DK95668] FX RM is supported by RO1DK95668. KN is supported in part by NIH grants U54MD007598, UL1TR000124, P30AG021684, and P20MD000182. NR 36 TC 23 Z9 24 U1 0 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD NOV PY 2013 VL 84 IS 5 BP 989 EP 997 DI 10.1038/ki.2013.145 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 245YG UT WOS:000326500400020 PM 23615501 ER PT J AU Enger, TB Samad-Zadeh, A Bouchie, MP Skarstein, K Galtung, HK Mera, T Walker, J Menko, AS Varelas, X Faustman, DL Jensen, JL Kukuruzinska, MA AF Enger, Tone B. Samad-Zadeh, Arman Bouchie, Meghan P. Skarstein, Kathrine Galtung, Hilde K. Mera, Toshiyuki Walker, Janice Menko, A. Sue Varelas, Xaralabos Faustman, Denise L. Jensen, Janicke L. Kukuruzinska, Maria A. TI The Hippo signaling pathway is required for salivary gland development and its dysregulation is associated with Sjogren's syndrome SO LABORATORY INVESTIGATION LA English DT Article DE E-cadherin adhesion; Hippo signaling; salivary gland; Sjogren's syndrome; TAZ ID TYPE-1 DIABETES-MELLITUS; SUBMANDIBULAR-GLAND; E-CADHERIN; BRANCHING MORPHOGENESIS; ALPHA-CATENIN; TRANSCRIPTIONAL COACTIVATOR; ABERRANT LOCALIZATION; GROWTH-CONTROL; HEARING-LOSS; EXPRESSION AB Sjogren's syndrome (SS) is a complex autoimmune disease that primarily affects salivary and lacrimal glands and is associated with high morbidity. Although the prevailing dogma is that immune system pathology drives SS, increasing evidence points to structural defects, including defective E-cadherin adhesion, to be involved in its etiology. We have shown that E-cadherin has pivotal roles in the development of the mouse salivary submandibular gland (SMG) by organizing apical-basal polarity in acinar and ductal progenitors and by signaling survival for differentiating duct cells. Recently, E-cadherin junctions have been shown to interact with effectors of the Hippo signaling pathway, a core pathway regulating the organ size, cell proliferation, and differentiation. We now show that Hippo signaling is required for SMG-branching morphogenesis and is involved in the pathophysiology of SS. During SMG development, a Hippo pathway effector, TAZ, becomes increasingly phosphorylated and associated with E-cadherin and alpha-catenin, consistent with the activation of Hippo signaling. Inhibition of Lats2, an upstream kinase that promotes TAZ phosphorylation, results in dysmorphogenesis of the SMG and impaired duct formation. SMGs from non-obese diabetic mice, a mouse model for SS, phenocopy the Lats2-inhibited SMGs and exhibit a reduction in E-cadherin junctional components, including TAZ. Importantly, labial specimens from human SS patients display mislocalization of TAZ from junctional regions to the nucleus, coincident with accumulation of extracellular matrix components, fibronectin and connective tissue growth factor, known downstream targets of TAZ. Our studies show that Hippo signaling has a crucial role in SMG-branching morphogenesis and provide evidence that defects in this pathway are associated with SS in humans. C1 [Enger, Tone B.; Jensen, Janicke L.] Univ Oslo, Dept Oral Surg & Oral Med, Oslo, Norway. [Samad-Zadeh, Arman; Bouchie, Meghan P.; Kukuruzinska, Maria A.] Boston Univ, Sch Dent Med, Dept Mol & Cell Biol, Boston, MA 02118 USA. [Skarstein, Kathrine] Univ Bergen, Haukeland Univ Hosp, Gade Inst, Sect Pathol, Bergen, Norway. [Galtung, Hilde K.] Univ Oslo, Dept Oral Biol, Oslo, Norway. [Mera, Toshiyuki; Faustman, Denise L.] Harvard Univ, Sch Med, Immunobiol Labs, Boston, MA USA. [Mera, Toshiyuki; Faustman, Denise L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walker, Janice; Menko, A. Sue] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Varelas, Xaralabos] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. RP Kukuruzinska, MA (reprint author), Boston Univ, Dept Mol & Cell Biol, Med Campus,72 Concord St,E428, Boston, MA 02118 USA. EM mkukuruz@bu.edu OI Varelas, Xaralabos/0000-0002-2882-4541 FU NIH [DE 014437]; Sjogren's Syndrome Foundation Research Grant; March of Dimes Foundation [5-FY11-578] FX Grant sponsor: NIH; RO1 Grant number DE 014437 (MAK and ASM). Sjogren's Syndrome Foundation Research Grant (MAK), and March of Dimes Foundation; Research Grant number 5-FY11-578 (XV). NR 48 TC 13 Z9 13 U1 1 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD NOV PY 2013 VL 93 IS 11 BP 1203 EP 1218 DI 10.1038/labinvest.2013.114 PG 16 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 244MN UT WOS:000326393200004 PM 24080911 ER PT J AU Kang, YK Ryu, MH Yoo, C Ryoo, BY Kim, HJ Lee, JJ Nam, BH Ramaiya, N Jagannathan, J Demetri, GD AF Kang, Yoon-Koo Ryu, Min-Hee Yoo, Changhoon Ryoo, Baek-Yeol Kim, Hyun Jin Lee, Jong Jin Nam, Byung-Ho Ramaiya, Nikhil Jagannathan, Jyothi Demetri, George D. TI Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial SO LANCET ONCOLOGY LA English DT Article ID SOLID TUMORS; MUTATIONS; MESYLATE; KIT; GUIDELINE; EFFICACY; SAFETY AB Background Few treatment options remain for patients with metastatic or unresectable gastrointestinal stromal tumours (GIST) after objective progression on approved tyrosine-kinase inhibitors. We aimed to assess efficacy of imatinib rechallenge in these patients. Methods In our prospective, randomised, double-blind trial, we enrolled adults (>= 18 years) who had previously benefited from first-line imatinib (initial response or stable disease for >= 6 months) but whose metastatic or unresectable GIST had progressed on at least imatinib and sunitinib. We randomly allocated participants in a 1: 1 ratio, with a centralised computer-generated allocation procedure (random permuted blocks of two, four, and six) and stratified by previous treatment and Eastern Cooperative Oncology Group performance status, to receive best supportive care with imatinib 400 mg per day or matched placebo. Crossover to open-label imatinib was allowed after investigator-adjudicated disease progression. The primary endpoint was progression-free survival (PFS), as determined by a masked external radiological review. All analyses were done for all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01151852. Findings Between July 20, 2010, and Jan 17, 2013, we randomly allocated 41 patients to the imatinib group and 40 patients to the placebo group. After a median follow-up of 5.2 months (IQR 3.4-9.4), median PFS was 1.8 months (95% CI 1.7-3.6) with imatinib compared with 0.9 months (0.9-1.7) with placebo (hazard ratio for progression or death 0.46, 95% CI 0.27-0.78; p=0.005). 37 (93%) patients in the placebo group crossed over to open-label imatinib after progression. The most common grade 3 or worse adverse events were anaemia (12 [29%] of 41 patients in the imatinib group vs three [8%] of 40 in the placebo group), fatigue (four [10%] vs none), and hyperbilirubinaemia (three [7%] vs one [3%]). Interpretation In patients with GIST that is refractory to treatment with all standard tyrosine-kinase inhibitors, the disease continues to harbour many clones that are sensitive to kinase inhibitors. Continued kinase suppression might slow, although not halt, disease progression. C1 [Kang, Yoon-Koo; Ryu, Min-Hee; Yoo, Changhoon; Ryoo, Baek-Yeol] Univ Ulsan, Dept Oncol, Asan Med Ctr, Coll Med, Seoul 138736, South Korea. [Kim, Hyun Jin] Univ Ulsan, Dept Radiol, Asan Med Ctr, Coll Med, Seoul 138736, South Korea. [Lee, Jong Jin] Univ Ulsan, Dept Nucl Med, Asan Med Ctr, Coll Med, Seoul 138736, South Korea. [Nam, Byung-Ho] Natl Canc Ctr, Biometr Res Branch, Goyang, South Korea. [Ramaiya, Nikhil; Jagannathan, Jyothi; Demetri, George D.] Dana Farber Canc Inst, Ludwig Ctr, Boston, MA 02115 USA. [Ramaiya, Nikhil; Jagannathan, Jyothi; Demetri, George D.] Harvard Univ, Sch Med, Boston, MA USA. RP Kang, YK (reprint author), Univ Ulsan, Dept Oncol, Asan Med Ctr, Coll Med, 88,Olymp Ro 43 Gil, Seoul 138736, South Korea. EM ykkang@amc.seoul.kr FU South Korean gastrointestinal stromal tumours (GIST) Patient Advocacy Group FX We thank the patients who participated in this trial, the South Korean gastrointestinal stromal tumours (GIST) Patient Advocacy Group for its support, and the clinical staff of the Asan Medical Center for their commitment to this study. NR 17 TC 40 Z9 46 U1 0 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD NOV PY 2013 VL 14 IS 12 BP 1175 EP 1182 DI 10.1016/S1470-2045(13)70453-4 PG 8 WC Oncology SC Oncology GA 242WK UT WOS:000326275300042 PM 24140183 ER PT J AU Basch, E Autio, K Ryan, CJ Mulders, P Shore, N Kheoh, T Fizazi, K Logothetis, CJ Rathkopf, D Smith, MR Mainwaring, PN Hao, YN Griffin, T Li, S Meyers, ML Molina, A Cleeland, C AF Basch, Ethan Autio, Karen Ryan, Charles J. Mulders, Peter Shore, Neal Kheoh, Thian Fizazi, Karim Logothetis, Christopher J. Rathkopf, Dana Smith, Matthew R. Mainwaring, Paul N. Hao, Yanni Griffin, Thomas Li, Susan Meyers, Michael L. Molina, Arturo Cleeland, Charles TI Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial SO LANCET ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; PAIN CLINICAL-TRIALS; IMMPACT RECOMMENDATIONS; END-POINTS; SURVIVAL; IMPACT; INHIBITOR; PLACEBO AB Background Abiraterone acetate plus prednisone significantly improves radiographic progression-free survival in asymptomatic or mildly symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer compared with prednisone alone. We describe analyses of data for patient-reported pain and functional status in a preplanned interim analysis of a phase 3 trial. Methods Between April 28, 2009, and June 23, 2010, patients with progressive, metastatic castration-resistant prostate cancer were enrolled into a multinational, double-blind, placebo-controlled trial. Patients were eligible if they were asymptomatic (score of 0 or 1 on item three of the Brief Pain Inventory Short Form [BPI-SF] questionnaire) or mildly symptomatic (score of 2 or 3) and had not previously received chemotherapy. Patients were randomly assigned (1:1) to receive oral abiraterone (1 g daily) plus prednisone (5 mg twice daily) or placebo plus prednisone in continuous 4-week cycles. Pain was assessed with the BPI-SF questionnaire, and health-related quality of life (HRQoL) with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. We analysed data with prespecified criteria for clinically meaningful pain progression and deterioration in HRQoL. All patients who underwent randomisation were included in analyses. This study is registered with ClinicalTrials.gov, number NCT00887198. Findings 1088 patients underwent randomisation:546 were assigned to abiraterone plus prednisone and 542 to placebo plus prednisone. At the time of the second prespecified interim analysis, median follow-up was 22.2 months (IQR 20.2-24.8). Median time to progression of mean pain intensity was longer in patients assigned to abiraterone plus prednisone (26.7 months [95% CI 19.3-not estimable]) than in those assigned to placebo plus prednisone (18.4 months [14.9-not estimable]; hazard ratio [HR] 0.82, 95% CI 0.67-1.00; p=0.0490), as was median time to progression of pain interference with daily activities (10.3 months [95% CI 9.3-13.0] vs 7.4 months [6.4-8.6]; HR 0.79, 95% CI 0.67-0.93; p=0.005). Median time to progression of worst pain was also longer with abiraterone plus prednisone (26.7 months [95% CI 19.4-not estimable]) than with placebo plus prednisone (19.4 months [16.6-not estimable]), but the difference was not significant (HR 0.85, 95% CI 0.69-1.04; p=0.109). Median time to HRQoL deterioration was longer in patients assigned to abiraterone plus prednisone than in those assigned to placebo plus prednisone as assessed by the FACT-P total score (12.7 months [95% CI 11.1-14.0] vs 8.3 months [7.4-10.6]; HR 0.78, 95% CI 0.66-0.92; p=0.003) and by the score on its prostate-cancer-specific subscale (11.1 months [8.6-13.8] vs 5.8 months [5.5-8.3]; HR 0.70, 95% CI 0.60-0.83; p<0.0001). Interpretation Abiraterone plus prednisone delays patient-reported pain progression and HRQoL deterioration in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. These results provide further support for the efficacy of abiraterone in this population. C1 [Basch, Ethan] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Autio, Karen; Rathkopf, Dana] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Ryan, Charles J.] Univ Calif San Francisco, Hellen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Mulders, Peter] Radboud Univ Nijmegen, Dept Urol, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Shore, Neal] Carolina Urol Res Ctr, Atlantic Urol Clin, Myrtle Beach, SC USA. [Kheoh, Thian; Griffin, Thomas; Molina, Arturo] Janssen Res & Dev, Los Angeles, CA USA. [Fizazi, Karim] Univ Paris 11, Inst Gustave Roussy, Villejuif, France. [Logothetis, Christopher J.] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA. [Cleeland, Charles] Univ Texas MD Anderson Canc Ctr, Dept Symptom Res, Houston, TX 77030 USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Dept Genitourinary Med Oncol, Boston, MA 02114 USA. [Mainwaring, Paul N.] Med Oncol Clin Australia, Brisbane, Qld, Australia. [Mainwaring, Paul N.] Hematol Clin Australia, Brisbane, Qld, Australia. [Mainwaring, Paul N.] Oncol Clin Australia, Brisbane, Qld, Australia. [Hao, Yanni] Janssen Global Serv, Raritan, NJ USA. [Li, Susan] Janssen Res & Dev, Spring House, PA USA. [Meyers, Michael L.] Janssen Res & Dev, Raritan, NJ USA. RP Basch, E (reprint author), Univ N Carolina, Dept Med, 170 Manning Dr, Chapel Hill, NC 27599 USA. EM ebasch@med.unc.edu RI Mulders, Peter/H-8076-2014; OI Rathkopf, Dana/0000-0002-4503-7582 FU Janssen Research Development; Janssen Global Services; Dominik Wolf of PAREXEL FX This study was sponsored by Ortho Biotech Oncology Research and Development (now Janssen Research & Development), which provided research support to the investigators or their institutions while this study was done at their sites. The analyses in this paper were funded by Janssen Global Services. Writing support was provided by Dominik Wolf of PAREXEL and was funded by Janssen Global Services. We thank Margaret Rothman for constructive comments during preparation of the report. NR 32 TC 47 Z9 49 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD NOV PY 2013 VL 14 IS 12 BP 1193 EP 1199 DI 10.1016/S1470-2045(13)70424-8 PG 7 WC Oncology SC Oncology GA 242WK UT WOS:000326275300044 PM 24075621 ER PT J AU Ramaswamy, V Remke, M Et, EB Faria, CC Perreault, S Cho, YJ Shih, DJ Luu, B Dubuc, AM Northcott, PA Schuller, U Gururangan, S McLendon, R Bigner, D Fouladi, M Ligon, KL Pomeroy, SL Dunn, S Triscott, J Jabado, N Fontebasso, A Jones, DTW Kool, M Karajannis, MA Gardner, SL Zagzag, D Nunes, SA Pimentel, J Mora, J Lipp, E Walter, AW Ryzhova, M Zheludkova, O Kumirova, E Alshami, J Croul, SE Rutka, JT Hawkins, C Tabori, U Codispoti, KET Packer, RJ Pfister, SM Korshunov, A Taylor, MD AF Ramaswamy, Vijay Remke, Marc Et, Eric Bouff Faria, Claudia C. Perreault, Sebastien Cho, Yoon-Jae Shih, David J. Luu, Betty Dubuc, Adrian M. Northcott, Paul A. Schueller, Ulrich Gururangan, Sridharan McLendon, Roger Bigner, Darell Fouladi, Maryam Ligon, Keith L. Pomeroy, Scott L. Dunn, Sandra Triscott, Joanna Jabado, Nada Fontebasso, Adam Jones, David T. W. Kool, Marcel Karajannis, Matthias A. Gardner, Sharon L. Zagzag, David Nunes, Sofi A. Pimentel, Jose Mora, Jaume Lipp, Eric Walter, Andrew W. Ryzhova, Marina Zheludkova, Olga Kumirova, Ella Alshami, Jad Croul, Sidney E. Rutka, James T. Hawkins, Cynthia Tabori, Uri Codispoti, Kari-Elise T. Packer, Roger J. Pfister, Stefan M. Korshunov, Andrey Taylor, Michael D. TI Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis SO LANCET ONCOLOGY LA English DT Article ID INTRATUMOR HETEROGENEITY; CHILDREN; DISTINCT; CANCER; CHEMOTHERAPY; ADOLESCENTS; ABERRATIONS; PROGRESSION; MUTATIONS; PROGNOSIS AB Background Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. Methods We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2:samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3:samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Results Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0.0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0.0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0.0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0.013) than with other subgroups, which was confirmed in cohort 2 (p=0.0075), but not cohort 3 (p=0.70). Interpretation Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. C1 [Ramaswamy, Vijay; Remke, Marc; Faria, Claudia C.; Shih, David J.; Dubuc, Adrian M.; Rutka, James T.; Hawkins, Cynthia; Taylor, Michael D.] Hosp Sick Children, Div Neurosurg, Toronto, ON M5G 1X8, Canada. [Et, Eric Bouff; Tabori, Uri] Hosp Sick Children, Div Pediat Hematol Oncol, Toronto, ON M5G 1X8, Canada. [Ramaswamy, Vijay; Remke, Marc; Et, Eric Bouff; Faria, Claudia C.; Shih, David J.; Luu, Betty; Dubuc, Adrian M.; Croul, Sidney E.; Rutka, James T.; Hawkins, Cynthia; Tabori, Uri; Taylor, Michael D.] Hosp Sick Children, Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1X8, Canada. [Ramaswamy, Vijay; Remke, Marc; Shih, David J.; Dubuc, Adrian M.; Rutka, James T.; Taylor, Michael D.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Faria, Claudia C.] Ctr Hosp Lisboa Norte, EPE, Hosp Santa Maria, Div Neurosurg, Lisbon, Portugal. [Pimentel, Jose] Ctr Hosp Lisboa Norte, EPE, Hosp Santa Maria, Neuropathol Lab, Lisbon, Portugal. [Perreault, Sebastien; Cho, Yoon-Jae] Stanford Univ, Dept Neurol, Palo Alto, CA 94304 USA. [Northcott, Paul A.; Jones, David T. W.; Kool, Marcel; Pfister, Stefan M.] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany. [Korshunov, Andrey] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, Heidelberg, Germany. [Schueller, Ulrich] Univ Munich, Ctr Neuropathol, Munich, Germany. [Gururangan, Sridharan; McLendon, Roger; Bigner, Darell; Lipp, Eric] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Durham, NC USA. [Fouladi, Maryam] Cincinnati Childrens Hosp, Div Hematol Oncol, Cincinnati, OH USA. [Ligon, Keith L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Pomeroy, Scott L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Ligon, Keith L.] Boston Childrens Hosp, Boston, MA USA. [Ligon, Keith L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Pomeroy, Scott L.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Dunn, Sandra; Triscott, Joanna] British Columbia Childrens Hosp, Div Hematol Oncol, Vancouver, BC V6H 3V4, Canada. [Jabado, Nada; Fontebasso, Adam; Alshami, Jad] Montreal Childrens Hosp, Div Pediat Hematol Oncol, Montreal, PQ H3H 1P3, Canada. [Karajannis, Matthias A.; Gardner, Sharon L.] NYU Langone Med Ctr, Div Pediat Hematol Oncol, New York, NY USA. [Zagzag, David] NYU Langone Med Ctr, Dept Pathol, New York, NY USA. [Zagzag, David] NYU Langone Med Ctr, Dept Neurosurg, New York, NY USA. [Nunes, Sofi A.] Inst Portugues Oncol Francisco Gentil, Unidade Neurooncol Pediat, Lisbon, Portugal. [Mora, Jaume] Hosp St Joan de Deu Barcelona, Dept Oncol, Barcelona, Spain. [Walter, Andrew W.] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Ryzhova, Marina] NN Burdenko Inst Neurosurg, Dept Neuropathol, Moscow, Russia. [Zheludkova, Olga; Kumirova, Ella] Dmitry Rogachev Fed Res Ctr Pediat Hematol Oncol, Dept Pediat Neurooncol, Moscow, Russia. [Codispoti, Kari-Elise T.; Packer, Roger J.] Childrens Natl Med Ctr, Ctr Neurosci & Behav Med, Washington, DC 20010 USA. [Pfister, Stefan M.] Univ Heidelberg Hosp, Dept Pediat Hematol & Oncol, Heidelberg, Germany. [Korshunov, Andrey] Heidelberg Univ, Dept Neuropathol, Heidelberg, Germany. RP Taylor, MD (reprint author), Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM mdtaylor@sickkids.ca RI Kool, Marcel/H-2541-2013; Shih, David/H-3186-2011; Pfister, Stefan/F-6860-2013; OI Shih, David/0000-0002-9802-4937; Pfister, Stefan/0000-0002-5447-5322; Tabori, Uri/0000-0002-5019-2683; Pimentel, Jose/0000-0002-6101-6650; Ramaswamy, Vijay/0000-0002-6557-895X; Remke, Marc/0000-0002-9404-9993; Karajannis, Matthias/0000-0002-7151-6528; gardner, sharon/0000-0002-8857-5487 FU CIHR Clinician Scientist Phase II award; Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children; University of Toronto; Canadian Institutes of Health Research; National Institutes of Health [R01CA159859, R01CA148699]; Pediatric Brain Tumor Foundation; CIHR fellowship; Alberta Innovates-Health Solutions Clinical Fellowship; National Center for Research Resources, National Institutes of Health [UL1TR000038]; National Cancer Institute [5P30CA016087-32]; Mildred Scheel Cancer Foundation; Deutsche Kinderkrebsstiftung FX MDT is supported by a CIHR Clinician Scientist Phase II award, funds from the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto, and operating funds from the Canadian Institutes of Health Research, the National Institutes of Health (R01CA159859 and R01CA148699) and the Pediatric Brain Tumor Foundation. VR is supported by a CIHR fellowship and an Alberta Innovates-Health Solutions Clinical Fellowship. SG, RM, and DB are supported by the Pediatric Brain Tumor Foundation. MK, SG, DZ are supported in part by grant UL1TR000038 from the National Center for Research Resources, National Institutes of Health and grant 5P30CA016087-32 from the National Cancer Institute. MR is supported by a fellowship from the Mildred Scheel Cancer Foundation. SMP is supported by a grant from the Deutsche Kinderkrebsstiftung. We thank Susan Archer for technical writing. NR 32 TC 57 Z9 58 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD NOV PY 2013 VL 14 IS 12 BP 1200 EP 1207 DI 10.1016/S1470-2045(13)70449-2 PG 8 WC Oncology SC Oncology GA 242WK UT WOS:000326275300045 PM 24140199 ER PT J AU Henriquez, OA Schlosser, RJ Mace, JC Smith, TL Soler, ZM AF Henriquez, Oswaldo A. Schlosser, Rodney J. Mace, Jess C. Smith, Timothy L. Soler, Zachary M. TI Impact of Synechiae After Endoscopic Sinus Surgery on Long-Term Outcomes in Chronic Rhinosinusitis SO LARYNGOSCOPE LA English DT Article DE Chronic; sinusitis; outcomes; assessment AB Objectives/HypothesisSynechiae are one of the most common unwanted outcomes after endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS). However, there has been scant investigation into the true significance of synechiae formation after ESS. The aim of this study was to evaluate the impact of synechiae formation on health-related quality of life (HRQoL) outcomes after ESS in patients with CRS. Study DesignProspective, multi-institutional cohort. MethodsRhinosinusitis Disability Index (RSDI) and Chronic Sinusitis Survey (CSS) scores were measured in adult patients before and after undergoing ESS for CRS. Differences in HRQoL were evaluated between those who developed sinonasal synechiae and those who did not, controlling for demographic factors, medical comorbidities, and measures of disease severity at baseline. ResultsA total of 286 patients underwent ESS, with 55 (19.2%) developing synechiae in the follow-up period. Patients developing synechiae reported significantly less improvement on the RSDI total scores (13.5 vs. 21.4, P=0.008), RSDI physical subscores (5.3 vs. 8.3, P=0.007), RSDI emotional subscores (2.9 vs. 5.8, P = 0.008), CSS total scores (14.5 vs. 21.2, P = 0.093), and CSS symptom subscores (19.9 vs 30.3, P = 0.069) compared to those who did not develop synechiae postoperatively. These differences persisted even after controlling for baseline differences in disease severity. ConclusionsSynechiae of the sinonasal cavity commonly occurs following ESS, particularly in those undergoing revision surgeries. Although both groups improve, the degree of HRQoL improvement appears to be less in those who form postoperative synechiae after surgery compared to those who do not. C1 [Henriquez, Oswaldo A.; Schlosser, Rodney J.; Soler, Zachary M.] Med Univ S Carolina, Div Rhinol & Sinus Surg, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. [Schlosser, Rodney J.] Ralph H Johnson VA Med Ctr, Dept Surg, Charleston, SC USA. [Mace, Jess C.; Smith, Timothy L.] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Div Rhinol & Sinus Surg, Oregon Sinus Ctr, Portland, OR 97201 USA. RP Soler, ZM (reprint author), Med Univ S Carolina, Div Rhinol & Sinus Surg, Dept Otolaryngol Head & Neck Surg, 135 Rutledge Ave,MSC 550, Charleston, SC 29425 USA. EM solerz@musc.edu FU National Institute on Deafness and Other Communication Disorders (NIDCD), one of the National Institutes of Health, Bethesda, MD [2R01 DC005805]; VA Merit; NeilMed; Medtronic; Arthrocare FX Zachary M. Soler, MD, MSc Jess C. Mace, MPH, and Timothy L. Smith, MD, MPH are supported by a grant from the National Institute on Deafness and Other Communication Disorders (NIDCD), one of the National Institutes of Health, Bethesda, MD. (2R01 DC005805; PI: T. L. Smith). Public clinical trial registration ID#NCT01332136: (http://www.clinicaltrials.gov). Timothy L. Smith, MD is also a consultant for Intersect ENT (Palo Alto, CA.), which is not affiliated in any way with this investigation. Rodney J. Schlosser, MD is a consultant for Brain-LAB, Olympus, and Sunovion and receives grant support from a VA Merit, NeilMed, Medtronic, and Arthrocare. None of these are affiliated with this study. The authors have no other funding, financial relationships, or conflicts of interest to disclose. NR 19 TC 9 Z9 10 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD NOV PY 2013 VL 123 IS 11 BP 2615 EP 2619 DI 10.1002/lary.24150 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 242IA UT WOS:000326231200018 PM 23670876 ER PT J AU Mahboubi, H Salibian, AA Wu, EC Patel, MS Armstrong, WB AF Mahboubi, Hossein Salibian, Ara A. Wu, Edward C. Patel, Madhukar S. Armstrong, William B. TI Contributing Factors to Adoption of Electronic Medical Records in Otolaryngology Offices SO LARYNGOSCOPE LA English DT Article DE Electronic medical record (EMR); electronic health record; otolaryngology; outpatients; National Ambulatory Medical Care Survey (NAMCS); physician office; meaningful use ID HEALTH RECORDS; INFORMATICS COMMITTEE; AMBULATORY-CARE; MEANINGFUL USE; PHYSICIANS; SYSTEMS; RECOMMENDATIONS; BENEFITS AB Objectives/Hypothesis(1) To determine the characteristics of outpatient otolaryngology offices with an electronic medical record (EMR) system, and (2) to compare those characteristics with the trends in surgical and medical specialties. Study DesignCross-sectional analysis of U.S. representative data from the National Ambulatory Medical Care Survey (NAMCS). MethodsThe 2005 to 2010 NAMCS datasets were analyzed. Physicians' specialty was recoded as otolaryngology, all surgical specialties, and all specialties combined. Physician offices with all- or partial-EMR system adoption were then compared to offices without EMR systems with respect to year; geographic region; urban setting; office setting; practice type; practice ownership; employment status; and revenues from Medicare, Medicaid, private insurance, and patient payment. ResultsUpon univariate analysis, EMR use was significantly higher among otolaryngology practices located in metropolitan areas and practices run or owned by larger groups of practitioners. Sources of patient revenue did not correlate with the likelihood of EMR use. Multivariate analysis revealed that EMR use by otolaryngologists was significantly associated with group practices and offices owned by institutions. Similar associations were observed with surgical specialties combined in addition to a higher EMR usage in practices with more than 25% of total revenue from private insurance. ConclusionsEMR utilization by otolaryngology practices appears similar to that of other specialties, and is more likely in metropolitan areas and larger practice settings. Despite the announcement of incentive programs under Medicare and Medicaid in 2009, EMR usage was not dependent on the percentage of physicians' total revenue from these sources. Level of EvidenceN/A. Laryngoscope, 123:2658-2663, 2013 C1 [Mahboubi, Hossein; Salibian, Ara A.; Armstrong, William B.] Univ Calif Irvine, Dept Otolaryngol Head & Neck Surg, Orange, CA 92868 USA. [Wu, Edward C.] Univ Calif Los Angeles, Dept Head & Neck Surg, Los Angeles Med Ctr, Los Angeles, CA USA. [Patel, Madhukar S.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Armstrong, WB (reprint author), Univ Calif Irvine, Dept Otolaryngol Head & Neck Surg, 101 City Dr S,Bldg 56,Ste 500, Orange, CA 92868 USA. EM wbarmstr@uci.edu OI Mahboubi, Hossein/0000-0003-4418-5302; Kuan, Edward/0000-0003-3475-0718 NR 30 TC 1 Z9 1 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD NOV PY 2013 VL 123 IS 11 BP 2658 EP 2663 DI 10.1002/lary.24205 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 242IA UT WOS:000326231200026 PM 23712468 ER PT J AU Chambers, KJ Setlur, J Hartnick, CJ AF Chambers, Kyle J. Setlur, Jennifer Hartnick, Christopher J. TI Chiari Type I Malformation: Presenting as Chronic Cough in Older Children SO LARYNGOSCOPE LA English DT Article DE Pediatric cough; chronic cough; Chiari type I malformation; cranial neuropathy; imaging ID INFANTS AB To highlight an unusual cause of chronic cough, we present two cases of chronic cough in older children referred to a pediatric otolaryngology outpatient clinic with persistent symptoms despite extensive previous workup and treatment. Cranial neuropathy was identified in each case. As a result, magnetic resonance imaging was performed revealing Chiari type I malformation. In each case, surgical decompression provided symptom improvement. Chronic cough is a rare presenting symptom in children with Chiari type I malformation. We emphasize the significance of awareness for unusual cases of cough to aid in the correct identification and treatment in children. Laryngoscope, 123:2888-2891, 2013 C1 [Hartnick, Christopher J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Hartnick, CJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM Christopher_hartnick@meei.harvard.edu NR 10 TC 1 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD NOV PY 2013 VL 123 IS 11 BP 2888 EP 2891 DI 10.1002/lary.24086 PG 4 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 242IA UT WOS:000326231200064 PM 23553277 ER PT J AU Oates, JC Mashmoushi, AK Shaftman, SR Gilkeson, GS AF Oates, J. C. Mashmoushi, A. K. Shaftman, S. R. Gilkeson, G. S. TI NADPH oxidase and nitric oxide synthase-dependent superoxide production is increased in proliferative lupus nephritis SO LUPUS LA English DT Article DE Lupus nephritis; systemic lupus erythematosus; nitric oxide; endothelial nitric oxide synthase; NADPH oxidase; proliferative lupus nephritis; superoxide; oxidation-reduction; inflammation ID HUMAN ENDOTHELIAL-CELLS; MRL-LPR/LPR MICE; AUTOIMMUNE-DISEASE; OXIDATIVE STRESS; GENETIC-ANALYSIS; ERYTHEMATOSUS; GLOMERULONEPHRITIS; 3-NITROTYROSINE; EXPRESSION; TETRAHYDROBIOPTERIN AB Objective Lupus nephritis (LN) is an immune complex-mediated glomerulonephritis. Proliferative LN (PLN, ISN/RPS classes III and IV)) often leads to renal injury or failure despite traditional induction and maintenance therapy. Successful targeted therapeutic development requires insight into mediators of inflammation in PLN. Superoxide (SO) and its metabolites are mediators of the innate immune response through their ability to mediate reduction-oxidation signaling. Endothelial nitric oxide synthase (eNOS) modulates inflammatory responses in endothelial cells. We hypothesized that markers of SO production would be increased in active PLN and that SO production would be dependent on the activity of select enzymes in the renal cortex. Methods Patients with systemic lupus erythematosus were enrolled at the time of renal biopsy for active LN of all classes. Serum collected at baseline was analyzed by HPLC with electrochemical detection for markers of SO production (durable modifications of serum protein Tyr ultimately requiring SO as a substrate). Renal cortex from MRL/MpJ-FAS(lpr) (MRL/lpr) mice with and without functional eNOS was analyzed during active disease for superoxide (SO) production with and without inhibitors of SO-producing enzymes. Results Serum protein modifications indicative of total SO production were significantly higher in patients with PLN. These markers were increased in association with more active, inflammatory PLN. Mice lacking functional eNOS had 80% higher levels of renal cortical SO during active disease, and inhibitors of nitric oxide synthase and NADPH oxidase reduced these levels by 60% and 77%, respectively. Conclusion These studies demonstrate that SO production is unique to active PLN in a NOS and NADPH oxidase-dependent fashion. These findings suggest the emulating or augmenting eNOS activity or inhibiting NADPH oxidase SO production may be targets of therapy in patients with PLN. The markers of SO production used in this study could rationally be used to select SO-modulating therapies and serve as pharmacodynamic indicators for dose titration. C1 [Oates, J. C.; Mashmoushi, A. K.; Gilkeson, G. S.] Med Univ S Carolina, Dept Med, Div Rheumatol, Charleston, SC 29425 USA. [Shaftman, S. R.] Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, Charleston, SC 29425 USA. [Oates, J. C.; Gilkeson, G. S.] Ralph H Johnson VA Med Ctr, Med Serv, Charleston, SC USA. RP Oates, JC (reprint author), Med Univ S Carolina, Dept Med, Div Rheumatol, 96 Jonathan Lucas St,MSC 637, Charleston, SC 29425 USA. EM oatesjc@musc.edu FU Arthritis Foundation, Atlanta, GA; University Research Committee at the Medical University of SC; Medical University of SC General Clinical Research Center [NIH] [MO1RR001070]; Medical University of SC Clinical and Translational Science Award [UL1TR000062, U54RR026107]; Division of Rheumatology and Immunology Multidisciplinary Clinical Research Center [P60AR062755]; National Institutes of Health [K08AR002193, AI047469, AR045476, AR04745]; Ralph H. Johnson VAMC Medical Research Service; Department of Veterans Affairs Career Development, Research Enhancement Awards FX This work was supported by the Arthritis Foundation, Atlanta, GA, the University Research Committee at the Medical University of SC, the Medical University of SC General Clinical Research Center [NIH grant number MO1RR001070], the Medical University of SC Clinical and Translational Science Award [grant number UL1TR000062, formerly U54RR026107], the Division of Rheumatology and Immunology Multidisciplinary Clinical Research Center [grant number P60AR062755], and National Institutes of Health [grant numbers K08AR002193, AI047469, AR045476, and AR04745], the Ralph H. Johnson VAMC Medical Research Service, and the Department of Veterans Affairs Career Development, Research Enhancement Awards. NR 47 TC 2 Z9 2 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0961-2033 EI 1477-0962 J9 LUPUS JI Lupus PD NOV PY 2013 VL 22 IS 13 BP 1361 EP 1370 DI 10.1177/0961203313507988 PG 10 WC Rheumatology SC Rheumatology GA 239GY UT WOS:000326011800006 PM 24106214 ER PT J AU Romero-Perez, L Lopez-Garcia, MA Diaz-Martin, J Biscuola, M Castilla, MA Tafe, LJ Garg, K Oliva, E Matias-Guiu, X Soslow, RA Palacios, J AF Romero-Perez, Laura Angeles Lopez-Garcia, M. Diaz-Martin, Juan Biscuola, Michele Angeles Castilla, M. Tafe, Laura J. Garg, Karuna Oliva, Esther Matias-Guiu, Xavier Soslow, Robert A. Palacios, Jose TI ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma SO MODERN PATHOLOGY LA English DT Article DE E-cadherin; miR-200s; undifferentiated endometrial carcinoma; ZEB1 ID EPITHELIAL-MESENCHYMAL TRANSITION; MIR-200 FAMILY; FEEDBACK LOOP; CANCER-CELLS; DEDIFFERENTIATED CARCINOMA; TARGETING ZEB1; BREAST-CANCER; EXPRESSION; HYPERMETHYLATION; PHENOTYPE AB Undifferentiated endometrial carcinomas are very aggressive high-grade endometrial carcinomas that are frequently under-recognized. This study aimed to analyze the molecular alterations underlying the development of these endometrial carcinomas, focusing on those related to dedifferentiation. We assessed a series of 120 tumors: 57 grade 1 and 2 endometrioid endometrial carcinomas, 15 grade 3 endometrioid endometrial carcinomas, 27 endometrial serous carcinomas, and 21 undifferentiated endometrial carcinomas. We found a high frequency of DNA mismatch repair deficiency (38%) and moderate rate of p53 overexpression (similar to 33%) in undifferentiated carcinomas. In contrast to the characteristic endometrioid phenotype, there was a dramatic downregulation of E-cadherin expression in the undifferentiated subtype. Quantitative methylation studies dismissed CDH1 promoter hypermethylation as the mechanism responsible for this change in gene expression, while immunohistochemistry revealed that the E-cadherin repressor ZEB1 was frequently overexpressed (62%) in undifferentiated endometrial carcinomas. This finding was accompanied by a sharp downregulation in the expression of the miR-200 family of microRNAs, well-known targets of ZEB1. Furthermore, there was enhanced expression of epithelial-to-mesenchymal transition markers in undifferentiated endometrial carcinomas, such as N-cadherin, cytoplasmic p120, and osteonectin. In addition, HMGA2, a regulator of epithelial-to-mesenchymal transition that is expressed in aggressive endometrial tumors, such as endometrial serous carcinomas and carcinosarcomas, was expressed in >20% of undifferentiated carcinomas. These results suggest that ZEB1 overexpression, associated with E-cadherin and miR-200s downregulation, and the expression of mesenchymal markers might enhance the metastatic potential of undifferentiated endometrial carcinomas, leading to a poor prognosis. In addition, our observations suggest that the immnohistochemical analysis of E-cadherin and ZEB1 can aid in the differential diagnosis of the more agressive undifferentiated endometrial carcinomas from grade 3 endometrioid carcinomas. C1 [Romero-Perez, Laura; Angeles Lopez-Garcia, M.; Diaz-Martin, Juan; Biscuola, Michele; Angeles Castilla, M.] Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Dept Pathol,Inst Biomed Sevilla IBiS, Seville, Spain. [Tafe, Laura J.] Darmouth Hitchcock Med Ctr, Dept Pathol, Lebanon, NH USA. [Garg, Karuna; Soslow, Robert A.] Mem Hosp, Mem Sloan Kettering Ctr, Dept Pathol, New York, NY 10065 USA. [Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Matias-Guiu, Xavier] Univ Lleida, Hosp Univ Arnau de Vilanova, Dept Pathol & Mol Genet, IRBLleida, Lleida, Spain. [Palacios, Jose] Hosp Univ Ramon y Cajal, Inst Invest Sanitaria Ramon y Cajal IRYCIS, Dept Pathol, Madrid 28034, Spain. RP Soslow, RA (reprint author), Mem Hosp, Mem Sloan Kettering Ctr, Dept Pathol, 1275 York Ave, New York, NY 10065 USA. EM soslowr@mskcc.org; jose.palacios@salud.madrid.org RI matias-guiu, xavier/C-3039-2009; Romero-Perez, Laura/C-8314-2015; Castilla, M Angeles/C-9454-2015; Diaz-Martin, Juan/F-4765-2015; IBIS, SARCOMAS/O-1893-2015; OI matias-guiu, xavier/0000-0002-7201-6605; Romero-Perez, Laura/0000-0003-3196-4382; Soslow, Robert/0000-0002-7269-5898 FU Instituto de Salud Carlos III (ISCIII) [PI080971]; European Development Regional Fund, 'A way to achieve Europe' EDRF [RD12/0036/0064]; Junta de Andalucia (Consejeria de Salud) [PI0581/2009]; Asociacion Espanola Contra el Cancer, Red de Grupos estables en Oncologia [AECC-2011]; PFIS [F109/00193]; Consejeria de Salud, Junta de Andalucia [PI0581/2009]; ISCIII-Red de Biobancos [RD09/0076/00085]; ISCIII [RD06/0020/0013]; [FISPI10/00922]; [2009SGR794]; [RD12/0036/0013] FX We thank Ana Santos, Ma Jose Hernandez, and Susana Ramiro for their excellent technical assistance. We would also like to acknowledge Dr David Huntman's and Osama Al-Agha's contributions during the early phases of this work. This work was supported by grants from the Instituto de Salud Carlos III (ISCIII; Grant No. PI080971) co-financed by the European Development Regional Fund, 'A way to achieve Europe' EDRF (Grant No. RD12/0036/0064); the Junta de Andalucia (Consejeria de Salud, Grant No. PI0581/2009) to JP; grants FISPI10/00922, 2009SGR794, RD12/0036/0013, and by a grant from the Asociacion Espanola Contra el Cancer, Red de Grupos estables en Oncologia (AECC-2011) to XM-G. LR-P is a PhD student recipient of a PFIS fellowship (Grant No. F109/00193). JD-M is a PhD researcher funded by the Consejeria de Salud, Junta de Andalucia (PI0581/2009). MB is a researcher funded by the ISCIII-Red de Biobancos RD09/0076/00085 and MAC is a PhD researcher funded by the ISCIII (Grant No. RD06/0020/0013). NR 35 TC 27 Z9 29 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD NOV PY 2013 VL 26 IS 11 BP 1514 EP 1524 DI 10.1038/modpathol.2013.93 PG 11 WC Pathology SC Pathology GA 248GV UT WOS:000326686700013 PM 23743934 ER PT J AU Park, E Kim, JM Primack, B Weinstock, DM Moreau, LA Parmar, K D'Andrea, AD AF Park, Eunmi Kim, Jung Min Primack, Benjamin Weinstock, David M. Moreau, Lisa A. Parmar, Kalindi D'Andrea, Alan D. TI Inactivation of Uaf1 Causes Defective Homologous Recombination and Early Embryonic Lethality in Mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FANCONI-ANEMIA PATHWAY; STRAND BREAK REPAIR; DNA-DAMAGE RESPONSE; MAMMALIAN-CELLS; UBIQUITIN; FANCD2; SENSITIVITY; INHIBITION; STABILITY; CHOICE AB The deubiquitinating enzyme heterodimeric complex USP1-UAF1 regulates the Fanconi anemia (FA) DNA repair pathway. Absence of this complex leads to increased cellular levels of ubiquitinated FANCD2 (FANCD2-Ub) and ubiquitinated PCNA (PCNA-Ub). Mice deficient in the catalytic subunit of the complex, USP1, exhibit an FA-like phenotype and have a cellular deficiency in homologous-recombination (HR) repair. Here, we have characterized mice deficient in the UAF1 subunit. Uaf1(+/-) mice were small at birth and exhibited reduced fertility, thus resembling Usp1(-/-) mice. Unexpectedly, homozygous Uaf1(-/-) embryos died at embryonic day 7.5 (E7.5). These mutant embryos were small and developmentally retarded. As expected, Uaf1 deficiency in mice led to increased levels of cellular Fancd2-Ub and Pcna-Ub. Uaf1(+/-) murine embryonic fibroblasts (MEFs) exhibited profound chromosome instability, genotoxin hypersensitivity, and a significant defect in homologous-recombination repair. Moreover, Uaf1(-/-) mouse embryonic stem cells (mESCs) showed chromosome instability, genotoxin hypersensitivity, and impaired Fancd2 focus assembly. Similar to USP1 knockdown, UAF1 knockdown in tumor cells caused suppression of tumor growth in vivo. Taken together, our data demonstrate the important regulatory role of the USP1-UAF1 complex in HR repair through its regulation of the FANCD2-Ub and PCNA-Ub cellular pools. C1 [Park, Eunmi; Kim, Jung Min; Primack, Benjamin; Moreau, Lisa A.; Parmar, Kalindi; D'Andrea, Alan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Weinstock, David M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. EM Alan_Dandrea@dfci.harvard.edu FU Susan G. Komen Foundation [KG101186]; NIH [R01DK43889, R01HL52725, P01HL048546]; Center of Excellence in Molecular Hematology grant [5P30 DK49216-19] FX E.P. was supported by postdoctoral fellowships from the Susan G. Komen Foundation (KG101186). This study was supported by NIH grants R01DK43889, R01HL52725, and P01HL048546 to A. D. D. This work was also supported in part by a Center of Excellence in Molecular Hematology grant (5P30 DK49216-19). NR 30 TC 13 Z9 13 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD NOV PY 2013 VL 33 IS 22 BP 4360 EP 4370 DI 10.1128/MCB.00870-13 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 240LX UT WOS:000326099000001 PM 24001775 ER PT J AU Qiao, DH Meyer, K Friedl, A AF Qiao, Dianhua Meyer, Kristy Friedl, Andreas TI Glypican 1 Stimulates S Phase Entry and DNA Replication in Human Glioma Cells and Normal Astrocytes (Retracted article. See vol. 36, pg. 2105, 2016) SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article; Retracted Publication ID SKP2 AUTOINDUCTION LOOP; TRANSGENIC MICE; BRAIN CANCER; CYCLE; GLIOBLASTOMA; GENE; P53; INSTABILITY; INHIBITORS; STABILITY AB Malignant gliomas are highly lethal neoplasms with limited treatment options. We previously found that the heparan sulfate proteoglycan glypican 1 (GPC1) is universally and highly expressed in human gliomas. In this study, we investigated the biological activity of GPC1 expression in both human glioma cells and normal astrocytes in vitro. Expression of GPC1 inactivates the G(1)/S checkpoint and strongly stimulates DNA replication. Constitutive expression of GPC1 causes DNA rereplication and DNA damage, suggesting a mutagenic activity for GPC1. GPC1 expression leads to a significant downregulation of the tumor suppressors pRb, Cip/Kip cyclin-dependent kinase inhibitors (CKIs), and CDH1, and upregulation of the pro-oncogenic proteins cyclin E, cyclin-dependent kinase 2 (CDK2), Skp2, and Cdt1. These GPC1-induced changes are accompanied by a significant reduction in all types of D cyclins, which is independent of serum supplementation. It is likely that GPC1 stimulates the so-called Skp2 autoinduction loop, independent of cyclin D-CDK4/6. Knockdown of Skp2, CDK2, or cyclin E, three key elements within the network modulated by GPC1, results in a reduction of the S phase and aneuploid fractions, implying a functional role for these regulators in GPC1-induced S phase entry and DNA rereplication. In addition, a significant activation of both the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways by GPC1 is seen in normal human astrocytes even in the presence of growth factor supplement. Both pathways are constitutively activated in human gliomas. The surprising magnitude and the mitogenic and mutagenic nature of the effect exerted by GPC1 on the cell cycle imply that GPC1 may play an important role in both glioma tumorigenesis and growth. C1 [Qiao, Dianhua; Meyer, Kristy; Friedl, Andreas] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. [Friedl, Andreas] William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, Dept Vet Affairs Med Ctr, Madison, WI 53705 USA. [Friedl, Andreas] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. RP Friedl, A (reprint author), Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. EM afriedl@wisc.edu FU UWCCC [P30 CA014520]; Biomedical Laboratory Research and Development Service of the VA Office of Research and Development [I01BX000137] FX This work was supported by UWCCC core grant P30 CA014520 and by award number I01BX000137 from the Biomedical Laboratory Research and Development Service of the VA Office of Research and Development. NR 45 TC 10 Z9 10 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD NOV PY 2013 VL 33 IS 22 BP 4408 EP 4421 DI 10.1128/MCB.00238-13 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 240LX UT WOS:000326099000005 PM 24019070 ER PT J AU Lee, RS Roberts, CWM AF Lee, Ryan S. Roberts, Charles W. M. TI Linking the SWI/SNF complex to prostate cancer SO NATURE GENETICS LA English DT Editorial Material ID PROGRESSION AB Genes encoding subunits of the SWI/SNF chromatin-remodeling complex constitute, collectively, one of the most frequently mutated targets in cancer. Although mutations in SWI/SNF genes are uncommon in prostate cancer, a new study shows that SChLAP1, a long noncoding RNA frequently expressed in aggressive prostate tumors, drives cancer by directly disrupting SNF5, a core subunit of the SWI/SNF complex. C1 [Lee, Ryan S.; Roberts, Charles W. M.] Boston Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Div Hematol Oncol, Boston, MA USA. [Lee, Ryan S.; Roberts, Charles W. M.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Lee, RS (reprint author), Boston Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Div Hematol Oncol, Boston, MA USA. EM charles_roberts@dfci.harvard.edu NR 15 TC 11 Z9 11 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1268 EP 1269 DI 10.1038/ng.2805 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100004 PM 24165726 ER PT J AU Willer, CJ Schmidt, EM Sengupta, S Peloso, GM Gustafsson, S Kanoni, S Ganna, A Chen, J Buchkovich, ML Mora, S Beckmann, JS Bragg-Gresham, JL Chang, HY Demirkan, A Den Hertog, HM Do, R Donnelly, LA Ehret, GB Esko, T Feitosa, MF Ferreira, T Fischer, K Fontanillas, P Fraser, RM Freitag, DF Gurdasani, D Heikkila, K Hypponen, E Isaacs, A Jackson, AU Johansson, A Johnson, T Kaakinen, M Kettunen, J Kleber, ME Li, XH Luan, JA Lyytikainen, LP Magnusson, PKE Mangino, M Mihailov, E Montasser, ME Muller-Nurasyid, M Nolte, IM O'Connell, JR Palmer, CD Perola, M Petersen, AK Sanna, S Saxena, R Service, SK Shah, S Shungin, D Sidore, C Song, C Strawbridge, RJ Surakka, I Tanaka, T Teslovich, TM Thorleifsson, G Van den Herik, EG Voight, BF Volcik, KA Waite, LL Wong, A Wu, Y Zhang, WH Absher, D Asiki, G Barroso, I Been, LF Bolton, JL Bonnycastle, LL Brambilla, P Burnett, MS Cesana, G Dimitriou, M Doney, ASF Doring, A Elliott, P Epstein, SE Eyjolfsson, GI Gigante, B Goodarzi, MO Grallert, H Gravito, ML Groves, CJ Hallmans, G Hartikainen, AL Hayward, C Hernandez, D Hicks, AA Holm, H Hung, YJ Illig, T Jones, MR Kaleebu, P Kastelein, JJP Khaw, KT Kim, E Klopp, N Komulainen, P Kumari, M Langenberg, C Lehtimaki, T Lin, SY Lindstrom, J Loos, RJF Mach, F McArdle, WL Meisinger, C Mitchell, BD Muller, G Nagaraja, R Narisu, N Nieminen, TVM Nsubuga, RN Olafsson, I Ong, KK Palotie, A Papamarkou, T Pomilla, C Pouta, A Rader, DJ Reilly, MP Ridker, PM Rivadeneira, F Rudan, I Ruokonen, A Samani, N Scharnagl, H Seeley, J Silander, K Stancakova, A Stirrups, K Swift, AJ Tiret, L Uitterlinden, AG van Pelt, LJ Vedantam, S Wainwright, N Wijmenga, C Wild, SH Willemsen, G Wilsgaard, T Wilson, JF Young, EH Zhao, JH Adair, LS Arveiler, D Assimes, TL Bandinelli, S Bennett, F Bochud, M Boehm, BO Boomsma, DI Borecki, IB Bornstein, SR Bovet, P Burnier, M Campbell, H Chakravarti, A Chambers, JC Chen, YDI Collins, FS Cooper, RS Danesh, J Dedoussis, G de Faire, U Feranil, AB Ferrieres, J Ferrucci, L Freimer, NB Gieger, C Groop, LC Gudnason, V Gyllensten, U Hamsten, A Harris, TB Hingorani, A Hirschhorn, JN Hofman, A Hovingh, GK Hsiung, CA Humphries, SE Hunt, SC Hveem, K Iribarren, C Jarvelin, MR Jula, A Kahonen, M Kaprio, J Kesaniemi, A Kivimaki, M Kooner, JS Koudstaal, PJ Krauss, RM Kuh, D Kuusisto, J Kyvik, KO Laakso, M Lakka, TA Lind, L Lindgren, CM Martin, NG Marz, W McCarthy, MI McKenzie, CA Meneton, P Metspalu, A Moilanen, L Morris, AD Munroe, PB Njolstad, I Pedersen, NL Power, C Pramstaller, PP Price, JF Psaty, BM Quertermous, T Rauramaa, R Saleheen, D Salomaa, V Sanghera, DK Saramies, J Schwarz, PEH Sheu, WHH Shuldiner, AR Siegbahn, A Spector, TD Stefansson, K Strachan, DP Tayo, BO Tremoli, E Tuomilehto, J Uusitupa, M van Duijn, CM Vollenweider, P Wallentin, L Wareham, NJ Whitfield, JB Wolffenbuttel, BHR Ordovas, JM Boerwinkle, E Palmer, CNA Thorsteinsdottir, U Chasman, DI Rotter, JI Franks, PW Ripatti, S Cupples, LA Sandhu, MS Rich, SS Boehnke, M Deloukas, P Kathiresan, S Mohlke, KL Ingelsson, E Abecasis, GR AF Willer, Cristen J. Schmidt, Ellen M. Sengupta, Sebanti Peloso, Gina M. Gustafsson, Stefan Kanoni, Stavroula Ganna, Andrea Chen, Jin Buchkovich, Martin L. Mora, Samia Beckmann, Jacques S. Bragg-Gresham, Jennifer L. Chang, Hsing-Yi Demirkan, Ayse Den Hertog, Heleen M. Do, Ron Donnelly, Louise A. Ehret, Georg B. Esko, Tonu Feitosa, Mary F. Ferreira, Teresa Fischer, Krista Fontanillas, Pierre Fraser, Ross M. Freitag, Daniel F. Gurdasani, Deepti Heikkila, Kauko Hyppoenen, Elina Isaacs, Aaron Jackson, Anne U. Johansson, Asa Johnson, Toby Kaakinen, Marika Kettunen, Johannes Kleber, Marcus E. Li, Xiaohui Luan, Jian'an Lyytikainen, Leo-Pekka Magnusson, Patrik K. E. Mangino, Massimo Mihailov, Evelin Montasser, May E. Mueller-Nurasyid, Martina Nolte, Ilja M. O'Connell, Jeffrey R. Palmer, Cameron D. Perola, Markus Petersen, Ann-Kristin Sanna, Serena Saxena, Richa Service, Susan K. Shah, Sonia Shungin, Dmitry Sidore, Carlo Song, Ci Strawbridge, Rona J. Surakka, Ida Tanaka, Toshiko Teslovich, Tanya M. Thorleifsson, Gudmar Van den Herik, Evita G. Voight, Benjamin F. Volcik, Kelly A. Waite, Lindsay L. Wong, Andrew Wu, Ying Zhang, Weihua Absher, Devin Asiki, Gershim Barroso, Ines Been, Latonya F. Bolton, Jennifer L. Bonnycastle, Lori L. Brambilla, Paolo Burnett, Mary S. Cesana, Giancarlo Dimitriou, Maria Doney, Alex S. F. Doering, Angela Elliott, Paul Epstein, Stephen E. Eyjolfsson, Gudmundur Ingi Gigante, Bruna Goodarzi, Mark O. Grallert, Harald Gravito, Martha L. Groves, Christopher J. Hallmans, Goran Hartikainen, Anna-Liisa Hayward, Caroline Hernandez, Dena Hicks, Andrew A. Holm, Hilma Hung, Yi-Jen Illig, Thomas Jones, Michelle R. Kaleebu, Pontiano Kastelein, John J. P. Khaw, Kay-Tee Kim, Eric Klopp, Norman Komulainen, Pirjo Kumari, Meena Langenberg, Claudia Lehtimaki, Terho Lin, Shih-Yi Lindstrom, Jaana Loos, Ruth J. F. Mach, Francois McArdle, Wendy L. Meisinger, Christa Mitchell, Braxton D. Mueller, Gabrielle Nagaraja, Ramaiah Narisu, Narisu Nieminen, Tuomo V. M. Nsubuga, Rebecca N. Olafsson, Isleifur Ong, Ken K. Palotie, Aarno Papamarkou, Theodore Pomilla, Cristina Pouta, Anneli Rader, Daniel J. Reilly, Muredach P. Ridker, Paul M. Rivadeneira, Fernando Rudan, Igor Ruokonen, Aimo Samani, Nilesh Scharnagl, Hubert Seeley, Janet Silander, Kaisa Stancakova, Alena Stirrups, Kathleen Swift, Amy J. Tiret, Laurence Uitterlinden, Andre G. van Pelt, L. Joost Vedantam, Sailaja Wainwright, Nicholas Wijmenga, Cisca Wild, Sarah H. Willemsen, Gonneke Wilsgaard, Tom Wilson, James F. Young, Elizabeth H. Zhao, Jing Hua Adair, Linda S. Arveiler, Dominique Assimes, Themistocles L. Bandinelli, Stefania Bennett, Franklyn Bochud, Murielle Boehm, Bernhard O. Boomsma, Dorret I. Borecki, Ingrid B. Bornstein, Stefan R. Bovet, Pascal Burnier, Michel Campbell, Harry Chakravarti, Aravinda Chambers, John C. Chen, Yii-Der Ida Collins, Francis S. Cooper, Richard S. Danesh, John Dedoussis, George de Faire, Ulf Feranil, Alan B. Ferrieres, Jean Ferrucci, Luigi Freimer, Nelson B. Gieger, Christian Groop, Leif C. Gudnason, Vilmundur Gyllensten, Ulf Hamsten, Anders Harris, Tamara B. Hingorani, Aroon Hirschhorn, Joel N. Hofman, Albert Hovingh, G. Kees Hsiung, Chao Agnes Humphries, Steve E. Hunt, Steven C. Hveem, Kristian Iribarren, Carlos Jarvelin, Marjo-Riitta Jula, Antti Kahonen, Mika Kaprio, Jaakko Kesaniemi, Antero Kivimaki, Mika Kooner, Jaspal S. Koudstaal, Peter J. Krauss, Ronald M. Kuh, Diana Kuusisto, Johanna Kyvik, Kirsten O. Laakso, Markku Lakka, Timo A. Lind, Lars Lindgren, Cecilia M. Martin, Nicholas G. Maerz, Winfried McCarthy, Mark I. McKenzie, Colin A. Meneton, Pierre Metspalu, Andres Moilanen, Leena Morris, Andrew D. Munroe, Patricia B. Njolstad, Inger Pedersen, Nancy L. Power, Chris Pramstaller, Peter P. Price, Jackie F. Psaty, Bruce M. Quertermous, Thomas Rauramaa, Rainer Saleheen, Danish Salomaa, Veikko Sanghera, Dharambir K. Saramies, Jouko Schwarz, Peter E. H. Sheu, Wayne H-H Shuldiner, Alan R. Siegbahn, Agneta Spector, Tim D. Stefansson, Kari Strachan, David P. Tayo, Bamidele O. Tremoli, Elena Tuomilehto, Jaakko Uusitupa, Matti van Duijn, Cornelia M. Vollenweider, Peter Wallentin, Lars Wareham, Nicholas J. Whitfield, John B. Wolffenbuttel, Bruce H. R. Ordovas, Jose M. Boerwinkle, Eric Palmer, Colin N. A. Thorsteinsdottir, Unnur Chasman, Daniel I. Rotter, Jerome I. Franks, Paul W. Ripatti, Samuli Cupples, L. Adrienne Sandhu, Manjinder S. Rich, Stephen S. Boehnke, Michael Deloukas, Panos Kathiresan, Sekar Mohlke, Karen L. Ingelsson, Erik Abecasis, Goncalo R. CA Global Lipids Genetics Consortium TI Discovery and refinement of loci associated with lipid levels SO NATURE GENETICS LA English DT Article ID CORONARY-ARTERY-DISEASE; DENSITY-LIPOPROTEIN CHOLESTEROL; GENOME-WIDE ASSOCIATION; HEART-DISEASE; CARDIOVASCULAR-DISEASE; SUSCEPTIBILITY LOCI; IDENTIFIES 13; RISK; GENE; METAANALYSIS AB Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research. C1 [Willer, Cristen J.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Willer, Cristen J.; Schmidt, Ellen M.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Willer, Cristen J.; Sengupta, Sebanti; Chen, Jin; Bragg-Gresham, Jennifer L.; Jackson, Anne U.; Sidore, Carlo; Teslovich, Tanya M.; Boehnke, Michael; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. 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EM cristen@umich.edu; mohlke@med.unc.edu; erik.ingelsson@medsci.uu.se; goncalo@umich.edu RI Schwarz, Peter/B-5127-2013; Wong, Andrew/M-8899-2016; Magnusson, Patrik/C-4458-2017; Beckmann, Jacques S /A-9772-2008; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Rivadeneira, Fernando/O-5385-2015; Lyytikainen, Leo-Pekka/C-8544-2016; Bovet, Pascal/F-4477-2011; Rudan, Igor/I-1467-2012; Papamarkou, Theodore/A-2958-2012; Kyvik, Kirsten /K-5680-2016; Study, GoDARTS/K-9448-2016; Bochud, Murielle/A-3981-2010; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Shah, Sonia/N-7547-2013; Colaus, PsyColaus/K-6607-2013; Deloukas, Panos/B-2922-2013; Strawbridge, Rona/H-5422-2012; Boehm, Bernhard/F-8750-2015; Hypponen, Elina/B-2596-2014; Meisinger, Christine/B-5358-2014; Hsiung, Chao Agnes/E-3994-2010; Wijmenga, Cisca/D-2173-2009; Grallert, Harald/B-3424-2013; Chang, Hsing-Yi /E-3973-2010; Palmer, Colin/C-7053-2008; Pramstaller, Peter/C-2357-2008 OI Kaakinen, Marika/0000-0002-9228-0462; Sidore, Carlo/0000-0001-7504-7477; Shungin, Dmitry/0000-0001-7900-5856; Seeley, Janet/0000-0002-0583-5272; Song, Ci/0000-0002-0947-9068; TREMOLI, ELENA/0000-0002-0929-6106; sanna, serena/0000-0002-3768-1749; Kivimaki, Mika/0000-0002-4699-5627; Johnson, Toby/0000-0002-5998-3270; Schwarz, Peter/0000-0001-6317-7880; Wong, Andrew/0000-0003-2079-4779; Beckmann, Jacques S /0000-0002-9741-1900; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Fraser, Ross/0000-0003-0488-2592; Willer, Cristen/0000-0001-5645-4966; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Rivadeneira, Fernando/0000-0001-9435-9441; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Bovet, Pascal/0000-0002-0242-4259; Rudan, Igor/0000-0001-6993-6884; Papamarkou, Theodore/0000-0002-9689-543X; Kyvik, Kirsten /0000-0003-2981-0245; Bochud, Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Johansson, Asa/0000-0002-2915-4498; Kleber, Marcus/0000-0003-0663-7275; Martin, Nicholas/0000-0003-4069-8020; Ganna, Andrea/0000-0002-8147-240X; Nieminen, Tuomo/0000-0003-1755-1688; Meisinger, Christa/0000-0002-9026-6544; Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Mitchell, Braxton/0000-0003-4920-4744; Kaprio, Jaakko/0000-0002-3716-2455; Esko, Tonu/0000-0003-1982-6569; Lakka, Timo/0000-0002-9199-2871; Gigante, Bruna/0000-0003-4508-7990; Humphries, Stephen E/0000-0002-8221-6547; Gieger, Christian/0000-0001-6986-9554; Wijmenga, Cisca/0000-0002-5635-1614; Franks, Paul/0000-0002-0520-7604; Kumari, Meena/0000-0001-9716-1035; Shah, Sonia/0000-0001-5860-4526; Deloukas, Panos/0000-0001-9251-070X; Strawbridge, Rona/0000-0001-8506-3585; Hypponen, Elina/0000-0003-3670-9399; Palmer, Colin/0000-0002-6415-6560; NR 48 TC 304 Z9 309 U1 10 U2 84 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1274 EP + DI 10.1038/ng.2797 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100007 ER PT J AU Lessard, CJ Li, H Adrianto, I Ice, JA Rasmussen, A Grundahl, KM Kelly, JA Dozmorov, MG Miceli-Richard, C Bowman, S Lester, S Eriksson, P Eloranta, ML Brun, JG Goransson, LG Harboe, E Guthridge, JM Kaufman, KM Kvarnstrom, M Jazebi, H Graham, DSC Grandits, ME Nazmul-Hossain, ANM Patel, K Adler, AJ Maier-Moore, JS Farris, AD Brennan, MT Lessard, JA Chodosh, J Gopalakrishnan, R Hefner, KS Houston, GD Huang, AJW Hughes, PJ Lewis, DM Radfar, L Rohrer, MD Stone, DU Wren, JD Vyse, TJ Gaffney, PM James, JA Omdal, R Wahren-Herlenius, M Illei, GG Witte, T Jonsson, R Rischmueller, M Ronnblom, L Nordmark, G Ng, WF Mariette, X Anaya, JM Rhodus, NL Segal, BM Scofield, RH Montgomery, CG Harley, JB Sivils, KL AF Lessard, Christopher J. Li, He Adrianto, Indra Ice, John A. Rasmussen, Astrid Grundahl, Kiely M. Kelly, Jennifer A. Dozmorov, Mikhail G. Miceli-Richard, Corinne Bowman, Simon Lester, Sue Eriksson, Per Eloranta, Maija-Leena Brun, Johan G. Goransson, Lasse G. Harboe, Erna Guthridge, Joel M. Kaufman, Kenneth M. Kvarnstrom, Marika Jazebi, Helmi Graham, Deborah S. Cunninghame Grandits, Martha E. Nazmul-Hossain, Abu N. M. Patel, Ketan Adler, Adam J. Maier-Moore, Jacen S. Farris, A. Darise Brennan, Michael T. Lessard, James A. Chodosh, James Gopalakrishnan, Rajaram Hefner, Kimberly S. Houston, Glen D. Huang, Andrew J. W. Hughes, Pamela J. Lewis, David M. Radfar, Lida Rohrer, Michael D. Stone, Donald U. Wren, Jonathan D. Vyse, Timothy J. Gaffney, Patrick M. James, Judith A. Omdal, Roald Wahren-Herlenius, Marie Illei, Gabor G. Witte, Torsten Jonsson, Roland Rischmueller, Maureen Ronnblom, Lars Nordmark, Gunnel Wan-Fai Ng Mariette, Xavier Anaya, Juan-Manuel Rhodus, Nelson L. Segal, Barbara M. Scofield, R. Hal Montgomery, Courtney G. Harley, John B. Sivils, Kathy L. CA UK Primary Sjogren's Syndrome Regi TI Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren's syndrome SO NATURE GENETICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; GENOME-WIDE ASSOCIATION; PRIMARY BILIARY-CIRRHOSIS; STRONG RISK-FACTOR; RHEUMATOID-ARTHRITIS; GENE-EXPRESSION; FUNCTIONAL POLYMORPHISM; SUSCEPTIBILITY LOCI; CLASS-II; B-CELLS AB Sjogren's syndrome is a common autoimmune disease (affecting similar to 0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjogren's syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (P-meta = 7.65 x 10(-114)), we establish associations with IRF5-TNPO3 (P-meta = 2.73 x 10(-19)), STAT4 (Pmeta = 6.80 x 10-15), IL12A (P-meta = 1.17 x 10(-10)), FAM167ABLK (P-meta = 4.97 x 10(-10)), DDX6-CXCR5 (P-meta = 1.10 x 10(-8)) and TNIP1 (P-meta = 3.30 x 10(-8)). We also observed suggestive associations (P-meta < 5 x 10(-5)) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjogren's syndrome. C1 [Lessard, Christopher J.; Li, He; Adrianto, Indra; Ice, John A.; Rasmussen, Astrid; Grundahl, Kiely M.; Kelly, Jennifer A.; Dozmorov, Mikhail G.; Guthridge, Joel M.; Adler, Adam J.; Maier-Moore, Jacen S.; Farris, A. Darise; Wren, Jonathan D.; Gaffney, Patrick M.; James, Judith A.; Scofield, R. Hal; Montgomery, Courtney G.; Sivils, Kathy L.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Lessard, Christopher J.; Li, He; James, Judith A.; Sivils, Kathy L.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Miceli-Richard, Corinne; Mariette, Xavier] Univ Paris 11, AP HP, Hop Univ Paris Sud, INSERM,U1012, Paris, France. [Bowman, Simon] Univ Hosp Birmingham, Dept Rheumatol, Birmingham, W Midlands, England. [Lester, Sue; Rischmueller, Maureen] Queen Elizabeth Hosp, Dept Rheumatol, Woodville South, SA, Australia. [Eriksson, Per] Linkoping Univ, Fac Hlth Sci, Dept Rheumatol Clin & Expt Med, Linkoping, Sweden. [Eloranta, Maija-Leena; Ronnblom, Lars; Nordmark, Gunnel] Uppsala Univ, Dept Med Sci, Rheumatol & Sci Life Lab, Uppsala, Sweden. [Brun, Johan G.] Univ Bergen, Dept Clin Sci, Rheumatol Sect, Bergen, Norway. [Brun, Johan G.; Jonsson, Roland] Haukeland Hosp, Dept Rheumatol, N-5021 Bergen, Norway. [Goransson, Lasse G.; Harboe, Erna; Omdal, Roald] Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway. [Kaufman, Kenneth M.; Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Div Rheumatol, Cincinnati, OH 45229 USA. [Kaufman, Kenneth M.; Harley, John B.] Dept Vet Affairs Med Ctr, Cincinnati, OH USA. [Kvarnstrom, Marika; Jazebi, Helmi; Wahren-Herlenius, Marie] Karolinska Inst, Dept Med, Stockholm, Sweden. [Jazebi, Helmi] Orebro Univ Hosp, Dept Rheumatol, Orebro, Sweden. [Graham, Deborah S. Cunninghame; Vyse, Timothy J.] Kings Coll London, Dept Med & Mol Genet, London, England. [Grandits, Martha E.] United Med Specialties, St Paul, MN USA. [Nazmul-Hossain, Abu N. M.] Univ Colorado, Sch Dent Med, Denver, CO 80202 USA. [Patel, Ketan] Univ Minnesota, Sch Dent, Dept Dev & Surg Sci, Div Oral & Maxillofacial Surg, Minneapolis, MN 55455 USA. [Maier-Moore, Jacen S.; James, Judith A.; Scofield, R. Hal] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Brennan, Michael T.] Carolinas Med Ctr, Dept Oral Med, Charlotte, NC 28203 USA. [Lessard, James A.] Valley Bone & Joint Clin, Grand Forks, ND USA. [Chodosh, James] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Gopalakrishnan, Rajaram] Univ Minnesota, Sch Dent, Dept Diagnost & Biol Sci, Div Oral & Maxillofacial Pathol, Minneapolis, MN 55455 USA. [Hefner, Kimberly S.] Hefner Eye Care & Opt Ctr, Oklahoma City, OK USA. [Houston, Glen D.; Lewis, David M.] Univ Oklahoma, Coll Dent, Dept Oral & Maxillofacial Pathol, Oklahoma City, OK USA. [Huang, Andrew J. W.] Washington Univ, Dept Ophthalmol & Visual Sci, St Louis, MO 63130 USA. [Radfar, Lida] Univ Oklahoma, Coll Dent, Oral Diag & Radiol Dept, Oklahoma City, OK USA. [Rohrer, Michael D.] Univ Minnesota, Sch Dent, Hard Tissue Res Lab, Minneapolis, MN 55455 USA. [Stone, Donald U.] Univ Oklahoma, Hlth Sci Ctr, Dept Ophthalmol, Oklahoma City, OK USA. [Wren, Jonathan D.] Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73190 USA. [Illei, Gabor G.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Witte, Torsten] Hannover Med Sch, Dept Clin Immunol & Rheumatol, Hannover, Germany. [Jonsson, Roland] Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway. [Rischmueller, Maureen] Univ Adelaide, Queen Elizabeth Hosp, Dept Rheumatol, Adelaide, SA 5005, Australia. [Rischmueller, Maureen] Univ Adelaide, Discipline Med, Adelaide, SA 5005, Australia. [Wan-Fai Ng] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Anaya, Juan-Manuel] Univ Rosario, Ctr Autoimmune Dis Res CREA, Bogota, Colombia. [Rhodus, Nelson L.] Univ Minnesota, Sch Dent, Dept Oral Surg, Minneapolis, MN 55455 USA. [Segal, Barbara M.] Univ Minnesota, Sch Med, Div Rheumatol, Minneapolis, MN 55455 USA. [Scofield, R. Hal] Dept Vet Affairs Med Ctr, Oklahoma City, OK USA. RP Sivils, KL (reprint author), Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM sivilsk@omrf.org RI Witte, Torsten/B-5783-2016; Anaya, Juan-Manuel/J-1960-2016; OI Anaya, Juan-Manuel/0000-0002-6444-1249; Universidad del Rosario, Biblioteca/0000-0003-3491-9392; Dozmorov, Mikhail/0000-0002-0086-8358; Houston, Graeme/0000-0002-9786-7975; Adrianto, Indra/0000-0002-9973-3057; Wahren-Herlenius, Marie/0000-0002-0915-7245; Huang, Andrew JW/0000-0003-1939-9149 FU NIH [P50 AR0608040, 5P01 AR049084-10, 5P30 AR053483, 1U01 AI101934, 5P30 GM103510]; Intramural Research Program of the National Institute of Dental and Craniofacial Research; American College of Rheumatology Research and Education Foundation/Abbott Health Professional Graduate Student Preceptorship Award FX We thank the following funding agencies for their support: this publication was made possible by grants P50 AR0608040 (K. L. S., C. J. L., R. H. S. and A. D. F.), 5R01 DE015223 (K. L. S. and J. B. H.), 5RC2 AR058959 (P. M. G.), 5P01 AR049084-10 (J. B. H.), 5P30 AR053483 (J. A. J. and J. M. G.), 5U19 AI082714 (K. L. S., J. A. J. and C. J. L.), 1R01 DE018209-02 (K. L. S. and J. B. H.), 5R01 DE018209 (K. L. S.), 8P20 GM103456 (P. M. G., C. J. L., J. D. W. and I. A.), P20 GM103636 (M. G. D. and J. D. W.), 5R37 AI024717-25 (J. B. H.), 5P01 AI083194-03 (K. L. S. and J. B. H.), 7S10 RR027190-02 (J. B. H.), 1U01 AI101934 (J. A. J. and J. M. G.), 1RC1 AR058554 (J. A. J. and J. M. G.) and 5P30 GM103510 (J. A. J. and J. M. G.) from the NIH. The contents are the sole responsibility of the authors and do not necessarily represent the official views of the NIH. Additional funding was obtained from Intramural Research Program of the National Institute of Dental and Craniofacial Research (G. G. I.), US Department of Veterans Affairs IMMA 9 (J. B. H.), US Department of Defense PR094002 (J. B. H.), American College of Rheumatology Research and Education Foundation/Abbott Health Professional Graduate Student Preceptorship Award 2009 (C. J. L. and K. L. S.), Oklahoma Medical Research Foundation (C. J. L. and K. L. S.), Sjogren's Syndrome Foundation (K. L. S.), Phileona Foundation (K. L. S.), the French ministry of health (PHRC 2006-AOM06133) and the French ministry of research (ANR-2010-BLAN-1133) (X. M. and C. M.-R.), The Strategic Research Program at Helse Bergen, Western Norway Regional Health Authority (L. G. G., J. G. B. and R. J.), The Broegelmann Foundation (J. G. B. and R. J.), Norwegian Foundation for Health and Rehabilitation (E. H.), KFO 250 TP03, WI 1031/6-1 (T. W.), KFO 250, Z1 (T. W.), Medical Research Council, UK G0800629 (W.-F. N. and S. B.), Northumberland, Tyne and Wear Comprehensive Local Research Network (CLRN) (W.-F. N.), The Swedish Research Council (M. W.-H. and L. R~nnblom), The King Gustaf the V-th 80-year Foundation (M. W.-H.), Knut and Alice Wallenberg Foundation (L. Ronnblom) and The Swedish Rheumatism Association (M. W.-H., G. N., L. Ronnblom and P. E.). This study made use of genotypes available through dbGAP, with acknowledgments provided in the Supplementary Note. NR 84 TC 97 Z9 99 U1 3 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1284 EP + DI 10.1038/ng.2792 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100008 PM 24097067 ER PT J AU Do, R Willer, CJ Schmidt, EM Sengupta, S Gao, C Peloso, GM Gustafsson, S Kanoni, S Ganna, A Chen, J Buchkovich, ML Mora, S Beckmann, JS Bragg-Gresham, JL Chang, HY Demirkan, A Den Hertog, HM Donnelly, LA Ehret, GB Esko, T Feitosa, MF Ferreira, T Fischer, K Fontanillas, P Fraser, RM Freitag, DF Gurdasani, D Heikkila, K Hypponen, E Isaacs, A Jackson, AU Johansson, A Johnson, T Kaakinen, M Kettunen, J Kleber, ME Li, XH Luan, JA Lyytikainen, LP Magnusson, PKE Mangino, M Mihailov, E Montasser, ME Muller-Nurasyid, M Nolte, IM O'Connell, JR Palmer, CD Perola, M Petersen, AK Sanna, S Saxena, R Service, SK Shah, S Shungin, D Sidore, C Song, C Strawbridge, RJ Surakka, I Tanaka, T Teslovich, TM Thorleifsson, G Van den Herik, EG Voight, BF Volcik, KA Waite, LL Wong, A Wu, Y Zhang, WH Absher, D Asiki, G Barroso, I Been, LF Bolton, JL Bonnycastle, LL Brambilla, P Burnett, MS Cesana, G Dimitriou, M Doney, ASF Doring, A Elliott, P Epstein, SE Eyjolfsson, GI Gigante, B Goodarzi, MO Grallert, H Gravito, ML Groves, CJ Hallmans, G Hartikainen, AL Hayward, C Hernandez, D Hicks, AA Holm, H Hung, YJ Illig, T Jones, MR Kaleebu, P Kastelein, JJP Khaw, KT Kim, E Klopp, N Komulainen, P Kumari, M Langenberg, C Lehtimaki, T Lin, SY Lindstrom, J Loos, RJF Mach, F McArdle, WL Meisinger, C Mitchell, BD Muller, G Nagaraja, R Narisu, N Nieminen, TVM Nsubuga, RN Olafsson, I Ong, KK Palotie, A Papamarkou, T Pomilla, C Pouta, A Rader, DJ Reilly, MP Ridker, PM Rivadeneira, F Rudan, I Ruokonen, A Samani, N Scharnagl, H Seeley, J Silander, K Stancakova, A Stirrups, K Swift, AJ Tiret, L Uitterlinden, AG van Pelt, LJ Vedantam, S Wainwright, N Wijmenga, C Wild, SH Willemsen, G Wilsgaard, T Wilson, JF Young, EH Zhao, JH Adair, LS Arveiler, D Assimes, TL Bandinelli, S Bennett, F Bochud, M Boehm, BO Boomsma, DI Borecki, IB Bornstein, SR Bovet, P Burnier, M Campbell, H Chakravarti, A Chambers, JC Chen, YDI Collins, FS Cooper, RS Danesh, J Dedoussis, G de Faire, U Feranil, AB Ferrieres, J Ferrucci, L Freimer, NB Gieger, C Groop, LC Gudnason, V Gyllensten, U Hamsten, A Harris, TB Hingorani, A Hirschhorn, JN Hofman, A Hovingh, GK Hsiung, CA Humphries, SE Hunt, SC Hveem, K Iribarren, C Jarvelin, MR Jula, A Kahonen, M Kaprio, J Kesaniemi, A Kivimaki, M Kooner, JS Koudstaal, PJ Krauss, RM Kuh, D Kuusisto, J Kyvik, KO Laakso, M Lakka, TA Lind, L Lindgren, CM Martin, NG Marz, W McCarthy, MI McKenzie, CA Meneton, P Metspalu, A Moilanen, L Morris, AD Munroe, PB Njolstad, I Pedersen, NL Power, C Pramstaller, PP Price, JF Psaty, BM Quertermous, T Rauramaa, R Saleheen, D Salomaa, V Sanghera, DK Saramies, J Schwarz, PEH Sheu, WHH Shuldiner, AR Siegbahn, A Spector, TD Stefansson, K Strachan, DP Tayo, BO Tremoli, E Tuomilehto, J Uusitupa, M van Duijn, CM Vollenweider, P Wallentin, L Wareham, NJ Whitfield, JB Wolffenbuttel, BHR Altshuler, D Ordovas, JM Boerwinkle, E Palmer, CNA Thorsteinsdottir, U Chasman, DI Rotter, JI Franks, PW Ripatti, S Cupples, LA Sandhu, MS Rich, SS Boehnke, M Deloukas, P Mohlke, KL Ingelsson, E Abecasis, GR Daly, MJ Neale, BM Kathiresan, S AF Do, Ron Willer, Cristen J. Schmidt, Ellen M. Sengupta, Sebanti Gao, Chi Peloso, Gina M. Gustafsson, Stefan Kanoni, Stavroula Ganna, Andrea Chen, Jin Buchkovich, Martin L. Mora, Samia Beckmann, Jacques S. Bragg-Gresham, Jennifer L. Chang, Hsing-Yi Demirkan, Ayse Den Hertog, Heleen M. Donnelly, Louise A. Ehret, Georg B. Esko, Tonu Feitosa, Mary F. Ferreira, Teresa Fischer, Krista Fontanillas, Pierre Fraser, Ross M. Freitag, Daniel F. Gurdasani, Deepti Heikkila, Kauko Hyppoenen, Elina Isaacs, Aaron Jackson, Anne U. Johansson, Asa Johnson, Toby Kaakinen, Marika Kettunen, Johannes Kleber, Marcus E. Li, Xiaohui Luan, Jian'an Lyytikainen, Leo-Pekka Magnusson, Patrik K. E. Mangino, Massimo Mihailov, Evelin Montasser, May E. Mueller-Nurasyid, Martina Nolte, Ilja M. O'Connell, Jeffrey R. Palmer, Cameron D. Perola, Markus Petersen, Ann-Kristin Sanna, Serena Saxena, Richa Service, Susan K. Shah, Sonia Shungin, Dmitry Sidore, Carlo Song, Ci Strawbridge, Rona J. Surakka, Ida Tanaka, Toshiko Teslovich, Tanya M. Thorleifsson, Gudmar Van den Herik, Evita G. Voight, Benjamin F. Volcik, Kelly A. Waite, Lindsay L. Wong, Andrew Wu, Ying Zhang, Weihua Absher, Devin Asiki, Gershim Barroso, Ines Been, Latonya F. Bolton, Jennifer L. Bonnycastle, Lori L. Brambilla, Paolo Burnett, Mary S. Cesana, Giancarlo Dimitriou, Maria Doney, Alex S. F. Doering, Angela Elliott, Paul Epstein, Stephen E. Eyjolfsson, Gudmundur Ingi Gigante, Bruna Goodarzi, Mark O. Grallert, Harald Gravito, Martha L. Groves, Christopher J. Hallmans, Goran Hartikainen, Anna-Liisa Hayward, Caroline Hernandez, Dena Hicks, Andrew A. Holm, Hilma Hung, Yi-Jen Illig, Thomas Jones, Michelle R. Kaleebu, Pontiano Kastelein, John J. P. Khaw, Kay-Tee Kim, Eric Klopp, Norman Komulainen, Pirjo Kumari, Meena Langenberg, Claudia Lehtimaki, Terho Lin, Shih-Yi Lindstrom, Jaana Loos, Ruth J. F. Mach, Francois McArdle, Wendy L. Meisinger, Christa Mitchell, Braxton D. Mueller, Gabrielle Nagaraja, Ramaiah Narisu, Narisu Nieminen, Tuomo V. M. Nsubuga, Rebecca N. Olafsson, Isleifur Ong, Ken K. Palotie, Aarno Papamarkou, Theodore Pomilla, Cristina Pouta, Anneli Rader, Daniel J. Reilly, Muredach P. Ridker, Paul M. Rivadeneira, Fernando Rudan, Igor Ruokonen, Aimo Samani, Nilesh Scharnagl, Hubert Seeley, Janet Silander, Kaisa Stancakova, Alena Stirrups, Kathleen Swift, Amy J. Tiret, Laurence Uitterlinden, Andre G. van Pelt, L. Joost Vedantam, Sailaja Wainwright, Nicholas Wijmenga, Cisca Wild, Sarah H. Willemsen, Gonneke Wilsgaard, Tom Wilson, James F. Young, Elizabeth H. Zhao, Jing Hua Adair, Linda S. Arveiler, Dominique Assimes, Themistocles L. Bandinelli, Stefania Bennett, Franklyn Bochud, Murielle Boehm, Bernhard O. Boomsma, Dorret I. Borecki, Ingrid B. Bornstein, Stefan R. Bovet, Pascal Burnier, Michel Campbell, Harry Chakravarti, Aravinda Chambers, John C. Chen, Yii-Der Ida Collins, Francis S. Cooper, Richard S. Danesh, John Dedoussis, George de Faire, Ulf Feranil, Alan B. Ferrieres, Jean Ferrucci, Luigi Freimer, Nelson B. Gieger, Christian Groop, Leif C. Gudnason, Vilmundur Gyllensten, Ulf Hamsten, Anders Harris, Tamara B. Hingorani, Aroon Hirschhorn, Joel N. Hofman, Albert Hovingh, G. Kees Hsiung, Chao Agnes Humphries, Steve E. Hunt, Steven C. Hveem, Kristian Iribarren, Carlos Jarvelin, Marjo-Riitta Jula, Antti Kahonen, Mika Kaprio, Jaakko Kesaniemi, Antero Kivimaki, Mika Kooner, Jaspal S. Koudstaal, Peter J. Krauss, Ronald M. Kuh, Diana Kuusisto, Johanna Kyvik, Kirsten O. Laakso, Markku Lakka, Timo A. Lind, Lars Lindgren, Cecilia M. Martin, Nicholas G. Maerz, Winfried McCarthy, Mark I. McKenzie, Colin A. Meneton, Pierre Metspalu, Andres Moilanen, Leena Morris, Andrew D. Munroe, Patricia B. Njolstad, Inger Pedersen, Nancy L. Power, Chris Pramstaller, Peter P. Price, Jackie F. Psaty, Bruce M. Quertermous, Thomas Rauramaa, Rainer Saleheen, Danish Salomaa, Veikko Sanghera, Dharambir K. Saramies, Jouko Schwarz, Peter E. H. Sheu, Wayne H-H Shuldiner, Alan R. Siegbahn, Agneta Spector, Tim D. Stefansson, Kari Strachan, David P. Tayo, Bamidele O. Tremoli, Elena Tuomilehto, Jaakko Uusitupa, Matti van Duijn, Cornelia M. Vollenweider, Peter Wallentin, Lars Wareham, Nicholas J. Whitfield, John B. Wolffenbuttel, Bruce H. R. Altshuler, David Ordovas, Jose M. Boerwinkle, Eric Palmer, Colin N. A. Thorsteinsdottir, Unnur Chasman, Daniel I. Rotter, Jerome I. Franks, Paul W. Ripatti, Samuli Cupples, L. Adrienne Sandhu, Manjinder S. Rich, Stephen S. Boehnke, Michael Deloukas, Panos Mohlke, Karen L. Ingelsson, Erik Abecasis, Goncalo R. Daly, Mark J. Neale, Benjamin M. Kathiresan, Sekar TI Common variants associated with plasma triglycerides and risk for coronary artery disease SO NATURE GENETICS LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; ISCHEMIC-HEART-DISEASE; TYPE-2 DIABETES-MELLITUS; MENDELIAN RANDOMIZATION; CARDIOVASCULAR-DISEASE; GENETIC EPIDEMIOLOGY; CHOLESTEROL LEVELS; LOCI; CONTRIBUTE; THERAPY AB Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD. C1 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. Uppsala Univ, Dept Med Sci, Uppsala, Sweden. Uppsala Univ, Sci Life Lab, Uppsala, Sweden. Wellcome Trust Sanger Inst, Cambridge, England. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Univ N Carolina, Dept Genet, Chapel Hill, NC USA. Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Lausanne Hosp, Serv Med Genet, Lausanne, Switzerland. Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. Natl Hlth Res Inst, Inst Populat Hlth Sci, Div Prevent Med & Hlth Serv Res, Zhunan, Taiwan. 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[Lind, Lars; Siegbahn, Agneta; Wallentin, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Martin, Nicholas G.; Whitfield, John B.] Royal Brisbane Hosp, Queensland Inst Med Res, Brisbane, Qld 4029, Australia. [Maerz, Winfried] Synlab Acad, Synlab Serv, Mannheim, Germany. [McKenzie, Colin A.] Univ W Indies, Res Inst Trop Med, Trop Metab Res Unit, Mona, Jamaica. [Meneton, Pierre] Ctr Rech Cordeliers, INSERM, U872, Paris, France. [Moilanen, Leena] Kuopio Univ Hosp, Dept Med, SF-70210 Kuopio, Finland. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Pramstaller, Peter P.] Med Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. 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[Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Tuomilehto, Jaakko] King Abdulaziz Univ, Fac Med, Jeddah 21413, Saudi Arabia. [Tuomilehto, Jaakko] Hosp Univ La Paz, Grp RD06 0014 0015, Red Red Temat Invest Cooperat Enfermedades Cardio, Madrid, Spain. [Uusitupa, Matti] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Uusitupa, Matti] Kuopio Univ Hosp, Res Unit, SF-70210 Kuopio, Finland. [Vollenweider, Peter] Univ Lausanne Hosp, Dept Med, Lausanne, Switzerland. [Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands. [Ordovas, Jose M.] Natl Ctr Cardiovasc Invest, Dept Cardiovasc Epidemiol & Populat Genet, Madrid, Spain. [Ordovas, Jose M.] Madrid Inst Adv Studies Alimentac, Madrid, Spain. [Ordovas, Jose M.] Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer USDA, Nutr & Genom Lab, Boston, MA 02111 USA. [Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Cupples, L. Adrienne] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Rich, Stephen S.; Neale, Benjamin M.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM mjdaly@atgu.mgh.harvard.edu; bneale@broadinstitute.org; skathiresan@partners.org RI Hayward, Caroline/M-8818-2016; Schwarz, Peter/B-5127-2013; Wong, Andrew/M-8899-2016; Magnusson, Patrik/C-4458-2017; Beckmann, Jacques S /A-9772-2008; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Grallert, Harald/B-3424-2013; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Rivadeneira, Fernando/O-5385-2015; Lyytikainen, Leo-Pekka/C-8544-2016; Bovet, Pascal/F-4477-2011; Rudan, Igor/I-1467-2012; Papamarkou, Theodore/A-2958-2012; Kyvik, Kirsten /K-5680-2016; Study, GoDARTS/K-9448-2016; Bochud, Murielle/A-3981-2010; mangino, massimo/F-5134-2011; Altshuler, David/A-4476-2009; Strawbridge, Rona/H-5422-2012; Boehm, Bernhard/F-8750-2015; Shah, Sonia/N-7547-2013; Colaus, PsyColaus/K-6607-2013; Hypponen, Elina/B-2596-2014; Meisinger, Christine/B-5358-2014; Hsiung, Chao Agnes/E-3994-2010; Wijmenga, Cisca/D-2173-2009; Chang, Hsing-Yi /E-3973-2010; Palmer, Colin/C-7053-2008; Pramstaller, Peter/C-2357-2008; Deloukas, Panos/B-2922-2013; OI Lakka, Timo/0000-0002-9199-2871; Gigante, Bruna/0000-0003-4508-7990; Humphries, Stephen E/0000-0002-8221-6547; Gieger, Christian/0000-0001-6986-9554; Wijmenga, Cisca/0000-0002-5635-1614; Franks, Paul/0000-0002-0520-7604; Kumari, Meena/0000-0001-9716-1035; Shungin, Dmitry/0000-0001-7900-5856; Seeley, Janet/0000-0002-0583-5272; Song, Ci/0000-0002-0947-9068; TREMOLI, ELENA/0000-0002-0929-6106; sanna, serena/0000-0002-3768-1749; Kivimaki, Mika/0000-0002-4699-5627; Johnson, Toby/0000-0002-5998-3270; Fraser, Ross/0000-0003-0488-2592; Esko, Tonu/0000-0003-1982-6569; Hayward, Caroline/0000-0002-9405-9550; Schwarz, Peter/0000-0001-6317-7880; Wong, Andrew/0000-0003-2079-4779; Beckmann, Jacques S /0000-0002-9741-1900; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Willer, Cristen/0000-0001-5645-4966; Kaakinen, Marika/0000-0002-9228-0462; Sidore, Carlo/0000-0001-7504-7477; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Rivadeneira, Fernando/0000-0001-9435-9441; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Bovet, Pascal/0000-0002-0242-4259; Rudan, Igor/0000-0001-6993-6884; Papamarkou, Theodore/0000-0002-9689-543X; Kyvik, Kirsten /0000-0003-2981-0245; Bochud, Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470; Altshuler, David/0000-0002-7250-4107; Strawbridge, Rona/0000-0001-8506-3585; Shah, Sonia/0000-0001-5860-4526; Hypponen, Elina/0000-0003-3670-9399; Palmer, Colin/0000-0002-6415-6560; Deloukas, Panos/0000-0001-9251-070X; Martin, Nicholas/0000-0003-4069-8020; Ganna, Andrea/0000-0002-8147-240X; Nieminen, Tuomo/0000-0003-1755-1688; Meisinger, Christa/0000-0002-9026-6544; Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Mitchell, Braxton/0000-0003-4920-4744; Kaprio, Jaakko/0000-0002-3716-2455; Johansson, Asa/0000-0002-2915-4498; Kleber, Marcus/0000-0003-0663-7275 FU Massachusetts General Hospital; Donovan Family Foundation; US National Institutes of Health [R01HL107816]; Fondation Leducq; Canadian Institutes of Health Research; National Heart, Lung, and Blood Institute [T32HL007208] FX We thank the Global Lipids Genetics Consortium for early access to the association results of the Metabochip study. S. Kathiresan is supported by a Research Scholar award from the Massachusetts General Hospital, the Howard Goodman Fellowship from Massachusetts General Hospital, the Donovan Family Foundation, R01HL107816 from the US National Institutes of Health and a grant from Fondation Leducq. R.D. is supported by a Banting Fellowship from the Canadian Institutes of Health Research. G. P. is supported by award T32HL007208 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the US National Institutes of Health. NR 34 TC 205 Z9 211 U1 2 U2 49 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1345 EP + DI 10.1038/ng.2795 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100015 PM 24097064 ER PT J AU Seddon, JM Yu, Y Miller, EC Reynolds, R Tan, PL Gowrisankar, S Goldstein, JI Triebwasser, M Anderson, HE Zerbib, J Kavanagh, D Souied, E Katsanis, N Daly, MJ Atkinson, JP Raychaudhuri, S AF Seddon, Johanna M. Yu, Yi Miller, Elizabeth C. Reynolds, Robyn Tan, Perciliz L. Gowrisankar, Sivakumar Goldstein, Jacqueline I. Triebwasser, Michael Anderson, Holly E. Zerbib, Jennyfer Kavanagh, David Souied, Eric Katsanis, Nicholas Daly, Mark J. Atkinson, John P. Raychaudhuri, Soumya TI Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration SO NATURE GENETICS LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; COMPLEMENT FACTOR-I; WHOLE-GENOME ASSOCIATION; DNA-SEQUENCING DATA; FACTOR-H; MISSENSE MUTATION; WIDE ASSOCIATION; COMMON VARIANTS; FACTOR B; SUSCEPTIBILITY AB To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within all reported AMD loci and related pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (odds ratio (OR) = 3.6; P = 2 x 10-8). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association with disease. We observed significant association with rare missense alleles in genes other than CFI. Genotyping in 5,115 independent samples confirmed associations with AMD of an allele in C3 encoding p. Lys155Gln (replication P = 3.5 x 10(-5), OR = 2.8; joint P = 5.2 x 10(-9), OR = 3.8) and an allele in C9 encoding p. Pro167Ser (replication P = 2.4 x 10(-5), OR = 2.2; joint P = 6.5 x 10(-7), OR = 2.2). Finally, we show that the allele of C3 encoding Gln155 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder. C1 [Seddon, Johanna M.; Yu, Yi; Reynolds, Robyn] Tufts Med Ctr, New England Eye Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA USA. [Seddon, Johanna M.] Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA. [Seddon, Johanna M.] Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. [Miller, Elizabeth C.; Triebwasser, Michael; Atkinson, John P.] Washington Univ, Sch Med, Dept Med, Div Rheumatol, St Louis, MO 63110 USA. [Tan, Perciliz L.; Katsanis, Nicholas] Duke Univ, Ctr Human Dis Modeling, Durham, NC USA. [Tan, Perciliz L.; Katsanis, Nicholas] Duke Univ, Dept Cell Biol, Durham, NC USA. [Tan, Perciliz L.; Katsanis, Nicholas] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Gowrisankar, Sivakumar; Raychaudhuri, Soumya] Partners HealthCare Ctr Personalized Genet Med, Boston, MA USA. [Goldstein, Jacqueline I.; Daly, Mark J.; Raychaudhuri, Soumya] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Goldstein, Jacqueline I.; Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Anderson, Holly E.; Kavanagh, David] Newcastle Univ, Int Ctr Life, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Zerbib, Jennyfer; Souied, Eric] Univ Paris Est Creteil, Hop Henri Mondor, Hop Intercommunal Creteil, Dept Ophthalmol, Creteil, France. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Univ Manchester, Fac Med & Human Sci, Manchester, Lancs, England. RP Seddon, JM (reprint author), Tufts Med Ctr, New England Eye Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA USA. EM jseddon@tuftsmedicalcenter.org; soumya@broadinstitute.org RI Kavanagh, David/E-8498-2011; OI Kavanagh, David/0000-0003-4718-0072; Goldstein, Jacqueline/0000-0003-1902-6916; Katsanis, Nicholas/0000-0002-2480-0171 FU US National Institutes of Health (NIH) [R01-EY11309, K08AR055688, U01HG0070033, F30HL103072]; Doris Duke Foundation; Edward N. & Della L. Thome Memorial Foundation; Massachusetts Lions Eye Research Fund, Inc.; Foundation Fighting Blindness; Macular Vision Research Foundation; New England Eye Center, Department of Ophthalmology, Tufts University School of Medicine FX We thank the participants and numerous ophthalmologists throughout the country who took part in this study as well as the Age-Related Eye Disease Study Research Group. This research was supported in part by grants R01-EY11309 (J. M. S.), K08AR055688 (S. R.), U01HG0070033 (S. R.), F30HL103072 (M. T.) and R01-AI041592 (J. P. A. and E. C. M.) from the US National Institutes of Health (NIH); The Doris Duke Foundation (S. R.); the Edward N. & Della L. Thome Memorial Foundation (J. P. A.); the Massachusetts Lions Eye Research Fund, Inc. (J. M. S.); the Foundation Fighting Blindness (J. M. S.); the Macular Vision Research Foundation (J. M. S.); a Research to Prevent Blindness Challenge Grant to the New England Eye Center, Department of Ophthalmology, Tufts University School of Medicine; the American Macular Degeneration Foundation (J. M. S.); The Arnold and Mabel Beckman Initiative for Macular Research (J. M. S. and S. R.); and the Macular Degeneration Research Fund of the Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine. N. K. is a Distinguished Brumley Professor. D. K. is a Wellcome Intermediate Clinical Fellow. We thank the French national Programme Hospitalier de Recherche Clinique (PHRC; E. S.). NR 56 TC 90 Z9 95 U1 4 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1366 EP + DI 10.1038/ng.2741 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100018 PM 24036952 ER PT J AU Zhan, XW Larson, DE Wang, CL Koboldt, DC Sergeev, YV Fulton, RS Fulton, LL Fronick, CC Branham, KE Bragg-Gresham, J Jun, G Hu, YN Kang, HM Liu, DJ Othman, M Brooks, M Ratnapriya, R Boleda, A Grassmann, F von Strachwitz, C Olson, LM Buitendijk, GHS Hofman, A van Duijn, CM Cipriani, V Moore, AT Shahid, H Jiang, YD Conley, YP Morgan, DJ Kim, IK Johnson, MP Cantsilieris, S Richardson, AJ Guymer, RH Luo, HR Ouyang, H Licht, C Pluthero, FG Zhang, MM Zhang, K Baird, PN Blangero, J Klein, ML Farrer, LA DeAngelis, MM Weeks, DE Gorin, MB Yates, JRW Klaver, CCW Pericak-Vance, MA Haines, JL Weber, BHF Wilson, RK Heckenlively, JR Chew, EY Stambolian, D Mardis, ER Swaroop, A Abecasis, GR AF Zhan, Xiaowei Larson, David E. Wang, Chaolong Koboldt, Daniel C. Sergeev, Yuri V. Fulton, Robert S. Fulton, Lucinda L. Fronick, Catrina C. Branham, Kari E. Bragg-Gresham, Jennifer Jun, Goo Hu, Youna Kang, Hyun Min Liu, Dajiang Othman, Mohammad Brooks, Matthew Ratnapriya, Rinki Boleda, Alexis Grassmann, Felix von Strachwitz, Claudia Olson, Lana M. Buitendijk, Gabrielle H. S. Hofman, Albert van Duijn, Cornelia M. Cipriani, Valentina Moore, Anthony T. Shahid, Humma Jiang, Yingda Conley, Yvette P. Morgan, Denise J. Kim, Ivana K. Johnson, Matthew P. Cantsilieris, Stuart Richardson, Andrea J. Guymer, Robyn H. Luo, Hongrong Ouyang, Hong Licht, Christoph Pluthero, Fred G. Zhang, Mindy M. Zhang, Kang Baird, Paul N. Blangero, John Klein, Michael L. Farrer, Lindsay A. DeAngelis, Margaret M. Weeks, Daniel E. Gorin, Michael B. Yates, John R. W. Klaver, Caroline C. W. Pericak-Vance, Margaret A. Haines, Jonathan L. Weber, Bernhard H. F. Wilson, Richard K. Heckenlively, John R. Chew, Emily Y. Stambolian, Dwight Mardis, Elaine R. Swaroop, Anand Abecasis, Goncalo R. TI Identification of a rare coding variant in complement 3 associated with age-related macular degeneration SO NATURE GENETICS LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; GENOME-WIDE ASSOCIATION; FACTOR-H POLYMORPHISM; COMMON DISEASES; SEQUENCING DATA; EYE DISEASE; FACTOR-B; RISK; SUSCEPTIBILITY; MUTATIONS AB Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p. Arg1210Cys encoded in the CFH gene (case frequency (f(case)) = 0.51%; control frequency (f(control)) = 0.02%; odds ratio (OR) = 23.11) and newly identified p. Lys155Gln encoded in the C3 gene (f(case) = 1.06%; f(control) = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology. C1 [Zhan, Xiaowei; Wang, Chaolong; Bragg-Gresham, Jennifer; Jun, Goo; Hu, Youna; Kang, Hyun Min; Liu, Dajiang; Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Larson, David E.; Koboldt, Daniel C.; Fulton, Robert S.; Fulton, Lucinda L.; Fronick, Catrina C.; Wilson, Richard K.; Mardis, Elaine R.] Washington Univ, Sch Med, Genome Inst, St Louis, MO USA. [Wang, Chaolong] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Sergeev, Yuri V.] NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Branham, Kari E.; Othman, Mohammad; Heckenlively, John R.] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Brooks, Matthew; Ratnapriya, Rinki; Boleda, Alexis; Swaroop, Anand] NEI, US Natl Inst Hlth, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. [Grassmann, Felix; Weber, Bernhard H. F.] Univ Regensburg, Inst Human Genet, D-93053 Regensburg, Germany. [von Strachwitz, Claudia] Southwest Eye Ctr, Stuttgart, Germany. [Olson, Lana M.; Haines, Jonathan L.] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37212 USA. [Olson, Lana M.; Haines, Jonathan L.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. [Buitendijk, Gabrielle H. S.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Buitendijk, Gabrielle H. S.; Hofman, Albert; van Duijn, Cornelia M.; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hofman, Albert] Netherlands Genom Initiat, Netherlands Consortium Hlth Aging, The Hague, Netherlands. [Cipriani, Valentina; Moore, Anthony T.; Yates, John R. W.] UCL, UCL Inst Ophthalmol, London, England. [Cipriani, Valentina; Moore, Anthony T.; Yates, John R. W.] Moorfields Eye Hosp, London, England. [Shahid, Humma; Yates, John R. W.] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge, England. [Shahid, Humma] Cambridge Univ Hosp Natl Hlth Serv NHS Fdn Trust, Cambridge, England. [Jiang, Yingda; Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Conley, Yvette P.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Promot & Dev, Pittsburgh, PA USA. [Morgan, Denise J.; DeAngelis, Margaret M.] Univ Utah, John A Moran Eye Ctr, Dept Ophthalmol & Visual Sci, Salt Lake City, UT USA. [Kim, Ivana K.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, Boston, MA USA. [Kim, Ivana K.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Johnson, Matthew P.; Blangero, John] Texas Biomed Res Inst, San Antonio, TX USA. [Cantsilieris, Stuart; Richardson, Andrea J.; Guymer, Robyn H.; Baird, Paul N.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, East Melbourne, Vic, Australia. [Luo, Hongrong; Ouyang, Hong; Zhang, Mindy M.; Zhang, Kang] Univ Calif San Diego, Dept Ophthalmol, Shiley Eye Ctr, La Jolla, CA 92093 USA. [Luo, Hongrong; Ouyang, Hong; Zhang, Mindy M.; Zhang, Kang] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Licht, Christoph] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Pluthero, Fred G.] Hosp Sick Children, Cell Biol Program, Toronto, ON M5G 1X8, Canada. [Klein, Michael L.] Oregon Hlth & Sci Univ, Casey Eye Inst, Macular Degenerat Ctr, Portland, OR 97201 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med, Sect Biomed Genet, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Gorin, Michael B.] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA. [Chew, Emily Y.] NEI, US Natl Inst Hlth, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Stambolian, Dwight] Univ Penn, Sch Med, Dept Ophthalmol & Human Genet, Philadelphia, PA 19104 USA. RP Abecasis, GR (reprint author), Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. EM goncalo@umich.edu RI Cipriani, Valentina/A-8549-2012; luo, hongrong/B-2714-2015; DeAngelis, e/J-7863-2015; Klaver, Caroline/A-2013-2016; Jun, Goo/M-5235-2016; Jun, Goo/F-1941-2017; OI Weeks, Daniel/0000-0001-9410-7228; Pluthero, Fred/0000-0002-0451-5840; Baird, Paul/0000-0002-1305-3502; Swaroop, Anand/0000-0002-1975-1141; Cipriani, Valentina/0000-0002-0839-9955; luo, hongrong/0000-0001-7994-1193; Jun, Goo/0000-0003-0891-0204; Jun, Goo/0000-0003-0891-0204; Farrer, Lindsay/0000-0001-5533-4225 FU US National Institutes of Health (National Eye Institute, National Human Genome Research Institute) [EY022005, HG007022, HG005552, EY016862, U54HG003079, EY09859]; Medical Research Council, UK [G0000067]; Deutsche Forschungsgemeinschaft [WE1259/19-2]; Thome Memorial Foundation; Harold and Pauline Price Foundation FX We thank all study participants for their generous volunteering. We thank B. Li, W. Chen, C. Sidore, T. Teslovich, L. Fritsche and M. Boehnke for useful discussion and suggestions. This project was supported by grants from the US National Institutes of Health (National Eye Institute, National Human Genome Research Institute; grants EY022005, HG007022, HG005552, EY016862, U54HG003079 and EY09859); the Medical Research Council, UK (grant G0000067); the Deutsche Forschungsgemeinschaft (grant WE1259/19-2); the Alcon Research Institute; The UK Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and the UCL Institute of Ophthalmology; Research to Prevent Blindness (New York); the Thome Memorial Foundation; the Harold and Pauline Price Foundation; and the National Health and Medical Research Council of Australia (NHMRC) Clinical Research Excellence (grant 529923, NHMRC practitioner fellowship 529905 and NHMRC Senior Research Fellowship 1028444). The study was also supported by the Intramural Research Program (Computational Medicine Initiative) of the National Eye Institute. The Centre for Eye Research Australia (CERA) receives operational infrastructure support from the Victorian Government. The views expressed in the publication are those of the authors and not necessarily those of their employers or the funders. NR 43 TC 63 Z9 63 U1 1 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1375 EP + DI 10.1038/ng.2758 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100020 PM 24036949 ER PT J AU Flannick, J Beer, NL Bick, AG Agarwala, V Molnes, J Gupta, N Burtt, NP Florez, JC Meigs, JB Taylor, H Lyssenko, V Irgens, H Fox, E Burslem, F Johansson, S Brosnan, MJ Trimmer, JK Newton-Cheh, C Tuomi, T Molven, A Wilson, JG O'Donnell, CJ Kathiresan, S Hirschhorn, JN Njolstad, PR Rolph, T Seidman, JG Gabriel, S Cox, DR Seidman, CE Groop, L Altshuler, D AF Flannick, Jason Beer, Nicola L. Bick, Alexander G. Agarwala, Vineeta Molnes, Janne Gupta, Namrata Burtt, Noel P. Florez, Jose C. Meigs, James B. Taylor, Herman Lyssenko, Valeriya Irgens, Henrik Fox, Ervin Burslem, Frank Johansson, Stefan Brosnan, M. Julia Trimmer, Jeff K. Newton-Cheh, Christopher Tuomi, Tiinamaija Molven, Anders Wilson, James G. O'Donnell, Christopher J. Kathiresan, Sekar Hirschhorn, Joel N. Njolstad, Pal R. Rolph, Tim Seidman, J. G. Gabriel, Stacey Cox, David R. Seidman, Christine E. Groop, Leif Altshuler, David TI Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes SO NATURE GENETICS LA English DT Article ID BURROWS-WHEELER TRANSFORM; NORWEGIAN MODY REGISTRY; BETA-CELL FUNCTION; FACTOR-I; NUCLEAR FACTOR-1-ALPHA; READ ALIGNMENT; ALPHA-GENE; YOUNG MODY; ONSET; MUTATIONS AB Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders1-7 and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates8-12. We sequenced seven genes for maturity-onset diabetes of the young (MODY) 13 in well-phenotyped population samples14,15 (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases. C1 [Flannick, Jason; Beer, Nicola L.; Bick, Alexander G.; Agarwala, Vineeta; Gupta, Namrata; Burtt, Noel P.; Florez, Jose C.; Newton-Cheh, Christopher; Kathiresan, Sekar; Hirschhorn, Joel N.; Njolstad, Pal R.; Gabriel, Stacey; Altshuler, David] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Flannick, Jason; Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Flannick, Jason] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Bick, Alexander G.; Hirschhorn, Joel N.; Seidman, J. G.; Seidman, Christine E.; Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Agarwala, Vineeta] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Agarwala, Vineeta] Harvard Univ, Grad Sch Arts & Sci, Program Biophys, Cambridge, MA 02138 USA. [Molnes, Janne; Irgens, Henrik; Johansson, Stefan; Molven, Anders; Njolstad, Pal R.] Univ Bergen, KG Jebsen Ctr Diabet Res, Dept Clin Sci, Bergen, Norway. [Florez, Jose C.; Newton-Cheh, Christopher; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.; Meigs, James B.; Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Taylor, Herman; Fox, Ervin] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Taylor, Herman] Jackson State Univ, Jackson, MS USA. [Taylor, Herman] Tougaloo Coll, Div Nat Sci, Tougaloo, MS USA. [Lyssenko, Valeriya; Groop, Leif] Lund Univ, Clin Res Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Irgens, Henrik; Njolstad, Pal R.] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway. [Burslem, Frank] Prescient Life Sci, Cardiovasc & Metab Dis Practice, London, England. [Johansson, Stefan] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Brosnan, M. Julia; Trimmer, Jeff K.; Rolph, Tim] Pfizer Inc, Cardiovasc & Metab Dis Res Unit, Cambridge, MA USA. [Newton-Cheh, Christopher; O'Donnell, Christopher J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Newton-Cheh, Christopher; O'Donnell, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Tuomi, Tiinamaija] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Tuomi, Tiinamaija] Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland. [Tuomi, Tiinamaija] Univ Helsinki, Cent Hosp, Res Program Mol Med, Helsinki, Finland. [Molven, Anders] Univ Bergen, Dept Clin Med, Gade Lab Pathol, Bergen, Norway. [Molven, Anders] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Cox, David R.] Pfizer Inc, Appl Quantitat Genotherapeut, San Francisco, CA USA. [Seidman, Christine E.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Seidman, Christine E.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Groop, Leif] Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland. RP Altshuler, D (reprint author), Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. EM altshuler@molbio.mgh.harvard.edu RI Altshuler, David/A-4476-2009; Johansson, Stefan/C-4394-2011; OI Altshuler, David/0000-0002-7250-4107; Johansson, Stefan/0000-0002-2298-7008; Tuomi, Tiinamaija/0000-0002-8306-6202 FU National Human Genome Research Institute of the US National Institutes of Health (NIH) [U54 HG003067]; Howard Hughes Medical Institute; Pfizer Inc.; NIH [5-T32-GM007748-33]; Fulbright Diabetes UK Fellowship [BDA 11/0004348]; Doris Duke Charitable Foundation [2006087]; National Institute of Diabetes and Digestive and Kidney Diseases grant [K24 DK080140]; NHLBI [N01-HC-95170, N01-HC95171, N01-HC-95172]; National Institute for Minority Health and Health Disparities; Norwegian Research Council; European Research Council FX We acknowledge the contribution of the participants of the Framingham and Jackson Heart Study, as well as the participants from the Malm Preventive Project, the Scania Diabetes Registry and the Botnia Study. This work was supported by grants from the National Human Genome Research Institute of the US National Institutes of Health (NIH) (Medical Sequencing Program grant U54 HG003067 to the Broad Institute principal investigator, E. Lander) and the Howard Hughes Medical Institute, as well as funding from Pfizer Inc. J. F. was supported in part by NIH training grant 5-T32-GM007748-33. N. L. B. was supported by a Fulbright Diabetes UK Fellowship (BDA 11/0004348). D. A. was supported by funding from the Doris Duke Charitable Foundation (2006087). J. M. acknowledges support from National Institute of Diabetes and Digestive and Kidney Diseases grant K24 DK080140. J. B. M. and J. C. F. acknowledge support from NIH grant R01 DK078616. A. G. B. and V. A. were supported by NIH Medical Scientist Training Program fellowship T32GM007753. J. G. S. and C. E. S. were supported by NIH RO1 2R01HL080494, the National Heart, Lung, and Blood Institute (NHLBI) and the LeDucq Foundation. The Jackson Heart Study is supported by contracts N01-HC-95170, N01-HC95171 and N01-HC-95172 from the NHLBI, the National Institute for Minority Health and Health Disparities and additional support from the National Institute of Biomedical Imaging and Bioengineering. The Framingham Heart Study was supported by contracts N01-HC-25195 and 6R01-NS 17950 from the NHLBI and genotyping services from Affymetrix, Inc. (contract N02-HL-6-4278 for the SNP Health Association Resource, SHARe, project). The Malm Preventive Project and the Scania Diabetes Registry were supported by a Swedish Research Council grant (Linne) to the Lund University Diabetes Centre. The Botnia study was supported by funding from the Sigrid Juselius Foundation and the Folkh lsan Research Foundation, as well as a European Research Council advanced research grant to L. G. (GA 269045). The MODY study was supported by grants from the KG Jebsen Foundation, the Norwegian Research Council, the University of Bergen, Helse Vest, Innovest and the European Research Council (AdG). NR 92 TC 37 Z9 37 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1380 EP + DI 10.1038/ng.2794 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100021 PM 24097065 ER PT J AU Jaffe, JD Wang, Y Chan, HM Zhang, JH Huether, R Kryukov, GV Bhang, HEC Taylor, JE Hu, M Englund, NP Yan, F Wang, ZF McDonald, ER Wei, L Ma, J Easton, J Yu, ZT deBeaumount, R Gibaja, V Venkatesan, K Schlegel, R Sellers, WR Keen, N Liu, J Caponigro, G Barretina, J Cooke, VG Mullighan, C Carr, SA Downing, JR Garraway, LA Stegmeier, F AF Jaffe, Jacob D. Wang, Yan Chan, Ho Man Zhang, Jinghui Huether, Robert Kryukov, Gregory V. Bhang, Hyo-eun C. Taylor, Jordan E. Hu, Min Englund, Nathan P. Yan, Feng Wang, Zhaofu McDonald, E. Robert, III Wei, Lei Ma, Jing Easton, John Yu, Zhengtian deBeaumount, Rosalie Gibaja, Veronica Venkatesan, Kavitha Schlegel, Robert Sellers, William R. Keen, Nicholas Liu, Jun Caponigro, Giordano Barretina, Jordi Cooke, Vesselina G. Mullighan, Charles Carr, Steven A. Downing, James R. Garraway, Levi A. Stegmeier, Frank TI Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia SO NATURE GENETICS LA English DT Article ID HISTONE METHYLTRANSFERASE; MULTIPLE-MYELOMA; LYSINE 27; MMSET; EZH2; GENE; H3; LYMPHOMA; HYPERTRIMETHYLATION; TRANSLOCATION AB Epigenetic dysregulation is an emerging hallmark of cancers. We developed a high-information-content mass spectrometry approach to profile global histone modifications in human cancers. When applied to 115 lines from the Cancer Cell Line Encyclopedia1, this approach identified distinct molecular chromatin signatures. One signature was characterized by increased histone 3 lysine 36 (H3K36) dimethylation, exhibited by several lines harboring translocations in NSD2, which encodes a methyltransferase. A previously unknown NSD2 p. Glu1099Lys (p. E1099K) variant was identified in nontranslocated acute lymphoblastic leukemia (ALL) cell lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2mutant lines and impaired the in vivo growth of an NSD2mutant ALL xenograft. Sequencing analysis of > 1,000 pediatric cancer genomes identified the NSD2 p. E1099K alteration in 14% of t (12; 21) ETV6-RUNX1-containing ALLs. These findings identify NSD2 as a potential therapeutic target for pediatric ALL and provide a general framework for the functional annotation of cancer epigenomes. C1 [Jaffe, Jacob D.; Kryukov, Gregory V.; Taylor, Jordan E.; Carr, Steven A.; Garraway, Levi A.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Wang, Yan; Englund, Nathan P.; Yan, Feng; Liu, Jun] Genom Inst, San Diego, CA USA. [Wang, Yan; Englund, Nathan P.; Yan, Feng; Liu, Jun] Novartis Res Fdn, San Diego, CA USA. [Chan, Ho Man; Bhang, Hyo-eun C.; McDonald, E. Robert, III; deBeaumount, Rosalie; Gibaja, Veronica; Venkatesan, Kavitha; Schlegel, Robert; Sellers, William R.; Keen, Nicholas; Caponigro, Giordano; Barretina, Jordi; Cooke, Vesselina G.; Stegmeier, Frank] Novartis Inst Biomed Res, Cambridge, MA USA. [Zhang, Jinghui; Huether, Robert; Wei, Lei] St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN 38105 USA. [Zhang, Jinghui; Huether, Robert; Wei, Lei; Ma, Jing; Easton, John; Mullighan, Charles; Downing, James R.] Washington Univ, St Jude Childrens Res Hosp, Pediat Canc Genome Project, Memphis, TN USA. [Kryukov, Gregory V.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Hu, Min; Wang, Zhaofu; Yu, Zhengtian] China Novartis Inst BioMed Res, Shanghai, Peoples R China. [Ma, Jing; Easton, John; Mullighan, Charles; Downing, James R.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [Garraway, Levi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kryukov, Gregory V.; Garraway, Levi A.] Harvard Univ, Sch Med, Boston, MA USA. RP Garraway, LA (reprint author), Broad Inst Harvard & MIT, Cambridge, MA USA. EM levi_garraway@dfci.harvard.edu; frank.stegmeier@novartis.com RI Huether, Robert/E-9638-2012; Kryukov, Gregory/A-9592-2008; OI Huether, Robert/0000-0001-7077-7470; Mullighan, Charles/0000-0002-1871-1850 FU American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital; Novartis Institutes for Biomedical Research; National Cancer Institute; U. S. Department of Defense; Pew Scholars Program in the Biomedical Sciences; St. Baldrick's Foundation Scholar Award FX We thank R. Pagliarini and R. Tiedt for their critical comments on the manuscript, and the NIBR-BROAD CCLE team for their guidance and contributions to the CCLE project. KMS11-TKO cells were generously provided by Horizon Discovery Ltd., UK. We are grateful for the technical assistance of X. Liu. We thank the members of the St. Jude Children's Research Hospital Washington University Pediatric Cancer Genome Project and the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital for funding. The global chromatin profiling project was enabled by a grant from the Novartis Institutes for Biomedical Research. Additional funding support was provided by the National Cancer Institute and the U. S. Department of Defense (L. A. G.), the Pew Scholars Program in the Biomedical Sciences (C. M.) and the St. Baldrick's Foundation Scholar Award (C.M.). NR 32 TC 87 Z9 89 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1386 EP + DI 10.1038/ng.2777 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100022 PM 24076604 ER PT J AU Chong, CR Janne, PA AF Chong, Curtis R. Jaenne, Pasi A. TI The quest to overcome resistance to EGFR-targeted therapies in cancer SO NATURE MEDICINE LA English DT Review ID EPIDERMAL-GROWTH-FACTOR; CELL LUNG-CANCER; TYROSINE KINASE INHIBITORS; METASTATIC COLORECTAL-CANCER; PHASE-III TRIAL; FACTOR-RECEPTOR GENE; EPITHELIAL-MESENCHYMAL-TRANSITION; GASTROINTESTINAL STROMAL TUMORS; CETUXIMAB PLUS IRINOTECAN; K-RAS MUTATIONS AB All patients with metastatic lung, colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factor receptor (EGFR)-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the Herculean challenge of killing tumors that are resistant to EGFR inhibitors. Our growing knowledge of resistance pathways provides an opportunity to develop new mechanism-based inhibitors and combination therapies to prevent or overcome therapeutic resistance in tumors. We present a comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeutic strategies that are designed to circumvent resistance. C1 [Chong, Curtis R.; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Chong, Curtis R.; Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. EM pjanne@partners.org FU US National Institutes of Health [RO1CA114465, R01CA135257, P01CA154303]; American Society of Clinical Oncology FX This study is supported by US National Institutes of Health grants RO1CA114465 (P.A.J.), R01CA135257 (P.A.J.) and P01CA154303 (P.A.J.) and by an American Society of Clinical Oncology Young Investigator Award (C.R.C.). NR 192 TC 236 Z9 244 U1 13 U2 112 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2013 VL 19 IS 11 BP 1389 EP 1400 DI 10.1038/nm.3388 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 251IF UT WOS:000326920300017 PM 24202392 ER PT J AU Vaishnavi, A Capelletti, M Le, AT Kako, S Butaney, M Ercan, D Mahale, S Davies, KD Aisner, DL Pilling, AB Berge, EM Kim, J Sasaki, H Park, SI Kryukov, G Garraway, LA Hammerman, PS Haas, J Andrews, SW Lipson, D Stephens, PJ Miller, VA Varella-Garcia, M Janne, PA Doebele, RC AF Vaishnavi, Aria Capelletti, Marzia Le, Anh T. Kako, Severine Butaney, Mohit Ercan, Dalia Mahale, Sakshi Davies, Kurtis D. Aisner, Dara L. Pilling, Amanda B. Berge, Eamon M. Kim, Jhingook Sasaki, Hidefumi Park, Seung-il Kryukov, Gregory Garraway, Levi A. Hammerman, Peter S. Haas, Julia Andrews, Steven W. Lipson, Doron Stephens, Philip J. Miller, Vince A. Varella-Garcia, Marileila Jaenne, Pasi A. Doebele, Robert C. TI Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer SO NATURE MEDICINE LA English DT Article ID GENE FUSIONS; KINASE INHIBITORS; CELL-LINES; RET; ADENOCARCINOMA; IDENTIFICATION; ALK; PROTEIN; GENOME; ROS1 AB We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein). Both the MPRIP-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth. Tumor samples from 3 of 91 patients with lung cancer (3.3%) without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions. C1 [Vaishnavi, Aria; Le, Anh T.; Davies, Kurtis D.; Pilling, Amanda B.; Berge, Eamon M.; Varella-Garcia, Marileila; Doebele, Robert C.] Univ Colorado, Sch Med, Div Med Oncol, Dept Med, Aurora, CO USA. [Capelletti, Marzia; Butaney, Mohit; Ercan, Dalia; Hammerman, Peter S.; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Kako, Severine; Mahale, Sakshi; Aisner, Dara L.; Varella-Garcia, Marileila; Doebele, Robert C.] Univ Colorado, Ctr Canc, Aurora, CO USA. [Aisner, Dara L.] Univ Colorado, Sch Med, Dept Pathol, Aurora, CO USA. [Kim, Jhingook] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Thorac Surg, Seoul, South Korea. [Sasaki, Hidefumi] Nagoya City Univ, Grad Sch Med Sci, Dept Oncol Immunol & Surg, Nagoya, Aichi, Japan. [Park, Seung-il] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Thorac Surg, Seoul, South Korea. [Kryukov, Gregory; Garraway, Levi A.] Broad Inst, Cambridge, MA USA. [Garraway, Levi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Haas, Julia; Andrews, Steven W.] Array BioPharma, Boulder, CO USA. [Lipson, Doron; Stephens, Philip J.; Miller, Vince A.] Fdn Med, Boston, MA USA. [Vaishnavi, Aria; Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA USA. RP Doebele, RC (reprint author), Univ Colorado, Sch Med, Div Med Oncol, Dept Med, Aurora, CO USA. EM pasi_janne@dfci.harvard.edu; robert.doebele@ucdenver.edu RI Kryukov, Gregory/A-9592-2008 FU Colorado Bioscience Discovery Evaluation Grant Program; National Institutes of Health (NIH) NCATS Colorado Clinical and Translational Sciences Institute [UL1 TR000154]; Boettcher Foundation's Webb-Waring Biomedical Research Program; Dana-Farber/Harvard Cancer Center Lung Cancer Specialized Programs of Research Excellence (SPORE) [P50 CA090578]; Cammarata Family Foundation Research Fund; Dana-Farber Cancer Institute; University of Colorado Lung Cancer SPORE [P50CA058187]; US National Cancer Institute Cancer Center [P30CA46934] FX This work was supported by the Colorado Bioscience Discovery Evaluation Grant Program, the National Institutes of Health (NIH) NCATS Colorado Clinical and Translational Sciences Institute Grant UL1 TR000154 (contents are the authors' sole responsibility and do not necessarily represent official NIH views) and the Boettcher Foundation's Webb-Waring Biomedical Research Program (R.C.D.), as well as the Dana-Farber/Harvard Cancer Center Lung Cancer Specialized Programs of Research Excellence (SPORE) P50 CA090578 (P.A.J.), the Cammarata Family Foundation Research Fund (M.C. and P.A.J.), the Nirenberg Fellowship at the Dana-Farber Cancer Institute (M.C. and P.A.J.) and the University of Colorado Lung Cancer SPORE grant P50CA058187 and the US National Cancer Institute Cancer Center Support Grant P30CA46934 (M.V.-G.). Ba/F3 cells were a gift from D. Theodorescu (University of Colorado, Anschutz Medical Campus). The cell lines KM12, HCT116, HCT15, HT29 and SW837 were gifts from S.G. Eckhardt (University of Colorado, Anschutz Medical Campus). The cell lines H3122, H1650, H1299 and HCC78 were gifts from J.D. Minna (University of Texas Southwestern). Aythymic nude mice were a gift from J. DeGregori (University of Colorado, Anschutz Medical Campus). NR 35 TC 117 Z9 119 U1 2 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2013 VL 19 IS 11 BP 1469 EP + DI 10.1038/nm.3352 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 251IF UT WOS:000326920300023 PM 24162815 ER PT J AU Krause, DS Fulzele, K Catic, A Sun, CC Dombkowski, D Hurley, MP Lezeau, S Attar, E Wu, JY Lin, HY Divieti-Pajevic, P Hasserjian, RP Schipani, E Van Etten, RA Scadden, DT AF Krause, Daniela S. Fulzele, Keertik Catic, Andre Sun, Chia Chi Dombkowski, David Hurley, Michael P. Lezeau, Sanon Attar, Eyal Wu, Joy Y. Lin, Herbert Y. Divieti-Pajevic, Paola Hasserjian, Robert P. Schipani, Ernestina Van Etten, Richard A. Scadden, David T. TI Differential regulation of myeloid leukemias by the bone marrow microenvironment SO NATURE MEDICINE LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; STEM-CELLS; MICE; PROGENITOR; ENGRAFTMENT; EXPRESSION; INDUCTION; RECEPTOR; HORMONE; MLL-AF9 AB Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM)(1) and may be the cause of relapse following chemotherapy(2). Targeting the niche is a new strategy to eliminate persistent and drug-resistant LSCs. CD44 (refs. 3,4) and interleukin-6 (ref. 5) have been implicated previously in the LSC niche. Transforming growth factor-beta 1 (TGF-beta 1) is released during bone remodeling(6) and plays a part in maintenance of CML LSCs7, but a role for TGF-beta 1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor(8,9) attenuates BCR-ABL1 oncogene-induced CML-like myeloproliferative neoplasia (MPN)(10) but enhances MLL-AF9 oncogene-induced AML(11) in mouse transplantation models, possibly through opposing effects of increased TGF-beta 1 on the respective LSCs. PTH treatment caused a 15-fold decrease in LSCs in wild-type mice with CML-like MPN and reduced engraftment of immune-deficient mice with primary human CML cells. These results demonstrate that LSC niches in CML and AML are distinct and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML. C1 [Krause, Daniela S.; Catic, Andre; Hurley, Michael P.; Lezeau, Sanon; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Krause, Daniela S.; Catic, Andre; Hurley, Michael P.; Lezeau, Sanon; Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Krause, Daniela S.; Catic, Andre; Hurley, Michael P.; Lezeau, Sanon; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Krause, Daniela S.; Catic, Andre; Hurley, Michael P.; Lezeau, Sanon; Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA USA. [Krause, Daniela S.; Dombkowski, David; Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Fulzele, Keertik; Wu, Joy Y.; Divieti-Pajevic, Paola] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Sun, Chia Chi; Lin, Herbert Y.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Attar, Eyal; Scadden, David T.] Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Boston, MA 02114 USA. [Schipani, Ernestina] Indiana Univ Sch Med, Div Endocrinol, Indianapolis, IN 46202 USA. [Van Etten, Richard A.] Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA USA. RP Scadden, DT (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM rvanetten@tuftsmedicalcenter.org; dscadden@mgh.harvard.edu FU Ellison Medical Foundation; US National Institute on Aging [K01AG036744]; [K08 CA138916-02]; [T32 CA009216]; [AR060221]; [R21AR060689]; [R01 CA090576]; [R01 HL089747]; [R01 HL044851]; [R01 CA148180] FX The authors thank A. Legedza and D. Neuberg for advice on statistical analysis and H.-H. Chen for helpful discussions. This work was supported by grants K08 CA138916-02 and T32 CA009216 to D. S. K., grant AR060221 to K. F. and P. D. P., grant R21AR060689 to E. S., grants R01 CA090576 and R01 HL089747 to R. A. V., grants R01 HL044851 and R01 CA148180 and a grant from The Ellison Medical Foundation to D.T.S. A.C. was supported by US National Institute on Aging grant K01AG036744. NR 25 TC 74 Z9 75 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2013 VL 19 IS 11 BP 1513 EP + DI 10.1038/nm.3364 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 251IF UT WOS:000326920300029 PM 24162813 ER PT J AU Filbin, MG Dabral, SK Pazyra-Murphy, MF Ramkissoon, S Kung, AL Pak, E Chung, J Theisen, MA Sun, YP Franchetti, Y Sun, Y Shulman, DS Redjal, N Tabak, B Beroukhim, R Wang, Q Zhao, J Dorsch, M Buonamici, S Ligon, KL Kelleher, JF Segal, RA AF Filbin, Mariella Gruber Dabral, Sukriti K. Pazyra-Murphy, Maria F. Ramkissoon, Shakti Kung, Andrew L. Pak, Ekaterina Chung, Jarom Theisen, Matthew A. Sun, Yanping Franchetti, Yoko Sun, Yu Shulman, David S. Redjal, Navid Tabak, Barbara Beroukhim, Rameen Wang, Qi Zhao, Jean Dorsch, Marion Buonamici, Silvia Ligon, Keith L. Kelleher, Joseph F. Segal, Rosalind A. TI Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities SO NATURE MEDICINE LA English DT Article ID CELL-CYCLE PROGRESSION; NEURONAL PRECURSORS; CORE PATHWAYS; CANCER-CELLS; STEM-CELLS; IN-VITRO; HEDGEHOG; KINASE; LINES; ANTAGONIST AB In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN)(1). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma. We demonstrate that the SHH and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and SHH signaling inhibitors not only suppressed the activation of both pathways but also abrogated S6 kinase (S6K) signaling. Accordingly, targeting both pathways simultaneously resulted in mitotic catastrophe and tumor apoptosis and markedly reduced the growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear to be safe in humans; therefore, this combination may provide a new targeted treatment for glioblastoma. C1 [Filbin, Mariella Gruber; Dabral, Sukriti K.; Pazyra-Murphy, Maria F.; Kung, Andrew L.; Pak, Ekaterina; Chung, Jarom; Sun, Yu; Shulman, David S.; Wang, Qi; Zhao, Jean; Segal, Rosalind A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Filbin, Mariella Gruber; Dabral, Sukriti K.; Pazyra-Murphy, Maria F.; Kung, Andrew L.; Pak, Ekaterina; Chung, Jarom; Sun, Yu; Shulman, David S.; Wang, Qi; Zhao, Jean; Segal, Rosalind A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Filbin, Mariella Gruber; Dabral, Sukriti K.; Pazyra-Murphy, Maria F.; Kung, Andrew L.; Pak, Ekaterina; Chung, Jarom; Sun, Yu; Shulman, David S.; Wang, Qi; Zhao, Jean; Segal, Rosalind A.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA USA. [Filbin, Mariella Gruber; Dabral, Sukriti K.; Pazyra-Murphy, Maria F.; Pak, Ekaterina; Chung, Jarom; Sun, Yu; Segal, Rosalind A.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Filbin, Mariella Gruber] Med Univ Vienna, Dept Pediat & Adolescent Med, Vienna, Austria. [Ramkissoon, Shakti; Theisen, Matthew A.; Tabak, Barbara; Beroukhim, Rameen; Ligon, Keith L.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Ramkissoon, Shakti; Ligon, Keith L.] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ramkissoon, Shakti; Ligon, Keith L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Kung, Andrew L.; Sun, Yanping] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02115 USA. [Franchetti, Yoko] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Franchetti, Yoko] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Redjal, Navid] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol Surg, Boston, MA USA. [Dorsch, Marion] Sanofi Aventis, Cambridge, MA USA. [Buonamici, Silvia; Kelleher, Joseph F.] Novartis Inst Biomed Res, Cambridge, MA USA. RP Segal, RA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM rosalind_segal@dfci.harvard.edu OI Kung, Andrew/0000-0002-9091-488X FU Austrian Programme for Advanced Research and Technology (APART) fellowship of the Austrian Academy of Sciences; US National Institutes of Health; Novartis Pharmaceuticals FX We thank V. Monrose and K. Jones for technical assistance and C. Stiles for helpful discussions. We thank N. Gray (Dana-Farber Cancer Institute) for PF-4708671 and C. David James (University of California San Francisco) for the hBT70 and hBT75 lines. This work was supported by an Austrian Programme for Advanced Research and Technology (APART) fellowship of the Austrian Academy of Sciences (M.G.F.), grants from the US National Institutes of Health (R.A.S.) and Novartis Pharmaceuticals. NR 39 TC 38 Z9 38 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2013 VL 19 IS 11 BP 1518 EP + DI 10.1038/nm.3328 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 251IF UT WOS:000326920300030 PM 24076665 ER PT J AU Galluzzi, L Kepp, O Vander Heiden, MG Kroemer, G AF Galluzzi, Lorenzo Kepp, Oliver Vander Heiden, Matthew G. Kroemer, Guido TI Metabolic targets for cancer therapy SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID PYRUVATE-KINASE M2; FATTY-ACID OXIDATION; CELL LUNG-CANCER; NF-KAPPA-B; REDUCTIVE GLUTAMINE-METABOLISM; HYPOXIA-INDUCIBLE FACTOR-1; HISTONE DEACETYLASE SIRT6; NOVO PYRIMIDINE SYNTHESIS; BCL-2 PROTEIN FAMILY; RANDOMIZED PHASE-II AB Malignant cells exhibit metabolic changes, when compared to their normal counterparts, owing to both genetic and epigenetic alterations. Although such a metabolic rewiring has recently been indicated as yet another general hallmark of cancer, accumulating evidence suggests that the metabolic alterations of each neoplasm represent a molecular signature that intimately accompanies and allows for different facets of malignant transformation. During the past decade, targeting cancer metabolism has emerged as a promising strategy for the development of selective antineoplastic agents. Here, we discuss the intimate relationship between metabolism and malignancy, focusing on strategies through which this central aspect of tumour biology might be turned into cancer's Achilles heel. C1 [Galluzzi, Lorenzo; Kepp, Oliver; Kroemer, Guido] Univ Paris 05, Sorbonne Paris Cite, F-75006 Paris, France. [Galluzzi, Lorenzo; Kepp, Oliver; Kroemer, Guido] Ctr Rech Cordeliers, Equipe Labellisee Ligue Natl Canc 11, F-75006 Paris, France. [Galluzzi, Lorenzo; Kepp, Oliver] Gustave Roussy, F-94805 Villejuif, France. [Kepp, Oliver; Kroemer, Guido] Gustave Roussy, INSERM, U848, F-94805 Villejuif, France. [Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kroemer, Guido] Gustave Roussy, Metabol & Cell Biol Platforms, F-94805 Villejuif, France. [Kroemer, Guido] Hop Europeen Georges Pompidou, APHP, Pole Biol, F-75015 Paris, France. RP Kroemer, G (reprint author), Univ Paris 05, Sorbonne Paris Cite, F-75006 Paris, France. EM kroemer@orange.fr FU Ligue contre le Cancer (equipe labellisee); Agence National de la Recherche (ANR); AXA Chair for Longevity Research; Association pour la recherche sur le cancer (ARC); Canceropole Ile-de-France; Institut National du Cancer (INCa); Fondation BettencourtSchueller; Fondation de France; Fondation pour la Recherche Medicale (FRM); European Commission (ArtForce); European Research Council (ERC); LabEx ImmunoOncology; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); SIRIC Cancer Research and Personalized Medicine (CARPEM); Paris Alliance of Cancer Research Institutes (PACRI) FX The authors are supported by the Ligue contre le Cancer (equipe labellisee); Agence National de la Recherche (ANR); AXA Chair for Longevity Research; Association pour la recherche sur le cancer (ARC); Canceropole Ile-de-France; Institut National du Cancer (INCa); Fondation BettencourtSchueller; Fondation de France; Fondation pour la Recherche Medicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx ImmunoOncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). NR 286 TC 183 Z9 185 U1 15 U2 151 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD NOV PY 2013 VL 12 IS 11 BP 829 EP 846 DI 10.1038/nrd4145 PG 18 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 245XX UT WOS:000326499100021 PM 24113830 ER PT J AU Garcez, AS Nunez, SC Azambuja, N Fregnani, ER Rodriguez, HMH Hamblin, MR Suzuki, H Ribeiro, MS AF Garcez, Aguinaldo S. Nunez, Silvia C. Azambuja, Nilton, Jr. Fregnani, Eduardo R. Rodriguez, Helena M. H. Hamblin, Michael R. Suzuki, Hideo Ribeiro, Martha S. TI Effects of Photodynamic Therapy on Gram-Positive and Gram-Negative Bacterial Biofilms by Bioluminescence Imaging and Scanning Electron Microscopic Analysis SO PHOTOMEDICINE AND LASER SURGERY LA English DT Article ID IN-VITRO; ENTEROCOCCUS-FAECALIS; PHOTOSENSITIZATION; INFECTIONS; REDUCTION AB Objective: The aim of this study was to test photodynamic therapy (PDT) as an alternative approach to biofilm disruption on dental hard tissue, We evaluated the effect of methylene blue and a 660nm diode laser on the viability and architecture of Gram-positive and Gram-negative bacterial biofilms. Materials and methods: Ten human teeth were inoculated with bioluminescent Pseudomonas aeruginosa or Enterococcus faecalis to form 3 day biofilms in prepared root canals. Bioluminescence imaging was used to serially quantify and evaluate the bacterial viability, and scanning electron microscopic (SEM) imaging was used to assess architecture and morphology of bacterial biofilm before and after PDT employing methylene blue and 40mW, 660nm diode laser light delivered into the root canal via a 300m fiber for 240sec, resulting in a total energy of 9.6J. The data were statistically analyzed with analysis of variance (ANOVA) followed by Tukey test. Results: The bacterial reduction showed a dose dependence; as the light energy increased, the bioluminescence decreased in both planktonic suspension and in biofilms. The SEM analysis showed a significant reduction of biofilm on the surface. PDT promoted disruption of the biofilm and the number of adherent bacteria was reduced. Conclusions: The photodynamic effect seems to disrupt the biofilm by acting both on bacterial cells and on the extracellular matrix. C1 [Garcez, Aguinaldo S.; Rodriguez, Helena M. H.; Suzuki, Hideo] Sao Leopoldo Mand Dent Res Ctr, Dept Orthodont, BR-05010000 Sao Paulo, Brazil. [Nunez, Silvia C.; Ribeiro, Martha S.] IPEN CNEN SP, Inst Energet & Nucl Res, Ctr Lasers & Applicat, Sao Paulo, Brazil. [Azambuja, Nilton, Jr.] Univ Sao Paulo, Dept Restorat Dent, Sao Paulo, Brazil. [Fregnani, Eduardo R.] Sirio Libanes Hosp, Dept Oral Med, Sao Paulo, Brazil. [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Garcez, AS (reprint author), Sao Leopoldo Mand Dent Res Ctr, Dept Orthodont, Rua Caiubi 181, BR-05010000 Sao Paulo, Brazil. EM garcez.segundo@gmail.com RI Ribeiro, Martha/G-3517-2012; Nunez, Silvia/C-7241-2017; Fregnani, Eduardo/I-4453-2013; OI Ribeiro, Martha/0000-0002-4203-1134; Nunez, Silvia/0000-0003-2101-8333; Fregnani, Eduardo/0000-0001-5196-7631; Hamblin, Michael/0000-0001-6431-4605 FU United States National Institutes of Health (US NIH) [R01AI050875]; FAPESP (Fundacao de Amparo e Pesquisa do Estado de Sao Paulo); CNPq (Conselho Nacional de Pesquisa e Desenvolvimento) FX Dr. Hamblin was supported by United States National Institutes of Health (US NIH) grant R01AI050875. M. S. Ribeiro thanks FAPESP (Fundacao de Amparo e Pesquisa do Estado de Sao Paulo) and CNPq (Conselho Nacional de Pesquisa e Desenvolvimento) for financial support. NR 30 TC 16 Z9 16 U1 1 U2 23 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-5418 EI 1557-8550 J9 PHOTOMED LASER SURG JI Photomed. Laser Surg. PD NOV 1 PY 2013 VL 31 IS 11 BP 519 EP 525 DI 10.1089/pho.2012.3341 PG 7 WC Surgery SC Surgery GA 244PE UT WOS:000326400700003 PM 23822168 ER PT J AU Dai, TH Gupta, A Huang, YY Sherwood, ME Murray, CK Vrahas, MS Kielian, T Hamblin, MR AF Dai, Tianhong Gupta, Asheesh Huang, Ying-Ying Sherwood, Margaret E. Murray, Clinton K. Vrahas, Mark S. Kielian, Tammy Hamblin, Michael R. TI Blue Light Eliminates Community-Acquired Methicillin-Resistant Staphylococcus aureus in Infected Mouse Skin Abrasions SO PHOTOMEDICINE AND LASER SURGERY LA English DT Article ID MRSA IN-VITRO; VISIBLE-LIGHT; PROPIONIBACTERIUM-ACNES; LOCALIZED INFECTIONS; PHOTODYNAMIC THERAPY; HELICOBACTER-PYLORI; HIGH-INTENSITY; INACTIVATION; BACTERIA; MODEL AB Background and objective: Bacterial skin and soft tissue infections (SSTI) affect millions of individuals annually in the United States. Treatment of SSTI has been significantly complicated by the increasing emergence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) strains. The objective of this study was to demonstrate the efficacy of blue light (415 +/- 10nm) therapy for eliminating CA-MRSA infections in skin abrasions of mice. Methods: The susceptibilities of a CA-MRSA strain (USA300LAC) and human keratinocytes (HaCaT) to blue light inactivation were compared by in vitro culture studies. A mouse model of skin abrasion infection was developed using bioluminescent USA300LAC::lux. Blue light was delivered to the infected mouse skin abrasions at 30min (acute) and 24h (established) after the bacterial inoculation. Bioluminescence imaging was used to monitor in real time the extent of infection in mice. Results: USA300LAC was much more susceptible to blue light inactivation than HaCaT cells (p=0.038). Approximately 4.75-log(10) bacterial inactivation was achieved after 170J/cm(2) blue light had been delivered, but only 0.29 log(10) loss of viability in HaCaT cells was observed. Transmission electron microscopy imaging of USA300LAC cells exposed to blue light exhibited disruption of the cytoplasmic content, disruption of cell walls, and cell debris. In vivo studies showed that blue light rapidly reduced the bacterial burden in both acute and established CA-MRSA infections. More than 2-log(10) reduction of bacterial luminescence in the mouse skin abrasions was achieved when 41.4 (day 0) and 108J/cm(2) (day 1) blue light had been delivered. Bacterial regrowth was observed in the mouse wounds at 24h after the blue light therapy. Conclusions: There exists a therapeutic window of blue light for bacterial infections where bacteria are selectively inactivated by blue light while host tissue cells are preserved. Blue light therapy has the potential to rapidly reduce the bacterial load in SSTI. C1 [Dai, Tianhong; Gupta, Asheesh; Huang, Ying-Ying; Sherwood, Margaret E.; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Vrahas, Mark S.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Dai, Tianhong; Huang, Ying-Ying; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Gupta, Asheesh] Def Inst Physiol & Allied Sci, Delhi, India. [Murray, Clinton K.] Brooke Army Med Ctr, Infect Dis Serv, Ft Sam Houston, TX 78234 USA. [Kielian, Tammy] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu OI Hamblin, Michael/0000-0001-6431-4605 FU Airlift Research Foundation Extremity Trauma Research Grant [109421]; Center for Orthopaedic Trauma Advancement (COTA)/Smith Nephew Grant [2012-16]; NIH [RO1AI050875] FX This study was supported in part by an Airlift Research Foundation Extremity Trauma Research Grant (grant #109421 to TD), a Center for Orthopaedic Trauma Advancement (COTA)/Smith & Nephew Grant (grant # 2012-16 to TD), and the NIH (grant RO1AI050875 to MRH). NR 39 TC 16 Z9 18 U1 0 U2 11 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-5418 EI 1557-8550 J9 PHOTOMED LASER SURG JI Photomed. Laser Surg. PD NOV 1 PY 2013 VL 31 IS 11 BP 531 EP 538 DI 10.1089/pho.2012.3365 PG 8 WC Surgery SC Surgery GA 244PE UT WOS:000326400700005 PM 23406384 ER PT J AU Pantazopoulos, H Boyer-Boiteau, A Holbrook, EH Jang, W Hahn, CG Arnold, SE Berretta, S AF Pantazopoulos, Harry Boyer-Boiteau, Anne Holbrook, Eric H. Jang, Woochan Hahn, Chang-Gyu Arnold, Steven E. Berretta, Sabina TI Proteoglycan abnormalities in olfactory epithelium tissue from subjects diagnosed with schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Extracellular matrix; Chondroitin sulfate proteoglycans; Olfactory epithelium; Postmortem ID NEURAL STEM-CELLS; CHONDROITIN SULFATE PROTEOGLYCANS; CENTRAL-NERVOUS-SYSTEM; NEUROLEPTIC-NAIVE PATIENTS; NEURITE OUTGROWTH; EXPRESSION; PROLIFERATION; LOCALIZATION; CORTEX; GROWTH AB Emerging evidence points to proteoglycan abnormalities in the pathophysiology of schizophrenia (SZ). In particular, markedly abnormal expression of chondroitin sulfate proteoglycans (CSPGs), key components of the extracellular matrix, was observed in the medial temporal lobe. CSPG functions, including regulation of neuronal differentiation and migration, are highly relevant to the pathophysiology of SZ. CSPGs may exert similar functions in the olfactory epithelium (OE), a continuously regenerating neural tissue that shows cell and molecular abnormalities in SZ. We tested the hypothesis that CSPG expression in OE may be altered in SZ. CSPG-positive cells in postmortem OE from non-psychiatric control (n = 9) and SZ (n = 10) subjects were counted using computer-assisted light microscopy. 'Cytoplasmic' CSPG (c-CSPG) labeling was detected in sustentacular cells and some olfactory receptor neurons (c-CSPG + ORNs), while 'pericellular' CSPG (p-CSPG) labeling was found in basal cells and some ORNs (p-CSPG + ORNs). Dual labeling for CSPG and markers for mature and immature ORNs suggests that c-CSPG + ORNs correspond to mature ORNs, and p-CSPG + ORNs to immature ORNs. Previous studies in the same cohort demonstrated that densities of mature ORNs were unaltered (Arnold et al., 2001). In the present study, numerical densities of c-CSPG + ORNs were significantly decreased in SZ (p < 0.025; 99.32% decrease), suggesting a reduction of CSPG expression in mature ORNs. Previous studies showed a striking increase in the ratios of immature neurons with respect to basal cells. In this study, we find that the ratio of p-CSPG + ORNs/CSPG + basal cells was significantly increased (p = 0.03) in SZ, while numerical density changes of p-CSPG + ORNs (110.71% increase) or CSPG + basal cells (53.71% decrease), did not reach statistical significance. Together, these results indicate that CSPG abnormalities are present in the OE of SZ and specifically point to a reduction of CSPG expression in mature ORNs in SZ. Given the role CSPGs play in OE cell differentiation and axon guidance, we suggest that altered CSPG expression may contribute to ORN lineage dysregulation, and olfactory identification abnormalities, observed in SZ. (C) 2013 Elsevier B. V. All rights reserved. C1 [Pantazopoulos, Harry; Berretta, Sabina] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Pantazopoulos, Harry; Boyer-Boiteau, Anne; Berretta, Sabina] McLean Hosp, Translat Neurosci Lab, Belmont, MA 02478 USA. [Holbrook, Eric H.] Harvard Univ, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. [Holbrook, Eric H.; Jang, Woochan] Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. [Hahn, Chang-Gyu; Arnold, Steven E.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Berretta, Sabina] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Berretta, S (reprint author), MRC3 McLean Hosp, Mailstop 149,115 Mill St, Belmont, MA 02478 USA. EM s.berretta@mclean.harvard.edu RI Pantazopoulos, Harry/M-1435-2016 OI Pantazopoulos, Harry/0000-0002-0540-1589 FU National Institutes of Health - NIMH [R01-MH091348] FX This work was funded by the National Institutes of Health - NIMH. R01-MH091348 to Sabina Berretta, M.D. NR 52 TC 13 Z9 13 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD NOV PY 2013 VL 150 IS 2-3 BP 366 EP 372 DI 10.1016/j.schres.2013.08.013 PG 7 WC Psychiatry SC Psychiatry GA 241PY UT WOS:000326180700009 PM 24035561 ER PT J AU Sun, LM Castellanos, N Grutzner, C Koethe, D Rivolta, D Wibral, M Kranaster, L Singer, W Leweke, MF Uhlhaas, PJ AF Sun, Limin Castellanos, Nazareth Gruetzner, Christine Koethe, Dagmar Rivolta, Davide Wibral, Michael Kranaster, Laura Singer, Wolf Leweke, Markus F. Uhlhaas, Peter J. TI Evidence for dysregulated high-frequency oscillations during sensory processing in medication-naive, first episode schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; High-frequency oscillations; Perceptual organization; Neural synchrony; First-episode; MEG ID GAMMA-BAND ACTIVITY; COGNITIVE CONTROL; AUDITORY-CORTEX; SYNCHRONIZATION; HYPOTHESIS; DYNAMICS; NEURONS; MEG; DESYNCHRONIZATION; ORGANIZATION AB Introduction: High-frequency oscillations are important for sensory processing and dysfunctions in the amplitude and synchrony of beta-and gamma-band oscillations have been demonstrated in schizophrenia (ScZ). However, the presence of aberrant high-frequency oscillations in first-episode (FE), medication-naive patients during sensory processing is unclear. Methods: Magnetoencephalographic (MEG) data were recorded from 15 never-medicated, FE-ScZ patients and 20 matched healthy controls during the perception of Mooney faces. MEG data were analysed for spectral power and single-sensor phase-locking in the beta (13-25 Hz) and gamma- (25-140 Hz) frequency range. Results: FE-ScZ patients were characterized by significantly impaired sensory processing as indicated by a reduced discrimination index (A'). Impaired behavioural performance in ScZ-patients was accompanied by decreased spectral power in the high- (60-120 Hz) gamma-band range. In contrast, oscillations in the lower (25-60 Hz) gamma-band were largely intact and beta-band oscillations were increased. Analysis of cross-frequency coupling showed a reduced correlation between 60 and 120 Hz amplitude values and beta-band power in FE-ScZ-patients relative to controls. Discussion: Our findings show that impaired sensory processing in medication-naive, FE-schizophrenia is related to a dysregulation of neural oscillations which involves both an impairment in the generation of high gamma-band activity as well as a failure to downregulate task-irrelevant beta-band activity. Because of the interrelationship of these dysfunctions and the role of inhibitory networks in the shaping of high-frequency activity, aberrant neural oscillations in FE-schizophrenia may be linked to dysfunctions in the excitation-inhibition (E/I)-balance. (C) 2013 Elsevier B. V. All rights reserved. C1 [Sun, Limin; Gruetzner, Christine; Rivolta, Davide; Singer, Wolf; Uhlhaas, Peter J.] Max Planck Inst Brain Res, Dept Neurophysiol, D-60528 Frankfurt, Germany. [Sun, Limin] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Cambridge, MA 02129 USA. [Castellanos, Nazareth; Singer, Wolf] Univ Politecn Madrid, Ctr Biomed Technol, Ctr Magnetoencephalog, Cognit & Computat Neurosci Grp, E-28040 Madrid, Spain. [Koethe, Dagmar; Kranaster, Laura] Heidelberg Univ, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, D-68159 Mannheim, Germany. [Rivolta, Davide; Leweke, Markus F.; Uhlhaas, Peter J.] Max Planck Gesell, Ernst Strungmann Inst ESI Neurosci, D-60528 Frankfurt, Germany. [Wibral, Michael] Goethe Univ Frankfurt, Brain Imaging Ctr, MEG Unit, D-60528 Frankfurt, Germany. [Singer, Wolf] Goethe Univ Frankfurt, Frankfurt Inst Adv Studies, D-60438 Frankfurt, Germany. [Uhlhaas, Peter J.] Univ Glasgow, Inst Neurosci & Psychol, Glasgow G12 8QB, Lanark, Scotland. RP Uhlhaas, PJ (reprint author), Univ Glasgow, Inst Neurosci & Psychol, Hillead Str 58, Glasgow G12 8QB, Lanark, Scotland. EM peter.uhlhaas@glasgow.ac.uk RI Singer, Wolf/D-6874-2012; Kiefer, Falk/E-8325-2012; OI Wibral, Michael/0000-0001-8010-5862 FU NARSAD; Neuronale Koordination Forschungsschwerpunkt Frankfurt (NeFF); Max-Planck Society FX This work was supported by NARSAD, the Neuronale Koordination Forschungsschwerpunkt Frankfurt (NeFF) and by the Max-Planck Society. NR 54 TC 30 Z9 30 U1 3 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD NOV PY 2013 VL 150 IS 2-3 BP 519 EP 525 DI 10.1016/j.schres.2013.08.023 PG 7 WC Psychiatry SC Psychiatry GA 241PY UT WOS:000326180700031 PM 24016727 ER PT J AU Yamashita, A Kawana, K Tomio, K Taguchi, A Isobe, Y Iwamoto, R Masuda, K Furuya, H Nagamatsu, T Nagasaka, K Arimoto, T Oda, K Wada-Hiraike, O Yamashita, T Taketani, Y Kang, JX Kozuma, S Arai, H Arita, M Osuga, Y Fujii, T AF Yamashita, Aki Kawana, Kei Tomio, Kensuke Taguchi, Ayumi Isobe, Yosuke Iwamoto, Ryo Masuda, Koji Furuya, Hitomi Nagamatsu, Takeshi Nagasaka, Kazunori Arimoto, Takahide Oda, Katsutoshi Wada-Hiraike, Osamu Yamashita, Takahiro Taketani, Yuji Kang, Jing X. Kozuma, Shiro Arai, Hiroyuki Arita, Makoto Osuga, Yutaka Fujii, Tomoyuki TI Increased tissue levels of omega-3 polyunsaturated fatty acids prevents pathological preterm birth SO SCIENTIFIC REPORTS LA English DT Article ID FAT-1 TRANSGENIC MICE; NECROSIS-FACTOR-ALPHA; MEDIATOR RESOLVIN E3; INFLAMMATORY MEDIATORS; MOUSE MODEL; MEDROXYPROGESTERONE ACETATE; ANTIINFLAMMATORY PROPERTIES; STEREOCHEMICAL ASSIGNMENT; PROSTAGLANDIN PRODUCTION; INTRAUTERINE INFECTION AB Omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) have anti-inflammatory effects. Preterm birth is an important problem in modern obstetrics and one of the main causes is an inflammation. We here showed that abundance of omega-3 fatty acids reduced the incidence of preterm birth induced by LPS with fat-1 mice, capable of converting omega-6 to omega-3 fatty acids. We also indicated that the gene expression of IL-6 and IL-1 beta in uteruses and the number of cervical infiltrating macrophages were reduced in fat-1 mice. The analyses of lipid metabolomics showed the high level of 18-hydroxyeicosapentaenoate in fat-1 mice, which was derived from EPA and was metabolized to anti-inflammatory product named resolvin E3 (RvE3). We finally showed that the administration of RvE3 to LPS-exposed pregnant wild type mice lowered the incidence of preterm birth. Our data suggest that RvE3 could be a potential new therapeutic for the prevention of preterm birth. C1 [Yamashita, Aki; Kawana, Kei; Tomio, Kensuke; Taguchi, Ayumi; Furuya, Hitomi; Nagamatsu, Takeshi; Nagasaka, Kazunori; Arimoto, Takahide; Oda, Katsutoshi; Wada-Hiraike, Osamu; Yamashita, Takahiro; Taketani, Yuji; Kozuma, Shiro; Osuga, Yutaka; Fujii, Tomoyuki] Univ Tokyo, Dept Obstet & Gynecol, Fac Med, Bunkyo Ku, Tokyo 1138655, Japan. [Isobe, Yosuke; Arai, Hiroyuki; Arita, Makoto] Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Hlth Chem, Bunkyo Ku, Tokyo 1130033, Japan. [Isobe, Yosuke; Iwamoto, Ryo; Masuda, Koji] Univ Tokyo, Grad Sch Pharmaceut Sci, Business Acad Collaborat Lab, Bunkyo Ku, Tokyo 1130033, Japan. [Masuda, Koji] Shionogi & Co Ltd, Med Res Labs, Osaka, Japan. [Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Charlestown, MA 02129 USA. [Kang, Jing X.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Kawana, K (reprint author), Univ Tokyo, Dept Obstet & Gynecol, Fac Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan. EM kkawana-tky@umin.ac.jp; marita@mol.f.u-tokyo.ac.jp OI Nagasaka, Kazunori/0000-0002-0696-5175 FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Tokyo IGAKUKAI; Japan Science and Technology agency Precursory Research for Embryonic Science and Technology (PRESTO); Ministry of Education, Culture, Sports, Science, and Technology of Japan FX We gratefully thank Dr. Danny J. Schust for careful editing of the manuscript, Dr. Terufumi Yokoyama for excellent comments and advice on experiments using murine models and Ms. Michiko Kamio for technical assistance on LC-MS/MS analyses. This work was supported by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (K.K., T.F.), by a grant-in-aid from the Tokyo IGAKUKAI (K.K.), by grant-in-aid from Japan Science and Technology agency Precursory Research for Embryonic Science and Technology (PRESTO) (M.A.), and by grant in aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (M.A.) NR 50 TC 10 Z9 10 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD NOV 1 PY 2013 VL 3 AR 3113 DI 10.1038/srep03113 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 245WF UT WOS:000326493800003 PM 24177907 ER PT J AU Ward, AM McLaren, DG Schultz, AP Chhatwal, J Boot, BP Hedden, T Sperling, RA AF Ward, Andrew M. McLaren, Donald G. Schultz, Aaron P. Chhatwal, Jasmeer Boot, Brendon P. Hedden, Trey Sperling, Reisa A. TI Daytime Sleepiness Is Associated with Decreased Default Mode Network Connectivity in Both Young and Cognitively Intact Elderly Subjects SO SLEEP LA English DT Article DE Epworth Sleepiness Scale; functional connectivity; neuroimaging; magnetic resonance imaging; sleep ID STATE FUNCTIONAL CONNECTIVITY; SLOW-WAVE SLEEP; ALZHEIMERS-DISEASE; BRAIN ACTIVITY; NEUROCOGNITIVE CONSEQUENCES; SENSORY STIMULATION; WORKING-MEMORY; QUALITY INDEX; DOSE-RESPONSE; OLDER-ADULTS AB Study Objectives: Sleep deprivation and daytime somnolence impair numerous aspects of physical, cognitive, and memory performance. However, most studies examining the effect of somnolence on brain function focus on acute sleep restriction in young adults. We examine the relationship between chronic daytime somnolence and connectivity in six brain networks in both young and elderly subjects using stimulus-free resting-state functional magnetic resonance imaging. Design: Cross-sectional. Setting: Outpatient research at the Massachusetts General Hospital. Participants: Young (n = 27) and elderly (n = 84) healthy, cognitively normal volunteers. Interventions: None. Measurements and Results: Compared with young subjects, cognitively normal elderly adults report less daytime somnolence on the Epworth Sleepiness Scale (ESS) (P = 0.019) and display reduced default mode network (DMN) connectivity (P = 0.004). Across all subjects, increasing daytime sleepiness was associated with decreasing functional connectivity in the DMN (P = 0.003, partial r of ESS = -0.29). There was no difference in the slope of this relationship between young adults and elderly subjects. No other cortical networks were correlated with daytime sleepiness. Daytime sleepiness and DMN connectivity were not related to sex, brain structure, or body mass index. Conclusions: These findings suggest that daytime sleepiness is associated with impaired connectivity of the DMN in a manner that is distinct from the effects of aging. This association is important to consider in any study using DMN connectivity as a biomarker. Additionally, these results may help identify those subjects at risk for future memory decline. C1 [Ward, Andrew M.; McLaren, Donald G.; Schultz, Aaron P.; Chhatwal, Jasmeer; Boot, Brendon P.; Hedden, Trey; Sperling, Reisa A.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ward, Andrew M.; Chhatwal, Jasmeer; Boot, Brendon P.; Sperling, Reisa A.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Ward, Andrew M.; McLaren, Donald G.; Schultz, Aaron P.; Chhatwal, Jasmeer; Boot, Brendon P.; Sperling, Reisa A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Hedden, Trey] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ward, Andrew M.; McLaren, Donald G.; Schultz, Aaron P.; Chhatwal, Jasmeer; Boot, Brendon P.; Hedden, Trey; Sperling, Reisa A.] Harvard Univ, Sch Med, Boston, MA USA. [McLaren, Donald G.] Edith Nourse Rogers Mem Vet Hosp, GRECC, Bedford, MA USA. [Boot, Brendon P.; Sperling, Reisa A.] Ctr Alzheimer Res & Treatment, Boston, MA USA. RP Sperling, RA (reprint author), 221 Longwood Ave, Boston, MA 02115 USA. EM rsperling@rics.bwh.harvard.edu OI Ward, Andrew/0000-0001-6948-4814; McLaren, Donald/0000-0002-0566-4610 FU NIA [AG027435, P01AG036694, P50 AG005134, K24 AG035007] FX This was not an industry supported study. The authors have indicated no financial conflicts of interest. This work was supported by NIA AG027435, P01AG036694, P50 AG005134, K24 AG035007 to Dr. Sperling. NR 80 TC 8 Z9 8 U1 1 U2 12 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD NOV 1 PY 2013 VL 36 IS 11 BP 1609 EP 1615 DI 10.5665/sleep.3108 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 246KW UT WOS:000326537800004 PM 24179292 ER PT J AU Marino, M Li, Y Rueschman, MN Winkelman, JW Ellenbogen, JM Solet, JM Dulin, H Berkman, LF Buxton, OM AF Marino, Miguel Li, Yi Rueschman, Michael N. Winkelman, J. W. Ellenbogen, J. M. Solet, J. M. Dulin, Hilary Berkman, Lisa F. Buxton, Orfeu M. TI Measuring Sleep: Accuracy, Sensitivity, and Specificity of Wrist Actigraphy Compared to Polysomnography SO SLEEP LA English DT Article DE Actigraphy; polysomnography; WASO; sensitivity; specificity; accuracy ID PRIMARY INSOMNIA; WAKE; VALIDATION; DURATION; RHYTHMS AB Objectives: We validated actigraphy for detecting sleep and wakefulness versus polysomnography (PSG). Design: Actigraphy and polysomnography were simultaneously collected during sleep laboratory admissions. All studies involved 8.5 h time in bed, except for sleep restriction studies. Epochs (30-sec; n = 232,849) were characterized for sensitivity (actigraphy = sleep when PSG = sleep), specificity (actigraphy = wake when PSG = wake), and accuracy (total proportion correct); the amount of wakefulness after sleep onset (WASO) was also assessed. A generalized estimating equation (GEE) model included age, gender, insomnia diagnosis, and daytime/nighttime sleep timing factors. Setting: Controlled sleep laboratory conditions. Participants: Young and older adults, healthy or chronic primary insomniac (PI) patients, and daytime sleep of 23 night-workers (n = 77, age 35.0 +/- 12.5, 30F, mean nights = 3.2). Interventions: N/A. Measurements and Results: Overall, sensitivity (0.965) and accuracy (0.863) were high, whereas specificity (0.329) was low; each was only slightly modified by gender, insomnia, day/night sleep timing (magnitude of change < 0.04). Increasing age slightly reduced specificity. Mean WASO/night was 49.1 min by PSG compared to 36.8 min/night by actigraphy (beta = 0.81; CI = 0.42, 1.21), unbiased when WASO < 30 min/night, and overestimated when WASO > 30 min/night. Conclusions: This validation quantifies strengths and weaknesses of actigraphy as a tool measuring sleep in clinical and population studies. Overall, the participant-specific accuracy is relatively high, and for most participants, above 80%. We validate this finding across multiple nights and a variety of adults across much of the young to midlife years, in both men and women, in those with and without insomnia, and in 77 participants. We conclude that actigraphy is overall a useful and valid means for estimating total sleep time and wakefulness after sleep onset in field and workplace studies, with some limitations in specificity. C1 [Marino, Miguel] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Marino, Miguel] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97201 USA. [Li, Yi] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Rueschman, Michael N.; Dulin, Hilary; Buxton, Orfeu M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Winkelman, J. W.; Solet, J. M.; Buxton, Orfeu M.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [Winkelman, J. W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Ellenbogen, J. M.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Solet, J. M.] Cambridge Hlth Alliance, Massachusetts Gen Hosp, Dept Med, Cambridge, MA USA. [Berkman, Lisa F.] Harvard Ctr Populat & Dev Studies, Cambridge, MA USA. [Berkman, Lisa F.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Buxton, Orfeu M.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Cambridge, MA 02138 USA. [Buxton, Orfeu M.] Penn State Univ, Dept Biobehav Hlth, University Pk, PA 16802 USA. RP Buxton, OM (reprint author), 221 Longwood Ave,BLI438-K, Boston, MA 02115 USA. EM Orfeu_Buxton@hms.harvard.edu FU Kennedy Shriver National Institute of Child Health and Human Development [U01HD051217, U01HD051218, U01HD051256, U01HD051276]; National Institute on Aging [U01AG027669]; National Heart, Lung and Blood Institute [R01HL107240]; Office of Behavioral and Social Sciences Research; National Institute for Occupational Safety and Health [U01OH008788, U01HD059773]; General Clinical Research Center [M01-RR02635]; Academy of Architecture for Health; Facilities Guidelines Institute; Center for Health Design; William T. Grant Foundation; Alfred P Sloan Foundation; Administration for Children and Families; Sepracor Inc; GlaxoSmithKline; Impax Pharmaceuticals FX This was not an industry supported study. Support was provided by the Kennedy Shriver National Institute of Child Health and Human Development (Grant # U01HD051217, U01HD051218, U01HD051256, U01HD051276), National Institute on Aging (Grant # U01AG027669), the National Heart, Lung and Blood Institute (R01HL107240), Office of Behavioral and Social Sciences Research, and National Institute for Occupational Safety and Health (Grant # U01OH008788, U01HD059773), and General Clinical Research Center grant M01-RR02635. Investigator-initiated grants from the Academy of Architecture for Health, the Facilities Guidelines Institute, The Center for Health Design, William T. Grant Foundation, Alfred P Sloan Foundation, and the Administration for Children and Families have provided additional funding. Dr. Buxton was a Research grant recipient 2009-2010 from Sepracor Inc (now Sunovion Inc) for an investigator-initiated research grant to entitled "Effects of Daytime Eszopiclone Administration in Shift Workers"; research completed in 2010; manuscript in preparation; http://clinicaltrials.gov/ct2/show/study/NCT00900159. Dr. Buxton serves as a consultant and expert witness for Dinsmore, LLC (plaintiff attorney) in a case unrelated to the current manuscript involving sleep, circadian rhythms, and diabetes in railroad workers. Dr. Buxton serves on the scientific advisory board of Matsutani America and as a consultant to the Wake Forest University Medical Center (NC) on an unrelated study of sleep and pediatric atopic dermatitis. Dr. Buxton participated in a speaking engagement at the National Postdoctoral Association (nationalpostdoc.org) 10th annual meeting in 2012. Dr. Winkelman serves on the Consultant/Advisory Board of Pfizer, UCB, Zeo Inc., Sunovion. Dr. Winkelman receives research support from GlaxoSmithKline and Impax Pharmaceuticals. Dr. Solet provides sleep science consultations related to the educational mission of Lark Technologies, a privately held start-up company, under a contract through which she receives stock which is vesting over time. The other authors have indicated no financial conflicts of interest. NR 31 TC 56 Z9 59 U1 6 U2 24 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD NOV 1 PY 2013 VL 36 IS 11 BP 1747 EP 1755 DI 10.5665/sleep.3142 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 246KW UT WOS:000326537800021 PM 24179309 ER PT J AU Yamada, S Fuchs, BC Fujii, T Shimoyama, Y Sugimoto, H Nomoto, S Takeda, S Tanabe, KK Kodera, Y Nakao, A AF Yamada, Suguru Fuchs, Bryan C. Fujii, Tsutomu Shimoyama, Yoshie Sugimoto, Hiroyuki Nomoto, Shuji Takeda, Shin Tanabe, Kenneth K. Kodera, Yasuhiro Nakao, Akimasa TI Epithelial-to-mesenchymal transition predicts prognosis of pancreatic cancer SO SURGERY LA English DT Article ID E-CADHERIN EXPRESSION; SQUAMOUS-CELL CARCINOMA; DUCTAL ADENOCARCINOMA; TUMOR-METASTASIS; PATIENT SURVIVAL; ALPHA-CATENIN; SNAIL; TWIST; EMT; IMMUNOREACTIVITY AB Background. Pancreatic cancer has a dismal prognosis that is attributed to common local invasiveness and metastasis. Epithelial-to-mesenchymal transition (EMT) plays an important role in cancer invasion and metastasis and is associated with early dissemination. The aim of this study was to evaluate the association between EMT and the prognoses for patients with pancreatic cancer. Methods. Immunohistochemistry of E-cadherin and vimentin was performed on surgical specimens from 174 patients who underwent resection of their pancreatic cancers. Tumoral stainings of E-cadherin and vimentin were graded, and EMT statuses were determined by calculating the ratio of vimentin to E-cadherin, whereby patients were categorized into 3 groups: epithelial, intermediate, and mesenchymal. The correlations between EMT statuses and clinicopathologic factors and prognoses were analyzed. Results. There was a significant correlation between EMT status and CA19-9 levels (P = .020); peritoneal washing cytology (P = .025); portal vein invasion (P = .038); and lymph node metastasis (P = .030). The median survival for patients with epithelial tumors was 40.2 months as compared to 13.7 months for patients with mesenchymal tumors. Multivariate analysis demonstrated that perineural invasion (P = .024); lymph node metastasis (1, = .033); and EMT status (P < .0001) were significant prognostic factors. It is interesting that adjuvant chemotherapy (gemcitabine and/or S-1) improved the median survival time from 10.8 to 16.1 months in patients with mesenchymal tumors (P = .002); however, no significant difference was seen in patients with epithelial tumors. Conclusion. EMT status is an important prognostic factor for pancreatic cancer and is associated with portal vein invasion and lymph node metastasis. C1 [Yamada, Suguru; Fujii, Tsutomu; Sugimoto, Hiroyuki; Nomoto, Shuji; Takeda, Shin; Kodera, Yasuhiro] Nagoya Univ, Dept Gastroenterol Surg Surg 2, Grad Sch Med, Nagoya, Aichi 4668550, Japan. [Fuchs, Bryan C.; Tanabe, Kenneth K.] Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. [Shimoyama, Yoshie] Nagoya Univ Hosp, Dept Pathol, Nagoya, Aichi, Japan. [Nakao, Akimasa] Nagoya Univ Hosp, Dept Surg, Nagoya, Aichi, Japan. RP Yamada, S (reprint author), Nagoya Univ, Dept Gastroenterol Surg Surg 2, Grad Sch Med, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan. EM suguru@med.nagoya-u.ac.jp RI Kodera, Yasuhiro/M-4912-2014; SHIMOYAMA, Yoshie/I-7361-2014; Fujii, Tsutomu/M-4838-2014 NR 35 TC 50 Z9 53 U1 0 U2 10 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 NOV PY 2013 VL 154 IS 5 BP 946 EP 954 DI 10.1016/j.surg.2013.05.004 PG 9 WC Surgery SC Surgery GA 245AU UT WOS:000326432100002 PM 24075276 ER PT J AU Choueiri, TK Cheng, SC Qu, AQ Pastorek, J Atkins, MB Signoretti, S AF Choueiri, Toni K. Cheng, Suchun Qu, Angela Q. Pastorek, Jaromir Atkins, Michael B. Signoretti, Sabina TI Carbonic anhydrase IX as a potential biomarker of efficacy in metastatic clear-cell renal cell carcinoma patients receiving sorafenib or placebo: Analysis from the treatment approaches in renal cancer global evaluation trial (TARGET) SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Renal cell carcinoma (RCC); Carbonic anhydrase IX; Sorafenib; Biomarker; Vascular endothelial growth factor; Prognostic marker ID INDEPENDENT PREDICTOR; THERAPY; SURVIVAL AB Objective: Retrospective data analyses have suggested that carbonic anhydrase IX (CAIX) may have a predictive role in patients with metastatic clear cell renal cell carcinoma (ccRCC) receiving high dose interleukin-2 or sorafenib. We examined the predictive value of CAD( in estimating treatment outcome in patients receiving sorafenib vs. placebo as part of the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) study. Materials and methods: Paraffin embedded tumor tissues were collected from 133 patients from the TARGET study (n = 903). The percentage of CAIX-positive cells was assessed by a single pathologist. The impact of CAIX expression on progression-free survival (PFS, primary endpoint) and tumor shrinkage (TS, secondary endpoint) was analyzed. Results: Clinical characteristics were similarly distributed between patients with low vs. high CAIX staining, as well as patients with available CAIX data vs. not Median PFS for patients,with high CAIX vs. low CAIX expression was 5.5 and 5.4 months, respectively, on the sorafenib arm (P = 0.97), and 1.5 and 1.7 months on the placebo arm (P = 0.76). Median TS for patients with high CAIX status was -14.9% vs. -12.6% in patients with low CAIX status (P = 0.63) on the sorafenib arm, and +1.3% (high CAIX) vs. +4.8% (low CAIX) in patients on the placebo arm (P = 0.60). Conclusions: Despite suggestive retrospective evidence, data from the TARGET study did not find CAIX expression status to be either predictive of clinical benefit for treatment with sorafenib or of prognostic value in patients with metastatic ccRCC following cytokine therapy. (C) 2013 Elsevier Inc. All rights reserved. C1 [Choueiri, Toni K.; Cheng, Suchun; Atkins, Michael B.; Signoretti, Sabina] Dana Farber Harvard Canc Ctr, Kidney Canc Program, Boston, MA 02215 USA. [Choueiri, Toni K.; Qu, Angela Q.; Signoretti, Sabina] Dana Farber Canc Inst, Boston, MA 02215 USA. [Choueiri, Toni K.; Signoretti, Sabina] Brigham & Womens Hosp, Boston, MA 02215 USA. [Atkins, Michael B.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Signoretti, S (reprint author), Dana Farber Harvard Canc Ctr, Kidney Canc Program, Boston, MA 02215 USA. EM ssignoretti@partners.org FU Dana-Farber/Harvard Cancer Center Kidney SPORE; National Cancer Institute [P50CA101942]; Trust Family Research Fund for Kidney Cancer FX This work was supported by the Dana-Farber/Harvard Cancer Center Kidney SPORE, National Cancer Institute (P50CA101942), and the Trust Family Research Fund for Kidney Cancer. NR 21 TC 14 Z9 15 U1 3 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD NOV PY 2013 VL 31 IS 8 BP 1788 EP 1793 DI 10.1016/j.urolonc.2012.07.004 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 246RN UT WOS:000326556900055 PM 23141780 ER PT J AU Fuentes-Orrego, JM Hayano, K Kambadakone, AR Hahn, PF Sahani, DV AF Fuentes-Orrego, Jorge M. Hayano, Koichi Kambadakone, Avinash R. Hahn, Peter F. Sahani, Dushyant V. TI Dose-modified 256-MDCT of the Abdomen Using Low Tube Current and Hybrid Iterative Reconstruction SO ACADEMIC RADIOLOGY LA English DT Article DE Radiation dose; abdomen; computed tomography; iterative reconstruction; image quality ID FILTERED BACK-PROJECTION; 256-DETECTOR ROW CT; IMAGE QUALITY; ABDOMINAL CT; MULTIDETECTOR CT; COMPUTED-TOMOGRAPHY; RADIATION-EXPOSURE; CONTRAST AGENT; CROHN DISEASE; DYNAMIC CT AB Rationale and Objectives: To evaluate the performance of hybrid iterative reconstruction technique (h-IRT) on image quality (IQ) in abdominal dose-modified (DM) scans, in phantom and in patients in comparison to filtered back projection (FBP). Materials and Methods: An anthropomorphic phantom was scanned using various kVp (80-140) and mAs (25-100) settings. Images were reconstructed with FBP and h-IRT levels (1-6). In 69 adults (59.6 +/- 13.54 years; 20 male, 49:female), DM computed tomography (CT) scans were performed using 120 kVp and 100-120 mAs. In 25/69,5-mm FBP and h-IRT (levels 1-4 and 5) images were analyzed to validate IQ. The subsequent 44/69 had FBP and h-IRT (level 4) images reconstructed. Two readers evaluated 188 image series for IQ, noise, and artifacts. Objective and subjective data were analyzed using t-test and Wilcoxon signed-rank test, respectively. In 46/69 patients, prior dose CT was available for dose comparison. Results: In the phantom, noise reduction ranged from 12% (h-IRT level 1) to 50% (level 6). In patients, h-IRT level 4 images were rated diagnostic in 69/69 exams but DM-FBP images were found nondiagnostic in 20/69 patients. The size-specific dose estimate (SSDE) was reduced by 55% in the dose-modified CT group, (SSDE:4.55 +/- 1.15 mGy) over the prior dose protocol (SSDE:10.21 +/- 3.5 mGy, P < .0001). Conclusion: h-IRT improved IQ in abdominal DM-CT scans in phantom and in patients. Dose improvements were greater in smaller patients than larger ones. C1 [Fuentes-Orrego, Jorge M.; Hayano, Koichi; Kambadakone, Avinash R.; Hahn, Peter F.; Sahani, Dushyant V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Abdominal Imaging & Intervent, Boston, MA 02115 USA. RP Sahani, DV (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Abdominal Imaging & Intervent, 55 Fruit St, Boston, MA 02115 USA. EM dsahani@partners.org OI Fuentes-Orrego, Jorge/0000-0002-9254-0746 NR 36 TC 4 Z9 5 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD NOV PY 2013 VL 20 IS 11 BP 1405 EP 1412 DI 10.1016/j.acra.2013.08.004 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 241AW UT WOS:000326139800011 PM 24119353 ER PT J AU Chuang, ML Leslie, RW Massaro, JM Manders, ES Fox, CS Hoffmann, U O'Donnell, CJ AF Chuang, Michael L. Leslie, Richard W. Massaro, Joseph M. Manders, Emily S. Fox, Caroline S. Hoffmann, Udo O'Donnell, Christopher J. TI Distribution of Abdominal Aortic Calcium by Computed Tomography: Impact of Analysis Method on Quantitative Calcium Score SO ACADEMIC RADIOLOGY LA English DT Article DE Abdominal aorta; calcium; population study; segment length; computed tomography ID CORONARY-ARTERY CALCIUM; HEART; ATHEROSCLEROSIS; CALCIFICATION; PREDICTOR; QUANTIFICATION; MORTALITY; COHORT; CT AB Rationale and Objectives: Abdominal aortic calcification (MC) can be quantified using computed tomography (CT), but imaging planes are prescribed based on bony landmarks, so that individual variation between the landmark and the aortoiliac junction can result in variable aortic coverage. In the Framingham CT substudy, we scanned a 15-cm (Z-direction) abdominal segment cranial to the Si vertebral body. We sought to determine the range and distribution of length of aorta scanned and the distribution of AAC within the abdominal aorta and to compare burden of AAC measured from fixed-length segments versus MC from all slices cranial to the aortoiliac bifurcation. Materials and Methods: MC was quantified by modified Agatston score (AS) in 100 Framingham Heart Study participants (60 13 years old, 51 men). We compared the AS measured from 5-cm and 8-cm segments with the AS(ALL) (total visualized aorta). Results: Of 100, 73 participants had MC >0. The total length of aorta imaged was >= 8 cm in 84% of participants. Qualitatively, 5-cm and 8-cm segments correctly identified 96% and 99%, respectively, of participants as having or not having MC. Quantitatively, AS(8cm) was within 20% of AS(ALL) in four-fifths and within 30% of AS(ALL) in nine-tenths of participant. AS(5cm) more severely underestimated AS(ALL). Conclusion: The use of 51 as the caudal imaging landmark in a 15-cm slab yields >= 8 cm aortic coverage in most adults. Both 5-cm and 8-cm analysis strategies are comparable to analyzing the total visualized abdominal aorta for prevalent MC, but only 8-cm segment analysis yields quantitatively similar measures of AAC. C1 [Chuang, Michael L.; Leslie, Richard W.; Massaro, Joseph M.; Manders, Emily S.; Fox, Caroline S.; O'Donnell, Christopher J.] Natl Heart Lung & Blood Inst, Framingham Heart Study, Framingham, MA 01702 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET & CT Program, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Fox, Caroline S.; Hoffmann, Udo; O'Donnell, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. RP O'Donnell, CJ (reprint author), Natl Heart Lung & Blood Inst, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM odonnellc@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study [N01-HC-25195, N01-HC-38038]; NHLBI Division of Intramural Research FX From the National Heart, Lung, and Blood Institute, The Framingham Heart Study, 73 Mt Wayte Avenue, Suite No. 2, Framingham, MA 01702-5827 (M.L.C, R.W.L, J.M.M., E.S.M., C.S.F., C.J.O.); Department of Biostatistics, Boston University School of Public Health, Boston, MA (J.M.M.); Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA (C.S.F.); Cardiac MR, PET and CT Program, Department of Radiology, Massachusetts General Hospital, Boston, MA (U.N.); Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA (C.J.O.); Harvard Medical School, Boston, MA (C.S.F., U.H., C.J.O.). Received April 2, 2013; accepted August 14, 2013. Source of funding: This project was supported by the National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study (contract Nos. N01-HC-25195 and N01-HC-38038). Dr O'Donnell is supported by the NHLBI Division of Intramural Research. There are no conflicts of interest. Address correspondence to: C.J.O. e-mail: odonnellc@nhlbi.nih.gov NR 17 TC 0 Z9 0 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD NOV PY 2013 VL 20 IS 11 BP 1422 EP 1428 DI 10.1016/j.acra.2013.08.008 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 241AW UT WOS:000326139800013 PM 24119355 ER PT J AU Hersch, RK Cook, RF Billings, DW Kaplan, S Murray, D Safren, S Goforth, J Spencer, J AF Hersch, Rebekah K. Cook, Royer F. Billings, Douglas W. Kaplan, Seth Murray, David Safren, Steven Goforth, Justin Spencer, Joy TI Test of a Web-Based Program to Improve Adherence to HIV Medications SO AIDS AND BEHAVIOR LA English DT Article DE Medication adherence; Web-based program; ART; Antiretroviral therapy ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; INJECTION-DRUG-USERS; DEPRESSION CBT-AD; SOCIETY-USA PANEL; ANTIRETROVIRAL MEDICATIONS; PROTEASE INHIBITORS; INCREASE ADHERENCE; HEALTH-PROMOTION; INTERVENTION AB We evaluated the effectiveness of a web-based version of the Life-Steps intervention combined with modules for stress reduction and mood management, designed to improve medication adherence among HIV infected individuals. 168 HIV+ adults were randomized into either the Life-Steps program or a waitlist control condition. All participants completed a baseline assessment and provided a 2-week electronic pill (MEMS) cap baseline reading. Follow up data collection was conducted at 3, 6 and 9 months. Patients in the web-based Life-Steps condition had significantly higher antiretroviral medication adherence rates than patients in the control group over the nine-month period as measured by the MEMS cap. In addition, analysis of viral load data indicated that the program also resulted in a significant decrease in viral load. These findings indicate that a web-based Life-Steps program can be a useful and implementable tool for helping patients living with HIV maintain medication adherence. C1 [Hersch, Rebekah K.; Cook, Royer F.; Billings, Douglas W.; Spencer, Joy] ISA Associates Inc, Alexandria, VA 22304 USA. [Kaplan, Seth] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Murray, David] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Safren, Steven] Harvard Univ, Sch Med, Massachusettes Gen Hosp, Boston, MA USA. [Goforth, Justin] Whitman Walker Hlth, Washington, DC USA. RP Hersch, RK (reprint author), ISA Associates Inc, 201 North Union St,Suite 330, Alexandria, VA 22304 USA. EM rhersch@isagroup.com FU NIDA NIH HHS [5RC1DA028505, RC1 DA028505] NR 41 TC 9 Z9 9 U1 3 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD NOV PY 2013 VL 17 IS 9 BP 2963 EP 2976 DI 10.1007/s10461-013-0535-8 PG 14 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 240QW UT WOS:000326113100012 PM 23760634 ER PT J AU Heckman, TG Heckman, BD Anderson, T Lovejoy, TI Mohr, D Sutton, M Bianco, JA Gau, JT AF Heckman, Timothy G. Heckman, Bernadette D. Anderson, Timothy Lovejoy, Travis I. Mohr, David Sutton, Mark Bianco, Joseph A. Gau, Jen-Tzer TI Supportive-Expressive and Coping Group Teletherapies for HIV-Infected Older Adults: A Randomized Clinical Trial SO AIDS AND BEHAVIOR LA English DT Article DE HIV; AIDS; Teletherapy; Supportive-expressive group therapy; Coping ID COGNITIVE-BEHAVIOR THERAPY; METASTATIC BREAST-CANCER; CHILDHOOD SEXUAL-ABUSE; ANTIRETROVIRAL THERAPY; GROUP-PSYCHOTHERAPY; GROUP INTERVENTION; RURAL PERSONS; DEPRESSION; HIV/AIDS; OUTCOMES AB This clinical trial tested whether telephone-administered supportive-expressive group therapy or coping effectiveness training reduce depressive symptoms in HIV-infected older adults. Participants from 24 states (N = 361) completed the Geriatric Depression Scale at pre-intervention, post-intervention, and 4- and 8-month follow-up and were randomized to one of three study arms: (1) 12 weekly sessions of telephone-administered, supportive-expressive group therapy (tele-SEGT; n = 122); (2) 12 weekly sessions of telephone-administered, coping effectiveness training (tele-CET; n = 118); or (3) a standard of care (SOC) control group (n = 121). Tele-SEGT participants reported fewer depressive symptoms than SOC controls at post-intervention (M-SEGT = 11.9, M-SOC = 14.3) and 4- (M-SEGT = 12.5, M-SOC = 14.4) and 8-month follow-up (M-SEGT = 12.7, M-SOC = 14.5) and fewer depressive symptoms than tele-CET participants at post-intervention (M-SEGT = 12.4, M-CET = 13.6) and 8-month follow-up (M-SEGT = 12.7, M-CET = 14.1). Tele-CET participants reported no statistically significant differences from SOC controls in GDS values at any assessment period. Tele-SEGT constitutes an efficacious treatment to reduce depressive symptoms in HIV-infected older adults. C1 [Heckman, Timothy G.; Sutton, Mark; Gau, Jen-Tzer] Ohio Univ, Dept Geriatr Med Gerontol, Heritage Coll Osteopath Med, Athens, OH 45701 USA. [Heckman, Timothy G.; Sutton, Mark] Univ Georgia, Coll Publ Hlth, Coverdell Ctr 130D, Athens, GA 30602 USA. [Heckman, Bernadette D.; Anderson, Timothy] Ohio Univ, Dept Psychol, Athens, OH 45701 USA. [Heckman, Bernadette D.] Univ Georgia, Dept Counseling & Human Dev Serv, Athens, GA 30602 USA. [Lovejoy, Travis I.] Portland VA Med Ctr, Mental Hlth & Clin Neurosci Div, Portland, OR USA. [Mohr, David] Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL USA. [Bianco, Joseph A.] Ohio Univ, Dept Social Med, Heritage Coll Osteopath Med, Athens, OH 45701 USA. RP Heckman, TG (reprint author), Univ Georgia, Coll Publ Hlth, Coverdell Ctr 130D, 500 DW Brooks Dr, Athens, GA 30602 USA. EM heckman@uga.edu FU NCATS NIH HHS [UL1 TR000150]; NIMH NIH HHS [R01 MH078749] NR 45 TC 8 Z9 9 U1 3 U2 16 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD NOV PY 2013 VL 17 IS 9 BP 3034 EP 3044 DI 10.1007/s10461-013-0441-0 PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 240QW UT WOS:000326113100018 PM 23474642 ER PT J AU Alam, M Dennison, MS Aussedat, B Vohra, Y Park, PK Fernandez-Tejada, A Stewart, S Jaeger, FH Anasti, K Blinn, JH Kepler, TB Liao, H Sodrosk, JG Danishefsky, SJ Haynes, BF AF Alam, M. Dennison, M. S. Aussedat, B. Vohra, Y. Park, P. K. Fernandez-Tejada, A. Stewart, S. Jaeger, F. H. Anasti, K. Blinn, J. H. Kepler, T. B. Liao, H. Sodrosk, J. G. Danishefsky, S. J. Haynes, B. F. TI High Affinity Recognition of Synthetic Glycopeptides by HIV-1 gp120 V1V2 Loop Broadly Neutralizing Antibodies and Their Unmutated Common Ancestors SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Alam, M.; Dennison, M. S.; Stewart, S.; Jaeger, F. H.; Anasti, K.; Blinn, J. H.; Liao, H.; Haynes, B. F.] Duke Univ, Med Ctr, Durham, NC USA. [Aussedat, B.; Vohra, Y.; Park, P. K.; Fernandez-Tejada, A.; Danishefsky, S. J.] Sloan Kettering Inst Canc Res, New York, NY USA. [Kepler, T. B.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Sodrosk, J. G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RI Fernandez-Tejada, Alberto/M-2439-2015 OI Fernandez-Tejada, Alberto/0000-0002-1680-0059 NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A185 EP A185 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500483 ER PT J AU Angin, M King, M Bhasin, MK Sharma, S Murooka, TT Mempel, TR Walker, BD Addo, MM AF Angin, M. King, M. Bhasin, M. K. Sharma, S. Murooka, T. T. Mempel, T. R. Walker, B. D. Addo, M. M. TI HIV-1 Infection Impairs Regulatory T Cell Function SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Angin, M.; King, M.; Sharma, S.; Walker, B. D.; Addo, M. M.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Bhasin, M. K.] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Murooka, T. T.; Mempel, T. R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A127 EP A127 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500329 ER PT J AU Dudek, TE Maldini, CR Vrbanac, VD Mellors, EF Tully, D Power, KA Batorsky, R Seung, E Deruaz, M Bryant, KF Altfeld, M Luster, AD Knipe, DM Tager, AM Allen, TM AF Dudek, T. E. Maldini, C. R. Vrbanac, V. D. Mellors, E. F. Tully, D. Power, K. A. Batorsky, R. Seung, E. Deruaz, M. Bryant, K. F. Altfeld, M. Luster, A. D. Knipe, D. M. Tager, A. M. Allen, T. M. TI Immunization of Humanized BLT Mice Against Gag Alters Early HIV-Specific CD8+T Cell Responses and Transiently Suppresses Viremia SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Dudek, T. E.; Maldini, C. R.; Mellors, E. F.; Tully, D.; Power, K. A.; Batorsky, R.; Altfeld, M.; Allen, T. M.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Vrbanac, V. D.; Seung, E.; Deruaz, M.; Luster, A. D.; Tager, A. M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bryant, K. F.; Knipe, D. M.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A163 EP A163 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500427 ER PT J AU Jost, S Rands, K Lichterfeld, M Gandhi, RT Altfeld, M AF Jost, S. Rands, K. Lichterfeld, M. Gandhi, R. T. Altfeld, M. TI Therapeutic Vaccination Using HIV-1 gp120/NefTat/AS02A Enhances Responsiveness of NK Cells Through the Induction of gp120-Specific CD4+T Cell Help SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Jost, S.; Rands, K.; Altfeld, M.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Lichterfeld, M.; Gandhi, R. T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A97 EP A97 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500247 ER PT J AU Korner, C Granoff, M Amero, M Jost, S Allen, T Rosenberg, ES Altfeld, M AF Korner, C. Granoff, M. Amero, M. Jost, S. Allen, T. Rosenberg, E. S. Altfeld, M. TI HLA-C2 Haplotype-Dependent Expansion of KIR2DL1+NK Cells in Early HIV-1 Infection Is Accompanied by Increased Polyfunctionality of KIR2DL1+NK Cells SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Korner, C.; Granoff, M.; Amero, M.; Jost, S.; Allen, T.; Altfeld, M.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Rosenberg, E. S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A99 EP A100 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500254 ER PT J AU Martin-Gayo, E Hickman, T Ouyang, Z Pimenova, D Pereyra, F Walker, BD Lichterfeld, M Yu, XG AF Martin-Gayo, E. Hickman, T. Ouyang, Z. Pimenova, D. Pereyra, F. Walker, B. D. Lichterfeld, M. Yu, X. G. TI HIV-1 Infection Induces Potent Type I IFN Signatures in Conventional Dendritic Cells from HIV-1-Elite Controllers SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Martin-Gayo, E.; Hickman, T.; Ouyang, Z.; Pimenova, D.; Pereyra, F.; Yu, X. G.] MIT & Harvard, Ragon Inst MGH, Cambridge, MA USA. [Walker, B. D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Lichterfeld, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A18 EP A18 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500039 ER PT J AU Scully, E Simmons, R Benedict, K Groden, EE Chang, JJ Rosenberg, E Lauffenburger, D Altfeld, M AF Scully, E. Simmons, R. Benedict, K. Groden, E. E. Chang, J. J. Rosenberg, E. Lauffenburger, D. Altfeld, M. TI HIV-1 Infection Induces IP-10 Production from Monocytes and Myeloid Dendritic Cells via TLR7/9 Dependent Pathways SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Scully, E.; Altfeld, M.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Simmons, R.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Benedict, K.; Lauffenburger, D.] MIT, Cambridge, MA 02139 USA. [Groden, E. E.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Chang, J. J.] Monash Univ, Melbourne, Vic 3004, Australia. [Rosenberg, E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A99 EP A99 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500252 ER PT J AU Stephenson, KE Pawlowski, N von Hoegen, P Reimer, U Rosenberg, ES Barouch, DH AF Stephenson, K. E. Pawlowski, N. von Hoegen, P. Reimer, U. Rosenberg, E. S. Barouch, D. H. TI HIV-1 Antibody Epitope Mapping of Individuals Treated with Antiretroviral Therapy During Acute/Early HIV-1-Infection SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Stephenson, K. E.; Barouch, D. H.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Pawlowski, N.; von Hoegen, P.; Reimer, U.] JPT Peptide Technol GmbH, Berlin, Germany. [Rosenberg, E. S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barouch, D. H.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A167 EP A167 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500437 ER PT J AU Vaidya, SA Korner, C Sirignano, MN Amero, M Bazner, S Rychert, J Rosenberg, ES Allen, TM Bosch, RJ Altfeld, M AF Vaidya, S. A. Korner, C. Sirignano, M. N. Amero, M. Bazner, S. Rychert, J. Rosenberg, E. S. Allen, T. M. Bosch, R. J. Altfeld, M. TI Inflammatory Biomarkers and Clinical Outcomes in Primary HIV-1 Infection SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Vaidya, S. A.; Korner, C.; Sirignano, M. N.; Amero, M.; Allen, T. M.; Altfeld, M.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Bazner, S.; Rychert, J.; Rosenberg, E. S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bosch, R. J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A97 EP A98 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500248 ER PT J AU Strobel, B McManus, L Leong, S Blow, F Slaymaker, V Berrettini, W Gordon, AJ O'Brien, C Oslin, D AF Strobel, Brittany McManus, Lauren Leong, Shirley Blow, Frederic Slaymaker, Valerie Berrettini, Wade Gordon, Adam J. O'Brien, Charles Oslin, David TI A Cross-Sectional Study of Attitudes About the Use of Genetic Testing for Clinical Care Among Patients with an Alcohol Use Disorder SO ALCOHOL AND ALCOHOLISM LA English DT Article ID MU-OPIOID-RECEPTOR; NALTREXONE RESPONSE; MALE TWINS; DEPENDENCE; ASSOCIATIONS; SAMPLE; ABUSE; OPRM1 AB Aim: Modification and individualization of medical treatments due to genetic testing has the potential to revolutionize healthcare delivery. As evidence mounts that genetic testing may improve treatment decisions for patients with alcohol use disorder (AUD), we explored patient concerns and attitudes toward genetic testing. Methods: Subjects of two USA cross-sectional AUD studies were surveyed regarding their attitudes regarding the use of genetic testing for AUD treatment. Results: Four hundred and fifty-seven participants were surveyed. Overall, subjects showed a high degree of willingness to provide DNA for clinical use and recognized genetics as important to the pathophysiology of a number of disorders including AUD. There were, however, significant concerns expressed related to insurance denial or employment problems. Conclusion: We found that patients enrolled in AUD studies had some concerns about use of genetic testing. The patients in these two samples were, however, willing and knowledgeable about providing DNA samples. C1 [Strobel, Brittany; McManus, Lauren; O'Brien, Charles] Univ Penn, Treatment Res Ctr, Philadelphia, PA 19104 USA. [Leong, Shirley] Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Blow, Frederic] UMATS, Ann Arbor, MI 48109 USA. [Slaymaker, Valerie] Hazelden Grad Sch Addict Studies, Ctr City, MN 55012 USA. [Berrettini, Wade] Univ Penn, Perelman Sch Med, Ctr Neurobiol & Behav, Philadelphia, PA 19104 USA. [Gordon, Adam J.] Univ Pittsburgh, Sch Med, VA Pittsburgh Healthcare Syst, MIRECC, Pittsburgh, PA 15206 USA. [Oslin, David] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Oslin, D (reprint author), Univ Penn, Perelman Sch Med, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM oslin@upenn.edu FU NIAAA [AA017164]; Department of Veteran Affairs; Huss Family FX Funding for this study was provided by NIAAA Grant AA017164; funding support was also provided by the Department of Veteran Affairs by the center grant for the VISN 4 Mental Illness Research, Education, and Clinical Center at the Philadelphia VA Medical Center. Funding was also provided from the Huss Family through a generous donation to the Hazelden foundation. None of the funding sources had a 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 1 Z9 1 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 EI 1464-3502 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD NOV-DEC PY 2013 VL 48 IS 6 BP 700 EP 703 DI 10.1093/alcalc/agt130 PG 4 WC Substance Abuse SC Substance Abuse GA 239AJ UT WOS:000325993500012 PM 23926212 ER PT J AU Marso, SP Poulter, NR Nissen, SE Nauck, MA Zinman, B Daniels, GH Pocock, S Steinberg, WM Bergenstal, RM Mann, JFE Ravn, LS Frandsen, KB Moses, AC Buse, JB AF Marso, Steven P. Poulter, Neil R. Nissen, Steven E. Nauck, Michael A. Zinman, Bernard Daniels, Gilbert H. Pocock, Stuart Steinberg, William M. Bergenstal, Richard M. Mann, Johannes F. E. Ravn, Lasse Steen Frandsen, Kirstine Brown Moses, Alan C. Buse, John B. CA LEADER Trial Investigators TI Design of the liraglutide effect and action in diabetes: Evaluation of cardiovascular outcome results (LEADER) trial SO AMERICAN HEART JOURNAL LA English DT Article ID GLP-1 RECEPTOR AGONISTS; GLUCAGON-LIKE PEPTIDE-1; MYOCARDIAL-INFARCTION; RISK; GLUCOSE; HYPERGLYCEMIA; METAANALYSIS; MANAGEMENT; METFORMIN; MELLITUS AB Background Diabetes is a multisystem disorder associated with a nearly twofold excess risk for a broad range of adverse cardiovascular outcomes including coronary heart disease, stroke, and cardiovascular death. Liraglutide is a human glucagon-like peptide receptor analog approved for use in patients with type 2 diabetes mellitus (T2DM). Study Design To formally assess the cardiovascular safety of liraglutide, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial was commenced in 2010. LEADER is a phase 3B, multicenter, international, randomized, double-blind, placebo-controlled clinical trial with long-term follow-up. Patients with T2DM at high risk for cardiovascular disease (CVD) who were either drug naive or treated with oral antihyperglycemic agents or selected insulin regimens (human NPH, long-acting analog, or premixed) alone or in combination with oral antihyperglycemics were eligible for inclusion. Randomized patients are being followed for up to 5 years. The primary end point is the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Conclusions LEADER commenced in September 2010, and enrollment concluded in April 2012. There were 9,340 patients enrolled at 410 sites in 32 countries. The mean age of patients was 64.3 +/- 7.2 years, 64.3% were men, and mean body mass index was 32.5 +/- 6.3 kg/m(2). There were 7,592 (81.3%) patients with prior CVD and 1,748 (18.7%) who were high risk but without prior CVD. It is expected that LEADER will provide conclusive data regarding the cardiovascular safety of liraglutide relative to the current standard of usual care for a global population of patients with T2DM. C1 [Marso, Steven P.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Poulter, Neil R.] Univ London Imperial Coll Sci Technol & Med, London, England. [Nissen, Steven E.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Nauck, Michael A.] Diabet Zentrum Bad Lauterberg, Lauterberg, Germany. [Zinman, Bernard] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Daniels, Gilbert H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pocock, Stuart] London Sch Hyg & Trop Med, Med Stat Unit London, London WC1, England. [Steinberg, William M.] George Washington Univ, Med Ctr, Rockville, MD USA. [Bergenstal, Richard M.] Int Diabet Ctr Pk Nicollet, Minneapolis, MN USA. [Mann, Johannes F. E.] Univ Erlangen Nurnberg, D-91054 Erlangen, Germany. [Ravn, Lasse Steen; Frandsen, Kirstine Brown; Moses, Alan C.] Novo Nordisk Inc, Bagsvaerd, DE, Denmark. [Buse, John B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. RP Marso, SP (reprint author), Univ Missouri, St Lukes Mid Amer Heart Inst, 4401 Wornall Rd, Kansas City, MO 64111 USA. EM smarso@saint-lukes.org RI Zinman, Bernard/E-7266-2013; BALCI, Mustafa Kemal/C-2979-2016; OI BALCI, Mustafa Kemal/0000-0002-6494-3249; Buse, John/0000-0002-9723-3876 FU Abbott; Amylin; Andromeda; AstraZeneca; Bayhill Therapeutics; BD Research Laboratories; Boehringer-Ingelheim; Bristol-Myers Squibb; Catabasis; Cebix; Diartis; Elcylex; Eli Lilly; Exsulin; Genentech; GI Dynamics; GlaxoSmithKline; Halozyme; Hoffman-LaRoche; Johnson Johnson; LipoScience; Medtronic; Merck; Metabolic Solutions Development Company; Metabolon; Novan; Novartis; Novo Nordisk; Orexigen; Osiris; Pfizer; Rhythm; Sanofi; Spherix; Takeda; Tolerex; TransPharma; Veritas; Verva; Medicines Company; Abbott Vascular; Amylin Pharmaceuticals; Volcano Corporation; St. Jude Medical; Terumo Medical; Hospital Foundation of Kansas City; Diabeteszentrum Bad Lauterberg, from Berlin-Chemie/Menarini; Novartis Pharma,; Sharp Dohme; Boehringer Ingelheim; MetaCure; Roche Pharma; Novo Nordisk Pharma; Tolerx Inc; Berlin-Chemie/Menarini; Diartis Pharmaceuticals; Intarcia Therapeutics; MannKind Corp; Novartis Pharma; Wyeth Research FX Dr Buse is an investigator and/or consultant without any direct financial benefit under contracts between his employer and the following companies: Abbott, Amylin, Andromeda, AstraZeneca, Bayhill Therapeutics, BD Research Laboratories, Boehringer-Ingelheim, Bristol-Myers Squibb, Catabasis, Cebix, Diartis, Elcylex, Eli Lilly, Exsulin, Genentech, GI Dynamics, GlaxoSmithKline, Halozyme, Hoffman-LaRoche, Johnson & Johnson, LipoScience, Medtronic, Merck, Metabolic Solutions Development Company, Metabolon, Novan, Novartis, Novo Nordisk, Orexigen, Osiris, Pfizer, Rhythm, Sanofi, Spherix, Takeda, Tolerex, TransPharma, Veritas, and Verva.; Dr Marso reports no personal conflicts of interest during the previous 12 months. All compensation for his research activities, including research grants and consulting fees from The Medicines Company, Novo Nordisk, Abbott Vascular, Amylin Pharmaceuticals, Volcano Corporation, St. Jude Medical, and Terumo Medical, are paid directly to the Saint Luke's Hospital Foundation of Kansas City.; Dr Nauck has received research grants payable to his institution, the Diabeteszentrum Bad Lauterberg, from Berlin-Chemie/Menarini, Eli Lilly, Merck, Sharp & Dohme, Novartis Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, MetaCure, Roche Pharma, Novo Nordisk Pharma, Tolerx Inc; consulting fees and/or honoraria for membership in advisory boards and/or honoraria for speaking from Amylin Pharmaceuticals, AstraZeneca, Berlin-Chemie/Menarini, Boehringer Ingelheim, BristolMyers Squibb, Diartis Pharmaceuticals, Eli Lilly, Hoffmann-LaRoche, GlaxoSmithKline, Intarcia Therapeutics, MannKind Corp, Merck, Sharp & Dohme, Novartis Pharma, Novo Nordisk, Sanofi, Takeda, and Wyeth Research, including reimbursement for travel expenses in connection with the previously mentioned activities. He owns no stock and is employed by Diabeteszentrum Bad Lauterberg, Germany. NR 25 TC 67 Z9 70 U1 6 U2 20 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD NOV PY 2013 VL 166 IS 5 BP 823 EP + DI 10.1016/j.ahj.2013.07.012 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 242IS UT WOS:000326233500007 PM 24176437 ER PT J AU Elmariah, S Budoff, MJ Delaney, JAC Hamirani, Y Eng, J Fuster, V Kronmal, RA Halperin, JL O'Brien, KD AF Elmariah, Sammy Budoff, Matthew J. Delaney, Joseph A. C. Hamirani, Yasmin Eng, John Fuster, Valentin Kronmal, Richard A. Halperin, Jonathan L. O'Brien, Kevin D. TI Risk factors associated with the incidence and progression of mitral annulus calcification: The multi-ethnic study of atherosclerosis SO AMERICAN HEART JOURNAL LA English DT Article ID CARDIAC COMPUTED-TOMOGRAPHY; AORTIC-VALVE CALCIFICATION; CORONARY-ARTERY; EXTRACORONARY MEASURES; HEART-DISEASE; MESA; CALCIUM; STROKE; ADULTS; REPRODUCIBILITY AB Background Significant cardiovascular morbidity has been associated with mitral annulus calcification (MAC), but limited data exist regarding its progression. The purpose of this study was to examine the natural history of and risk factors for MAC progression. Methods The MESA is a longitudinal cohort study of participants aged 45 to 84 years without clinical cardiovascular disease who underwent serial cardiac computed tomography studies with quantification of MAC. Regression models were used to identify risk factors associated with MAC incidence and progression. Results Prevalent MAC was observed in 534 (9%) of 5,895 participants. Over a median 2.3 years, 280 (5%) developed incident MAC. After adjustment, age was the strongest predictor of incident MAC (adjusted OR, 2.25 per 10 years; 95% CI, 1.97-2.58; P < .0001). Female gender, white ethnicity, body mass index, diabetes, hypertension, hyperlipidemia, serum cholesterol, smoking, and interleukin-6 were also significant predictors of incident MAC. In participants with prevalent MAC, the median rate of change was 10.1 [IQR, -6.7 to 60.7] Agatston units (AU)/year. Baseline MAC severity was the predominant predictor of rate of MAC progression (beta-coefficient per 10 AU, 0.88; 95% CI, 0.85-0.91; P < .0001), although ethnicity and smoking status possessed modest influence. Conclusions Several cardiovascular risk factors predicted incident MAC, as did female gender. Severity of baseline MAC was the primary predictor of MAC progression, suggesting that, while atherosclerotic processes may initiate MAC, they are only modestly associated with its progression over these time frames. C1 [Elmariah, Sammy] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA 02114 USA. [Elmariah, Sammy] Harvard Clin Res Inst, Boston, MA USA. [Budoff, Matthew J.; Hamirani, Yasmin] Harbor UCLA, Los Angeles Biomed Res Inst, Dept Med, Div Cardiol, Torrance, CA USA. [Delaney, Joseph A. C.; Kronmal, Richard A.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Eng, John] Johns Hopkins Univ Hosp, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Fuster, Valentin; Halperin, Jonathan L.] Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, New York, NY USA. [Fuster, Valentin] CNIC, Madrid, Spain. [O'Brien, Kevin D.] Univ Washington, Dept Med, Div Cardiol, Seattle, WA USA. RP Elmariah, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,GRB 800, Boston, MA 02114 USA. EM elmariah@gmail.com RI Fuster, Valentin/H-4319-2015 OI Fuster, Valentin/0000-0002-9043-9986 FU NCRR NIH HHS [UL1 RR024156, UL1 RR025005]; NHLBI NIH HHS [N01 HC095162, N01 HC095159, N01 HC095160, N01 HC095161, N01 HC095163, N01 HC095164, N01 HC095165, N01 HC095166, N01 HC095167, N01 HC095168, N01 HC095169, R01 HL071739] NR 34 TC 13 Z9 13 U1 1 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD NOV PY 2013 VL 166 IS 5 BP 904 EP 912 DI 10.1016/j.ahj.2013.08.015 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 242IS UT WOS:000326233500017 PM 24176447 ER PT J AU Wu, CC Khorashadi, L Abbott, GF Shepard, JAO AF Wu, Carol C. Khorashadi, Leila Abbott, Gerald F. Shepard, Jo-Anne O. TI Common Blind Spots on Chest CT: Where Are They All Hiding? Part 2, Extrapulmonary Structures SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Editorial Material DE chest CT; extrapulmonary structures ID INCIDENTAL BREAST-LESIONS; COMPUTED-TOMOGRAPHY; MALIGNANT-MELANOMA; PHEOCHROMOCYTOMA; PREVALENCE; DISCOVERY C1 [Wu, Carol C.; Abbott, Gerald F.; Shepard, Jo-Anne O.] Massachusetts Gen Hosp, Dept Radiol, Div Thorac Imaging & Intervent, Boston, MA 02114 USA. [Khorashadi, Leila] Mt Auburn Hosp, Dept Radiol, Cambridge, MA 02238 USA. RP Wu, CC (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Thorac Imaging & Intervent, 55 Fruit St Founders 202, Boston, MA 02114 USA. EM cwu8@partners.org NR 21 TC 0 Z9 0 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD NOV PY 2013 VL 201 IS 5 BP W671 EP W677 DI 10.2214/AJR.12.9355 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 240LO UT WOS:000326097900002 PM 24147495 ER PT J AU Schuetz, C Dong, N Smoot, E Elias, N Schoenfeld, DA Markmann, JF Yeh, H AF Schuetz, C. Dong, N. Smoot, E. Elias, N. Schoenfeld, D. A. Markmann, J. F. Yeh, H. TI HCC Patients Suffer Less From Geographic Differences in Organ Availability SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Hepatocellular carcinoma; liver transplantation; MELD score; donation service area; organ allocation ID STAGE LIVER-DISEASE; HEPATOCELLULAR-CARCINOMA; ALLOCATION SYSTEM; WAITING-LIST; UNITED-STATES; TRANSPLANTATION; MODEL; SURVIVAL; MELD; CANDIDATES AB It has been suggested that the number of exception model for end-stage liver disease (MELD) points for hepatocellular carcinoma (HCC) overestimates mortality risk. Average MELD at transplant, a measure of organ availability, correlates with mortality on an intent-to-treat basis and varies by donation service area (DSA). We analyzed Scientific Registry of Transplant Recipients data from 2005 to 2010, comparing transplant and death parameters for patients transplanted with HCC exception points to patients without HCC diagnosis (non-HCC), to determine whether the two groups were impacted differentially by DSA organ availability. HCC candidates are transplanted at higher rates than non-HCC candidates and are less likely to die on the waitlist. Overall risk of death trends downward by 1% per MELD point (p=0.65) for HCC, but increases by 7% for non-HCC patients (p<0.0001). The difference in the change of mortality with MELD is statistically significant between HCC and non-HCC candidates p<0.0001. Posttransplant risk of death trends downward by 2% per MELD point (p=0.28) for HCC patients, but increases by 3% per MELD point in non-HCC patients (p=0.027), with the difference being statistically significant with p<0.005. In summary, increasing wait time impacts HCC candidates less than non-HCC candidates and under increased competition for donor organs, HCC candidates' advantage increases. An analysis of geographic disparities in liver transplantation shows that overall mortality for patients with hepatocellular carcinoma exception points does not increase with longer wait times, suggesting that this patient group can afford to wait longer between diagnosis and transplant. See editorial by Charlton on page 2794. C1 [Schuetz, C.; Elias, N.; Markmann, J. F.; Yeh, H.] Massachusetts Gen Hosp, Dept Surg, Div Transplantat, Boston, MA 02114 USA. [Dong, N.; Smoot, E.; Schoenfeld, D. A.] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. RP Yeh, H (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Transplantat, Boston, MA 02114 USA. EM hyeh@partners.org RI Schuetz, Christian/K-5234-2013 OI Schuetz, Christian/0000-0002-6828-4543 FU Harvard Catalyst (National Center for Research Resources, National Institutes of Health) [8UL1TR000170-05]; Harvard Catalyst (National Center for Advancing Translational Sciences, National Institutes of Health) [8UL1TR000170-05]; Harvard University FX The data reported here have been supplied by the Minneapolis Medical Research Foundation (MMRF) as the contractor for the Scientific Registry of Transplant Recipients (SRTR). The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the SRTR or the U.S. Government. This study used data from the SRTR. The SRTR data system includes data on all donor, waitlisted candidates and transplant recipients in the United States, submitted by the members of the Organ Procurement and Transplantation Network (OPTN), and has been described elsewhere. The Health Resources and Services Administration (HRSA), U. S. Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors. This work was conducted with support from Harvard Catalyst (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award 8UL1TR000170-05, and financial contributions from Harvard University and its affiliated academic healthcare centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. NR 27 TC 15 Z9 15 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD NOV PY 2013 VL 13 IS 11 BP 2989 EP 2995 DI 10.1111/ajt.12441 PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA 241AI UT WOS:000326138400026 PM 24011291 ER PT J AU Zhou, YB Wu, JM Kucik, DF White, NB Redden, DT Szalai, AJ Bullard, DC Edberg, JC AF Zhou, Yebin Wu, Jianming Kucik, Dennis F. White, Nathan B. Redden, David T. Szalai, Alexander J. Bullard, Daniel C. Edberg, Jeffrey C. TI Multiple Lupus-Associated ITGAM Variants Alter Mac-1 Functions on Neutrophils SO ARTHRITIS AND RHEUMATISM LA English DT Article ID I DOMAIN; INTEGRIN REGULATION; LEUKOCYTE ADHESION; LATERAL MOBILITY; FC-GAMMA; RECEPTOR; ERYTHEMATOSUS; CD11B; PHAGOCYTOSIS; SUSCEPTIBILITY AB ObjectiveMultiple studies have demonstrated that single-nucleotide polymorphisms (SNPs) in the ITGAM locus (including the nonsynonymous SNPs rs1143679, rs1143678, and rs1143683) are associated with systemic lupus erythematosus (SLE). ITGAM encodes the protein CD11b, a subunit of the 2 integrin Mac-1. The purpose of this study was to determine the effects of ITGAM genetic variation on the biologic functions of neutrophil Mac-1. MethodsNeutrophils from ITGAM-genotyped and -sequenced healthy donors were isolated for functional studies. The phagocytic capacity of neutrophil ITGAM variants was probed with complement-coated erythrocytes, serum-treated zymosan, heat-treated zymosan, and IgG-coated erythrocytes. The adhesion capacity of ITGAM variants, in adhering to either purified intercellular adhesion molecule 1 or tumor necrosis factor -stimulated endothelial cells, was assessed in a flow chamber. Expression levels of total CD11b and activation of CD11b were assessed by flow cytometry. ResultsMac-1-mediated neutrophil phagocytosis, determined in cultures with 2 different complement-coated particles, was significantly reduced in individuals with nonsynonymous variant alleles of ITGAM. This reduction in phagocytosis was related to variation at either rs1143679 (in the -propeller region) or rs1143678/rs1143683 (highly linked SNPs in the cytoplasmic/calf-1 regions). Phagocytosis mediated by Fc receptors was also significantly reduced in donors with variant ITGAM alleles. Similarly, firm adhesion of neutrophils was significantly reduced in individuals with variant ITGAM alleles. These functional alterations were not attributable to differences in total receptor expression or activation. ConclusionThe nonsynonymous ITGAM variants rs1143679 and rs1143678/rs113683 contribute to altered Mac-1 function on neutrophils. These results underscore the need to consider multiple nonsynonymous SNPs when assessing the functional consequences of ITGAM variation on immune cell processes and the risk of SLE. C1 [Zhou, Yebin; Wu, Jianming; Kucik, Dennis F.; White, Nathan B.; Redden, David T.; Szalai, Alexander J.; Bullard, Daniel C.; Edberg, Jeffrey C.] Univ Alabama Birmingham, Birmingham, AL 35294 USA. [Kucik, Dennis F.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Edberg, JC (reprint author), Univ Alabama Birmingham, Dept Med, Div Clin Immunol & Rheumatol, 1825 Univ Blvd,Room 207 Shelby Bldg, Birmingham, AL 35294 USA. EM jedberg@uab.edu OI Zhou, Yebin/0000-0002-4410-1909 FU NIH [P01-AR-49084, 5P30-AR-048311, R21-AR-058864, R21-DA-026956]; NIH (National Center for Advancing Translational Sciences) [UL1-TR-000165]; Lupus Research Institute FX Supported by the NIH (grants P01-AR-49084, 5P30-AR-048311, R21-AR-058864, and R21-DA-026956, and grant UL1-TR-000165 from the National Center for Advancing Translational Sciences) and the Lupus Research Institute. NR 44 TC 16 Z9 16 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 EI 1529-0131 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD NOV PY 2013 VL 65 IS 11 BP 2907 EP 2916 DI 10.1002/art.38117 PG 10 WC Rheumatology SC Rheumatology GA 241AG UT WOS:000326138200020 PM 23918739 ER PT J AU Danz, MS Hempel, S Lim, YW Shanman, R Motala, A Stockdale, S Shekelle, P Rubenstein, L AF Danz, Margie Sherwood Hempel, Susanne Lim, Yee-Wei Shanman, Roberta Motala, Aneesa Stockdale, Susan Shekelle, Paul Rubenstein, Lisa TI Incorporating evidence review into quality improvement: meeting the needs of innovators SO BMJ QUALITY & SAFETY LA English DT Article DE Quality improvement; Evidence-based medicine; Medical homes ID FULL SYSTEMATIC REVIEWS; EVIDENCE-BASED MEDICINE; COLLABORATIVE CARE; POLICY-MAKERS; DEPRESSION; INTERVENTIONS AB Background Achieving quality improvement (QI) aims often requires local innovation. Without objective evidence review, innovators may miss previously tested approaches, rely on biased information, or use personal preferences in designing and implementing local QI programmes. Aim To develop a practical, responsive approach to evidence review for QI innovations aimed at both achieving the goals of the Patient Centered Medical Home (PCMH) and developing an evidence-based QI culture. Design Descriptive organisational case report. Methods As part of a QI initiative to develop and spread innovations for achieving the Veterans Affairs (VA) PCMH (termed Patient Aligned Care Team, or PACT), we involved a professional evidence review team (consisting of review experts, an experienced librarian, and administrative support) in responding to the evidence needs of front-line primary care innovators. The review team developed a systematic approach to responsive innovation evidence review (RIER) that focused on innovator needs in terms of time frame, type of evidence and method of communicating results. To assess uptake and usefulness of the RIERs, and to learn how the content and process could be improved, we surveyed innovation leaders. Results In the first 16months of the QI initiative, we produced 13 RIERs on a variety of topics. These were presented as 6-15-page summaries and as slides at a QI collaborative. The RIERs focused on innovator needs (eg, topic overviews, how innovations are carried out, or contextual factors relevant to implementation). All 17 innovators who responded to the survey had read at least one RIER; 50% rated the reviews as very useful and 31%, as probably useful. Conclusions These responsive evidence reviews appear to be a promising approach to integrating evidence review into QI processes. C1 [Danz, Margie Sherwood; Hempel, Susanne; Lim, Yee-Wei; Shanman, Roberta; Motala, Aneesa; Shekelle, Paul; Rubenstein, Lisa] RAND Corp, Santa Monica, CA 90401 USA. [Danz, Margie Sherwood; Stockdale, Susan; Shekelle, Paul; Rubenstein, Lisa] Vet Affairs Greater Los Angeles Healthcare Syst, North Hills, CA USA. [Lim, Yee-Wei] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Epidemiol & Publ Hlth, Singapore 117595, Singapore. RP Danz, MS (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90401 USA. EM mjsdanz@gmail.com FU VA Office of Patient Care Services FX This work was undertaken as part of the Veterans Affairs PACT Demonstration Laboratory initiative, supporting and evaluating VA transition to a patient-centred medical home. Funding for the PACT Demonstration Laboratory initiative is provided by the VA Office of Patient Care Services. Study# 2011-0521: Patient Centered Medical Home Innovation Evidence-Based Support and Evaluation. NR 24 TC 2 Z9 2 U1 0 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-5415 EI 2044-5423 J9 BMJ QUAL SAF JI BMJ Qual. Saf. PD NOV PY 2013 VL 22 IS 11 BP 931 EP 939 DI 10.1136/bmjqs-2012-001722 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 239TO UT WOS:000326048700009 PM 23832925 ER PT J AU Michaud, DS Izard, J Rubin, Z Johansson, I Weiderpass, E Tjonneland, A Olsen, A Overvad, K Boutron-Ruault, MC Clavel-Chapelon, F Dossus, L Kaaks, R Katzke, VA Boeing, H Foerster, J Trichopoulou, A Naska, A Ziara, G Vineis, P Grioni, S Palli, D Tumino, R Mattiello, A Peeters, PHM Siersema, PD Barricarte, A Huerta, JM Molina-Montes, E Dorronsoro, M Quiros, JR Duell, EJ Ohlsson, B Jeppsson, B Johansson, A Lif, P Khaw, KT Wareham, N Travis, RC Key, TJ Freisling, H Duarte-Salles, T Stepien, M Riboli, E Bueno-de-Mesquita, HB AF Michaud, Dominique S. Izard, Jacques Rubin, Zachary Johansson, Ingegerd Weiderpass, Elisabete Tjonneland, Anne Olsen, Anja Overvad, Kim Boutron-Ruault, Marie Christine Clavel-Chapelon, Francoise Dossus, Laure Kaaks, Rudolf Katzke, Verena A. Boeing, Heiner Foerster, Jana Trichopoulou, Antonia Naska, Androniki Ziara, Giana Vineis, Paolo Grioni, Sara Palli, Domenico Tumino, Rosario Mattiello, Amalia Peeters, Petra H. M. Siersema, Peter D. Barricarte, Aurelio Huerta, Jose-Maria Molina-Montes, Esther Dorronsoro, Miren Ramon Quiros, J. Duell, Eric J. Ohlsson, Bodil Jeppsson, Bengt Johansson, Anders Lif, Pernilla Khaw, Kay-Tee Wareham, Nick Travis, Ruth C. Key, Tim J. Freisling, Heinz Duarte-Salles, Talita Stepien, Magdalena Riboli, Elio Bueno-de-Mesquita, H. Bas TI Lifestyle, dietary factors, and antibody levels to oral bacteria in cancer-free participants of a European cohort study SO CANCER CAUSES & CONTROL LA English DT Article DE Antibodies to oral bacteria; Smoking; Lifestyle factors ID PERIODONTAL-DISEASE; SERUM ANTIBODY; TOOTH LOSS; IN-VITRO; HEALTH; MICROBIOME; SMOKING; IMPACT; NUTRITION; MORTALITY AB Increasing evidence suggests that oral microbiota play a pivotal role in chronic diseases, in addition to the well-established role in periodontal disease. Moreover, recent studies suggest that oral bacteria may also be involved in carcinogenesis; periodontal disease has been linked to several cancers. In this study, we examined whether lifestyle factors have an impact on antibody levels to oral bacteria. Data on demographic characteristics, lifestyle factors, and medical conditions were obtained at the time of blood sample collection. For the current analysis, we measured antibody levels to 25 oral bacteria in 395 cancer-free individuals using an immunoblot array. Combined total immunoglobin G (IgG) levels were obtained by summing concentrations for all oral bacteria measured. IgG antibody levels were substantially lower among current and former smokers (1,697 and 1,677 ng/mL, respectively) than never smokers (1,960 ng/mL; p trend = 0.01), but did not vary by other factors, including body mass index, diabetes, physical activity, or by dietary factors, after adjusting for age, sex, education, country, and smoking status. The highest levels of total IgG were found among individuals with low education (2,419 ng/mL). Our findings on smoking are consistent with previous studies and support the notion that smokers have a compromised humoral immune response. Moreover, other major factors known to be associated with inflammatory markers, including obesity, were not associated with antibody levels to a large number of oral bacteria. C1 [Michaud, Dominique S.; Rubin, Zachary] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Michaud, Dominique S.; Vineis, Paolo; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Izard, Jacques] Forsyth Inst, Cambridge, MA USA. [Izard, Jacques] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Johansson, Ingegerd; Johansson, Anders; Lif, Pernilla] Umea Univ, Dept Odontol Cardiol, Umea, Sweden. [Johansson, Ingegerd; Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Weiderpass, Elisabete] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Tjonneland, Anne; Olsen, Anja] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Overvad, Kim] Aarhus Univ, Dept Publ Hlth, Aarhus, Denmark. [Boutron-Ruault, Marie Christine; Clavel-Chapelon, Francoise; Dossus, Laure] Inst Gustave Roussy, INSERM, Ctr Res Epidemiol & Populat Hlth, U1018, F-94805 Villejuif, France. [Boutron-Ruault, Marie Christine; Clavel-Chapelon, Francoise; Dossus, Laure] Paris South Univ, UMRS 1018, F-94805 Villejuif, France. [Kaaks, Rudolf; Katzke, Verena A.] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Boeing, Heiner; Foerster, Jana] German Inst Human Nutr Potsdam Rehbrucke, Dept Epidemiol, Nuthetal, Germany. [Trichopoulou, Antonia; Naska, Androniki] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, WHO Collaborating Ctr Food & Nutr Policies, GR-11527 Athens, Greece. [Trichopoulou, Antonia; Ziara, Giana] Hellen Hlth Fdn, Athens, Greece. [Vineis, Paolo] Ctr Canc Prevent CPO Piemonte, Turin, Italy. [Vineis, Paolo] Human Genet Fdn HuGeF, Turin, Italy. [Grioni, Sara] Fdn IRCCS Ist Nazl Tumori, Epidemiol & Prevent Unit, Milan, Italy. [Palli, Domenico] Canc Res & Prevent Inst, ISPO, Mol & Nutr Epidemiol Unit, Florence, Italy. [Tumino, Rosario] Civile MP Arezzo Hosp, Canc Registry, Ragusa, Italy. [Tumino, Rosario] Civile MP Arezzo Hosp, Histopathol Unit, Ragusa, Italy. [Mattiello, Amalia] Univ Naples Federico II, Dept Clin & Expt Med, Naples, Italy. [Peeters, Petra H. M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Siersema, Peter D.; Bueno-de-Mesquita, H. Bas] UMCU, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Barricarte, Aurelio] Publ Hlth Inst Navarra, Pamplona, Spain. [Barricarte, Aurelio; Huerta, Jose-Maria; Molina-Montes, Esther] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Huerta, Jose-Maria] Murcia Reg Hlth Author, Dept Epidemiol, Murcia, Spain. [Molina-Montes, Esther] Andalusian Sch Publ Hlth, Granada, Spain. [Dorronsoro, Miren] Basque Reg Hlth Dept, Publ Hlth Div Gipuzkoa, San Sebastian, Spain. [Ramon Quiros, J.] Hlth & Hlth Care Serv Council, Publ Hlth & Participat Directorate, Asturias, Spain. [Duell, Eric J.] Catalan Inst Oncol ICO IDIBELL, Canc Epidemiol Res Programme, Unit Nutr Environm & Canc, Barcelona, Spain. [Ohlsson, Bodil] Lund Univ, Skane Univ Hosp, Dept Clin Sci, Div Gastroenterol, Malmo, Sweden. [Jeppsson, Bengt] Lund Univ, Dept Surg, Malmo, Sweden. [Jeppsson, Bengt] Skane Univ Hosp, Malmo, Sweden. [Khaw, Kay-Tee] Univ Cambridge, Sch Clin Med, Cambridge, England. [Wareham, Nick] MRC Epidemiol Unit, Cambridge, England. [Travis, Ruth C.; Key, Tim J.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Freisling, Heinz; Duarte-Salles, Talita; Stepien, Magdalena] Int Agcy Res Canc IARC WHO, Lyon, France. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. RP Michaud, DS (reprint author), Brown Univ, Sch Publ Hlth, Dept Epidemiol, Box G-S121-2, Providence, RI 02912 USA. EM Dominique_Michaud@brown.edu RI Clavel-Chapelon, Francoise/G-6733-2014; Michaud, Dominique/I-5231-2014; Boutron-Ruault, Marie-Christine/H-3936-2014; Huerta, Jose Maria/N-8654-2015; Mattiello, Amalia/K-5112-2016; Weiderpass, Elisabete/M-4029-2016; Grioni, Sara/K-5320-2016; OI PALLI, Domenico/0000-0002-5558-2437; Izard, Jacques/0000-0002-5904-5436; Duarte-Salles, Talita/0000-0002-8274-0357; Huerta, Jose Maria/0000-0002-9637-3869; Mattiello, Amalia/0000-0003-3676-7353; Weiderpass, Elisabete/0000-0003-2237-0128; Grioni, Sara/0000-0002-5891-8426; Foerster, Jana/0000-0003-4589-2682; Duell, Eric J/0000-0001-5256-0163 FU Cancer Research UK [14136]; Medical Research Council [G0401527, G1000143]; NCI NIH HHS [R21 CA139193] NR 35 TC 4 Z9 4 U1 1 U2 19 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD NOV PY 2013 VL 24 IS 11 BP 1901 EP 1909 DI 10.1007/s10552-013-0265-2 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 238JJ UT WOS:000325942000001 PM 23901020 ER PT J AU Chitnis, T AF Chitnis, Tanuja TI Role of puberty in multiple sclerosis risk and course SO CLINICAL IMMUNOLOGY LA English DT Review DE Autoimmune; Multiple sclerosis; Puberty; Pediatric; Risk factor; Environment ID ACUTE DISSEMINATED ENCEPHALOMYELITIS; SECONDARY SEXUAL CHARACTERISTICS; CLINICAL LONGITUDINAL STANDARDS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; NUTRITION EXAMINATION SURVEY; KINGDOM-BORN CHILDREN; EPSTEIN-BARR-VIRUS; BODY-MASS INDEX; UNITED-KINGDOM; BRAIN-DEVELOPMENT AB Multiple sclerosis (MS) overwhelmingly presents during the reproductive years, and is more common in females than males. The sexual dimorphism observed in post-pubertal cases is absent in pre-pubertal cases, suggesting that puberty is a key risk period for development of disease, particularly in females. Research has identified several risk factors for MS that occur during the adolescent, or post-pubertal reproductive years, which are associated with clinical presentations later in life. These observations necessitate examination of the biological changes associated with puberty, their interactions with MS risk factors, and potential effects on disease immunopathogenesis. Pediatric and adolescent presentations of MS provide a unique opportunity to study the effects of neuroendocrine changes occurring during puberty and its effect on disease development and disease course. Reviewed is the relationship of MS risk factors and puberty, and differences in disease presentation of pre- and post-pubertal children with MS. Further avenues of research are discussed. (C) 2013 Elsevier Inc. All rights reserved. C1 [Chitnis, Tanuja] Massachusetts Gen Hosp, Partners Pediat Multiple Sclerosis Ctr, Dept Child Neurol, Boston, MA 02114 USA. [Chitnis, Tanuja] Brigham & Womens Hosp, Dept Neurol, Partners Multiple Sclerosis Ctr, Boston, MA 02115 USA. [Chitnis, Tanuja] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. RP Chitnis, T (reprint author), 75 Fruit St,ACC708, Boston, MA 02114 USA. EM tchitnis@partners.org NR 108 TC 9 Z9 9 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 EI 1521-7035 J9 CLIN IMMUNOL JI Clin. Immunol. PD NOV PY 2013 VL 149 IS 2 BP 192 EP 200 DI 10.1016/j.clim.2013.03.014 PG 9 WC Immunology SC Immunology GA 241AU UT WOS:000326139600005 PM 23623473 ER PT J AU Spiegelhalder, K Regen, W Baglioni, C Riemann, D Winkelman, JW AF Spiegelhalder, Kai Regen, Wolfram Baglioni, Chiara Riemann, Dieter Winkelman, John W. TI Neuroimaging Studies in Insomnia SO CURRENT PSYCHIATRY REPORTS LA English DT Article DE Insomnia; Sleep disorders; Neuroimaging; Neurobiology; Psychiatry ID MAGNETIC-RESONANCE-SPECTROSCOPY; EMISSION COMPUTED-TOMOGRAPHY; HEART-RATE-VARIABILITY; GOOD SLEEPER CONTROLS; CORTICAL GABA LEVELS; SLOW-WAVE SLEEP; NREM SLEEP; HIPPOCAMPAL VOLUME; ATTENTIONAL BIAS; NEURAL CIRCUITRY AB Chronic insomnia is one of the most prevalent psychiatric disorders and has a significant impact on individual's health. However, the pathophysiology of the disorder is poorly understood. The current review focuses on neuroimaging findings in insomnia. In summary, the current data suggest the following: (1) insomnia is characterized by corticolimbic overactivity during sleep and wakefulness that interferes with sleep initiation and/or maintenance; (2) insomnia patients' daytime performance is associated with a hypoactivation of task-related areas; (3) neurochemically, insomnia patients are probably characterized by reduced cortical GABA levels; (4) insomnia may be associated with abnormal brain morphometry in the frontal cortex, hippocampus and/or anterior cingulate cortex. Future investigations should include larger sample sizes or longitudinal within-subject comparisons. Other possible methodological improvements are discussed. C1 [Spiegelhalder, Kai; Regen, Wolfram; Baglioni, Chiara; Riemann, Dieter] Univ Freiburg, Med Ctr, Dept Psychiat & Psychotherapy, D-79104 Freiburg, Germany. [Spiegelhalder, Kai] Univ Freiburg, Freiburg Inst Adv Studies FRIAS, D-79104 Freiburg, Germany. [Winkelman, John W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Spiegelhalder, K (reprint author), Univ Freiburg, Med Ctr, Dept Psychiat & Psychotherapy, Hauptstr 5, D-79104 Freiburg, Germany. EM Kai.Spiegelhalder@uniklinik-freiburg.de; Wolfram.Regen@uniklinik-freiburg.de; Chiara.Baglioni@uniklinik-freiburg.de; Dieter.Riemann@uniklinik-freiburg.de; jwwinkelman@partners.org OI Riemann, Dieter/0000-0002-1968-6220 FU GlaxoSmithKline; Impax Pharmaceutical; UCB Pharma FX John W. Winkelman has served on the scientific advisory board for Zeo, has served as a consultant for Impax Pharmaceutical and UCB Pharma, and has received research support from GlaxoSmithKline, Impax Pharmaceutical and UCB Pharma. NR 73 TC 10 Z9 10 U1 1 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 EI 1535-1645 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD NOV PY 2013 VL 15 IS 11 AR 405 DI 10.1007/s11920-013-0405-0 PG 6 WC Psychiatry SC Psychiatry GA 241SG UT WOS:000326187300002 PM 24057158 ER PT J AU El-Serag, HB Alsarraj, A Richardson, P Davila, JA Kramer, JR Durfee, J Kanwal, F AF El-Serag, Hashem B. Alsarraj, Abeer Richardson, Peter Davila, Jessica A. Kramer, Jennifer R. Durfee, Janet Kanwal, Fasiha TI Hepatocellular Carcinoma Screening Practices in the Department of Veterans Affairs: Findings from a National Facility Survey SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Viral hepatitis; Epidemiology; Hepatoma; Liver cancer ID UNITED-STATES; SURVEILLANCE AB Previous studies suggest low rates of hepatocellular carcinoma (HCC) screening in clinical practice. There is little information on the provider- and healthcare-facility-related factors that explain the use of HCC screening. We used data from the 2007 Survey to Assess Hepatitis C Care in Veterans Health Administration that collected information regarding the care of patients with hepatitis C virus (HCV) from 138 of 140 Veterans Administration healthcare facilities nationwide. All providers caring for veterans with HCV were invited to respond. In addition, each facility was asked to identify a lead HCV clinician to respond to facility-specific questions. Our outcome was a response concordant with HCC screening guidelines [HCC screening in patients with cirrhosis or in patients with chronic hepatitis B virus (HBV), and screening every 6 or 12 months]. A total of 268 providers responded (98 % facility participation rate). Of these, 190 respondents (70.9 %) reported recommending HCC screening with guideline-concordant risk groups and frequency. Providers reporting guideline-concordant HCC screening practices were significantly more likely to have expertise in liver disease (MD, gastroenterologists or hepatologists), routinely screen for varices, prescribe HCV treatment, and refer or manage patients with liver transplant. The availability of HCC-specific treatments on site was the main facility factor associated with guideline-concordant HCC screening. Self-reported rates of guideline-concordant HCC screening are considerably higher than those seen in routine VA practice. Provider expertise in liver disease and the perceived availability of HCC treatment including transplantation in the local facility are important factors driving self-reported HCC screening practices. C1 [El-Serag, Hashem B.; Alsarraj, Abeer; Richardson, Peter; Davila, Jessica A.; Kramer, Jennifer R.; Kanwal, Fasiha] Michael E DeBakey VA Med Ctr, Houston HSR&D Ctr Excellence, Houston, TX 77030 USA. [El-Serag, Hashem B.; Kanwal, Fasiha] Michael E DeBakey VA Med Ctr, Sect Gastroenterol & Hepatol, Houston, TX USA. [El-Serag, Hashem B.; Alsarraj, Abeer; Richardson, Peter; Davila, Jessica A.; Kramer, Jennifer R.; Kanwal, Fasiha] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Alsarraj, Abeer; Richardson, Peter; Davila, Jessica A.; Kramer, Jennifer R.] Michael E DeBakey VA Med Ctr, Sect Hlth Serv Res, Houston, TX USA. [Durfee, Janet] US Dept Vet Affairs, Off Publ Hlth, Washington, DC USA. RP El-Serag, HB (reprint author), Michael E DeBakey VA Med Ctr, Houston HSR&D Ctr Excellence, 2002 Holcombe Blvd 152, Houston, TX 77030 USA. EM hasheme@bcm.edu FU NIH [R01 CA125487]; Houston VA HSR&D Center of Excellence [HFP90-020] FX This work is funded in part by NIH grant R01 CA125487 and in part by the Houston VA HSR&D Center of Excellence (HFP90-020). NR 15 TC 5 Z9 5 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD NOV PY 2013 VL 58 IS 11 BP 3117 EP 3126 DI 10.1007/s10620-013-2794-7 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 241SU UT WOS:000326188800012 PM 23868438 ER PT J AU Paquin, AM Zimmerman, KM Kostas, TR Pelletier, L Hwang, A Simone, M Skarf, LM Rudolph, JL AF Paquin, Allison M. Zimmerman, Kristin M. Kostas, Tia R. Pelletier, Lindsey Hwang, Angela Simone, Mark Skarf, Lara M. Rudolph, James L. TI Complexity perplexity: a systematic review to describe the measurement of medication regimen complexity SO EXPERT OPINION ON DRUG SAFETY LA English DT Review DE burden; medication safety; regimen; treatment complexity ID QUALITY-OF-LIFE; OLDER-ADULTS; ADHERENCE; IMPACT; INDEX; MANAGEMENT; RISK; HOSPITALIZATION; VALIDATION; EPILEPSY AB Introduction: Complex medication regimens are error prone and challenging for patients, which may impact medication adherence and safety. No universal method to assess the complexity of medication regimens (CMRx) exists. The authors aim to review literature for CMRx measurements to establish consistencies and, secondarily, describe CMRx impact on healthcare outcomes. Areas covered: A search of EMBASE and PubMed for studies analyzing at least two medications and complexity components, among those self-managing medications, was conducted. Out of 1204 abstracts, 38 studies were included in the final sample. The majority (74%) of studies used one of five validated CMRx scales; their components and scoring were compared. Expert opinion: Universal CMRx assessment is needed to identify and reduce complex regimens, and, thus, improve safety. The authors highlight commonalities among five scales to help build consensus. Common components (i.e., regimen factors) included dosing frequency, units per dose, and non-oral routes. Elements (e.g., twice daily) of these components (e.g., dosing frequency) and scoring varied. Patient-specific factors (e.g., dexterity, cognition) were not addressed, which is a shortcoming of current scales and a challenge for future scales. As CMRx has important outcomes, notably adherence and healthcare utilization, a standardized tool has potential for far-reaching clinical, research, and patient-safety impact. C1 [Paquin, Allison M.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Zimmerman, Kristin M.] Massachusetts Coll Pharm & Hlth Sci, Boston, MA 02115 USA. [Kostas, Tia R.; Rudolph, James L.] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA 02130 USA. [Kostas, Tia R.; Simone, Mark] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kostas, Tia R.; Simone, Mark; Skarf, Lara M.] Harvard Univ, Sch Med, Boston, MA USA. [Pelletier, Lindsey; Hwang, Angela] Northeastern Univ, Boston, MA 02115 USA. RP Paquin, AM (reprint author), VA Boston Healthcare Syst, 150 South Huntington Ave, Boston, MA 02130 USA. EM allison.paquin@va.gov FU VA Rehabilitation Research Career Development Award; VA Transformational grant; John A. Hartford Foundation Center of Excellence Award; HRSA Geriatric Academic Career Award [K01HP23811] FX Doctors Paquin, Kostas, Skarf, and Rudolph are U. S. Government employees. JL Rudolph is supported by a VA Rehabilitation Research Career Development Award. AM Paquin and JL Rudolph are supported by a VA Transformational grant to develop non-institutional alternatives to longterm care - the PILL Project. T Kostas is supported by the John A. Hartford Foundation Center of Excellence Award. M Simone is supported by a HRSA Geriatric Academic Career Award (Grant No. K01HP23811). K Zimmerman, L Pelletier, and A Hwang have nothing to disclose. NR 47 TC 7 Z9 8 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1474-0338 EI 1744-764X J9 EXPERT OPIN DRUG SAF JI Expert Opin. Drug Saf. PD NOV PY 2013 VL 12 IS 6 BP 829 EP 840 DI 10.1517/14740338.2013.823944 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 238TR UT WOS:000325973600005 PM 23984969 ER PT J AU Ananthakrishnan, AN Khalili, H Konijeti, GG Higuchi, LM De Silva, P Korzenik, JR Fuchs, CS Willett, WC Richter, JM Chan, AT AF Ananthakrishnan, Ashwin N. Khalili, Hamed Konijeti, Gauree G. Higuchi, Leslie M. De Silva, Punyanganie Korzenik, Joshua R. Fuchs, Charles S. Willett, Walter C. Richter, James M. Chan, Andrew T. TI A Prospective Study of Long-term Intake of Dietary Fiber and Risk of Crohn's Disease and Ulcerative Colitis SO GASTROENTEROLOGY LA English DT Article DE Population-Based Study; Diet; Fruits; Vegetables ID INFLAMMATORY-BOWEL-DISEASE; ARYL-HYDROCARBON RECEPTOR; COLORECTAL-CANCER; ESCHERICHIA-COLI; GUT MICROBIOTA; NURSES HEALTH; CONSUMPTION; WOMEN; QUESTIONNAIRE; EPIDEMIOLOGY AB BACKGROUND & AIMS: Increased intake of dietary fiber has been proposed to reduce the risk of inflammatory bowel disease (Crohn's disease [CD] and ulcerative colitis [UC]). However, few prospective studies have examined associations between long-term intake of dietary fiber and risk of incident CD or UC. METHODS: We collected and analyzed data from 170,776 women, followed up over 26 years, who participated in the Nurses' Health Study, followed up for 3,317,425 person-years. Dietary information was prospectively ascertained via administration of a validated semiquantitative food frequency questionnaire every 4 years. Self-reported CD and UC were confirmed through review of medical records. Cox proportional hazards models, adjusting for potential confounders, were used to calculate hazard ratios (HRs). RESULTS: We confirmed 269 incident cases of CD (incidence, 8/100,000 person-years) and 338 cases of UC (incidence, 10/100,000 person-years). Compared with the lowest quintile of energyadjusted cumulative average intake of dietary fiber, intake of the highest quintile (median of 24.3 g/day) was associated with a 40% reduction in risk of CD (multivariate HR for CD, 0.59; 95% confidence interval, 0.39-0.90). This apparent reduction appeared to be greatest for fiber derived from fruits; fiber from cereals, whole grains, or legumes did not modify risk. In contrast, neither total intake of dietary fiber (multivariate HR, 0.82; 95% confidence interval, 0.58-1.17) nor intake of fiber from specific sources appeared to be significantly associated with risk of UC. CONCLUSIONS: Based on data from the Nurses' Health Study, long-term intake of dietary fiber, particularly from fruit, is associated with lower risk of CD but not UC. Further studies are needed to determine the mechanisms that mediate this association. C1 [Ananthakrishnan, Ashwin N.; Khalili, Hamed; Konijeti, Gauree G.; De Silva, Punyanganie; Richter, James M.; Chan, Andrew T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol, Boston, MA 02115 USA. [Higuchi, Leslie M.; Fuchs, Charles S.] Harvard Univ, Childrens Hosp, Sch Med, Div Gastroenterol & Nutr, Boston, MA 02115 USA. [Korzenik, Joshua R.] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Fuchs, Charles S.; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Fuchs, Charles S.; Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Willett, Walter C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@partners.org FU American Gastroenterological Association; Crohn's and Colitis Foundation of America; Broad Medical Research Program of the Broad Foundation; National Institutes of Health [K24 DK098311, P01 CA87969, P30 DK04335, K08 DK064256, K23 DK091742, K23 DK099681, UM1 CA176276] FX Supported by a Research Scholars Award from the American Gastroenterological Association (A.N.A), the Crohn's and Colitis Foundation of America (H.K.), the Broad Medical Research Program of the Broad Foundation (A.T.C), and the National Institutes of Health (K24 DK098311, P01 CA87969, P30 DK043351, K08 DK064256, K23 DK091742, K23 DK099681, and UM1 CA176276). NR 48 TC 70 Z9 71 U1 2 U2 31 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2013 VL 145 IS 5 BP 970 EP 977 DI 10.1053/j.gastro.2013.07.050 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 238UV UT WOS:000325977600023 PM 23912083 ER PT J AU Boldt, MD Brill, JV Davis, GL Gordon, SC Kim, AY Kosinski, LR Levy, AG Nahass, RG Allen, JI AF Boldt, Mark D. Brill, Joel V. Davis, Gary L. Gordon, Stuart C. Kim, Arthur Y. Kosinski, Lawrence R. Levy, Arnold G. Nahass, Ronald G. Allen, John I. CA Hepatitis C Task Force TI Hepatitis C Screening: Summary of Recommendations From the Clinical Decision Tool SO GASTROENTEROLOGY LA English DT Article C1 [Davis, Gary L.] Baylor Univ, Med Ctr Dallas, Waco, TX 76798 USA. [Gordon, Stuart C.] Henry Ford Hlth Syst, Detroit, MI USA. [Kim, Arthur Y.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nahass, Ronald G.; Allen, John I.] Yale Univ, Sch Med, New Haven, CT 06520 USA. RP Boldt, MD (reprint author), AGA Natl Off, Clin Practice & Qual Management Comm, 4930 Del Ray Ave, Bethesda, MD 20814 USA. EM lclote@gastro.org FU Abbvie Pharmaceuticals; Bristol-Myers Squibb; Gilead Pharmaceuticals; GlaxoSmithKline; Intercept Pharmaceuticals; Merck; Vertex Pharmaceuticals FX The authors disclose the following: Stuart C. Gordon has received grant/research support from Abbvie Pharmaceuticals, Bristol-Myers Squibb, Gilead Pharmaceuticals, GlaxoSmithKline, Intercept Pharmaceuticals, Merck, and Vertex Pharmaceuticals, is a consultant/adviser for Bristol-Myers Squibb, CVS Caremark, Gilead Pharmaceuticals, Merck, Novartis, and Vertex Pharmaceuticals, and is member on the Data Monitoring Board of Tibotec/Janssen. Mark D. Boldt is on the advisory board of Gilead and Janssen. Arthur Y. Kim is a consultant for Gilead Sciences and Abbvie Pharmaceuticals and has received research grants and support from Bristol-Myers Squibb. Joel V. Brill is a member of The American Association for the Study of Liver Diseases, American Gastroenterological Association, and American Medical Association-convened Physician Consortium for Performance Improvement (R) workgroup that developed the Hepatitis C Performance Measurement Set. Gary L. Davis is a member on the Data and Safety Monitoring Boards for Gilead and BMS. Ronald G. Nahass is a speaker for Merck and Vertex, completed clinical research for Merck, Gilead, Janssen, Abbvie Pharmaceuticals, and BMS and is on the advisory board for Janssen and Merck. The remaining authors disclose no conflicts. NR 6 TC 3 Z9 3 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2013 VL 145 IS 5 BP 1146 EP 1149 DI 10.1053/j.gastro.2013.09.007 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 238UV UT WOS:000325977600041 ER PT J AU Chaudhury, A AF Chaudhury, Arun TI Evidence for Dual Pathway for Nitrergic Neuromuscular Transmission in Doubt: Evidence Favors Lack of Role of ICC SO GASTROENTEROLOGY LA English DT Letter ID NITRIC-OXIDE; NEUROTRANSMISSION; ANTAGONISM C1 [Chaudhury, Arun] VA Boston HealthCare Syst, Boston, MA USA. [Chaudhury, Arun] Harvard Univ, Sch Med, Boston, MA USA. RP Chaudhury, A (reprint author), VA Boston HealthCare Syst, Boston, MA USA. NR 8 TC 3 Z9 3 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2013 VL 145 IS 5 BP 1160 EP 1161 DI 10.1053/j.gastro.2013.09.039 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 238UV UT WOS:000325977600042 PM 24070723 ER PT J AU David, S Congleton, C AF David, Susan Congleton, Christina TI Emotional Agility SO HARVARD BUSINESS REVIEW LA English DT Article AB The prevailing wisdom says that negative thoughts and feelings have no place at the office. But that goes against basic biology. All healthy human beings have an inner stream of thoughts and feelings that include criticism, doubt, and fear. David and Congleton have worked with leaders in various industries to build a critical skill they call emotional agility, which enables people to approach their inner experiences in a mindful, values-driven, and productive way rather than buying into or trying to suppress them. The authors offer four practices (adapted from Acceptance and Commitment Therapy, or ACT) designed to help readers do the same: Recognize your patterns. You have to realize that you're stuck before you can initiate change. Label your thoughts and emotions. Labeling allows you to see them as transient sources of data that may or may not prove helpful. Accept them. Respond to your ideas and emotions with an open attitude, paying attention and letting yourself experience them. They may be signaling that something important is at stake. Act on your values. Is your response going to serve your organization in the long term and take you toward being the leader you most want to be? C1 [David, Susan] Harvard Univ, Cambridge, MA 02138 USA. [David, Susan] Harvard Univ, Inst Coaching, Cambridge, MA 02138 USA. [Congleton, Christina] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP David, S (reprint author), Harvard Univ, Cambridge, MA 02138 USA. NR 0 TC 3 Z9 3 U1 6 U2 20 PU HARVARD BUSINESS SCHOOL PUBLISHING CORPORATION PI WATERTOWN PA 300 NORTH BEACON STREET, WATERTOWN, MA 02472 USA SN 0017-8012 J9 HARVARD BUS REV JI Harv. Bus. Rev. PD NOV PY 2013 VL 91 IS 11 BP 125 EP + PG 3 WC Business; Management SC Business & Economics GA 240VB UT WOS:000326124700042 ER PT J AU Schneider, R Randolph, GW Sekulla, C Phelan, E Thanh, PN Bucher, M Machens, A Dralle, H Lorenz, K AF Schneider, Rick Randolph, Gregory W. Sekulla, Carsten Phelan, Eimear Phuong Nguyen Thanh Bucher, Michael Machens, Andreas Dralle, Henning Lorenz, Kerstin TI Continuous intraoperative vagus nerve stimulation for identification of imminent recurrent laryngeal nerve injury SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE vagus nerve stimulation; vagal electrode; APS electrode; Continuous intraoperative nerve monitoring; loss of signal; recurrent laryngeal nerve injury; vocal cord palsy ID THYROID-SURGERY; PARATHYROID SURGERY; ANCHOR ELECTRODE; CLINICAL-TRIAL; MECHANISMS AB BackgroundConventional intraoperative nerve monitoring, predicated on intermittent stimulation, can predict recurrent laryngeal nerve (RLN) palsy only after the damage has been done. MethodsFifty-two patients (52 nerves at risk) who underwent continuous intraoperative nerve monitoring (CIONM) for thyroid surgery via vagus nerve stimulation had their electromyographic (EMG) tracings recorded and correlated with surgical maneuvers and postoperative RLN function. ResultsThere was 1 imminent loss of signal (LOS) with intraoperative signal recovery and there were 4 losses of signal with corresponding unilateral transient RLN palsy. When EMG amplitude decreased >50% and EMG latency increased >10%, LOS and postoperative RLN palsy were noted in 4 of 8 patients (50%) who had multiple combined events. In 9 of 13 patients (70%) who developed adverse EMG changes, modification of the causative surgical maneuver resulted in recovery of those EMG changes and aversion of impending RLN palsy. ConclusionCIONM reliably signaled impending nerve injury, enabling immediate corrective action. (c) 2012 Wiley Periodicals, Inc. Head Neck, 35: 1591-1598, 2013 C1 [Schneider, Rick; Sekulla, Carsten; Phuong Nguyen Thanh; Machens, Andreas; Dralle, Henning; Lorenz, Kerstin] Univ Halle Wittenberg, Dept Gen Visceral & Vasc Surg, D-06108 Halle, Saale, Germany. [Randolph, Gregory W.; Phelan, Eimear] Harvard Univ, Sch Med, Dept Otolaryngol, Massachusetts Eye & Ear Infirm,Div Thyroid & Para, Boston, MA 02115 USA. [Bucher, Michael] Univ Halle Wittenberg, Dept Anesthesiol & Intens Care Med, D-06108 Halle, Saale, Germany. RP Schneider, R (reprint author), Univ Halle Wittenberg, Dept Gen Visceral & Vasc Surg, D-06108 Halle, Saale, Germany. EM rick.schneider@uk-halle.de NR 24 TC 46 Z9 47 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD NOV PY 2013 VL 35 IS 11 BP 1591 EP 1598 DI 10.1002/hed.23187 PG 8 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 238XU UT WOS:000325986200018 PM 23169450 ER PT J AU Bankoff, SM Valentine, SE Jackson, MA Schacht, RL Pantalone, DW AF Bankoff, Sarah M. Valentine, Sarah E. Jackson, Michelle A. Schacht, Rebecca L. Pantalone, David W. TI Compensatory Weight Control Behaviors of Women in Emerging Adulthood: Associations Between Childhood Abuse Experiences and Adult Relationship Avoidance SO JOURNAL OF AMERICAN COLLEGE HEALTH LA English DT Article DE adult dating relationships; childhood abuse; emerging adulthood; weight control; women ID EARLY SEPARATION ANXIETY; BRIEF SYMPTOM INVENTORY; BINGE-EATING DISORDER; SEXUAL-ABUSE; PSYCHOLOGICAL SYMPTOMS; BODY DISSATISFACTION; INSECURE ATTACHMENT; DIAGNOSTIC PROFILE; ADOLESCENT GIRLS; COLLEGE-WOMEN AB Objective: To examine correlates of compensatory weight control behaviors among women in transition between adolescence and adulthood. Participants: The authors recruited a sample of undergraduate women (N = 759) at a large northwestern university during the 2009-2010 academic year. Methods: Logistic regression was used to assess relations among childhood abuse, psychosocial functioning, adult dating relationship factors, and women's endorsement of compensatory weight control behaviors. Results: The final model reliably distinguished between participants who endorsed versus denied use of compensatory behaviors ((2)[5, N = 747] = 36.37, p < .001), with global psychosocial functioning and relationship avoidance accounting for the most variance. Conclusions: These findings illustrate the importance of considering childhood abuse histories and adult relationships while assessing young women's compensatory weight control behaviors. C1 [Bankoff, Sarah M.] VA Boston Healthcare Syst, Psychol Serv, Boston, MA 02130 USA. [Valentine, Sarah E.; Jackson, Michelle A.] Suffolk Univ, Dept Psychol, Boston, MA 02114 USA. [Schacht, Rebecca L.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Pantalone, David W.] Univ Massachusetts, Coll Liberal Arts, Boston, MA 02125 USA. RP Bankoff, SM (reprint author), VA Boston Healthcare Syst, Psychol Serv 116B, 150 South Huntington Ave, Boston, MA 02130 USA. EM sarah.bankoff@va.gov OI Schacht, Rebecca/0000-0002-2122-8384 NR 46 TC 0 Z9 0 U1 1 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0744-8481 EI 1940-3208 J9 J AM COLL HEALTH JI J. Am. Coll. Health PD NOV 1 PY 2013 VL 61 IS 8 BP 468 EP 475 DI 10.1080/07448481.2013.833515 PG 8 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 239HI UT WOS:000326012800004 PM 24152024 ER PT J AU Matsunaga, J Schlax, PJ Haake, DA AF Matsunaga, James Schlax, Paula J. Haake, David A. TI Role for cis-Acting RNA Sequences in the Temperature-Dependent Expression of the Multiadhesive Lig Proteins in Leptospira interrogans SO JOURNAL OF BACTERIOLOGY LA English DT Article ID THERMOSENSOR CONTROLS EXPRESSION; RPOS MESSENGER-RNA; ESCHERICHIA-COLI; OUTER-MEMBRANE; BORRELIA-BURGDORFERI; GENE-EXPRESSION; TRANSLATIONAL EFFICIENCY; EXTRACELLULAR RELEASE; QUANTITATIVE-ANALYSIS; SECONDARY STRUCTURE AB The spirochete Leptospira interrogans causes a systemic infection that provokes a febrile illness. The putative lipoproteins LigA and LigB promote adhesion of Leptospira to host proteins, interfere with coagulation, and capture complement regulators. In this study, we demonstrate that the expression level of the LigA and LigB proteins was substantially higher when L. interrogans proliferated at 37 C instead of the standard culture temperature of 30 degrees C. The RNA comprising the 175-nucleotide 5' untranslated region (UTR) and first six lig codons, whose sequence is identical in ligA and ligB, is predicted to fold into two distinct stem-loop structures separated by a single-stranded region. The ribosome-binding site is partially sequestered in double-stranded RNA within the second structure. Toeprint analysis revealed that in vitro formation of a 30S-tRNA(fMet)-mRNA ternary complex was inhibited unless a 5' deletion mutation disrupted the second stem-loop structure. To determine whether the lig sequence could mediate temperature-regulated gene expression in vivo, the 5' UTR and the first six codons were inserted between the Escherichia coli L-arabinose promoter and bgaB (beta-galactosidase from Bacillus stearothermophilus) to create a translational fusion. The lig fragment successfully conferred thermoregulation upon the beta-galactosidase reporter in E. coli. The second stem-loop structure was sufficient to confer thermoregulation on the reporter, while sequences further upstream in the 5' UTR slightly diminished expression at each temperature tested. Finally, the expression level of beta-galactosidase was significantly higher when point mutations predicted to disrupt base pairs in the second structure were introduced into the stem. Compensatory mutations that maintained base pairing of the stem without restoring the wild-type sequence reinstated the inhibitory effect of the 5' UTR on expression. These results indicate that ligA and ligB expression is limited by double-stranded RNA that occludes the ribosome-binding site. At elevated temperatures, the ribosome-binding site is exposed to promote translation initiation. C1 [Matsunaga, James] Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA. [Haake, David A.] Vet Affairs Greater Los Angeles Healthcare Syst, Div Infect Dis, Los Angeles, CA USA. [Matsunaga, James; Haake, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Haake, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Haake, David A.] Univ Calif Los Angeles, Dept Microbiol & Mol Genet, Los Angeles, CA 90024 USA. [Schlax, Paula J.] Bates Coll, Program Biol Chem, Lewiston, ME 04240 USA. RP Matsunaga, J (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA. EM jamesm@ucla.edu FU Veterans Affairs Merit Review award; Public Health Service from the National Institute of Allergy and Infectious Diseases [AI-034431]; National Center for Research Resources [5P20RR016463]; National Institute of General Medical Sciences from the National Institutes of Health [8 P20 GM103423] FX This study was supported by a Veterans Affairs Merit Review award (to J.M.) and Public Health Service grant AI-034431 from the National Institute of Allergy and Infectious Diseases (to D. A. H.). P.J.S. was supported by National Center for Research Resources grant 5P20RR016463 and National Institute of General Medical Sciences grant 8 P20 GM103423 from the National Institutes of Health. NR 72 TC 12 Z9 12 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD NOV PY 2013 VL 195 IS 22 BP 5092 EP 5101 DI 10.1128/JB.00663-13 PG 10 WC Microbiology SC Microbiology GA 240JR UT WOS:000326092400012 PM 24013626 ER PT J AU Dandamudi, UB Ghebremichael, M Sosman, JA Clark, JI McDermott, DF Atkins, MB Dutcher, JP Urba, WJ Regan, MM Puzanov, I Crocenzi, TS Curti, BD Vaishampayan, UN Crosby, NA Margolin, KA Ernstoff, MS AF Dandamudi, Uday B. Ghebremichael, Musie Sosman, Jeffrey A. Clark, Joseph I. McDermott, David F. Atkins, Michael B. Dutcher, Janice P. Urba, Walter J. Regan, Meredith M. Puzanov, Igor Crocenzi, Todd S. Curti, Brendan D. Vaishampayan, Ulka N. Crosby, Nancy A. Margolin, Kim A. Ernstoff, Marc S. TI A Phase II Study of Bevacizumab and High-dose Interleukin-2 in Patients With Metastatic Renal Cell Carcinoma: A Cytokine Working Group (CWG) Study SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE immunotherapy; antiangiogenesis; renal cell cancer; interleukin-2 ID ENDOTHELIAL GROWTH-FACTOR; INTERFERON-ALPHA; IMMUNE SUPPRESSION; TARGETED THERAPY; RANDOMIZED-TRIAL; DENDRITIC CELLS; DOUBLE-BLIND; T-CELLS; CANCER; EFFICACY AB Overexpression of vascular endothelial growth factor in renal cell carcinoma (RCC) leads to angiogenesis, tumor progression, and inhibition of immune function. We conducted the first phase II study to estimate the efficacy and safety of bevacizumab with high-dose interleukin-2 (IL-2) therapy in patients with metastatic RCC. Eligible patients had predominantly clear cell metastatic RCC, measurable disease, a Karnofsky Performance Status of 80%, and adequate end-organ function. IL-2 (600,000 IU/kg) was infused intravenously every 8 hours (maximum 28 doses) during two 5-day cycles on days 1 and 15 of each 84-day course. Bevacizumab (10 mg/kg) was infused intravenously every 2 weeks beginning 2 weeks before initiating IL-2. Fifty of 51 eligible patients from 8 centers were enrolled. Median progression-free survival (PFS) was 11.2 months (90% confidence interval, 5.7-17.7), and 2-year PFS was 18% (90% confidence interval, 8%-27%). Responses included 4 complete (8%) and 11 partial (22%) responses. Toxicities did not exceed those expected from each agent alone. Combining IL-2 plus bevacizumab is feasible, with a response rate and PFS at least as high as reported previously for the single agents. The regimen did not appear to enhance the rate of durable major responses over that of IL-2 alone. C1 [Dandamudi, Uday B.; Crosby, Nancy A.; Ernstoff, Marc S.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Ghebremichael, Musie] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02115 USA. [Regan, Meredith M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Sosman, Jeffrey A.; Puzanov, Igor] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Clark, Joseph I.] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. [Atkins, Michael B.] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. [Dutcher, Janice P.] St Lukes Roosevelt Hosp, New York, NY USA. [Urba, Walter J.; Crocenzi, Todd S.] Providence Canc Ctr, Portland, OR USA. [Vaishampayan, Ulka N.] Wayne State Univ, Dept Oncol, Karmanos Canc Inst, Detroit, MI USA. [Margolin, Kim A.] Univ Washington, Dept Med, Div Oncol, Seattle Canc Care Alliance, Seattle, WA 98195 USA. RP Ernstoff, MS (reprint author), Norris Cotton Canc Ctr, Dartmouth Hitchcock Med Ctr, Sect Hematol Oncol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM marc.s.ernstoff@hitchcock.org FU Novartis; Genentech; Medical Oncology Immunotherapy Program Dartmouth Hitchcock Medical Center FX Supported in part by grants from Novartis and Genentech and from the Medical Oncology Immunotherapy Program Dartmouth Hitchcock Medical Center. NR 38 TC 15 Z9 15 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1524-9557 EI 1537-4513 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2013 VL 36 IS 9 BP 490 EP 495 DI 10.1097/CJI.0000000000000003 PG 6 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 242WH UT WOS:000326275000005 PM 24145360 ER PT J AU Goyal, RK AF Goyal, Raj K. TI Revised role of interstitial cells of Cajal in cholinergic neurotransmission in the gut SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Letter ID JUNCTIONS; STOMACH C1 Harvard Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA 02115 USA. RP Goyal, RK (reprint author), Harvard Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA 02115 USA. EM raj_goyal@hms.harvard.edu NR 10 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD NOV 1 PY 2013 VL 591 IS 21 BP 5413 EP 5414 DI 10.1113/jphysiol.2013.264135 PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 243IV UT WOS:000326311000019 PM 24187080 ER PT J AU Van Daele, CM De Meyer, T De Buyzere, ML Gillebert, TC Denil, SLIJ Bekaert, S Chirinos, JA De Backer, GG De Bacquer, D Rietzschel, ER AF Van Daele, Caroline M. De Meyer, Tim De Buyzere, Marc L. Gillebert, Thierry C. Denil, Simon L. I. J. Bekaert, Sofie Chirinos, Julio A. De Backer, Guy G. De Bacquer, Dirk Rietzschel, Ernst R. CA Asklepios Investigators TI Family History of Cardiovascular Disease and Offspring Echocardiographic Left Ventricular Structure and Function: The Asklepios Study SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article DE Left ventricular structure; Left ventricular function; Echocardiography; Family history; Cardiovascular disease ID CORONARY-HEART-DISEASE; ENVIRONMENTAL-INFLUENCES; ARTERIAL PULSE; PLACENTAL SIZE; BLOOD-PRESSURE; RISK-FACTOR; ADULT LIFE; BODY-SIZE; MASS; FAILURE AB Background: Moderate to small heritability has been observed for left ventricular (LV) structure and function in genetic epidemiology and genomewide association studies. The aim of this study was to explore whether this would be mirrored in an independent association between LV structure and function and a family history (FH) of cardiovascular disease (CVD) in a large population of middle-aged adults. Methods: Subjects enrolled in the Asklepios Study, a population-based sample of 2,524 male and female volunteers, aged 35 to 55 years, free of overt CVD at baseline, were studied. LV structure and function were assessed using transthoracic echocardiography (by a single sonographer). FH data spanning 4 generations were acquired using a questionnaire. Results: In unadjusted analyses, only small effects of FH of CVD on LV structure (relative wall thickness, P =.042; interventricular septal thickness, P =.002; LV mass, P =.038; allometrically adjusted LV mass, P =.014) and diastolic function (mitral annular e', P =.02) were observed. After adjusting for the more adverse risk factor profile associated with FH, no significant associations persisted. These results did not appreciably change using a more extended definition of FH of CVD or FH of hypertension. Conclusions: A positive FH for CVD was associated with differences in offspring cardiac structure and function, largely mediated by (but not independent from) a more adverse risk profile in those subjects with positive FH. C1 [Van Daele, Caroline M.; De Buyzere, Marc L.; Gillebert, Thierry C.; Rietzschel, Ernst R.] Ghent Univ Hosp, Dept Cardiovasc Dis, Ghent, Belgium. [De Meyer, Tim; Denil, Simon L. I. J.] Univ Ghent, Fac Biosci Engn, Dept Math Modelling Stat & Bioinformat, B-9000 Ghent, Belgium. [Bekaert, Sofie] Ghent Univ Hosp, Clin Res Ctr Ghent, Bimetra, Ghent, Belgium. [Chirinos, Julio A.] Univ Penn, Perelman Sch Med, Hosp Univ Penn, Philadelphia, PA 19104 USA. [Chirinos, Julio A.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [De Backer, Guy G.; De Bacquer, Dirk; Rietzschel, Ernst R.] Univ Ghent, Fac Med & Hlth Sci, Dept Publ Hlth, B-9000 Ghent, Belgium. RP Van Daele, CM (reprint author), Univ Ghent, Dept Cardiovasc Dis, Pintelaan 185,Bldg 10K12IE, B-9000 Ghent, Belgium. EM caroline.vandaele@ugent.be OI Gillebert, Thierry/0000-0002-3832-919X FU Fund for Scientific Research-Flanders (FWO) [G042703, G083810N] FX The Asklepios Study is supported by the Fund for Scientific Research-Flanders (FWO research grants G042703 and G083810N). NR 56 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD NOV PY 2013 VL 26 IS 11 BP 1290 EP U197 DI 10.1016/j.echo.2013.07.024 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 242IN UT WOS:000326232600008 PM 23993692 ER PT J AU Rodrigues, AC Picard, MH Carbone, A Arruda, AL Flores, T Klohn, J Furtado, M Lira, EB Cerri, GG Andrade, JL AF Rodrigues, Ana Clara Picard, Michael H. Carbone, Aime Arruda, Ana Lucia Flores, Thais Klohn, Juliana Furtado, Meive Lira-Filho, Edgar B. Cerri, Giovanni G. Andrade, Jose L. TI Importance of Adequately Performed Valsalva Maneuver to Detect Patent Foramen Ovale during Transesophageal Echocardiography SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article DE Patent foramen ovale; Transesophageal echocardiography; Transthoracic echocardiography; Valsalva maneuver ID TRANSTHORACIC CONTRAST ECHOCARDIOGRAPHY; TO-LEFT SHUNT; CEREBROVASCULAR EVENTS; ENHANCED DETECTION; STROKE PATIENTS; EMBOLIC EVENTS; DIAGNOSIS; ASSOCIATION; QUANTIFICATION; SENSITIVITY AB Background: Transesophageal echocardiography (TEE) plays an important role in evaluating cardioembolic sources of emboli. The identification of a patent foramen ovale (PFO) is reportedly improved with TEE compared with transthoracic echocardiography (TTE), but the Valsalva maneuver during TEE may be difficult or suboptimal. The aim of this study was to assess the efficacy of the Valsalva maneuver for PFO diagnosis using TEE compared with TTE by evaluating patients with ischemic stroke referred for echocardiography. Methods: Only patients able to perform the Valsalva maneuver during TTE were included; efficacy was defined by a 20 cm/sec decrease in transmitral E velocity. A PFO was judged present when microbubbles of agitated intravenous saline were seen in the left chambers within three cycles after right atrial opacification. Results: Of 108 patients (mean age, 55615 years; 61 men), 48 (44%) were judged to have PFOs by TEE and/or TTE. In 36 patients (33% of the total, 75% of those with PFOs), microbubbles were observed both by TEE and TTE, in seven patients only during TTE, and in five patients only during TEE. In patients able to satisfactorily perform the Valsalva maneuver during TEE, 22 PFOs were found, and two shunts (9%) were missed, whereas in patients unable to perform this maneuver, 26 PFOs were observed, with five shunts missed (19%) (P <.05). When a PFO was missed by TTE, either the echocardiographic window was suboptimal or the shunt was small. Conclusions: An adequate Valsalva maneuver is crucial for diagnosis of PFO; most patients with stroke may be screened using TTE with contrast and the Valsalva maneuver, with TEE indicated in case of suboptimal transthoracic images. C1 [Rodrigues, Ana Clara; Carbone, Aime; Arruda, Ana Lucia; Flores, Thais; Klohn, Juliana; Furtado, Meive; Lira-Filho, Edgar B.; Cerri, Giovanni G.; Andrade, Jose L.] Univ Sao Paulo, Hosp Clin, Echocardiog Lab, Radiol Inst,InRad, BR-05403900 Sao Paulo, Brazil. [Picard, Michael H.] Massachusetts Gen Hosp, Echocardiog Lab, Boston, MA 02114 USA. RP Rodrigues, AC (reprint author), Univ Sao Paulo, Hosp Clin, Dept Echocardiog, Radiol Inst InRad, Rua Particular S-N, BR-05403900 Sao Paulo, Brazil. EM claratude@yahoo.com OI Picard, Michael/0000-0002-9264-3243 NR 39 TC 14 Z9 17 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD NOV PY 2013 VL 26 IS 11 BP 1337 EP 1343 DI 10.1016/j.echo.2013.07.016 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 242IN UT WOS:000326232600015 PM 23993693 ER PT J AU Cudkowicz, ME van den Berg, LH Shefner, JM Mitsumoto, H Mora, JS Ludolph, A Hardiman, O Bozik, ME Ingersoll, EW Archibald, D Meyers, AL Dong, YW Farwell, WR Kerr, DA AF Cudkowicz, Merit E. van den Berg, Leonard H. Shefner, Jeremy M. Mitsumoto, Hiroshi Mora, Jesus S. Ludolph, Albert Hardiman, Orla Bozik, Michael E. Ingersoll, Evan W. Archibald, Donald Meyers, Adam L. Dong, Yingwen Farwell, Wildon R. Kerr, Douglas A. CA EMPOWER Investigators TI Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial SO LANCET NEUROLOGY LA English DT Article ID CLINICAL-TRIALS; ALS; PROGRESSION; LITHIUM; PRAMIPEXOLE; MULTICENTER; ENANTIOMER; RILUZOLE; SURVIVAL AB Background In a phase 2 study, dexpramipexole (25-150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease. Methods In our randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), we enrolled participants aged 18-80 years (with first amyotrophic lateral sclerosis symptom onset 24 months or less before baseline) at 81 academic medical centres in 11 countries. We randomly allocated eligible participants (1:1) with a centralised voice-interactive online system to twice-daily dexpramipexole 150 mg or matched placebo for 12-18 months, stratified by trial site, area of disease onset (bulbar vs other areas), and previous use of riluzole. The primary endpoint was the combined assessment of function and survival (CAFS) score, based on changes in amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) total scores and time to death up to 12 months. We assessed the primary endpoint in all participants who received at least one dose and had at least one post-dose ALSFRS-R measurement or died. We monitored adverse events in all participants. This study is registered with ClinicalTrials.gov, number NCT01281189. Findings Between March 28, 2011, and Sept 30, 2011, we enrolled 943 participants (474 randomly allocated dexpramipexole, 468 randomly allocated placebo, and one withdrew). Least-square mean CAFS scores at 12 months did not differ between participants in the dexpramipexole group (score 441-76, 95% CI 415.43-468.08) and those in the placebo group (438.84, 412.81-464.88; p=0.86). At 12 months, we noted no differences in mean change from baseline in ALSFRS-R total score (-13.34 in the dexpramipexole group vs -13-42 in the placebo group; p=0.90) or time to death (74 [16%] vs 79 [17%]; hazard ratio 1.03 [0.75-1.43]; p=0.84). 37 (8%) participants in the dexpramipexole group developed neutropenia compared with eight (2%) participants in the placebo group, and incidence of other adverse events was similar between groups. Interpretation Dexpramipexole was generally well tolerated but did not differ from placebo on any prespecified efficacy endpoint measurement. Our trial can inform the design of future clinical research strategies in amyotrophic lateral sclerosis. C1 [Cudkowicz, Merit E.] Massachusetts Gen Hosp, Neurol Clin Res Inst, Charlestown, MA USA. [van den Berg, Leonard H.] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands. [Shefner, Jeremy M.] Upstate Med Univ, Syracuse, NY USA. [Mitsumoto, Hiroshi] Columbia Univ, Med Ctr, New York, NY USA. [Mora, Jesus S.] Hosp Carlos III, Madrid, Spain. [Ludolph, Albert] Univ Ulm, D-89069 Ulm, Germany. [Hardiman, Orla] Trinity Coll Dublin, Dublin, Ireland. [Hardiman, Orla] Beaumont Hosp, Dublin 9, Ireland. [Bozik, Michael E.; Archibald, Donald] Knopp Biosci, Pittsburgh, PA USA. [Meyers, Adam L.; Dong, Yingwen; Farwell, Wildon R.; Kerr, Douglas A.] Biogen Idec Inc, Cambridge, MA USA. RP Cudkowicz, ME (reprint author), Neurol Clin Res Inst, 13th St,Bldg 149,Room 2274, Charlestown, MA 02129 USA. EM mcudkowicz@partners.org RI Al-Chalabi, Ammar/E-5361-2010; Grosskreutz, Julian/G-2293-2010; Kiernan, Matthew/E-4460-2011; LICEND, CEMND/F-1296-2015; OI Al-Chalabi, Ammar/0000-0002-4924-7712; Grosskreutz, Julian/0000-0001-9525-1424; Hardiman, Orla/0000-0003-2610-1291; Gamez, Josep/0000-0003-3127-7486 FU Biogen Idec. FX Funding Biogen Idec. NR 35 TC 57 Z9 58 U1 0 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD NOV PY 2013 VL 12 IS 11 BP 1059 EP 1067 DI 10.1016/S1474-4422(13)70221-7 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 239ZC UT WOS:000326063500008 PM 24067398 ER PT J AU Huang, EY Devkota, S Moscoso, D Chang, EB Leone, VA AF Huang, Edmond Y. Devkota, Suzanne Moscoso, Dagmara Chang, Eugene B. Leone, Vanessa A. TI The role of diet in triggering human inflammatory disorders in the modern age SO MICROBES AND INFECTION LA English DT Review DE Gut microbiota; Western diet; High-fat; Inflammatory disease; Systemic inflammation; Immunity ID FATTY LIVER-DISEASE; CLOSTRIDIUM-DIFFICILE INFECTION; EARLY RHEUMATOID-ARTHRITIS; GERM-FREE MICE; GUT MICROBIOTA; BOWEL DISEASES; INDUCED OBESITY; NONALCOHOLIC STEATOHEPATITIS; INSULIN-RESISTANCE; FECAL MICROBIOTA AB Previously uncommon human inflammatory disorders are emerging with alarming frequency, possibly triggered by environmental factors introduced through Westernization. This review highlights how Western diets heighten the inflammatory state promoting development of disease. Evidence that this can occur directly or indirectly through perturbations of host-microbe interactions are reviewed. (C) 2013 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. C1 [Huang, Edmond Y.; Moscoso, Dagmara; Chang, Eugene B.; Leone, Vanessa A.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Devkota, Suzanne] Harvard Univ, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Huang, EY (reprint author), Univ Chicago, Dept Med, 900 East 57th St, Chicago, IL 60637 USA. EM eyhuang@uchicago.edu NR 78 TC 12 Z9 12 U1 0 U2 24 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD NOV PY 2013 VL 15 IS 12 BP 765 EP 774 DI 10.1016/j.micinf.2013.07.004 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 237YL UT WOS:000325907500003 PM 23876436 ER PT J AU Chauhan, VP Jain, RK AF Chauhan, Vikash P. Jain, Rakesh K. TI Strategies for advancing cancer nanomedicine SO NATURE MATERIALS LA English DT Editorial Material ID HUMAN TUMOR XENOGRAFT; IN-VIVO; SOLID TUMORS; VASCULAR-PERMEABILITY; BREAST-CANCER; MICROVASCULAR PERMEABILITY; EXTRACELLULAR-MATRIX; LIPID-COMPOSITION; MOLECULAR-SIZE; DRUG-DELIVERY C1 [Chauhan, Vikash P.; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. [Chauhan, Vikash P.; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Chauhan, Vikash P.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. RP Chauhan, VP (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu FU NCI NIH HHS [R01 CA126642, P01 CA080124, P01-CA080124, R01 CA163815, R01-CA126642, R01-CA163815, T32 CA073479, T32-CA073479] NR 83 TC 172 Z9 172 U1 20 U2 173 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1476-1122 EI 1476-4660 J9 NAT MATER JI Nat. Mater. PD NOV PY 2013 VL 12 IS 11 BP 958 EP 962 DI 10.1038/nmat3792 PG 5 WC Chemistry, Physical; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Materials Science; Physics GA 240LZ UT WOS:000326099300010 PM 24150413 ER PT J AU Shaw, AT Hsu, PP Awad, MM Engelman, JA AF Shaw, Alice T. Hsu, Peggy P. Awad, Mark M. Engelman, Jeffrey A. TI Tyrosine kinase gene rearrangements in epithelial malignancies SO NATURE REVIEWS CANCER LA English DT Review ID CELL LUNG-CANCER; PAPILLARY THYROID CARCINOMAS; ANAPLASTIC LYMPHOMA KINASE; RECURRENT CHROMOSOMAL TRANSLOCATIONS; ATOMIC-BOMB SURVIVORS; EML4-ALK FUSION GENE; PAN-FGFR INHIBITOR; RET PROTOONCOGENE; RET/PTC REARRANGEMENTS; GENOME INSTABILITY AB Chromosomal rearrangements that lead to oncogenic kinase activation are observed in many epithelial cancers. These cancers express activated fusion kinases that drive the initiation and progression of malignancy, and often have a considerable response to small-molecule kinase inhibitors, which validates these fusion kinases as 'druggable' targets. In this Review, we examine the aetiologic, pathogenic and clinical features that are associated with cancers harbouring oncogenic fusion kinases, including anaplastic lymphoma kinase (ALK), ROS1 and RET. We discuss the clinical outcomes with targeted therapies and explore strategies to discover additional kinases that are activated by chromosomal rearrangements in solid tumours. C1 [Shaw, Alice T.; Hsu, Peggy P.; Awad, Mark M.; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Shaw, AT (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM ashaw1@partners.org; jengelman@partners.org FU US National Institutes of Health (NIH) [5R01CA164273-02]; V Foundation for Cancer Research; Uniting Against Lung Cancer FX The authors are supported by grants from the US National Institutes of Health (NIH) 5R01CA164273-02 (A.T.S. and J.A.E.), V Foundation for Cancer Research (A.T.S. and J.A.E.), and Uniting Against Lung Cancer (A.T.S.). A.T.S. is the Charles W. and Jennifer C. Johnson Koch Institute Clinical Investigator. The authors thank I. Klein for his helpful comments, and Be a Piece of the Solution and the Evan Spirito Memorial Foundation for support of lung cancer research. NR 176 TC 83 Z9 84 U1 2 U2 24 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 NOV PY 2013 VL 13 IS 11 BP 772 EP 787 DI 10.1038/nrc3612 PG 16 WC Oncology SC Oncology GA 242WM UT WOS:000326275700008 PM 24132104 ER PT J AU Schecter, A Constable, JD AF Schecter, Arnold Constable, John D. TI Letter commentary on Tai et al: dioxin exposure in breast milk and infant neurodevelopment in Vietnam SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Letter ID AGENT-ORANGE; CONTAMINATION C1 [Schecter, Arnold] Univ Texas Sch Publ Hlth, Occupat & Envnironmental Hlth Sci Program, Dallas, TX 75248 USA. [Constable, John D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Schecter, A (reprint author), Univ Texas Sch Publ Hlth, Occupat & Envnironmental Hlth Sci Program, 16606 Loch Maree Lane, Dallas, TX 75248 USA. EM arnold.schecter@utsouthwestern.edu NR 5 TC 2 Z9 2 U1 1 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD NOV PY 2013 VL 70 IS 11 BP 824 EP 824 DI 10.1136/oemed-2013-101727 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 239TN UT WOS:000326048600013 PM 24143021 ER PT J AU Maxwell, JL Keysor, JJ Niu, JB Singh, JA Wise, BL Frey-Law, L Nevitt, MC Felson, DT AF Maxwell, Jessica L. Keysor, Julie J. Niu, Jingbo Singh, Jasvinder A. Wise, Barton L. Frey-Law, Laura Nevitt, Michael C. Felson, David T. TI Participation Following Knee Replacement: The MOST Cohort Study SO PHYSICAL THERAPY LA English DT Article ID JOINT REPLACEMENT; OLDER-ADULTS; TOTAL HIP; ARTHROPLASTY; OUTCOMES; DISABILITY; HEALTH; PREDICTORS; LIMITATIONS; POPULATION AB Background. Participation is an important, yet seldom studied, outcome after total knee replacement (TKR). Objective. The purpose of this study was to investigate the extent and predictors of participation and participation restriction among people after TKR. Materials and Methods. This study investigated the changes in pain, function, and participation scores (measured using a subscale of the Late-Life Function and Disability Instrument) from pre-TKR to >= 1 year post-TKR among a subsample of participants from the Multicenter Osteoarthritis Study (MOST) longitudinal cohort (MOST is funded by the National Institutes of Health). The proportions of individuals with participation restriction pre-TKR and >= 1 and >= 2 years post-TKR were calculated for all participants and for important demographic subgroups. The association between demographic and clinical factors and participation was estimated using linear regression. The association between demographic and clinical factors and participation restriction was estimated using logistic regression. Results. There were 292 individuals with outcome data >= 1 year post-TKR. Of these, 218 (75%) had data pre-TKR and >= 1 year post-TKR and 160 (55%) had data >= 2 years post-TKR. There were mean improvements in pain, function, and participation at >= 1 and 2 years. However, approximately 30% of the study sample had participation restriction pre-TKR and post-TKR, and the proportion decreased significantly only for those <65 years old. Non-whites had a higher proportion of participation restriction than any other subgroup (41% >= 1 year, 48% >= 2 years). Female sex and non-white race were associated with a worse participation score, and several demographic and modifiable factors were associated with participation restriction following TKR. Limitations. The time between pre-TKR and post-TKR assessment varied across study participants, and data were not available on their rehabilitation utilization. Conclusions. Although there was a mean increase in participation >= 1 year following TKR, participation restriction was common. The likelihood of low participation was increased among women, non-whites, and those with depressive symptoms, severe pain in either knee, or worse pre-TKR function. C1 [Maxwell, Jessica L.] Boston Univ, Dept Phys Therapy & Athlet Training, Coll Hlth & Rehabil Sci, Sargent Coll, Boston, MA 02215 USA. [Keysor, Julie J.] Boston Univ, Sch Med, Coll Hlth & Rehabil Sci, Clin Epidemiol Res & Training Unit, Boston, MA 02215 USA. [Niu, Jingbo; Felson, David T.] Boston Univ, Sch Med, Clin Epidemiol Res & Training Unit, Boston, MA 02215 USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Dept Med, Div Rheumatol, Birmingham, AL 35294 USA. [Wise, Barton L.] Univ Calif Davis, Dept Internal Med, Div Rheumatol Allergy & Clin Immunol, Sch Med, Davis, CA 95616 USA. [Frey-Law, Laura] Univ Iowa, Dept Phys Therapy & Rehabil Sci, Carver Coll Med, Iowa City, IA USA. [Nevitt, Michael C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Maxwell, JL (reprint author), Boston Univ, Dept Phys Therapy & Athlet Training, Coll Hlth & Rehabil Sci, Sargent Coll, 635 Commonwealth Ave,Room 623, Boston, MA 02215 USA. EM jmaxwell@bu.edu OI Wise, Barton/0000-0002-6540-6031 FU National Institute on Aging; National Institutes of Health [U01-AG18820, U01-AG19069, U01-AG18832, U01-AG18947, AR47785]; American College of Rheumatology Rheumatology Research Foundation Rheumatology Scientist Development Award; NIDRR [H133B100003-11] FX The MOST Study was supported by the National Institute on Aging and by the following National Institutes of Health grants: U01-AG18820 (Dr Felson), U01-AG19069 (Dr Nevitt), U01-AG18832, U01-AG18947, and AR47785. Funding for this project also was provided by the American College of Rheumatology Rheumatology Research Foundation Rheumatology Scientist Development Award (Dr Maxwell) and by NIDRR H133B100003-11 (Dr Maxwell). NR 28 TC 7 Z9 7 U1 0 U2 12 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 EI 1538-6724 J9 PHYS THER JI Phys. Ther. PD NOV PY 2013 VL 93 IS 11 BP 1467 EP 1474 DI 10.2522/ptj.20130109 PG 8 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 242BM UT WOS:000326212400004 PM 23813082 ER PT J AU Morgan, TA Avrin, DE Carr, CD Dreyer, KJ Flanders, AE Khorasani, R Langlotz, CP Arenson, RL AF Morgan, Tara A. Avrin, David E. Carr, Christopher D. Dreyer, Keith J. Flanders, Adam E. Khorasani, Ramin Langlotz, Curtis P. Arenson, Ronald L. TI Meaningful Use for Radiology: Current Status and Future Directions SO RADIOLOGY LA English DT Editorial Material ID HEALTH-CARE REFORM C1 [Morgan, Tara A.; Avrin, David E.; Arenson, Ronald L.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Carr, Christopher D.] Radiol Soc North Amer, Dept Informat, Oak Brook, IL USA. [Dreyer, Keith J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Flanders, Adam E.] Thomas Jefferson Univ, Dept Radiol, Philadelphia, PA 19107 USA. [Khorasani, Ramin] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Langlotz, Curtis P.] Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Morgan, TA (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, 505 Parnassus Ave, San Francisco, CA 94143 USA. EM Tara.morgan@ucsf.edu NR 14 TC 1 Z9 1 U1 0 U2 1 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 NOV PY 2013 VL 269 IS 2 BP 318 EP 321 DI 10.1148/radiol.13131034 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 240JO UT WOS:000326092100003 PM 24009350 ER PT J AU Bencardino, JT Gyftopoulos, S Palmer, WE AF Bencardino, Jenny T. Gyftopoulos, Soterios Palmer, William E. TI Imaging in Anterior Glenohumeral Instability SO RADIOLOGY LA English DT Review ID GLENOID BONE LOSS; LABRAL-LIGAMENTOUS COMPLEX; HILL-SACHS DEFECTS; SHOULDER DISLOCATION; MR ARTHROGRAPHY; EXTERNAL ROTATION; IRREDUCIBLE ANTERIOR; HUMERAL AVULSION; THROWING ATHLETE; BANKART REPAIR AB In the shoulder, the advantages of range of motion are traded for the disadvantages of vulnerability to injury and the development of instability. Glenohumeral instability encompasses a broad spectrum of clinical complaints and presentations. The diagnosis can be obvious or entirely unsuspected. Imaging findings depend on numerous factors and range from gross osseous defects to equivocal labral abnormalities and undetectable capsular lesions. This review focuses on the imaging findings in three distinct clinical scenarios: acute first-time shoulder dislocation, chronic instability with repeated dislocation, and chronic instability without repeated dislocation. The biomechanics of dislocation and the pathophysiology of labral-ligamentous injury are discussed. The authors distinguish the findings that occur in the acutely traumatized shoulder from those that typify the chronic unstable joint. The roles of different imaging modalities are also distinguished, including magnetic resonance arthrography and the value of specialized imaging positions. The goal of imaging depends on the clinical scenario. Image interpretation and reporting may need to emphasize diagnosis and the identification of lesions that are associated with instability or the characterization of lesions for treatment planning. (C) RSNA, 2013 C1 [Bencardino, Jenny T.; Gyftopoulos, Soterios] NYU, Sch Med, Ctr Musculoskeletal Care, Hosp Joint Dis,Langone Med Ctr,Dept Radiol, New York, NY 10003 USA. [Palmer, William E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. RP Bencardino, JT (reprint author), NYU, Sch Med, Ctr Musculoskeletal Care, Hosp Joint Dis,Langone Med Ctr,Dept Radiol, 301 E 17th St,6th Floor, New York, NY 10003 USA. EM Jenny.Bencardino@nyumc.org NR 114 TC 5 Z9 5 U1 0 U2 4 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 NOV PY 2013 VL 269 IS 2 BP 322 EP 336 DI 10.1148/radiol.13121926 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 240JO UT WOS:000326092100004 ER PT J AU Bredella, MA Gill, CM Gerweck, AV Landa, MG Kumar, V Daley, SM Torriani, M Miller, KK AF Bredella, Miriam A. Gill, Corey M. Gerweck, Anu V. Landa, Melissa G. Kumar, Vidhya Daley, Scott M. Torriani, Martin Miller, Karen K. TI Ectopic and Serum Lipid Levels Are Positively Associated with Bone Marrow Fat in Obesity SO RADIOLOGY LA English DT Article ID MINERAL DENSITY; BODY-COMPOSITION; RESONANCE SPECTROSCOPY; POSTMENOPAUSAL WOMEN; INSULIN-RESISTANCE; VISCERAL FAT; STEM-CELLS; FRACTURES; OSTEOPOROSIS; MECHANISMS AB Purpose: To investigate the associations between ectopic and serum lipid levels and bone marrow fat, as a marker of stem cell differentiation, in young obese men and women, with the hypothesis that ectopic and serum lipid levels would be positively associated with bone marrow fat. Materials and Methods: The study was institutional review board approved and complied with HIPAA guidelines. Written informed consent was obtained. The study group comprised 106 healthy young men and women (mean age, 33.7 years +/- 6.8 [standard deviation]; range, 19-45 years; mean body mass index (BMI), 33.1 kg/m(2) +/- 7.1; range, 18.1-48.8 kg/m(2)) who underwent hydrogen 1(1H) magnetic resonance (MR) spectroscopy by using a point-resolved spatially localized spectroscopy sequence at 3.0 T of L4 for bone marrow fat content, of soleus muscle for intramyocellular lipids (IMCL), and liver for intrahepatic lipids (IHL), serum cholesterol level, serum triglyceride level, and measures of insulin resistance (IR). Exercise status was assessed with the Paffenbarger activity questionnaire. Results: There was a positive correlation between bone marrow fat and IHL (r = 0.21, P = .048), IMCL (r = 0.27, P = .02), and serum triglyceride level (r = 0.33, P = .001), independent of BMI, age, IR, and exercise status (P < .05). High-density lipoprotein cholesterol levels were inversely associated with bone marrow fat content, independent of BMI, age, IR, and exercise status (r = -0.21, P = .019). Conclusion: Results of this study suggest that ectopic and serum lipid levels are positively associated with bone marrow fat in obese men and women. (C)RSNA, 2013 C1 [Bredella, Miriam A.; Gill, Corey M.; Kumar, Vidhya; Daley, Scott M.; Miller, Karen K.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Gerweck, Anu V.; Landa, Melissa G.; Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Bredella, MA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. EM mbredella@partners.org FU National Institutes of Health [R01 HL-077674, UL1 RR-025758, K23 RR-23090] FX This research was supported by the National Institutes of Health (grants R01 HL-077674, UL1 RR-025758, and K23 RR-23090). NR 34 TC 12 Z9 12 U1 1 U2 5 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 NOV PY 2013 VL 269 IS 2 BP 533 EP 540 DI 10.1148/radiol.13130375 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 240JO UT WOS:000326092100028 ER PT J AU Ford, JM Mathalon, DH Roach, BJ Keedy, SK Reilly, JL Gershon, ES Sweeney, JA AF Ford, Judith M. Mathalon, Daniel H. Roach, Brian J. Keedy, Sarah K. Reilly, James L. Gershon, Elliot S. Sweeney, John A. TI Neurophysiological Evidence of Corollary Discharge Function During Vocalization in Psychotic Patients and Their Nonpsychotic First-Degree Relatives SO SCHIZOPHRENIA BULLETIN LA English DT Article DE psychosis; corollary discharge; ERP; N1; first-degree relatives ID AUDITORY-CORTEX; CORTICAL RESPONSIVENESS; SPEECH PRODUCTION; SCHIZOPHRENIA; DYSFUNCTION; SYMPTOMS; SCALE; HALLUCINATIONS; DISORDERS; PROBANDS AB Predictions about sensations resulting from motor acts are instantiated through neural mechanisms such as the corollary discharge. With each action, the corollary discharge provides an unconscious comparison between predicted and actual sensations resulting from the action; closer matches result in greater suppression of sensation. This mechanism is disrupted in schizophrenia (SZ) and may contribute to, or reflect a failure to, distinguish self- from externally generated experiences, a hallmark of psychosis. We asked whether disruption is specific to SZ or is seen in other psychotic illnesses and in first-degree relatives of psychotic patients. Corollary discharge function was assessed in SZ patients (n = 30), schizoaffective (SA) patients (n = 19), bipolar patients with a history of psychosis (BPP; n = 39), nonpsychotic relatives of SZ (n = 30), SA (n = 23), and BPP (n = 50) patients, and healthy controls (n = 43). The N1 component of the event-related potential, reflecting auditory cortical responses to sounds, was elicited by speech sound onset as subjects talked and later when they listened to a recording of those sounds. N1 was suppressed during talking compared to N1 during listening, consistent with the suppressive action of the corollary discharge mechanism. Suppression was significantly reduced in SZ and BPP patients, with a similar trend in the smaller SA group. Patient groups did not differ, and unaffected relatives did not differ from controls or probands. The failure to monitor sensations resulting from self-generated actions, implicating corollary discharge dysfunction, may be a common feature across affective and nonaffective psychosis. Data from unaffected family members do not indicate that this is a marker of psychosis risk. C1 [Ford, Judith M.; Mathalon, Daniel H.; Roach, Brian J.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Ford, Judith M.; Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Keedy, Sarah K.; Gershon, Elliot S.] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Reilly, James L.] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. [Sweeney, John A.] Univ Texas, Dept Psychiat, Southwestern Dallas, TX USA. [Sweeney, John A.] Univ Texas, Dept Pediat, Southwestern Dallas, TX USA. RP Ford, JM (reprint author), San Francisco VA Med Ctr, Psychiat Serv 116D, 4150 Clement St, San Francisco, CA 94121 USA. EM Judith.ford@ucsf.edu RI Keedy, Sarah/H-6557-2014; OI Keedy, Sarah/0000-0002-2139-9271; Roach, Brian/0000-0002-3264-1465; Mathalon, Daniel/0000-0001-6090-4974 FU Veterans Administration [1l01CX000497-01]; National Institute of Mental Health [MH-58262, MH077862, MH085485] FX This work was supported by the Veterans Administration (Merit Review 1l01CX000497-01, Research Career Scientist to Dr Ford), and National Institute of Mental Health (MH-58262 to Dr Ford, Dr Roach, Dr Mathalon; MH077862 and MH085485 to Dr Sweeney, Dr Reilly, Dr Keedy, Dr Gershon). NR 45 TC 11 Z9 11 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD NOV PY 2013 VL 39 IS 6 BP 1272 EP 1280 DI 10.1093/schbul/sbs129 PG 9 WC Psychiatry SC Psychiatry GA 241TC UT WOS:000326189700014 PM 23155183 ER PT J AU San-Juan, D Mayorga, APM Calcaneo, JDD Gonzalez-Aragon, MF Alonso-Vanegas, M Rico, CD Staba, RJ Anschel, DJ Cole, AJ AF San-Juan, Daniel Mayorga, Adriana Patricia M. Del Castillo Calcaneo, Juan de Dios Fernandez Gonzalez-Aragon, Maricarmen Alonso-Vanegas, Mario Dominguez Rico, Carolina Staba, Richard J. Anschel, David J. Cole, Andrew J. TI Periodic epileptiform discharges in mesial temporal lobe epilepsy with hippocampal sclerosis SO SEIZURE-EUROPEAN JOURNAL OF EPILEPSY LA English DT Article DE PLEDs; Periodic epileptiform discharges; Outcome; Seizures; Mesial temporal lobe epilepsy; Hippocampal sclerosis ID CLINICAL-SIGNIFICANCE; EEG PATTERNS; PLEDS; SEIZURES; CLASSIFICATION; PSYCHOSIS; ETIOLOGY AB Purpose: Periodic epileptiform discharges (PEDs) are an uncommon, abnormal EEG pattern seen usually in patients with acute diseases and less frequently in chronic conditions, such as mesial temporal lobe epilepsy (mTLE). Evaluate the clinical histories, neuroimaging findings, and serial electrophysiological studies prior to the appearance of PEDs in patients with mTLE secondary to hippocampal sclerosis (HS). Methods: We searched 19,375 EEGs (2006-2012) for the presence of PEDs secondary to mTLE due to HS. Results: 12 patients were included. The patients with PEDs had a high prevalence of psychiatric comorbilities, including major depression (50%), interictal psychosis (16%) and dementia (8%). All of the patients had intractable epilepsy with similar clinical findings. We observed a sequential neurophysiological worsening of the EEG patterns prior to the appearance of PEDs. Five patients with PEDs underwent epilepsy surgery and four were seizure free at follow-up 15 (+/- 9) months. Conclusions: PEDs are rare in patients with mTLE and HS and their presence in these cases could reflect clinical severity and neurophysiologic worsening, clinically manifested by intractable epilepsy and severe psychiatric comorbidities. The presence of PEDs in EEGs of patients with mTLE, however, was not associated with poor postsurgical seizure-freedom. (C) 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. C1 [San-Juan, Daniel; Mayorga, Adriana Patricia M.; Del Castillo Calcaneo, Juan de Dios; Fernandez Gonzalez-Aragon, Maricarmen] Natl Inst Neurol, Neurophysiol Serv, Mexico City, DF, Mexico. [Alonso-Vanegas, Mario] Natl Inst Neurol, Neurosurg Dept, Mexico City, DF, Mexico. [Dominguez Rico, Carolina] Univ Nacl Autonoma Mexico, Fac Med, Mexico City 04510, DF, Mexico. [Staba, Richard J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Anschel, David J.] St Charles Hosp, Comprehens Epilepsy Ctr Long Isl, Port Jefferson, NY USA. [Cole, Andrew J.] Massachusetts Gen Hosp, Epilepsy Serv, Boston, MA 02114 USA. [Alonso-Vanegas, Mario] Ctr Med ABC, Ctr Neurol, Santa Fe, Mexico. RP San-Juan, D (reprint author), Av Insurgentes Sur 3877, Mexico City 14269, DF, Mexico. EM pegaso31@yahoo.com NR 41 TC 0 Z9 0 U1 0 U2 3 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1059-1311 EI 1532-2688 J9 SEIZURE-EUR J EPILEP JI Seizure PD NOV PY 2013 VL 22 IS 9 BP 735 EP 742 DI 10.1016/j.seizure.2013.05.013 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 241DF UT WOS:000326145900011 PM 23787169 ER PT J AU McFarland, LV Raugi, GJ Reiber, GE AF McFarland, Lynne V. Raugi, Gregory J. Reiber, Gayle E. TI Primary Care Provider and Imaging Technician Satisfaction with a Teledermatology Project in Rural Veterans Health Administration Clinics SO TELEMEDICINE AND E-HEALTH LA English DT Article DE teledermatology; quality improvement; satisfaction; Veterans Affairs ID RANDOMIZED-CONTROLLED-TRIAL; TECHNOLOGY ACCEPTANCE MODEL; PATIENT SATISFACTION; TELEMEDICINE; TELEHEALTH; DERMATOLOGY; ADOPTION; QUESTIONNAIRE; MANAGEMENT; DIFFUSION AB Objective:Assessment of a multisite rural teledermatology project between 2009 and 2012 in four Pacific Northwest states that trained primary care providers and imaging technicians in state-of-the-art techniques of telemedicine.Materials and Methods:In 2012, we assessed provider and imaging technician acceptability and satisfaction with a 32-item survey instrument based on the Patient Satisfaction Questionnaire developed by Ware et al. (Eval Program Plann 1983;6:247-63) and modified for telemedicine by Kraai et al. (J Card Fail 2011;17:684-690). Survey questions covered eight satisfaction domains: interpersonal manner, technical quality, accessibility, finances, efficacy, continuity, physical environment, and availability.Results:Overall, 71% of the primary care providers and 94% of the imaging technicians reported being satisfied or extremely satisfied with the teledermatology project. Most (95%) providers found the continuing education classes on dermatology diagnosis and treatment topics useful, and 86% reported teledermatology was a good addition to regular patient services. Most (97%) of the imaging technicians were satisfied with the ability of teledermatology to improve the description of dermatology conditions using images of the lesions or rashes, and 91% were satisfied with the convenience of teledermatology. Challenges reported by both providers and imaging technicians include an increase in workload due to more patient visits related to dermatology care and limited information technology support.Conclusions:Given the Veterans Health Administration's initiatives to promote accessible health care to underserved Veterans using telehealth, these findings can inform future program designs for teledermatology. C1 [McFarland, Lynne V.; Raugi, Gregory J.; Reiber, Gayle E.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Dept Vet Affairs, Seattle, WA 98101 USA. [McFarland, Lynne V.] Univ Washington, Dept Med Chem, Sch Publ Hlth, Seattle, WA 98195 USA. [Reiber, Gayle E.] Univ Washington, Dept Hlth Serv, Sch Publ Hlth, Seattle, WA 98195 USA. [Reiber, Gayle E.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Raugi, Gregory J.] VA Puget Sound Hlth Care Syst, Hosp & Specialty Med Serv, Teledermatol Sect, Dept Vet Affairs, Seattle, WA 98101 USA. RP McFarland, LV (reprint author), VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Dept Vet Affairs, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM Lynne.McFarland@va.gov FU Office of Rural Health, Veterans Health Administration, U.S. Department of Veterans Affairs; VA Health Services Research and Development for the Senior Career Scientist Award [RCS 98-353] FX The authors acknowledge the rural primary care providers and imaging technicians in VISN 20 who dedicated their time and energy to this project in this project. This material is based on work supported by the Office of Rural Health, Veterans Health Administration, U.S. Department of Veterans Affairs, and support from VA Health Services Research and Development for the Senior Career Scientist Award RCS 98-353 to G.E.R. NR 39 TC 12 Z9 12 U1 1 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 EI 1556-3669 J9 TELEMED E-HEALTH JI Telemed. e-Health PD NOV 1 PY 2013 VL 19 IS 11 BP 815 EP 825 DI 10.1089/tmj.2012.0327 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 241QU UT WOS:000326183100003 PM 24053115 ER PT J AU Moss, AC Brinks, V Carpenter, JF AF Moss, A. C. Brinks, V. Carpenter, J. F. TI Review article: immunogenicity of anti-TNF biologics in IBD - the role of patient, product and prescriber factors SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Review ID INFLAMMATORY-BOWEL-DISEASE; MULTIPLE-SCLEROSIS PATIENTS; INFLIXIMAB DOSE INTENSIFICATION; ANTIBODIES-TO-INFLIXIMAB; HUMAN INTERFERON-BETA; CROHNS-DISEASE; RHEUMATOID-ARTHRITIS; ULCERATIVE-COLITIS; CLINICAL-RESPONSE; SERUM INFLIXIMAB AB BackgroundAnti-drug antibodies (ADAs) to biologic therapies contribute to the loss of response and infusion reactions to anti-TNF drugs in patients with inflammatory bowel disease (IBD). The reasons behind this immunogenicity are complex, and have not been the focus of a dedicated review for prescribers. AimTo provide an overview of the patient, product and prescriber factors, which have been associated with the immunogenicity of anti-TNF therapy, and draw conclusions for clinical practice. MethodsReview of representative observational studies and clinical trials from the IBD and other literature, which report associations with ADA development, with a focus on infliximab and adalimumab. ResultsADAs develop in 10-20% of patients receiving anti-TNF maintenance therapy, and these patients are three times more likely to lose response as ADA-negative patients. Patient genotype plays a role in ADA risk in a minority of patients, but age or disease type is not a major factor. Drug mishandling, such as agitation or freeze-thaw cycles, can induce protein aggregates, which are known to be immunogenic. Prescription of maintenance therapy with concomitant immunomodulators, and achieving suitable trough drug levels, reduces the risk of ADAs in patients with IBD. ConclusionsPatients and prescribers can take several steps to reduce the risk of development of anti-drug antibodies to anti-TNF antibodies. Further research is required to determine if immunogenic factors identified in other situations apply to use of anti-TNFs in IBD. C1 [Moss, A. C.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Brinks, V.] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Pharmaceut, Utrecht, Netherlands. [Carpenter, J. F.] Univ Colorado, Dept Pharmaceut Sci, Aurora, CO USA. RP Moss, AC (reprint author), BIDMC, Ctr Inflammatory Bowel Dis, 330 Brookline Ave, Boston, MA 02215 USA. EM amoss@bidmc.harvard.edu FU NIH [K23DK084338] FX ACM is supported by NIH grant K23DK084338. NR 82 TC 23 Z9 23 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD NOV PY 2013 VL 38 IS 10 BP 1188 EP 1197 DI 10.1111/apt.12507 PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 238UW UT WOS:000325977700004 PM 24118102 ER PT J AU Sankaran, VG Agrawal, PB AF Sankaran, Vijay G. Agrawal, Pankaj B. TI Stimulating erythropoiesis in neonates SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Editorial Material ID BLOOD-CELL TRANSFUSION; BIRTH-WEIGHT INFANTS; NECROTIZING ENTEROCOLITIS; PRETERM INFANTS; INTENSIVE-CARE C1 [Sankaran, Vijay G.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Sankaran, Vijay G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Sankaran, Vijay G.] Broad Inst, Cambridge, MA USA. [Agrawal, Pankaj B.] Harvard Univ, Sch Med, Boston Childrens Hosp, Manton Ctr Orphan Dis Res,Genom Program, Boston, MA USA. [Agrawal, Pankaj B.] Harvard Univ, Sch Med, Boston Childrens Hosp, Manton Ctr Orphan Dis Res,Div Genet, Boston, MA USA. [Agrawal, Pankaj B.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Newborn Med, Boston, MA USA. RP Sankaran, VG (reprint author), Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. EM san-karan@broadinstitute.org; pagrawal@enders.tch.harvard.edu NR 13 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD NOV PY 2013 VL 88 IS 11 BP 930 EP 931 DI 10.1002/ajh.23573 PG 2 WC Hematology SC Hematology GA 239NX UT WOS:000326033600010 PM 23963872 ER PT J AU Jenkins, RW Clarke, CJ Lucas, JT Shabbir, M Wu, BX Simbari, F Mueller, J Hannun, YA Lazarchick, J Shirai, K AF Jenkins, Russell W. Clarke, Christopher J. Lucas, John Thomas, Jr. Shabbir, Munira Wu, Bill X. Simbari, Fabio Mueller, Joan Hannun, Yusuf A. Lazarchick, John Shirai, Keisuke TI Evaluation of the role of secretory sphingomyelinase and bioactive sphingolipids as biomarkers in hemophagocytic lymphohistiocytosis SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID ACID SPHINGOMYELINASE; CLINICAL-FEATURES; MASS-SPECTROMETRY; SEVERE SEPSIS; ADULT-ONSET; METABOLISM; PLASMA; CERAMIDE; CELLS; MICE AB Hemophagocytic lymphohistiocytosis (HLH) is a rare systemic inflammatory syndrome that results from unrestrained immune cell activation. Despite significant advances in the understanding of the pathophysiology of HLH, interventions remain limited for this often-fatal condition. Secretory sphingomyelinase (S-SMase) is a pro-inflammatory lipid hydrolase that is upregulated in several inflammatory conditions, including HLH. S-SMase promotes the formation of ceramide, a bioactive lipid implicated in several human disease states. However, the role of the S-SMase/ceramide pathway in HLH remains unexplored. To further evaluate the role of S-SMase upregulation in HLH, we tested the serum of patients with HLH (n=16; primary=3, secondary=13) and healthy control patients (n=25) for serum S-SMase activity with tandem sphingolipid metabolomic profiling. Patients with HLH exhibited elevated levels of serum S-SMase activity, with concomitant elevations in several ceramide species and sphingosine, while levels of sphingosine-1-phosphate were significantly decreased. Importantly, the ratio of C-16-ceramide:sphingosine was uniquely elevated in HLH patients that died despite appropriate treatment, but remained low in HLH patients that survived, suggesting that this ratio may be of prognostic significance. Together, these results demonstrate upregulation of the S-SMase/ceramide pathway in HLH, and suggest that the balance of ceramide and sphingosine determine clinical outcomes in HLH. Am. J. Heamtol. 88:E265-E272, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Jenkins, Russell W.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Clarke, Christopher J.; Hannun, Yusuf A.] SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA. [Lucas, John Thomas, Jr.] Wake Forest Univ, Dept Radiat Oncol, Winston Salem, NC 27109 USA. [Shabbir, Munira; Shirai, Keisuke] Med Univ S Carolina, Dept Med, Div Hematol & Oncol, Charleston, SC 29425 USA. [Shabbir, Munira] Aga Khan Univ Hosp, Karachi, Pakistan. [Wu, Bill X.] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Simbari, Fabio] CSIC, Inst Adv Chem Catalonia, Dept Biomed Chem, Barcelona, Spain. [Mueller, Joan; Lazarchick, John] Med Univ S Carolina, Dept Pathol, Charleston, SC 29425 USA. RP Shirai, K (reprint author), 96 Jonathan Lucas St,CSB 903, Charleston, SC 29403 USA. EM shirai@musc.edu RI Lucas Jr., John/K-5243-2013 OI Lucas Jr., John/0000-0002-4139-4160 FU NIH/NCI [P01 CA097132]; American Heart Association [AHA 081509E]; NIH MSTP Training Grant [GM08716]; MUSC Hollings Cancer Center Abney Foundation Scholarship; Ministerio de Educacion y Ciencia (Spain) Predoctoral Fellowship [AP2006-02190] FX Contract grant sponsor: NIH/NCI; Contract grant number: P01 CA097132 (to Y.A.H.); Contract grant sponsor: American Heart Association PreDoctoral Fellowship; Contract grant number: AHA 081509E (to R.W.J.); Contract grant sponsor: NIH MSTP Training Grant; Contract grant number: GM08716 (to R.W.J.); Contract grant sponsors: MUSC Hollings Cancer Center Abney Foundation Scholarship (to R.W.J.), SCE&G Scholarship (to R.W.J.); Contract grant sponsor: Ministerio de Educacion y Ciencia (Spain) Predoctoral Fellowship; Contract grant number: AP2006-02190 (to F.S.). NR 47 TC 7 Z9 7 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD NOV PY 2013 VL 88 IS 11 BP E265 EP E272 DI 10.1002/ajh.23535 PG 8 WC Hematology SC Hematology GA 239NX UT WOS:000326033600005 PM 23828274 ER PT J AU Kliger, AS Foley, RN Goldfarb, DS Goldstein, SL Johansen, K Singh, A Szczech, L AF Kliger, Alan S. Foley, Robert N. Goldfarb, David S. Goldstein, Stuart L. Johansen, Kirsten Singh, Ajay Szczech, Lynda TI KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID CHRONIC KIDNEY-DISEASE; LOW TRANSFERRIN SATURATION; INTRAVENOUS IRON TREATMENT; HEMODIALYSIS-PATIENTS; FERRIC GLUCONATE; NANDROLONE DECANOATE; CHILDREN; THERAPY; TRIAL; ERYTHROPOIETIN AB The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for Anemia in Chronic Kidney Disease provides clinicians with comprehensive evidence-based recommendations to improve patient care. In this commentary, we review these recommendations and the underlying evidence. Most recommendations are well reasoned. For some, the evidence is unclear and recommendations require some qualification. While the KDIGO guideline stresses the potential risks of intravenous iron therapy, withholding iron might have its own risks. The recommendation to avoid hemoglobin levels falling below 9 g/dL sets a lower bound of "acceptability" that may increase blood transfusion. Given the lack of research supporting the optimal transfusion strategy for end-stage renal disease patients, it is difficult to weigh the risks and benefits of red blood cell transfusion. We find a paucity of evidence that hemoglobin concentration targeted between 11 and 11.5 g/dL is associated with a safety risk. Although the evidence that erythropoiesis-stimulating agent use improves patient quality of life is poor, it is possible that the instruments used to measure quality of life may not be well attuned to the needs of chronic kidney disease or dialysis patients. Our last section focuses specifically on the recommendations to treat anemia in children. (C) 2013 by the National Kidney Foundation, Inc. C1 [Kliger, Alan S.] Yale Univ, Sch Med, New Haven, CT USA. [Kliger, Alan S.] Yale New Haven Med Ctr, New Haven, CT 06504 USA. [Foley, Robert N.] Minneapolis Med Res Fdn Inc, Minneapolis, MN USA. [Goldfarb, David S.] US Dept Vet Affairs, New York, NY USA. [Goldstein, Stuart L.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Goldstein, Stuart L.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Johansen, Kirsten] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Singh, Ajay] Brigham & Womens Hosp, Boston, MA 02115 USA. [Szczech, Lynda] Durham Nephrol Associates, Durham, NC USA. RP Kliger, AS (reprint author), Yale New Haven Hlth Syst, 300 George St,Rm 487, New Haven, CT 06510 USA. EM alan.kliger@ynhh.org OI Goldfarb, David/0000-0002-9215-1273 NR 33 TC 35 Z9 37 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD NOV PY 2013 VL 62 IS 5 BP 849 EP 859 DI 10.1053/j.ajkd.2013.06.008 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 238XP UT WOS:000325985600003 PM 23891356 ER PT J AU Ingelfinger, JR AF Ingelfinger, Julie R. TI Past Mortality Risk and Survival: Living Well and Growing Up SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID STAGE RENAL-DISEASE; KIDNEY-DISEASE; YOUNG-ADULTS; CHILDREN; DIALYSIS; TRANSPLANTATION; FAILURE; TRENDS C1 [Ingelfinger, Julie R.] Harvard Univ, Massachusetts Gen Hosp, MassGen Hosp Children, Boston, MA 02115 USA. RP Ingelfinger, JR (reprint author), Massachusetts Gen Hosp, MassGen Hosp Children, Yawkey 6C,55 Fruit St, Boston, MA 02114 USA. EM jingelfinger@partners.org NR 12 TC 0 Z9 0 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD NOV PY 2013 VL 62 IS 5 BP 880 EP 882 DI 10.1053/j.ajkd.2013.09.001 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 238XP UT WOS:000325985600007 PM 24157272 ER PT J AU Dubeau, L Drapkin, R AF Dubeau, L. Drapkin, R. TI Coming into focus: the nonovarian origins of ovarian cancer SO ANNALS OF ONCOLOGY LA English DT Article DE coelomic epithelium; extrauterine Mullerian epithelium; fallopian tube fimbriae; ovarian carcinoma; primary peritoneal carcinoma ID GRADE SEROUS CARCINOMA; TUBE EPITHELIAL-CELLS; PROPHYLACTIC OOPHORECTOMY SPECIMENS; BRCA MUTATION CARRIERS; DISTAL FALLOPIAN-TUBE; SURFACE EPITHELIUM; MOUSE MODEL; INTRAEPITHELIAL CARCINOMA; BORDERLINE TUMORS; GRANULOSA-CELLS AB The traditional view of epithelial ovarian cancer asserts that all tumor subtypes share a common origin in the ovarian surface epithelium (OSE) A literature review was carried out to summarize the emerging understanding of extraovarian sources of epithelial ovarian carcinomas. Historically, there were no diagnostic criteria for documenting the origin of ovarian epithelial carcinomas. Moreover, there are no normal epithelial tissues in the ovary with morphologic similarities to these tumors. In fact, no precursor lesions have ever been reproducibly identified in the ovary. However, there is a strong correlation between extrauterine Mullerian tissue and the development of ovarian carcinomas, tumors of low malignant potential, and cystadenomas. The most recent support for this hypothesis comes from the careful analysis of risk-reducing bilateral salpingo-oopherectomy specimens from BRCA1 or BRCA2 mutation carriers. These studies showed that a significant majority of high-grade serous ovarian carcinomas, the most common subtype, arise from the fallopian tube fimbriae rather than the OSE. Mounting evidence indicates that the vast majority of epithelial ovarian carcinomas are not ovarian in origin. Extrauterine Mullerian epithelium from various sites in the reproductive tract likely accounts for the diverse morphology and behavior of these tumors. C1 [Dubeau, L.] Univ So Calif, USC Norris Comprehens Canc Ctr & Hosp, Dept Pathol, Los Angeles, CA 90098 USA. [Drapkin, R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Drapkin, R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Dubeau, L (reprint author), Univ So Calif, Keck Sch Med, USC Norris Comprehens Canc Ctr, Ezralow Tower 6338,1441 Eastlake Ave, Los Angeles, CA 90098 USA. EM ldubeau@usc.edu; ronny_drapkin@dfci.harvard.edu RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 FU National Institutes of Health [R01 CA133117, R01 CA119078, U01 CA152990, P50 CA105009, R21 CA156021]; Ovarian Cancer Research Fund; Adelson Medical Research Foundation; Mary Kay Foundation; Robert and Debra First Fund; Gamel Ovarian Cancer Research Fund; Honorable Tina Brozman Foundation FX This work was supported by grants from the National Institutes of Health (R01 CA133117 and R01 CA119078 to LD, and U01 CA152990, P50 CA105009, and R21 CA156021 to RD); the Ovarian Cancer Research Fund (RD); the Adelson Medical Research Foundation (RD); the Mary Kay Foundation (RD); The Robert and Debra First Fund (RD); the Gamel Ovarian Cancer Research Fund (RD); the Honorable Tina Brozman Foundation (RD), and a gift from the Ovarian Cancer Coalition of Greater California (LD). NR 73 TC 30 Z9 31 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD NOV PY 2013 VL 24 SU 8 BP 28 EP 35 DI 10.1093/annonc/mdt308 PG 8 WC Oncology SC Oncology GA 239AX UT WOS:000325994900006 ER PT J AU Tanabe, KK Hoshida, Y AF Tanabe, Kenneth K. Hoshida, Yujin TI Prognostic Gene Signatures for Hepatocellular Carcinoma: What Are We Measuring? SO ANNALS OF SURGICAL ONCOLOGY LA English DT Editorial Material ID EXPRESSION C1 [Tanabe, Kenneth K.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [Hoshida, Yujin] Mt Sinai, Liver Canc Program, Tisch Canc Inst, Div Liver Dis,Dept Med,Icahn Sch Med, New York, NY USA. RP Tanabe, KK (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. EM ktanabe@partners.org; yujin.hoshida@mssm.edu FU NIDDK NIH HHS [R01 DK099558] NR 11 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2013 VL 20 IS 12 BP 3707 EP 3708 DI 10.1245/s10434-013-3071-x PG 2 WC Oncology; Surgery SC Oncology; Surgery GA 236CF UT WOS:000325770600002 PM 23797752 ER PT J AU Conrad, C Vauthey, JN AF Conrad, Claudius Vauthey, Jean-Nicolas TI When Does Invasion Mean the War is Lost? SO ANNALS OF SURGICAL ONCOLOGY LA English DT Editorial Material ID HEPATOCELLULAR-CARCINOMA; TRANSARTERIAL CHEMOEMBOLIZATION; HEPATECTOMY; VALIDATION; CRITERIA C1 [Conrad, Claudius] Harvard Univ, Sch Med, Dept Surg, Div Surg Oncol,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Vauthey, Jean-Nicolas] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Div Surg, Houston, TX 77030 USA. RP Conrad, C (reprint author), Harvard Univ, Sch Med, Dept Surg, Div Surg Oncol,Massachusetts Gen Hosp, Boston, MA 02115 USA. EM jvauthey@mdanderson.org NR 15 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2013 VL 20 IS 12 BP 3709 EP 3711 DI 10.1245/s10434-013-3078-3 PG 3 WC Oncology; Surgery SC Oncology; Surgery GA 236CF UT WOS:000325770600003 PM 23838907 ER PT J AU Hyder, O Marsh, JW Salem, R Petre, EN Kalva, S Liapi, E Cosgrove, D Neal, D Kamel, I Zhu, AX Sofocleous, CT Geschwind, JFH Pawlik, TM AF Hyder, Omar Marsh, J. Wallis Salem, Riad Petre, Elena N. Kalva, Sanjeeva Liapi, Eleni Cosgrove, David Neal, Donielle Kamel, Ihab Zhu, Andrew X. Sofocleous, Constantinos T. Geschwind, Jean-Francois H. Pawlik, Timothy M. TI Intra-arterial Therapy for Advanced Intrahepatic Cholangiocarcinoma: A Multi-institutional Analysis SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID UNRESECTABLE HEPATOCELLULAR-CARCINOMA; TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION; RANDOMIZED CONTROLLED TRIAL; DRUG-ELUTING BEADS; TRANSARTERIAL CHEMOEMBOLIZATION; TUMOR RESPONSE; SINGLE-INSTITUTION; PROGNOSTIC-FACTORS; SOLID TUMORS; PHASE-II AB Many patients with intrahepatic cholangiocarcinoma (ICC) present with advanced and inoperable disease. Data on the safety and efficacy of intra-arterial therapy (IAT) for ICC are limited. Between 1992 and 2012, a total of 198 patients with advanced ICC treated with IAT were retrospectively identified from the databases of five major hepatobiliary institutions. Data on clinicopathological factors, morbidity, response rates, and overall survival were collected and analyzed. Median patient age was 61 years. Median tumor size was 8.1 cm, and 47.5 % patients had a solitary lesion. IAT consisted of conventional transarterial chemoembolization (cTACE) (64.7 %), drug-eluting beads (DEB) (5.6 %), bland embolization (TAE) (6.6 %), or yttrium-90 radioembolization (23.2 %). Median number of IAT sessions was 2 (range 1-8). The median time between IAT sessions was 48 days. The periprocedural morbidity was 29.8 %; most complications were minor (n = 43); however, 16 patients had a grade 3-4 complication. Assessment of tumor response revealed complete or partial response in 25.5 % patients, while 61.5 % had stable disease; 13.0 % had progressive disease. Median overall survival was 13.2 months and did not differ on the basis of the type of IAT (cTACE, 13.4 months vs. DEB 10.5 months vs. TAE, 14.3 months vs. yttrium-90, 11.3 months; P = 0.46). IAT response on modified response evaluation criteria in solid tumors (mRECIST; hazard ratio for complete-partial response 0.49, 95 % confidence interval 0.30-0.81; P < 0.001) was independently associated with better survival. IAT for ICC was safe and led to stable disease or partial to complete response in up to three-quarters of patients. Among patients with an IAT response, overall survival was prolonged. The role of IAT therapy for ICC warrants further prospective evaluation in clinical trials. C1 [Hyder, Omar; Liapi, Eleni; Cosgrove, David; Kamel, Ihab; Geschwind, Jean-Francois H.; Pawlik, Timothy M.] Johns Hopkins Sch Med, Div Surg Oncol, Dept Surg, Baltimore, MD 21218 USA. [Hyder, Omar; Liapi, Eleni; Cosgrove, David; Kamel, Ihab; Geschwind, Jean-Francois H.; Pawlik, Timothy M.] Johns Hopkins Sch Med, Div Surg Oncol, Dept Intervent Radiol, Baltimore, MD USA. [Hyder, Omar; Liapi, Eleni; Cosgrove, David; Kamel, Ihab; Geschwind, Jean-Francois H.; Pawlik, Timothy M.] Johns Hopkins Sch Med, Div Surg Oncol, Dept Radiol, Baltimore, MD USA. [Marsh, J. Wallis; Neal, Donielle] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Salem, Riad] Northwestern Univ, Chicago, IL 60611 USA. [Petre, Elena N.; Sofocleous, Constantinos T.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kalva, Sanjeeva; Zhu, Andrew X.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hyder, O (reprint author), Johns Hopkins Sch Med, Div Surg Oncol, Dept Surg, Baltimore, MD 21218 USA. EM tpawlik1@jhmi.edu RI Hyder, Omar/D-1441-2013; Liapi, Eleni/B-5195-2013 OI Hyder, Omar/0000-0002-0965-5543; Liapi, Eleni/0000-0001-5864-4448 NR 42 TC 27 Z9 28 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2013 VL 20 IS 12 BP 3779 EP 3786 DI 10.1245/s10434-013-3127-y PG 8 WC Oncology; Surgery SC Oncology; Surgery GA 236CF UT WOS:000325770600013 PM 23846786 ER PT J AU Balch, CM Soong, SJ Gershenwald, JE Thompson, JF Coit, DG Atkins, MB Ding, SL Cochran, AJ Eggermont, AMM Flaherty, KT Gimotty, PA Johnson, TM Kirkwood, JM Leong, SP McMasters, KM Mihm, MC Morton, DL Ross, MI Sondak, VK AF Balch, Charles M. Soong, Seng-Jaw Gershenwald, Jeffrey E. Thompson, John F. Coit, Daniel G. Atkins, Michael B. Ding, Shouluan Cochran, Alistair J. Eggermont, Alexander M. M. Flaherty, Keith T. Gimotty, Phyllis A. Johnson, Timothy M. Kirkwood, John M. Leong, Stanley P. McMasters, Kelly M. Mihm, Martin C., Jr. Morton, Donald L. Ross, Merrick I. Sondak, Vernon K. TI Age as a Prognostic Factor in Patients with Localized Melanoma and Regional Metastases SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID LYMPH-NODE BIOPSY; PRIMARY CUTANEOUS MELANOMA; AMERICAN JOINT COMMITTEE; MULTIFACTORIAL ANALYSIS; PEDIATRIC MELANOMA; UNITED-STATES; MELANOCYTIC TUMORS; ADULT MELANOMA; SINGLE-CENTER; SURVIVAL AB We postulated that the worse prognosis of melanoma with advancing age reflected more aggressive tumor biology and that in younger patients the prognosis would be more favorable. The expanded AJCC melanoma staging database contained 11,088 patients with complete data for analysis, including mitotic rate. With increasing age by decade, primary melanomas were thicker, exhibited higher mitotic rates, and were more likely to be ulcerated. In a multivariate analysis of patients with localized melanoma, thickness and ulceration were highly significant predictors of outcome at all decades of life (except for patients younger than 20 years). Mitotic rate was significantly predictive in all age groups except patients < 20 and > 80 years. For patients with stage III melanoma, there were four independent variables associated with patient survival: number of nodal metastases, patient age, ulceration, and mitotic rate. Patients younger than 20 years of age had primary tumors with slightly more aggressive features, a higher incidence of sentinel lymph node metastasis, but, paradoxically, more favorable survival than all other age groups. In contrast, patients > 70 years old had primary melanomas with the most aggressive prognostic features, were more likely to be head and neck primaries, and were associated with a higher mortality rate than the other age groups. Surprisingly, however, these patients had a lower rate of sentinel lymph node metastasis per T stage. Among patients between the two age extremes, clinicopathologic features and survival tended to be more homogeneous. Melanomas in patients at the extremes of age have a distinct natural history. C1 [Balch, Charles M.] Univ Texas SW Med Ctr Dallas, Dept Surg, Div Surg Oncol, Dallas, TX 75390 USA. [Soong, Seng-Jaw] Univ Alabama Birmingham, Birmingham, AL USA. [Gershenwald, Jeffrey E.; Ross, Merrick I.] UTMD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX USA. [Thompson, John F.] Melanoma Inst Australia, Sydney, NSW, Australia. [Coit, Daniel G.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Atkins, Michael B.] MedStar Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Ding, Shouluan] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Cochran, Alistair J.] Univ Calif Los Angeles, Sch Med, Dept Pathol, Los Angeles, CA 90024 USA. [Cochran, Alistair J.] Univ Calif Los Angeles, Sch Med, Dept Lab Med, Los Angeles, CA USA. [Eggermont, Alexander M. M.] Canc Inst Gustave Roussy, Villejuif, France. [Flaherty, Keith T.] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. [Gimotty, Phyllis A.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Johnson, Timothy M.] Univ Michigan, Dept Dermatol, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Kirkwood, John M.] Univ Pittsburgh, Sch Med, Dept Med, Div Oncol, Pittsburgh, PA 15213 USA. [Leong, Stanley P.] Calif Pacific Med Ctr & Res Inst, Dept Surg, San Francisco, CA USA. [McMasters, Kelly M.] Univ Louisville, Dept Surg, Louisville, KY 40292 USA. [Mihm, Martin C., Jr.] Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. [Morton, Donald L.] John Wayne Canc Inst, Santa Monica, CA USA. [Sondak, Vernon K.] Univ S Florida, H Lee Moffitt Canc Ctr, Div Cutaneous Oncol, Tampa, FL 33682 USA. RP Balch, CM (reprint author), Univ Texas SW Med Ctr Dallas, Dept Surg, Div Surg Oncol, Dallas, TX 75390 USA. EM charles.balch@utsouthwestern.edu FU American Joint Committee on Cancer; National Cancer Institute [P30 CA13148, P50 CA93459]; Schering-Plough (Kenilworth, NJ) FX The study of the AJCC/UICC Melanoma Staging Committee was supported by a grant from the American Joint Committee on Cancer and by grants from the National Cancer Institute (P30 CA13148 at the University of Alabama at Birmingham and P50 CA93459 SPORE grant in melanoma at The University of Texas M. D. Anderson Cancer Center in Houston, TX). Three meetings held by the Committee were partially supported by an unrestricted educational grant from Schering-Plough (Kenilworth, NJ). The authors thank Ms. Gwen Berry at the John Wayne Cancer Institute for her editorial assistance. NR 41 TC 26 Z9 26 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2013 VL 20 IS 12 BP 3961 EP 3968 DI 10.1245/s10434-013-3100-9 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA 236CF UT WOS:000325770600038 PM 23838920 ER PT J AU Wilkins, AD Venner, E Marciano, DC Erdin, S Atri, B Lua, RC Lichtarge, O AF Wilkins, Angela D. Venner, Eric Marciano, David C. Erdin, Serkan Atri, Benu Lua, Rhonald C. Lichtarge, Olivier TI Accounting for epistatic interactions improves the functional analysis of protein structures SO BIOINFORMATICS LA English DT Article ID EVOLUTIONARY TRACE; BINDING-ENERGY; 3D STRUCTURES; RESIDUES; SITES; PREDICTION; CONSERVATION; SPECIFICITY; SEQUENCE; SELECTION AB Motivation: The constraints under which sequence, structure and function coevolve are not fully understood. Bringing this mutual relationship to light can reveal the molecular basis of binding, catalysis and allostery, thereby identifying function and rationally guiding protein redesign. Underlying these relationships are the epistatic interactions that occur when the consequences of a mutation to a protein are determined by the genetic background in which it occurs. Based on prior data, we hypothesize that epistatic forces operate most strongly between residues nearby in the structure, resulting in smooth evolutionary importance across the structure. Methods and Results: We find that when residue scores of evolutionary importance are distributed smoothly between nearby residues, functional site prediction accuracy improves. Accordingly, we designed a novel measure of evolutionary importance that focuses on the interaction between pairs of structurally neighboring residues. This measure that we term pair-interaction Evolutionary Trace yields greater functional site overlap and better structure-based proteomewide functional predictions. Conclusions: Our data show that the structural smoothness of evolutionary importance is a fundamental feature of the coevolution of sequence, structure and function. Mutations operate on individual residues, but selective pressure depends in part on the extent to which a mutation perturbs interactions with neighboring residues. In practice, this principle led us to redefine the importance of a residue in terms of the importance of its epistatic interactions with neighbors, yielding better annotation of functional residues, motivating experimental validation of a novel functional site in LexA and refining protein function prediction. C1 [Wilkins, Angela D.; Marciano, David C.; Lua, Rhonald C.; Lichtarge, Olivier] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Wilkins, Angela D.; Lichtarge, Olivier] Baylor Coll Med, CIBR Ctr Computat & Integrat Biomed Res, Houston, TX 77030 USA. [Venner, Eric; Atri, Benu; Lichtarge, Olivier] Baylor Coll Med, Program Struct & Computat Biol & Mol Biophys, Houston, TX 77030 USA. [Erdin, Serkan] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Lichtarge, O (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. EM lichtarge@bcm.edu RI Erdin, Serkan/B-4988-2008 OI Erdin, Serkan/0000-0001-6587-2625 FU National Institutes of Health [NIH-GM079656, NIH-GM066099, NLM 5T15LM07093]; National Science Foundation [NSF CCF-0905536, NSF DBI-1062455] FX National Institutes of Health (NIH-GM079656, NIH-GM066099, NLM 5T15LM07093); National Science Foundation (NSF CCF-0905536, NSF DBI-1062455). NR 59 TC 10 Z9 10 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD NOV 1 PY 2013 VL 29 IS 21 BP 2714 EP 2721 DI 10.1093/bioinformatics/btt489 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 239BW UT WOS:000325997500007 PM 24021383 ER PT J AU Choueiri, TK Escudier, B Powles, T Cella, D Lee, Y Laird, DA Scheffold, C Motzer, RJ AF Choueiri, T. K. Escudier, B. Powles, T. Cella, D. Lee, Y. Laird, D. A. Scheffold, C. Motzer, R. J. TI A phase 3 randomized study of cabozantinib (XL184) vs everolimus in subjects with clear cell renal cell carcinoma (METEOR) SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 12th International Kidney Cancer Symposium CY OCT 25-26, 2013 CL Chicago, IL C1 [Choueiri, T. K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Escudier, B.] Inst Gustave Roussy, Dept Med Oncol, Villejuif, France. [Powles, T.] Queen Mary Univ, Barts Canc Inst, London, England. [Cella, D.] Northwestern Univ, Dept Med Social Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Lee, Y.; Laird, D. A.; Scheffold, C.] Exelixis Inc, San Francisco, CA USA. [Motzer, R. J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD NOV PY 2013 VL 112 SU 3 SI SI MA 7 BP 4 EP 4 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 238ZY UT WOS:000325992100008 ER PT J AU Mckay, RR Aizer, AA Urun, Y Kibel, AS Nguyen, PL Choueiri, TK AF Mckay, R. R. Aizer, A. A. Urun, Y. Kibel, A. S. Nguyen, P. L. Choueiri, T. K. TI Role of cytoreductive nephrectomy (CN) in patients with metastatic non-clear cell renal cell carcinoma (nccRCC): results from a surveillance, epidemiology, and end results (SEER) database analysis of over 4,900 patients SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 12th International Kidney Cancer Symposium CY OCT 25-26, 2013 CL Chicago, IL C1 [Mckay, R. R.; Urun, Y.; Kibel, A. S.; Nguyen, P. L.; Choueiri, T. K.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Aizer, A. A.] Harvard Radiat Oncol Program, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD NOV PY 2013 VL 112 SU 3 SI SI MA 10 BP 5 EP 6 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 238ZY UT WOS:000325992100011 ER PT J AU Feldman, AS Deshmukh, SM Dhyani, M Barrisford, G Rodriguez, D Mcgovern, FJ Mcdougal, WS Olumi, A Dahl, DM Samir, A Blute, ML AF Feldman, A. S. Deshmukh, S. M. Dhyani, M. Barrisford, G. Rodriguez, D. Mcgovern, F. J. Mcdougal, W. S. Olumi, A. Dahl, D. M. Samir, A. Blute, M. L. TI Proposal of an algorithm for utilization of percutaneous renal mass biopsy based on the results of 1000 case series SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 12th International Kidney Cancer Symposium CY OCT 25-26, 2013 CL Chicago, IL C1 [Feldman, A. S.; Deshmukh, S. M.; Barrisford, G.; Rodriguez, D.; Mcgovern, F. J.; Mcdougal, W. S.; Olumi, A.; Dahl, D. M.; Blute, M. L.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Dhyani, M.; Samir, A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD NOV PY 2013 VL 112 SU 3 SI SI MA 13 BP 8 EP 9 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 238ZY UT WOS:000325992100014 ER PT J AU Drake, CG Mcdermott, DF Sznol, M Choueiri, TK Kluger, HM Powderly, JD Smith, DC Sankar, V Gutierrez, AA Wigginton, JM Gupta, A Atkins, MB AF Drake, C. G. Mcdermott, D. F. Sznol, M. Choueiri, T. K. Kluger, H. M. Powderly, J. D. Smith, D. C. Sankar, V. Gutierrez, A. A. Wigginton, J. M. Gupta, A. Atkins, M. B. TI Safety, durable clinical benefit, and remission resulting from nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase 1 trial in patients with previously treated metastatic renal cell carcinoma (mRCC); long-term patient follow-up SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 12th International Kidney Cancer Symposium CY OCT 25-26, 2013 CL Chicago, IL C1 [Drake, C. G.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Mcdermott, D. F.; Choueiri, T. K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sznol, M.; Kluger, H. M.] Yale Canc Ctr, New Haven, CT USA. [Powderly, J. D.] Carolina BioOncol Inst, Huntersville, NC USA. [Smith, D. C.] Univ Michigan, Ann Arbor, MI 48109 USA. [Sankar, V.; Gutierrez, A. A.; Wigginton, J. M.; Gupta, A.] Bristol Myers Squibb Co, Princeton, NJ USA. [Atkins, M. B.] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD NOV PY 2013 VL 112 SU 3 SI SI MA 14 BP 9 EP 10 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 238ZY UT WOS:000325992100015 ER PT J AU Slopen, N McLaughlin, KA Dunn, EC Koenen, KC AF Slopen, Natalie McLaughlin, Katie A. Dunn, Erin C. Koenen, Karestan C. TI Reply to Letter Re: Childhood adversity and cell-mediated immunity in young adulthood SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Letter C1 [Slopen, Natalie; McLaughlin, Katie A.] Harvard Univ, Ctr Developing Child, Cambridge, MA 02138 USA. [Slopen, Natalie] Harvard Univ, Dept Soc Human Dev & Hlth, Sch Publ Hlth, Cambridge, MA 02138 USA. [McLaughlin, Katie A.] Boston Childrens Hosp, Dept Psychiat, Div Gen Pediat, Boston, MA USA. [McLaughlin, Katie A.; Dunn, Erin C.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Dunn, Erin C.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Koenen, Karestan C.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10027 USA. RP Slopen, N (reprint author), Harvard Univ, Ctr Developing Child, Cambridge, MA 02138 USA. EM nslopen@hsph.harvard.edu RI Koenen, Karestan/K-5402-2014; OI Koenen, Karestan/0000-0003-3293-4281; McLaughlin, Katie/0000-0002-1362-2410 FU NIMH NIH HHS [K01 MH092526] NR 3 TC 4 Z9 4 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD NOV PY 2013 VL 34 BP 177 EP 179 DI 10.1016/j.bbi.2013.08.002 PG 3 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 237AJ UT WOS:000325840300022 PM 23954376 ER PT J AU Ban-Hoefen, M Vanderplas, A Crosby-Thompson, AL Abel, GA Czuczman, MS Gordon, LI Kaminski, MS Kelly, J Millenson, M Nademanee, AP Rodriguez, MA Zelenetz, AD Niland, J LaCasce, AS Friedberg, JW AF Ban-Hoefen, Makiko Vanderplas, Ann Crosby-Thompson, Allison L. Abel, Gregory A. Czuczman, Myron S. Gordon, Leo I. Kaminski, Mark S. Kelly, Jennifer Millenson, Michael Nademanee, Auayporn P. Rodriguez, Maria A. Zelenetz, Andrew D. Niland, Joyce LaCasce, Ann S. Friedberg, Jonathan W. TI Transformed non-Hodgkin lymphoma in the rituximab era: analysis of the NCCN outcomes database SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE rituximab era; non-Hodgkin lymphoma; histological transformation; stem-cell transplantation; diffuse large B-cell lymphoma ID B-CELL LYMPHOMA; HIGH-DOSE THERAPY; GRADE FOLLICULAR LYMPHOMA; LONG-TERM SURVIVAL; GENE-EXPRESSION; TRANSPLANTATION; SUPPORT; REMISSIONS AB Histological transformation (HT) is a major cause of morbidity and mortality in patients with indolent non-Hodgkin lymphoma (NHL). The multicentre National Cancer Comprehensive Network database for NHL provides a unique opportunity to investigate the natural history of HT in the rituximab era. 118 patients with biopsy-confirmed indolent lymphoma and subsequent biopsy-confirmed HT were identified. Treatments for HT included autologous stem-cell transplant (auto-SCT) (n=50), allogeneic SCT (allo-SCT) (n=18), and treatment without transplant (n=50). The 2-year overall survival (OS) for the entire cohort was 68%. For auto-SCT patients aged 60years (n=24), the 2-year OS was 74%. For non-transplanted patients aged 60years (n=19), the 2-year OS was 59%. The 2-year OS of patients naive to chemotherapy prior to HT was superior to patients who were exposed to chemotherapy prior to HT (100% vs. 35%, P=003). In this largest prospective cohort of patients of strictly defined HT in the rituximab era, the natural history of HT appears more favourable than historical studies. Younger patients who were not exposed to chemotherapy prior to HT experienced a prolonged survival even without transplantation. This study serves as a benchmark for future trials of novel approaches for HT in the Rituximab era. C1 [Ban-Hoefen, Makiko; Kelly, Jennifer; Friedberg, Jonathan W.] Univ Rochester, Dept Hematol & Oncol, James P Wilmot Canc Ctr, Rochester, NY USA. [Vanderplas, Ann; Nademanee, Auayporn P.; Niland, Joyce] City Hope Comprehens Canc Ctr, Dept Biostat, Duarte, CA USA. [Crosby-Thompson, Allison L.; Abel, Gregory A.; LaCasce, Ann S.] Dana Farber Canc Ctr, Dept Hematol & Oncol, Boston, MA USA. [Czuczman, Myron S.] Roswell Pk Canc Inst, Dept Hematol & Oncol, Buffalo, NY 14263 USA. [Gordon, Leo I.] Robert H Lurie Comprehens Canc Ctr, Dept Hematol & Oncol, Chicago, IL USA. [Kaminski, Mark S.] Univ Michigan, Ctr Comprehens Canc, Dept Hematol & Oncol, Ann Arbor, MI 48109 USA. [Millenson, Michael] Fox Chase Canc Ctr, Dept Hematol & Oncol, Philadelphia, PA 19111 USA. [Rodriguez, Maria A.] Univ Texas MD Anderson Canc Ctr, Dept Hematol & Oncol, Houston, TX 77030 USA. [Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, Dept Hematol & Oncol, New York, NY 10021 USA. RP Friedberg, JW (reprint author), James P Wilmot Canc Ctr, Dept Hematol & Oncol, 601 Elmwood Ave, Rochester, NY 14610 USA. EM jonathan_friedberg@urmc.rochester.edu OI Zelenetz, Andrew/0000-0003-1403-6883; Gordon, Leo/0000-0003-1666-7064 FU University of Rochester SPORE in lymphoma CA [130805] FX Research support was obtained from the University of Rochester SPORE in lymphoma CA 130805. Dr. Friedberg is a Scholar in Clinical Research of the Leukemia & Lymphoma Society. Jennifer Kelly is a Leukemia Research Foundation Postdoctoral Fellow. NR 36 TC 20 Z9 22 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD NOV PY 2013 VL 163 IS 4 BP 487 EP 495 DI 10.1111/bjh.12570 PG 9 WC Hematology SC Hematology GA 239OD UT WOS:000326034200009 PM 24111533 ER PT J AU Steenkamp, MM Nash, WP Lebowitz, L Litz, BT AF Steenkamp, Maria M. Nash, William P. Lebowitz, Leslie Litz, Brett T. TI How Best to Treat Deployment-Related Guilt and Shame: Commentary on Smith, Duax, and Rauch (2013) SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Editorial Material DE PTSD; combat; war; guilt; shame; adaptive disclosure ID POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE-PROCESSING THERAPY; PROLONGED EXPOSURE; VETERANS; VIETNAM; PTSD AB We comment on Smith, Duax, and Rauch' s (2013-this issue) explication of their approach to treating perpetration-related guilt and shame using prolonged exposure (PE) therapy, with the aim of promoting a discourse about the mechanisms, techniques, and assumptions that underlie the treatment of moral injury in veterans and service members. We first discuss the theoretical foundation underlying PE and consider the extent to which it accounts for the phenomenology of moral injury. We then examine the treatment strategies used in the PE approach and the mechanisms by which these techniques ameliorate perpetration-related guilt and shame. We also briefly highlight points of similarity and contrast between PE and adaptive disclosure, a brief cognitive behavioral intervention targeting combat-related moral injury and traumatic loss. C1 [Steenkamp, Maria M.; Litz, Brett T.] VA Boston Healthcare Syst, Boston, MA USA. [Nash, William P.] Boston VA Res Inst, Boston, MA USA. [Litz, Brett T.] Boston Univ, Boston, MA 02215 USA. RP Steenkamp, MM (reprint author), 150 S Huntington Ave,13B-73, Jamaica Plain, MA 02130 USA. EM Maria.Steenkamp2@va.gov NR 32 TC 4 Z9 4 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1077-7229 EI 1878-187X J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD NOV PY 2013 VL 20 IS 4 BP 471 EP 475 PG 5 WC Psychology, Clinical SC Psychology GA 238OA UT WOS:000325956100010 ER PT J AU Maguen, S Burkman, K AF Maguen, Shira Burkman, Kristine TI Combat-Related Killing: Expanding Evidence-Based Treatments for PTSD SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Editorial Material DE posttraumatic stress disorder; killing; veteran; treatment ID MENTAL-HEALTH SYMPTOMS; IMPACT; WAR AB Despite its prevalence, killing in war is an experience that may not fit neatly into existing models of posttraumatic stress disorder (PTSD) and its treatment. The context in which killing occurred may be complex. Furthermore, while killing may certainly be fear based, an individual may have also killed in response to losing someone close and experiencing sadness and anger, as opposed to fear. While evidence-based treatments for PTSD may be a good starting point for killing-related trauma, we argue that existing treatments need to be expanded. Complex killing-related cognitions that may not be anticipated or identified, moral injury, self-forgiveness, and loss are all important issues that arise that may need to be addressed in greater detail. Consequently, we have developed a 6- to 8-session individual treatment module for those impacted by killing in war, expressly designed for use with existing evidence-based treatments for PTSD, currently being validated for use in clinical practice. We see this module as supplementary, rather than as a replacement, building on the skills that veterans have already learned within these treatments. By expanding the types of treatments we offer those who have killed in war, we can ensure that we are providing veterans with comprehensive treatment that takes the complexities of war and its aftermath into account. C1 [Maguen, Shira] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Maguen, S (reprint author), San Francisco VA Med Ctr, 4150 Clement St 116-P, San Francisco, CA 94121 USA. EM Shira.Maguen@va.gov NR 10 TC 9 Z9 9 U1 1 U2 23 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1077-7229 EI 1878-187X J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD NOV PY 2013 VL 20 IS 4 BP 476 EP 479 PG 4 WC Psychology, Clinical SC Psychology GA 238OA UT WOS:000325956100011 ER PT J AU Rauch, SAM Smith, E Duax, J Tuerk, P AF Rauch, Sheila A. M. Smith, Erin Duax, Jeanne Tuerk, Peter TI A Data-Driven Perspective: Response to Commentaries by Maguen and Burkman (2013) and Steenkamp et al. (2013) SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Editorial Material DE PTSD; treatment; combat; moral injury; guilt ID POSTTRAUMATIC-STRESS-DISORDER; PROLONGED EXPOSURE THERAPY; COGNITIVE-PROCESSING THERAPY; INJECTION-INJURY PHOBIA; THREAT-RELEVANT STIMULI; FEMALE RAPE VICTIMS; PTSD; VETERANS; DISGUST; TRIAL AB We respond to commentary from Maguen and Burkman (2013-this issue) and Steenkamp et al. (2013-this issue) on our presentation of how to use PE to treat PTSD resulting from perceived perpetration (Smith et al., 2013-this issue). We focus our response on the distinction between moral injury, which can result in many potential mental health outcomes, with various treatment plans coming out of the patient's presentation, and treatment of PTSD resulting from trauma that may or may not include moral injury. We then focus on the strong evidence base that supports the use of PE for PTSD across trauma types and across many complicated patient presentations, including evidence within veteran populations. We respond to common misunderstandings of PE and Emotional Processing Theory that underlie this treatment model. Specifically, we discuss the flexibility that is inherent in the PE model, reassert that PE focuses on whatever emotion/s are present and provoked by direct confrontation of traumatic material (e.g., reminders, memories), and discuss that habituation is not the only process at work in PE. As such, shame and guilt related to moral injury can be effectively addressed, as noted in Smith et al. Finally, rather than developing a new and unproven model of treatment as the commentaries propose, we assert that given the strong evidence base for efficacy and effectiveness of PE for PTSD and the significant and ongoing investment in dissemination of PE, continued support for providers on how to effectively use PE with difficult patients is warranted. C1 [Rauch, Sheila A. M.; Smith, Erin; Duax, Jeanne] VA Ann Arbor Healthcare Syst, Ann Arbor, MI 48105 USA. [Rauch, Sheila A. M.; Smith, Erin; Duax, Jeanne] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Tuerk, Peter] Ralph H Johnson VAMC, Charleston, SC USA. [Tuerk, Peter] Med Univ S Carolina, Charleston, SC 29425 USA. RP Rauch, SAM (reprint author), VA Ann Arbor Healthcare Syst, PTSD Clin Team, 2215 Fuller Rd 116C, Ann Arbor, MI 48105 USA. EM sherauch@med.umich.edu RI Rauch, Sheila/K-4450-2015 OI Rauch, Sheila/0000-0001-9686-4011 NR 31 TC 2 Z9 2 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1077-7229 EI 1878-187X J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD NOV PY 2013 VL 20 IS 4 BP 480 EP 484 PG 5 WC Psychology, Clinical SC Psychology GA 238OA UT WOS:000325956100012 ER PT J AU Lam, PY Kamei, CN Mangos, S Mudumana, S Liu, Y Drummond, IA AF Lam, Pui-Ying Kamei, Caramai N. Mangos, Steve Mudumana, Sudha Liu, Yan Drummond, Iain A. TI odd-skipped related 2 is Required for Fin Chondrogenesis in Zebrafish SO DEVELOPMENTAL DYNAMICS LA English DT Article DE odd-skipped related 2; chondrogenesis; pectoral fin; zebrafish ID ODD-SKIPPED GENES; CHONDROCYTE DIFFERENTIATION; KIDNEY DEVELOPMENT; DANIO-RERIO; CELL FATE; EXPRESSION; DROSOPHILA; SOX9; EMBRYOS; MUTANT AB Background:odd-skipped related 2 (osr2) encodes a vertebrate ortholog of the Drosophila odd-skipped zinc-finger transcription factor. Osr2 in mouse is required for proper palate, eyelid, and bone development. Zebrafish knock-down experiments have also suggested a role for osr2, along with its paralog osr1, in early pectoral fin specification and pronephric development.Results: We show here that osr2 has a specific function later in development, independent of osr1, in the regulation of sox9a expression and promoting fin chondrogenesis. mRNA in situ hybridization demonstrated osr2 expression in the developing floorplate and later during organogenesis in the pronephros and gut epithelium. In the pectoral fin buds, osr2 was specifically expressed in fin mesenchyme. osr2 knock down in zebrafish embryos disrupted both three and five zinc finger alternatively spliced osr2 isoforms and eliminated wild-type osr2 mRNA. osr2 morphants exhibited normal pectoral fin bud specification but exhibited defective fin chondrogenesis, with loss of differentiated chondrocytes. Defects in chondrogenesis were paralleled by loss of sox9a as well as subsequent col2a1 expression, linking osr2 function to essential regulators of chondrogenesis.Conclusions: The zebrafish odd-skipped related 2 gene regulates sox9a and col2a1 expression in chondrocyte development and is specifically required for zebrafish fin morphogenesis. Developmental Dynamics 242:1284-1292, 2013. (c) 2013 Wiley Periodicals, Inc. C1 Massachusetts Gen Hosp, Dept Med, Div Nephrol, Charlestown, MA USA. Harvard Univ, Sch Med, Dept Genet, Charlestown, MA USA. RP Drummond, IA (reprint author), Nephrol Div MGH, 149-8000,149 13th St, Charlestown, MA 02129 USA. EM idrummon@receptor.mgh.harvard.edu FU NIDDK [RO1 DK071041, F32 DK091998] FX Grant sponsor: NIDDK; Grant numbers: RO1 DK071041 and F32 DK091998. NR 46 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1058-8388 EI 1097-0177 J9 DEV DYNAM JI Dev. Dyn. PD NOV PY 2013 VL 242 IS 11 BP 1284 EP 1292 DI 10.1002/dvdy.24026 PG 9 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 238SO UT WOS:000325969400006 PM 23913342 ER PT J AU Hanlon, J Schmader, K AF Hanlon, Joseph T. Schmader, Kenneth E. TI The Medication Appropriateness Index at 20: Where It Started, Where It Has Been, and Where It May Be Going SO DRUGS & AGING LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; ADVERSE DRUG-REACTIONS; OLDER-ADULTS; PRIMARY-CARE; HOSPITALIZED-PATIENTS; PRESCRIBING CRITERIA; GERIATRIC INPATIENTS; ELDERLY-PATIENTS; RELIABILITY; OUTPATIENTS AB Potentially inappropriate prescribing for older adults is a major public health concern. While there are multiple measures of potentially inappropriate prescribing, the medication appropriateness index (MAI) is one of the most common implicit approaches published in the scientific literature. The objective of this narrative review is to describe findings regarding the MAI's reliability, comparison of the MAI with other quality measures of potentially inappropriate prescribing, its predictive validity with important health outcomes, and its responsiveness to change within the framework of randomized controlled trials. A search restricted to English-language literature involving humans aged 65+ years from January 1992 to June 2013 was conducted using MEDLINE and EMBASE databases using the search term 'medication appropriateness index'. A manual search of the reference lists from identified articles and the authors' article files, book chapters, and recent reviews was conducted to identify additional articles. A total of 26 articles were identified for inclusion in this narrative review. The main findings were that the MAI has acceptable inter- and intra-rater reliability, it more frequently detects potentially inappropriate prescribing than a commonly used set of explicit criteria, it predicts adverse health outcomes, and it is able to demonstrate the positive impact of interventions to improve this public health problem. We conclude that the MAI may serve as a valuable tool for measuring potentially inappropriate prescribing in older adults. C1 [Hanlon, Joseph T.] Univ Pittsburgh, Dept Med, Div Geriatr, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Sch Med, Geriatr Pharmaceut Outcomes & Geroinformat Res &, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Dept Geriatr Med, Pittsburgh, PA 15213 USA. [Schmader, Kenneth E.] Duke Univ, Med Ctr, Sch Med, Dept Med,Div Geriatr, Durham, NC 27710 USA. [Schmader, Kenneth E.] Durham Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Durham, NC USA. RP Hanlon, J (reprint author), Univ Pittsburgh, Dept Geriatr Med, Kaufman Med Bldg Suite 514,3471 5th Ave, Pittsburgh, PA 15213 USA. EM jth14@pitt.edu FU National Institute on Aging Grants [R01-AG 027017, P30-AG02482, K07-AG033174, P30-AG028716]; Healthcare Research and Quality Grant [R01-HS018721] FX Supported in part by the National Institute on Aging Grants (R01-AG 027017, P30-AG024827, K07-AG033174, P30-AG028716), and an Agency for Healthcare Research and Quality Grant (R01-HS018721). The authors report no potential conflicts of interest. NR 46 TC 21 Z9 22 U1 1 U2 17 PU ADIS INT LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND SN 1170-229X EI 1179-1969 J9 DRUG AGING JI Drugs Aging PD NOV PY 2013 VL 30 IS 11 BP 893 EP 900 DI 10.1007/s40266-013-0118-4 PG 8 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA 236VL UT WOS:000325827400005 PM 24062215 ER PT J AU Pavlides, SC Huang, KT Reid, DA Wu, L Blank, SV Mittal, K Guo, LK Rothenberg, E Rueda, B Cardozo, T Gold, LI AF Pavlides, Savvas C. Huang, Kuang-Tzu Reid, Dylan A. Wu, Lily Blank, Stephanie V. Mittal, Khushbakhat Guo, Lankai Rothenberg, Eli Rueda, Bo Cardozo, Timothy Gold, Leslie I. TI Inhibitors of SCF-Skp2/Cks1 E3 Ligase Block Estrogen-Induced Growth Stimulation and Degradation of Nuclear p27(kip1): Therapeutic Potential for Endometrial Cancer SO ENDOCRINOLOGY LA English DT Article ID SCF UBIQUITIN LIGASE; SMALL-MOLECULE INHIBITORS; SKP2-MEDIATED P27 DEGRADATION; CELL-CYCLE; SUBCELLULAR-LOCALIZATION; CYTOPLASMIC P27; BREAST-CANCER; IN-VITRO; SKP2; PHOSPHORYLATION AB In many human cancers, the tumor suppressor, p27(kip1) (p27), a cyclin-dependent kinase inhibitor critical to cell cycle arrest, undergoes perpetual ubiquitin-mediated proteasomal degradation by the E3 ligase complex SCF-Skp2/Cks1 and/or cytoplasmic mislocalization. Lack of nuclear p27 causes aberrant cell cycle progression, and cytoplasmic p27 mediates cell migration/metastasis. We previously showed that mitogenic 17-beta-estradiol (E2) induces degradation of p27 by the E3 ligase Skp1-Cullin1-F-Box-S phase kinase-associated protein2/cyclin dependent kinase regulatory subunit 1 in primary endometrial epithelial cells and endometrial carcinoma (ECA) cell lines, suggesting a pathogenic mechanism for type I ECA, an E2-induced cancer. The current studies show that treatment of endometrial carcinoma cells-1 (ECC-1) with small molecule inhibitors of Skp2/Cks1 E3 ligase activity (Skp2E3LIs) stabilizes p27 in the nucleus, decreases p27 in the cytoplasm, and prevents E2-induced proliferation and degradation of p27 in endometrial carcinoma cells-1 and primary ECA cells. Furthermore, Skp2E3LIs increase p27 half-life by 6 hours, inhibit cell proliferation (IC50, 14.3 mu M), block retinoblastoma protein (pRB) phosphorylation, induce G(1) phase block, and are not cytotoxic. Similarly, using super resolution fluorescence localization microscopy and quantification, Skp2E3LIs increase p27 protein in the nucleus by 1.8-fold. In vivo, injection of Skp2E3LIs significantly increases nuclear p27 and reduces proliferation of endometrial epithelial cells by 42%-62% in ovariectomized E2-primed mice. Skp2E3LIs are specific inhibitors of proteolytic degradation that pharmacologically target the binding interaction between the E3 ligase, SCF-Skp2/Cks1, and p27 to stabilize nuclear p27 and prevent cell cycle progression. These targeted inhibitors have the potential to be an important therapeutic advance over general proteasome inhibitors for cancers characterized by SCF-Skp2/Cks1-mediated destruction of nuclear p27. C1 [Mittal, Khushbakhat; Gold, Leslie I.] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Pavlides, Savvas C.; Huang, Kuang-Tzu; Blank, Stephanie V.; Gold, Leslie I.] NYU, Sch Med, Dept Med, New York, NY 10016 USA. [Reid, Dylan A.; Wu, Lily; Rothenberg, Eli; Cardozo, Timothy] NYU, Sch Med, Dept Mol Pharmacol & Biochem, New York, NY 10016 USA. [Pavlides, Savvas C.; Huang, Kuang-Tzu; Gold, Leslie I.] NYU, Sch Med, Div Translat Med, New York, NY 10016 USA. [Blank, Stephanie V.] NYU, Sch Med, Div Gynecol Oncol, New York, NY 10016 USA. [Gold, Leslie I.] NYU, Sch Med, New York Univ Canc Inst, New York, NY 10016 USA. [Guo, Lankai; Rueda, Bo] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Rueda, Bo] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. RP Gold, LI (reprint author), Dept Med, Div Translat Med, 550 First Ave,NB17E4, New York, NY 10016 USA. EM leslie.gold@nyumc.org FU National Institutes of Health, National Cancer Institute [CA 89175]; New York University Cancer Institute; Office of the National Institutes of Health Director [OD004631]; Advanced Medical Research Foundation; Vincent Memorial Research funds FX This work was supported by the National Institutes of Health, National Cancer Institute Grant CA 89175 and a Pilot Project grant from New York University Cancer Institute (to L. I. G.), by Office of the National Institutes of Health Director Grant OD004631 (to T. C.), and by Advanced Medical Research Foundation and Vincent Memorial Research funds (to B.R.). NR 65 TC 23 Z9 24 U1 0 U2 12 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD NOV PY 2013 VL 154 IS 11 BP 4030 EP 4045 DI 10.1210/en.2013-1757 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 238HI UT WOS:000325935200015 PM 24035998 ER PT J AU Schwartz, DR Briggs, ER Qatanani, M Sawaya, H Sebag, IA Picard, MH Scherrer-Crosbie, M Lazar, MA AF Schwartz, Daniel R. Briggs, Erika R. Qatanani, Mohammed Sawaya, Heloisa Sebag, Igal A. Picard, Michael H. Scherrer-Crosbie, Marielle Lazar, Mitchell A. TI Human Resistin in Chemotherapy-Induced Heart Failure in Humanized Male Mice and in Women Treated for Breast Cancer SO ENDOCRINOLOGY LA English DT Article ID DOXORUBICIN-INDUCED CARDIOMYOPATHY; INDUCED CARDIAC DYSFUNCTION; TUMOR-BEARING MICE; SERUM RESISTIN; IN-VITRO; PROGNOSTIC-SIGNIFICANCE; MOUSE CARDIOMYOCYTES; INSULIN-RESISTANCE; LONG-TERM; EXPRESSION AB Resistin is a circulating mediator of insulin resistance mainly expressed in human monocytes and responsive to inflammatory stimuli. Recent clinical studies have connected elevated resistin levels with the development and severity of heart failure. To further our understanding of the role of human resistin in heart failure, we studied a humanized mouse model lacking murine resistin but transgenic for the human Retn gene (Hum-Retn mice), which exhibits basal and inflammation-stimulated resistin levels similar to humans. Specifically, we explored whether resistin underlies acute anthracycline-induced cardiotoxicity. Remarkably, doxorubicin (25mg/kg ip) led to a 4-fold induction of serum resistin levels in Hum-Retn mice. Moreover, doxorubicin-induced cardiotoxicity was greater in the Hum-Retn mice than in littermate controls not expressing human resistin (Retn(-/-)). Hum-Retn mice showed increased cardiac mRNA levels of inflammatory and cell adhesion genes compared with Retn(-/-) mice. Macrophages, but not cardiomyocytes, from Hum-Retn mice treated with doxorubicin in vitro showed dramatic induction of hRetn (human resistin) mRNA and protein expression. We also examined resistin levels in anthracycline-treated breast cancer patients with and without cardiotoxicity. Intriguingly, serum resistin levels in women undergoing anthracycline-containing chemotherapy increased significantly at 3 months and remained elevated at 6 months in those with subsequent cardiotoxicity. Further, elevation in resistin correlated with decline in ejection fraction in these women. These results suggest that elevated resistin is a biomarker of anthracycline-induced cardiotoxicity and may contribute in the development of heart failure via its direct effects on macrophages. These results further implicate resistin as a link between inflammation, metabolism, and heart disease. C1 [Schwartz, Daniel R.; Briggs, Erika R.; Lazar, Mitchell A.] Univ Penn, Perelman Sch Med, Div Endocrinol Diabet & Metab, Dept Med, Philadelphia, PA 19104 USA. [Schwartz, Daniel R.] Univ Penn, Perelman Sch Med, Div Cardiol, Dept Med, Philadelphia, PA 19104 USA. [Schwartz, Daniel R.; Briggs, Erika R.; Qatanani, Mohammed; Lazar, Mitchell A.] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Sawaya, Heloisa; Picard, Michael H.; Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Div Cardiol, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Sawaya, Heloisa; Picard, Michael H.; Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Sawaya, Heloisa; Picard, Michael H.; Scherrer-Crosbie, Marielle] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Sebag, Igal A.] Sir Mortimer B Davis Jewish Hosp, Echocardiog Lab, Montreal, PQ H3T 1E2, Canada. [Sebag, Igal A.] Sir Mortimer B Davis Jewish Hosp, Div Cardiol, Dept Med, Montreal, PQ H3T 1E2, Canada. [Sebag, Igal A.] McGill Univ, Montreal, PQ H3T 1E2, Canada. RP Lazar, MA (reprint author), Smilow Ctr Translat Res, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM lazar@mail.med.upenn.edu OI Picard, Michael/0000-0002-9264-3243 FU National Institutes of Health [NIK P01 DK49210, P30 DK19525, 5-T32 HLO007843]; Susan G. Komen for the Cure Foundation FX This work was supported by National Institutes of Health Grants NIK P01 DK49210 and P30 DK19525 (to M.A.L.) and 5-T32 HLO007843 (to D.R.S.) and by an investigator-initiated grant from the Susan G. Komen for the Cure Foundation (M.S.-C.). NR 61 TC 2 Z9 3 U1 1 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD NOV PY 2013 VL 154 IS 11 BP 4206 EP 4214 DI 10.1210/en.2013-1399 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 238HI UT WOS:000325935200030 PM 23981771 ER PT J AU Lawson, EA Holsen, LM DeSanti, R Santin, M Meenaghan, E Herzog, DB Goldstein, JM Klibanski, A AF Lawson, Elizabeth A. Holsen, Laura M. DeSanti, Rebecca Santin, McKale Meenaghan, Erinne Herzog, David B. Goldstein, Jill M. Klibanski, Anne TI Increased hypothalamic-pituitary-adrenal drive is associated with decreased appetite and hypoactivation of food-motivation neurocircuitry in anorexia nervosa SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID CORTICOTROPIN-RELEASING-FACTOR; DISORDERED EATING PSYCHOPATHOLOGY; FAT REDISTRIBUTION; STEROID RECEPTORS; CORTISOL RHYTHM; WEIGHT-GAIN; RAT-BRAIN; WOMEN; METABOLISM; HUNGER AB Objective: Corticotrophin-releasing hormone (CRH)-mediated hypercortisolemia has been demonstrated in anorexia nervosa (AN), a psychiatric disorder characterized by food restriction despite low body weight. While CRH is anorexigenic, downstream cortisol stimulates hunger. Using a food-related functional magnetic resonance imaging (fMRI) paradigm, we have demonstrated hypoactivation of brain regions involved in food motivation in women with AN, even after weight recovery. The relationship between hypothalamic-pituitary-adrenal (HPA) axis dysregulation and appetite and the association with food-motivation neurocircuitry hypoactivation are unknown in AN. We investigated the relationship between HPA activity, appetite, and food-motivation neurocircuitry hypoactivation in AN. Design: Cross-sectional study of 36 women (13 AN, ten weight- recovered AN (ANWR), and 13 healthy controls (HC)). Methods: Peripheral cortisol and ACTH levels were measured in a fasting state and 30, 60, and 120 min after a standardized mixed meal. The visual analog scale was used to assess homeostatic and hedonic appetite. fMRI was performed during visual processing of food and non-food stimuli to measure the brain activation pre- and post-meal. Results: In each group, serum cortisol levels decreased following the meal. Mean fasting, 120 min postmeal, and nadir cortisol levels were high in AN vs HC. Mean postprandial ACTH levels were high in ANWR compared with HC and AN subjects. Cortisol levels were associated with lower fasting homeostatic and hedonic appetite, independent of BMI and depressive symptoms. Cortisol levels were also associated with between-group variance in activation in the food-motivation brain regions (e.g. hypothalamus, amygdala, hippocampus, orbitofrontal cortex, and insula). Conclusions: HPA activation may contribute to the maintenance of AN by the suppression of appetitive drive. C1 [Lawson, Elizabeth A.; DeSanti, Rebecca; Santin, McKale; Meenaghan, Erinne; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Lawson, Elizabeth A.; DeSanti, Rebecca; Santin, McKale; Meenaghan, Erinne; Herzog, David B.; Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Holsen, Laura M.; Goldstein, Jill M.] Brigham & Womens Hosp, Dept Med, Div Womens Hlth, Boston, MA 02120 USA. [Holsen, Laura M.; Goldstein, Jill M.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02120 USA. [Holsen, Laura M.; Goldstein, Jill M.] Harvard Univ, Sch Med, Boston, MA 02120 USA. [Herzog, David B.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Lawson, EA (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. EM ealawson@partners.org FU NIH [UL1 RR025758, K12 HD051959, K23 MH092560] FX This work was supported by the NIH (awards: UL1 RR025758, K12 HD051959, and K23 MH092560). NR 35 TC 12 Z9 12 U1 0 U2 18 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD NOV PY 2013 VL 169 IS 5 BP 639 EP 647 DI 10.1530/EJE-13-0433 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 239JZ UT WOS:000326020600018 PM 23946275 ER PT J AU Chen, XY Wang, J Shah, D Wu, MX AF Chen, Xinyuan Wang, Ji Shah, Dilip Wu, Mei X. TI An update on the use of laser technology in skin vaccination SO EXPERT REVIEW OF VACCINES LA English DT Review DE adjuvant; intradermal injection; laser; skin vaccination; stratum corneum; transcutaneous delivery; vaccine ID ERBIUM-YAG LASER; TRANSDERMAL DRUG-DELIVERY; RANDOMIZED CONTROLLED-TRIAL; FRACTIONAL PHOTOTHERMOLYSIS; MOLECULAR MIMICRY; FEMTOSECOND LASER; STRATUM-CORNEUM; TRANSCUTANEOUS VACCINATION; SMOKING-CESSATION; IMMUNE-RESPONSES AB Vaccination via skin often induces stronger immune responses than via muscle. This, in line with potential needle-free, painless delivery, makes skin a very attractive site for immunization. Yet, despite decades of effort, effective skin delivery is still in its infant stage and safe and potent adjuvants for skin vaccination remain largely undefined. We have shown that laser technologies including both fractional and non-fractional lasers can greatly augment vaccine-induced immune response without incurring any significant local and systemic side effects. Laser illumination at specific settings can accelerate the motility of antigen-presenting cells or trigger release of danger' signals stimulating the immune system. Moreover, several other groups including the authors explore laser technologies for needle-free transcutaneous vaccine delivery. As these laser-mediated resurfacing technologies are convenient, safe and cost-effective, their new applications in vaccination warrant clinical studies in the very near future. C1 [Chen, Xinyuan; Wang, Ji; Shah, Dilip] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed,Dept Dermatol, Boston, MA 02114 USA. [Wu, Mei X.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Wu, MX (reprint author), MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM mwu2@partners.org FU National Institutes of Health [AI070785, RC1 DA028378]; American Society for Laser Medicine and Surgery [NSP0511] FX This work is supported in part by the National Institutes of Health grants AI070785 and RC1 DA028378 (to MX Wu), Bullock-Wellman Fellowship, and A Ward Ford Memorial Research Grant #NSP0511 from American Society for Laser Medicine and Surgery (to X Chen). X Chen, D Shah, J Wang. designs and performs the experiments, analyzes the data. X Chen and J Wang prepare the manuscript. MX Wu participates in data analysis and experimental design and writes the paper. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 96 TC 12 Z9 12 U1 1 U2 19 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 EI 1744-8395 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD NOV PY 2013 VL 12 IS 11 BP 1313 EP 1323 DI 10.1586/14760584.2013.844070 PG 11 WC Immunology SC Immunology GA 240OD UT WOS:000326105500010 PM 24127871 ER PT J AU Luessi, M Babacan, SD Molina, R Katsaggelos, AK AF Luessi, Martin Babacan, S. Derin Molina, Rafael Katsaggelos, Aggelos K. TI Bayesian Simultaneous Sparse Approximation With Smooth Signals SO IEEE TRANSACTIONS ON SIGNAL PROCESSING LA English DT Article DE Bayesian methods; sparse Bayesian learning; sparse signal recovery; sparsity; MEG/EEG source localization ID MULTIPLE-MEASUREMENT VECTORS; INVERSE PROBLEM; RECONSTRUCTION; DISTRIBUTIONS; REGRESSION AB In the simultaneous sparse approximation problem, several latent vectors corresponding to independent random realizations from a common sparsity profile are recovered from an undercomplete set of measurements. In this paper, we address an extension of this problem, where in addition to the common sparsity profile, the vectors of interest are assumed to have a high correlation among each other. Specifically, we consider the case when the non-zero rows in the combined latent signal vectors are considered to be temporally smooth signals. We present a Bayesian formulation of the problem and develop a greedy inference algorithm based on sparse Bayesian learning for independent observations. A difficulty is that unlike for existing greedy methods, there is no closed form expression for the maximizer of the objective function in the greedy algorithm when row correlations are introduced. We derive two methods to maximize the objective function, one based on the EM algorithm and another on a fixed-point iteration. Empirical results show that the proposed method provides better reconstruction results compared to existing methods, especially when the signal-to-noise ratio is low and the latent signal vectors are highly correlated. We also demonstrate the application of the proposed method to source localization in magnetoencephalography, where it obtains a temporally smooth solution with accurate localization of the brain activity. C1 [Luessi, Martin; Katsaggelos, Aggelos K.] Northwestern Univ, Dept Elect Engn & Comp Sci, Evanston, IL 60201 USA. [Babacan, S. Derin] Google Inc, Mountain View, CA 94043 USA. [Molina, Rafael] Univ Granada, Dept Ciencias Comp & IA, E-18071 Granada, Spain. RP Luessi, M (reprint author), Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Boston, MA 02138 USA. EM mluessi@nmr.mgh.harvard.edu; dbabacan@gmail.com; rms@decsai.ugr.es; aggk@eecs.northwestern.edu RI Katsaggelos, Aggelos/B-7233-2009; Molina Soriano, Rafael/B-1849-2012 OI Molina Soriano, Rafael/0000-0003-4694-8588 FU NSF [0958669]; U. S. Department of Energy [DENA0000457]; Ministerio de Ciencia e Innovacion [TIN2010-15137]; CEI BioTic at the Universidad de Granada FX Manuscript received March 29, 2011; revised June 17, 2012, November 28, 2012, and March 28, 2013; accepted August 21, 2013. Date of publication September 05, 2013; date of current version October 16, 2013. The associate editor coordinating the review of this manuscript and approving it for publication was Prof. Sofia Charlotta Olhede. This work was partially supported by the NSFGrant 0958669, U. S. Department of Energy Grant DENA0000457, by the "Ministerio de Ciencia e Innovacion" under contract TIN2010-15137, and the CEI BioTic at the Universidad de Granada. NR 38 TC 7 Z9 7 U1 0 U2 8 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1053-587X EI 1941-0476 J9 IEEE T SIGNAL PROCES JI IEEE Trans. Signal Process. PD NOV PY 2013 VL 61 IS 22 BP 5716 EP 5729 DI 10.1109/TSP.2013.2280441 PG 14 WC Engineering, Electrical & Electronic SC Engineering GA 240MZ UT WOS:000326102300019 ER PT J AU Papakostas, GI Culpepper, L Fayyad, RS Musgnung, J Guico-Pabia, CJ AF Papakostas, George I. Culpepper, Larry Fayyad, Rana S. Musgnung, Jeff Guico-Pabia, Christine J. TI Efficacy of desvenlafaxine 50 mg compared with placebo in patients with moderate or severe major depressive disorder: a pooled analysis of six randomized, double-blind, placebo-controlled studies SO INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE antidepressants; depression; desvenlafaxine; treatment efficacy ID SEROTONIN REUPTAKE INHIBITORS; BASE-LINE SEVERITY; CLINICAL-TRIALS; INTEGRATED ANALYSIS; REMISSION RATES; 100 MG/DAY; VENLAFAXINE; METAANALYSIS; ANTIDEPRESSANTS; TOLERABILITY AB This study assessed the efficacy of desvenlafaxine 50 mg/day compared with placebo for treating moderate or severe major depressive disorder (MDD). Data were pooled from six double-blind, placebo-controlled, desvenlafaxine 50 mg/day fixed-dose studies in adults with MDD. The primary endpoint was improvement in 17-item Hamilton Rating Scale for Depression (HAM-D-17) scores from baseline at week 8. HAM-D-17 changes were evaluated in patients with moderate (18 0.8). Predictions were similarly robust for the universal calculator vs procedure-specific calculators (eg, colorectal). Surgeons demonstrated considerable agreement on the case scenario scoring (80% to 100% agreement), suggesting reliable score assignment between surgeons. CONCLUSIONS: The ACS NSQIP surgical risk calculator is a decision-support tool based on reliable multi-institutional clinical data, which can be used to estimate the risks of most operations. The ACS NSQIP surgical risk calculator will allow clinicians and patients to make decisions using empirically derived, patient-specific postoperative risks. ((C) 2013 by the American College of Surgeons) C1 [Bilimoria, Karl Y.; Liu, Yaoming; Paruch, Jennifer L.; Zhou, Lynn; Ko, Clifford Y.; Cohen, Mark E.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL 60611 USA. [Bilimoria, Karl Y.; Kmiecik, Thomas E.] Northwestern Univ, Feinberg Sch Med, Dept Surg, Surg Outcomes & Qual Improvement Ctr, Chicago, IL 60611 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 Bilimoria, KY (reprint author), Amer Coll Surg, Div Res & Optimal Patient Care, 633 N St Clair St,22nd Floor, Chicago, IL 60611 USA. EM kbilimoria@facs.org FU NCATS NIH HHS [L30 TR000300] NR 24 TC 146 Z9 146 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD NOV PY 2013 VL 217 IS 5 BP 833 EP + DI 10.1016/j.jamcollsurg.2013.07.385 PG 13 WC Surgery SC Surgery GA 235YO UT WOS:000325759500011 PM 24055383 ER PT J AU Brunner, AM Costa, DB Heist, RS Garcia, E Lindeman, NI Sholl, LM Oxnard, GR Johnson, BE Hammerman, PS AF Brunner, Andrew M. Costa, Daniel B. Heist, Rebecca S. Garcia, Elizabeth Lindeman, Neal I. Sholl, Lynette M. Oxnard, Geoffrey R. Johnson, Bruce E. Hammerman, Peter S. TI Treatment-Related Toxicities in a Phase II Trial of Dasatinib in Patients with Squamous Cell Carcinoma of the Lung SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Squamous cell cancer; Dasatinib; Lung neoplasms; Discoidin receptor ID SOMATIC MUTATIONS; CANCER; INHIBITION; GEFITINIB; ERLOTINIB AB Introduction: Advanced squamous cell carcinoma (SqCC) of the lung carries a poor prognosis, and new therapeutic targets are needed. Several studies have examined dasatinib in non-small cell lung cancer; these report not only significant toxicities, but also responses in patients found to harbor mutations in discoidin domain receptor tyrosine kinase 2 or BRAF. An open-label phase II trial with dasatinib was carried out to determine the response rates in patients with SqCC who had previously failed standard chemotherapy and to correlate responses with patient genotype. Methods: Patients were treated with dasatinib 140mg daily in 28-day cycles. Patients were included if they had stage IIIb/IV SqCC, Eastern Cooperative Oncology Group performance status of 0 or 1, and for whom treatment with standard chemotherapy had failed. Results: The study was halted after enrolling five patients, all of whom were discontinued from the trial because of excess toxicity of dasatinib administered at 140mg/day. The patients were treated for 9, 14, 24, 40, and 42 days. Three of five patients (60%) experienced grade 3 or more toxicities (dyspnea, fatigue, elevated level of aspartate transaminase, anorexia, nausea). Intolerable grade 2 pleural effusions were noted in two of five patients. Four of five patients died after 44, 52, 127, and 226 days; one patient remains alive at 279 days. No deaths were associated with the study drug. Conclusions: Similar to other studies, this study too found that dasatinib administered at 140mg/day for the treatment of advanced SqCC of the lung is associated with excess adverse events, so is not recommended in unselected patients. Further work to identify patients likely to benefit from dasatinib and to manage dasatinib-related toxicities is needed. C1 [Brunner, Andrew M.; Heist, Rebecca S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Costa, Daniel B.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Garcia, Elizabeth; Lindeman, Neal I.; Sholl, Lynette M.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Garcia, Elizabeth; Lindeman, Neal I.; Sholl, Lynette M.] Brigham & Womens Hosp, Ctr Adv Mol Diagnost, Boston, MA 02115 USA. [Oxnard, Geoffrey R.; Johnson, Bruce E.; Hammerman, Peter S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Hammerman, PS (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM phammerman@partners.org OI Costa, Daniel/0000-0002-0689-395X FU Bristol Myers Squibb; National Institutes of Health/National Cancer Institute (NIH/NCI), Dana-Farber/Harvard Cancer Center (DF/HCC) Lung Cancer SPORE grant [P50 CA090578] FX This trial was funded by Bristol Myers Squibb, who also provided the study drug. Research funding was also provided in part through an National Institutes of Health/National Cancer Institute (NIH/NCI) P50 CA090578 Dana-Farber/Harvard Cancer Center (DF/HCC) Lung Cancer SPORE grant. NR 15 TC 19 Z9 19 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD NOV PY 2013 VL 8 IS 11 BP 1434 EP 1437 DI 10.1097/JTO.0b013e3182a47162 PG 4 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 239LO UT WOS:000326026000025 PM 24128713 ER PT J AU Piccinotti, S Kirchhausen, T Whelan, SPJ AF Piccinotti, Silvia Kirchhausen, Tomas Whelan, Sean P. J. TI Uptake of Rabies Virus into Epithelial Cells by Clathrin-Mediated Endocytosis Depends upon Actin SO JOURNAL OF VIROLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; MAJOR SURFACE GLYCOPROTEIN; INDUCED MEMBRANE-FUSION; MONOCLONAL-ANTIBODIES; COATED PITS; ENTRY; PATHWAY; TRANSMISSION; PATHOGENESIS; RECEPTORS AB Rabies virus (RABV) causes a fatal zoonotic encephalitis. Disease symptoms require replication and spread of the virus within neuronal cells; however, in infected animals as well as in cell culture the virus replicates in a broad range of cell types. Here we use a single-cycle RABV and a recombinant vesicular stomatitis virus (rVSV) in which the glycoprotein (G) was replaced with that of RABV (rVSV RABV G) to examine RABV uptake into the African green monkey kidney cell line BS-C-1. Combining biochemical studies and real-time spinning-disk confocal fluorescence microscopy, we show that the predominant entry pathway of RABV particles into BS-C-1 cells is clathrin dependent. Viral particles enter cells in pits with elongated structures and incomplete clathrin coats which depend upon actin to complete the internalization process. By measuring the time of internalization and the abundance of the clathrin adaptor protein AP2, we further show that the pits that internalize RABV particles are similar to those that internalize VSV particles. Pharmacological perturbations of dynamin or of actin polymerization inhibit productive infection, linking our observations on particle uptake with viral infectivity. This work extends to RABV particles the finding that clathrin-mediated endocytosis of rhabdoviruses proceeds through incompletely coated pits which depend upon actin. C1 [Piccinotti, Silvia; Whelan, Sean P. J.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02114 USA. [Piccinotti, Silvia; Kirchhausen, Tomas; Whelan, Sean P. J.] Harvard Univ, Sch Med, Program Virol, Boston, MA USA. [Kirchhausen, Tomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [Kirchhausen, Tomas] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. RP Whelan, SPJ (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02114 USA. EM kirchhausen@crystal.harvard.edu; swhelan@hms.harvard.edu FU NIH [AI081842]; NERCE grant [U54AI057159]; Giovanni Armenise-Harvard Ph.D. Award; Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Award FX This work was funded by NIH grant AI081842 and NERCE grant U54AI057159. S.P.J.W. is a recipient of the Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Award, and S.P. is a recipient of the Giovanni Armenise-Harvard Ph.D. Award. NR 43 TC 22 Z9 22 U1 1 U2 33 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 NOV PY 2013 VL 87 IS 21 BP 11637 EP 11647 DI 10.1128/JVI.01648-13 PG 11 WC Virology SC Virology GA 237IR UT WOS:000325863400028 PM 23966407 ER PT J AU Raposo, RAS Abdel-Mohsen, M Bilska, M Montefiori, DC Nixon, DF Pillai, SK AF Raposo, Rui Andre Saraiva Abdel-Mohsen, Mohamed Bilska, Miroslawa Montefiori, David C. Nixon, Douglas F. Pillai, Satish K. TI Effects of Cellular Activation on Anti-HIV-1 Restriction Factor Expression Profile in Primary Cells SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-1 IN-VIVO; ANTIRETROVIRAL FACTOR; TYPE-1 HIV-1; PROTEIN; INFECTION; REPLICATION; INHIBITION; RELEASE; SAMHD1 AB Expression of cell-intrinsic antiviral factors suppresses HIV-1 replication. We hypothesized that cellular activation modulates host restriction and susceptibility to HIV-1 infection. We measured the gene expression of 34 antiviral factors in healthy peripheral blood mononuclear cells (PBMC). Cellular activation induced expression of interferon-stimulated gene 15 (ISG15), tripartite motif 5 alpha (TRIM5 alpha), bone marrow stromal cell antigen 2 (BST-2)/tetherin, and certain apolipoprotein B mRNA editing enzyme 3 (APOBEC3) family members. Expression of RTF1, RNA polymerase II-associated factor 1 (PAF1), TRIM11, TRIM26, and BST-2/tetherin correlated with decreased HIV-1 infectivity. This report demonstrates synchronous effects of activation-induced antiviral genes on HIV-1 infectivity, providing candidates for pharmacological manipulation. C1 [Raposo, Rui Andre Saraiva; Nixon, Douglas F.] Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94143 USA. [Abdel-Mohsen, Mohamed; Pillai, Satish K.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Bilska, Miroslawa; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Lab AIDS Vaccine Res & Dev, Durham, NC 27710 USA. [Pillai, Satish K.] Blood Syst Res Inst, San Francisco, CA USA. [Pillai, Satish K.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. RP Raposo, RAS (reprint author), Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94143 USA. EM Andre.Raposo@ucsf.edu OI Raposo, R. Andre/0000-0001-5435-0290; Nixon, Douglas/0000-0002-2801-1786 FU National Institutes of Health [AI093179, 1K01DA024654]; Peter and Shelagh Godsoe Family Foundation through the AIDS Research Institute at UCSF; UCSF-Gladstone Institute of Virology & Immunology Center for AIDS Research [P30-AI027763]; Academic Senate under the UCSF RAP awards program FX This work was supported by grants from the National Institutes of Health (AI093179 to D.F.N. and 1K01DA024654 to S. K. P.), the Peter and Shelagh Godsoe Family Foundation through the AIDS Research Institute at UCSF (to D.F.N.), and the UCSF-Gladstone Institute of Virology & Immunology Center for AIDS Research (P30-AI027763 to R. A. S. R.) and in part by a grant provided by the Academic Senate under the UCSF RAP awards program (to D.F.N.). NR 45 TC 15 Z9 15 U1 0 U2 7 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 NOV PY 2013 VL 87 IS 21 BP 11924 EP 11929 DI 10.1128/JVI.02128-13 PG 6 WC Virology SC Virology GA 237IR UT WOS:000325863400055 PM 23966394 ER PT J AU Singh, G Robinson, CM Dehghan, S Jones, MS Dyer, DW Seto, D Chodosh, J AF Singh, Gurdeep Robinson, Christopher M. Dehghan, Shoaleh Jones, Morris S. Dyer, David W. Seto, Donald Chodosh, James TI Homologous Recombination in E3 Genes of Human Adenovirus Species D SO JOURNAL OF VIROLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; REPLICATING HUMAN ADENOVIRUS; ACUTE RESPIRATORY-DISEASE; CELL-SURFACE EXPRESSION; GROWTH-FACTOR RECEPTOR; FAS-INDUCED APOPTOSIS; C HUMAN ADENOVIRUSES; CLASS-I ANTIGENS; EPIDEMIC KERATOCONJUNCTIVITIS; COMPUTATIONAL ANALYSIS AB Genes within the E3 transcription unit of human adenoviruses modulate host immune responses to infection. A comprehensive genomics and bioinformatics analysis of the E3 transcription unit for 38 viruses within human adenovirus species D (HAdV-D) revealed distinct and surprising patterns of homologous recombination. Homologous recombination was identified in open reading frames for E3 CR1 alpha, CR1 beta, and CR1 gamma, similar to that previously observed with genes encoding the three major structural capsid proteins, the penton base, hexon, and fiber. C1 [Singh, Gurdeep; Robinson, Christopher M.; Chodosh, James] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Howe Lab, Boston, MA 02115 USA. [Dehghan, Shoaleh; Seto, Donald] George Mason Univ, Sch Syst Biol, Bioinformat & Computat Biol Program, Manassas, VA USA. [Dehghan, Shoaleh] American Univ, Dept Chem, Washington, DC 20016 USA. [Jones, Morris S.] Naval Med Ctr, Div Infect Dis, San Diego, CA USA. [Dyer, David W.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73190 USA. RP Chodosh, J (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Howe Lab, Boston, MA 02115 USA. EM james_chodosh@meei.harvard.edu FU NIH [EY013124, P30EY014104]; Research to Prevent Blindness, Inc., New York, NY; Massachusetts Lions Eye Research Fund FX This work was supported by NIH grants EY013124 and P30EY014104, a Senior Scientific Investigator Award (to J.C.) from Research to Prevent Blindness, Inc., New York, NY, and the Massachusetts Lions Eye Research Fund. NR 83 TC 14 Z9 15 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2013 VL 87 IS 22 BP 12481 EP 12488 DI 10.1128/JVI.01927-13 PG 8 WC Virology SC Virology GA 237JJ UT WOS:000325865400047 PM 24027303 ER PT J AU Amstadter, AB Sumner, JA Acierno, R Ruggiero, KJ Koenen, KC Kilpatrick, DG Galea, S Gelernter, J AF Amstadter, A. B. Sumner, J. A. Acierno, R. Ruggiero, K. J. Koenen, K. C. Kilpatrick, D. G. Galea, S. Gelernter, J. TI Support for association of RORA variant and post traumatic stress symptoms in a population-based study of hurricane exposed adults SO MOLECULAR PSYCHIATRY LA English DT Letter ID GENOME-WIDE ASSOCIATION; POSTTRAUMATIC-STRESS; DISORDER; RISK C1 [Amstadter, A. B.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23284 USA. [Sumner, J. A.; Acierno, R.; Ruggiero, K. J.; Kilpatrick, D. G.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Acierno, R.; Ruggiero, K. J.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Koenen, K. C.; Galea, S.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Gelernter, J.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Gelernter, J.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Gelernter, J.] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA. [Gelernter, J.] VA CT Healthcare Ctr, West Haven, CT USA. RP Amstadter, AB (reprint author), Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23284 USA. EM abamstadter@vcu.edu FU NIMH NIH HHS [R21 MH074469] NR 10 TC 11 Z9 12 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD NOV PY 2013 VL 18 IS 11 BP 1148 EP 1149 DI 10.1038/mp.2012.189 PG 2 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 240KN UT WOS:000326094800001 PM 23319003 ER PT J AU Lam, TI Bingham, D Chang, TJ Lee, CC Shi, J Wang, DM Massa, S Swanson, RA Liu, JL AF Lam, Tina I. Bingham, Deborah Chang, Ting Ju Lee, Chih Cheng Shi, Jian Wang, Dongmin Massa, Stephen Swanson, Raymond A. Liu, Jialing TI Beneficial Effects of Minocycline and Botulinum Toxin-Induced Constraint Physical Therapy Following Experimental Traumatic Brain Injury SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE controlled cortical impact; constraint-induced movement therapy (CIMT); botox; rehabilitation; microglia; glial fibrillary acidic protein (GFAP) ID INDUCED MOVEMENT THERAPY; MICROGLIAL ACTIVATION; ANIMAL-MODELS; STROKE; METAANALYSIS; CNS; MECHANISMS; PLASTICITY; DISORDERS; CHILDREN AB Background. Effective recovery from functional impairments caused by traumatic brain injury (TBI) requires appropriate rehabilitation therapy. Multiple pathways are involved in secondary injury and recovery suggesting a role for multimodal approaches. Objective. Here, we examined the efficacy of the anti-inflammatory agent minocycline and botulinum toxin (botox)-induced limb constraint with structured physical therapy, delivered alone or in combination, after a severe TBI produced by a controlled cortical impact in rats. Methods. Minocycline was administered at 25 mg/kg daily for 2 weeks beginning 1 day after TBI or sham surgery. For constraint/physical therapy, botox-type A was injected into the nonaffected forearm muscle 1 day after injury and 2 weeks of physical therapy commenced at 5 days after injury. Functional evaluations were conducted 8 weeks after injury. Results. Minocycline, either as a monotherapy or as combination treatment with botox/physical therapy significantly reduced impairments of spatial learning and memory in the water maze test, whereas botox/physical therapy reduced forelimb motor asymmetry and improved manual dexterity in the cylinder and vermicelli handling tests, A synergistic effect between the 2 treatments was observed when rats performed tasks requiring dexterity. Inflammation was attenuated in the peri-contusion cortex and hippocampus in all TBI groups receiving mono or combination therapies, though there was no significant difference in lesion size among groups. Conclusion. These data provide a rationale for incorporating anti-inflammatory treatment during rehabilitation therapy. C1 [Lam, Tina I.; Bingham, Deborah; Chang, Ting Ju; Lee, Chih Cheng; Shi, Jian; Wang, Dongmin; Massa, Stephen; Swanson, Raymond A.; Liu, Jialing] San Francisco VA Med Ctr, San Francisco, CA USA. [Lam, Tina I.; Shi, Jian; Wang, Dongmin; Massa, Stephen; Swanson, Raymond A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Lam, Tina I.] USDA, Foodborne Contaminants Res Unit, Western Reg Res Ctr, Res Serv, Albany, CA USA. [Bingham, Deborah; Chang, Ting Ju; Lee, Chih Cheng; Liu, Jialing] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. RP Liu, JL (reprint author), Univ Calif San Francisco, Dept Neurol Surg 112C, 4150 Clement St, San Francisco, CA 94121 USA. EM jialing.liu@ucsf.edu RI Liu, Jialing/A-8627-2012; OI Liu, Jialing/0000-0003-4420-4382; Swanson, Raymond/0000-0002-3664-5359 FU Veterans Affairs Research Enhancement Award; Veterans Affairs merit awards FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a Veterans Affairs Research Enhancement Award (RAS), and Veterans Affairs merit awards (JL, SM).]. NR 41 TC 14 Z9 14 U1 2 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 EI 1552-6844 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD NOV PY 2013 VL 27 IS 9 BP 889 EP 899 DI 10.1177/1545968313491003 PG 11 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 229IL UT WOS:000325256000013 PM 23778701 ER PT J AU Caspers, KM Romitti, PA Lin, S Olney, RS Holmes, LB Werler, MM AF Caspers, Kristin M. Romitti, Paul A. Lin, Shao Olney, Richard S. Holmes, Lewis B. Werler, Martha M. CA Natl Birth Defects Prevention TI Maternal Periconceptional Exposure to Cigarette Smoking and Congenital Limb Deficiencies SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE case-control studies; limb deficiencies; congenital; maternal exposure; musculoskeletal abnormalities; pregnancy; smoking; folic acid ID NONSMOKING PREGNANT-WOMEN; BIRTH-DEFECTS PREVENTION; RED-BLOOD-CELLS; FOLIC-ACID; REDUCTION DEFECTS; PASSIVE SMOKING; TOBACCO-SMOKE; NEURAL-TUBE; HOMOCYSTEINE; GROWTH AB BackgroundCongenital limb deficiencies (LD)s are characterised by the failure or disruption in formation of limbs or digits. Epidemiological research on maternal exposure to cigarette smoke and LDs is inconclusive. MethodsData from the National Birth Defects Prevention Study were used to examine LDs and maternal exposure to active or passive cigarette smoke. Mothers of LD case (n=906) and unaffected control (n=8352) pregnancies from October 1997 through December 2007 reported on exposure type and quantity. Logistic regression was used to estimate adjusted odds ratio (OR) and 95% confidence interval [95% CI]; interactions with folic acid (FA) intake were tested. ResultsFor any LD, ORs were elevated for active (1.24 [95% CI 1.01, 1.53]), passive (home) (1.28 [95% CI 1.03, 1.59]), and active and passive' (1.34 [95% CI 1.05, 1.70]) exposures. The ORs for longitudinal LDs were elevated for passive (home) (1.62 [95% CI 1.14, 2.31]) and active and passive' (1.62 [95% CI 1.09, 2.41]) exposures. The OR for pre-axial LDs were elevated for any (1.39 [95% CI 1.01, 1.90]), active (1.53 [95% CI 1.03, 2.29]), passive (home) (1.82 [95% CI 1.23, 2.69]), and active and passive' (1.87 [95% CI 1.20, 2.92]) exposures. For lower limbs, ORs were elevated for passive (home) (1.44 [95% CI 1.01, 2.04]) and smoking 15 or more cigarettes/day (2.25 [95% CI 1.27, 3.97]). Interactions showed that ORs for any passive smoke exposure were 0.43 and 0.59 higher in the absence of FA intake for any and terminal transverse LDs. ConclusionsMaternal active smoking and exposure to passive cigarette smoke emerged as a potential teratogen that affects limb and digit formation. FA was not found to mitigate the impact. C1 [Caspers, Kristin M.; Romitti, Paul A.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA 52242 USA. [Lin, Shao] New York State Dept Hlth, Albany, NY USA. [Olney, Richard S.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Holmes, Lewis B.] Massachusetts Gen Hosp, Genet & Teratol Unit, Boston, MA 02114 USA. [Werler, Martha M.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. RP Romitti, PA (reprint author), Univ Iowa, Dept Epidemiol, Coll Publ Hlth, S416 CPHB,105 River St, Iowa City, IA 52242 USA. EM paul-romitti@uiowa.edu OI Lin, Shao/0000-0002-5535-7504 FU Centers for Disease Control and Prevention [PA 96043, PA 02081, FOA DD09-001] FX This work was supported by cooperative agreements under Program Announcements (PA) PA 96043, PA 02081, and FOA DD09-001 from the Centers for Disease Control and Prevention to the Centers for Birth Defects Research and Prevention participating in the National Birth Defects Prevention Study (NBDPS) (U01DD000492). Coding of drug information in NBDPS used the Slone Drug Dictionary, under license from the Slone Epidemiology Center at Boston University, Boston, MA. We would also like to acknowledge Drs Charlotte Hobbs, Gary Shaw, Marlene Anderka, Charlotte Druschel, Andrew Olshan, Robert Meyer, Mark Canfield, Peter Langlois, and Marcia Feldkamp. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. There are no stated conflicts of interest. NR 32 TC 5 Z9 5 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD NOV PY 2013 VL 27 IS 6 BP 509 EP 520 DI 10.1111/ppe.12075 PG 12 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 238WZ UT WOS:000325983800002 PM 24134526 ER PT J AU Oaklander, AL Herzog, ZD Downs, HM Klein, MM AF Oaklander, Anne Louise Herzog, Zeva Daniela Downs, Heather M. Klein, Max M. TI Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia SO PAIN LA English DT Article DE Chronic pain; Human-subject research; Peripheral neuropathy; Peripheral nerve; Skin biopsy; Autonomic function testing ID PRACTICE PARAMETER EVALUATION; AMERICAN-ACADEMY; SKIN BIOPSY; ELECTRODIAGNOSTIC MEDICINE; PERIPHERAL NEUROPATHY; DIAGNOSTIC-CRITERIA; PHYSICAL MEDICINE; WIDESPREAD PAIN; NERVE-FIBERS; HEALTH AB Fibromyalgia is a common, disabling syndrome that includes chronic widespread pain plus diverse additional symptoms. No specific objective abnormalities have been identified, which precludes definitive testing, disease-modifying treatments, and identification of causes. In contrast, small-fiber polyneuropathy (SFPN), despite causing similar symptoms, is definitionally a disease caused by the dysfunction and degeneration of peripheral small-fiber neurons. SFPN has established causes, some diagnosable and definitively treatable, eg, diabetes. To evaluate the hypothesis that some patients labeled as having fibromyalgia have unrecognized SFPN that is causing their illness symptoms, we analyzed SFPN-associated symptoms, neurological examinations, and pathological and physiological markers in 27 patients with fibromyalgia and in 30 matched normal controls. Patients with fibromyalgia had to satisfy the 2010 American College of Rheumatology criteria plus present evidence of a physician's actual diagnosis of fibromyalgia. The study's instruments comprised the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, plus autonomic-function testing (AFT). We found that 41% of skin biopsies from subjects with fibromyalgia vs 3% of biopsies from control subjects were diagnostic for SFPN, and MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects (all P <= 0.001). Abnormal AFTs were equally prevalent, suggesting that fibromyalgia-associated SFPN is primarily somatic. Blood tests from subjects with fibromyalgia and SFPN-diagnostic skin biopsies provided insights into causes. All glucose tolerance tests were normal, but 8 subjects had dysimmune markers, 2 had hepatitis C serologies, and 1 family had apparent genetic causality. These findings suggest that some patients with chronic pain labeled as fibromyalgia have unrecognized SFPN, a distinct disease that can be tested for objectively and sometimes treated definitively. (C) 2013 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved. C1 [Oaklander, Anne Louise; Herzog, Zeva Daniela; Downs, Heather M.; Klein, Max M.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Oaklander, Anne Louise] Massachusetts Gen Hosp, Dept Pathol Neuropathol, Boston, MA 02114 USA. RP Oaklander, AL (reprint author), Massachusetts Gen Hosp, Nerve Injury Unit, Dept Neurol, Warren 310,275 Charles St, Boston, MA 02114 USA. EM aoaklander@partners.org FU Public Health Service [NINDS K24NS059892, UIL RR025758]; Department of Defense Gulf War Illness Research Program [GW093049] FX Supported in part by the Public Health Service (NINDS K24NS059892, UIL RR025758), the Department of Defense Gulf War Illness Research Program (GW093049), and a charitable donation from Ms. Jane Cheever Powell. Presented in abstract form to the 2012 meeting of the American Neurological Association. We thank the subjects for their participation and Kate O'Neil and Siena Napoleon for their assistance. NR 52 TC 73 Z9 74 U1 2 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD NOV PY 2013 VL 154 IS 11 BP 2310 EP 2316 DI 10.1016/j.pain.2013.06.001 PG 7 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 238FG UT WOS:000325927500012 PM 23748113 ER PT J AU Oaklander, AL Herzog, ZD Downs, HM Klein, MM AF Oaklander, Anne Louise Herzog, Zeva Daniela Downs, Heather M. Klein, Max M. TI Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia Reply SO PAIN LA English DT Letter ID SENSORY NEUROPATHY; WIDESPREAD PAIN; GANGLIONITIS; PREVALENCE C1 [Oaklander, Anne Louise; Herzog, Zeva Daniela; Downs, Heather M.; Klein, Max M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Oaklander, Anne Louise] Massachusetts Gen Hosp, Dept Pathol Neuropathol, Boston, MA 02114 USA. RP Oaklander, AL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM aoaklander@partners.org NR 24 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD NOV PY 2013 VL 154 IS 11 BP 2569 EP 2571 DI 10.1016/j.pain.2013.07.016 PG 4 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 238FG UT WOS:000325927500042 PM 23891683 ER PT J AU Shields, AE Najafzadeh, M Schachter, AB AF Shields, Alexandra Elizabeth Najafzadeh, Mehdi Schachter, Anna Boonin TI Bumps along the translational pathway: anticipating uptake of tailored smoking cessation treatment SO PERSONALIZED MEDICINE LA English DT Article DE genetic testing; pharmacogenomics; pharmacogenomic treatment for smoking; pharmacotherapy; racial differences in pharmacotherapy use; smoking ID NICOTINE REPLACEMENT THERAPY; PRIMARY-CARE PHYSICIANS; UNITED-STATES; TRANSDERMAL NICOTINE; ETHNIC DISPARITIES; TOBACCO DEPENDENCE; RACIAL-DIFFERENCES; AFRICAN-AMERICAN; CLINICAL INTEGRATION; CIGARETTE-SMOKING AB Aim: To assess potential barriers to clinical integration of tailored smoking cessation treatment among African American and white smokers in the USA. Methods: A total of 392 smokers (203 white and 189 African American) identified within a national random digit dial survey (response rate: 40.1%; 81.2% among households with whom we were able to make contact) of 1200 African Americans and 1200 white Americans. Respondents answered several closed-ended survey items addressing beliefs regarding what influences a smoker's ability to quit, past pharmacotherapy use, and their willingness to undergo genetic assessment in order to be matched to optimal treatment, among other items. Results: In this first nationally representative survey of US smokers, 77% of respondents expressed willingness to undergo genetic testing in order to be matched to optimal pharmacotherapy, yet only 18% had ever used pharmacotherapy in a previous quit attempt. Smokers who rated medications and counseling' as very important in quitting were significantly more likely to endorse genetic testing (odds ratio [OR]: 8.94; 95% CI: 1.86-43.06), while those rating having God's help' as very important were significantly less likely to express willingness to undergo testing (OR: 0.11; 95% CI: 0.02-0.71). African American smokers were more likely than white smokers to express willingness to undergo genetic testing (OR: 3.80; 95% CI: 1.09-13.22), despite lower rates of previous pharmacotherapy use. Conclusion: While smokers reported high rates of willingness to undergo genetic testing to be matched to optimal treatment, these results suggest that smokers' willingness to use medications indicated by genetic test results may prove a significant barrier to realizing the promise of tailored smoking cessation treatment. The role of spirituality in smokers' willingness to use medication is an area for further study. C1 [Shields, Alexandra Elizabeth; Schachter, Anna Boonin] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Harvard MGH Ctr Genom Vulnerable Populat & Hlth D, Boston, MA 02114 USA. [Shields, Alexandra Elizabeth] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Najafzadeh, Mehdi] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA. RP Shields, AE (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Harvard MGH Ctr Genom Vulnerable Populat & Hlth D, 50 Staniford St,Suite 901, Boston, MA 02114 USA. EM ashields@partners.org FU National Human Genomics Research Institute [R01 HG003475-03]; Canadian Institutes for Health Research Fellowship FX This work is supported by The National Human Genomics Research Institute (R01 HG003475-03, A Shields Principle Investigator) and the Canadian Institutes for Health Research Fellowship (M Najafzadeh). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 75 TC 3 Z9 3 U1 3 U2 8 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 EI 1744-828X J9 PERS MED JI Pers. Med. PD NOV PY 2013 VL 10 IS 8 BP 813 EP 825 DI 10.2217/pme.13.89 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 235VA UT WOS:000325747600013 ER PT J AU Micheli, JE Chinn, LW Shugarts, SB Patel, A Martin, JN Bangsberg, DR Kroetz, DL AF Micheli, Janine E. Chinn, Leslie W. Shugarts, Sarah B. Patel, Ashish Martin, Jeffrey N. Bangsberg, David R. Kroetz, Deanna L. TI Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms: towards addressing the missing heritability in pharmacogenetic phenotypes? SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE CYP2B6; human immunodeficiency virus; nevirapine; pharmacogenetics; pharmacokinetics ID HIV-INFECTED PATIENTS; MULTILOCUS GENOTYPE DATA; PLASMA-CONCENTRATIONS; CYP2B6; POPULATION; EFAVIRENZ; ASSOCIATIONS; VARIABILITY; INFERENCE; DRUGS AB ObjectiveNevirapine is an important component of highly active antiretroviral therapy used in the treatment of HIV infection. There is a considerable variation in the pharmacokinetics of nevirapine and this variation can impact the efficacy and toxicity of nevirapine. Although some of this variation can be attributed to environmental factors, the degree to which heritability influences nevirapine pharmacokinetics is unknown. This study aims to estimate how much variation in nevirapine pharmacokinetics is due to genetic factors and to investigate the contribution of selected polymorphisms to this variability.MethodsTwo doses of immediate-release nevirapine were administered to European (n=11) and African American (n=6) participants recruited from the Research in Access to Care in the Homeless cohort. A repeated drug administration method was then used to determine the relative genetic contribution (r(GC)) to variability in nevirapine AUC(0-6) (h). Nevirapine plasma levels were quantified using LC/MS/MS. Patients were also genotyped for selected polymorphisms in candidate genes that may influence nevirapine pharmacokinetics.ResultsA significant r(GC) for nevirapine AUC(0-6) (h) was found in Europeans (P=0.02) and African Americans (P=0.01). A trend toward higher nevirapine AUC(0-6) (h) for the CYP2B6 516TT (rs3745274; Q172H) genotype was observed in European Americans (P=0.19).ConclusionThis study demonstrates that there is a significant genetic component to variability in nevirapine pharmacokinetics. Although genetic variants such as CYP2B6 polymorphisms attributed to some of this variation, these data suggest that there may be additional genetic factors that influence nevirapine pharmacokinetics. C1 [Micheli, Janine E.; Chinn, Leslie W.; Shugarts, Sarah B.; Patel, Ashish; Kroetz, Deanna L.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Kroetz, Deanna L.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Global Hlth,Ragon Inst Massachusetts Gen Hosp, Boston, MA USA. RP Kroetz, DL (reprint author), 1550 4th St,Rock Hall 584E,Box 2911, San Francisco, CA 94158 USA. EM deanna.kroetz@ucsf.edu FU NIH [GM61390, MH54907, T32 GM007175] FX This work was funded by NIH grants GM61390 and MH54907. Janine Micheli was supported by NIH T32 GM007175. NR 33 TC 7 Z9 7 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 EI 1744-6880 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD NOV PY 2013 VL 23 IS 11 BP 591 EP 596 DI 10.1097/FPC.0b013e32836533a5 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 235BR UT WOS:000325690200002 PM 23982262 ER PT J AU Shum, WWC Hill, E Brown, D Breton, S AF Shum, Winnie W. C. Hill, Eric Brown, Dennis Breton, Sylvie TI Plasticity of basal cells during postnatal development in the rat epididymis SO REPRODUCTION LA English DT Article ID MALE REPRODUCTIVE-TRACT; S-TRANSFERASE-P; LUMINAL ACIDIFICATION; EPITHELIAL-CELLS; EFFERENT DUCTS; STEM-CELLS; MURINE EPIDIDYMIS; STEROID-HORMONES; VAS-DEFERENS; EXPRESSION AB Our previous study has shown that basal cells sense luminal factors by forming a narrow body projection that can cross epithelial tight junctions. As a first step toward characterizing the structural plasticity of basal cells, in this study, we followed their appearance and morphology in the rat epididymis and vas deferens (VD) during postnatal development and examined their modulation by androgens in adulthood. Immunofluorescence labeling for cytokeratin 5 showed that basal cells are absent at birth. They progressively appear in a retrograde manner from the VD and cauda epididymis to the initial segments during the postnatal weeks PNW1-3. At the onset of differentiation, basal cells are in contact with the lumen and their nucleus is located at the same level as that of adjacent epithelial cells. Basal cells then position their nucleus to the base of the epithelium, and while some are still in contact with the lumen, others have a 'dome-shaped' appearance. At PNW5-6, basal cells form a loose network at the base of the epithelium, and luminal-reaching basal cells are rarely detected. The arrival of spermatozoa during PNW7-8 did not trigger the development of projections in basal cells. However, cells with a narrow luminal-reaching projection began to reappear between PNW8 and PNW12 in the corpus and the cauda. Treatment with flutamide from PNW10 to PNW12 significantly reduced the number of luminal-reaching basal cell projections. In summary, basal cells exhibit significant structural plasticity during differentiation. Fewer apical-reaching projections were detected after flutamide treatment in adulthood, indicating the role of androgens in the luminal-sensing function of basal cells. C1 [Shum, Winnie W. C.] Harvard Univ, Massachusetts Gen Hosp, Program Membrane Biol, Med Sch,Ctr Syst Biol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Div Nephrol, Med Sch,Ctr Syst Biol, Boston, MA 02114 USA. RP Shum, WWC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Program Membrane Biol, Med Sch,Ctr Syst Biol, 185 Cambridge St Simches Res Ctr, Boston, MA 02114 USA. EM shum.winnie@mgh.harvard.edu FU NIH [DK085715, HD040793]; MGH ECOR; Boston Area Diabetes and Endocrinology Research Center [DK57521]; Center for the Study of Inflammatory Bowel Disease [DK43341]; MGH FX This work was supported by NIH grants DK085715 and HD040793 to S Breton and by an MGH ECOR Fund for Medical Discovery Award to W W C Shum. The Microscopy Core facility of the MGH Program in Membrane Biology receives support from the Boston Area Diabetes and Endocrinology Research Center (DK57521) and the Center for the Study of Inflammatory Bowel Disease (DK43341). S Breton is a recipient of the Charles and Ann Sanders Research Scholar Award at MGH. NR 72 TC 11 Z9 12 U1 0 U2 5 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1470-1626 J9 REPRODUCTION JI Reproduction PD NOV PY 2013 VL 146 IS 5 BP 455 EP 469 DI 10.1530/REP-12-0510 PG 15 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 239BJ UT WOS:000325996200008 PM 23960170 ER PT J AU Moskowitz, MA Iadecola, C Norrving, B AF Moskowitz, Michael A. Iadecola, Costantino Norrving, Bo TI Bo K. Siesjo, MD, PhD January 8, 1930, to June 27, 2013 SO STROKE LA English DT Biographical-Item C1 [Moskowitz, Michael A.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Moskowitz, Michael A.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Iadecola, Costantino] Weill Cornell Med Coll, Brain & Mind Res Inst, New York, NY USA. [Norrving, Bo] Lund Univ, Div Neurol, Dept Clin Sci, Lund, Sweden. RP Norrving, B (reprint author), Lund Univ, Div Neurol, Dept Clin Sci, Lund, Sweden. EM bo.norrving@med.lu.se NR 1 TC 0 Z9 0 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD NOV PY 2013 VL 44 IS 11 BP 2985 EP 2986 DI 10.1161/STROKEAHA.113.003311 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 238YE UT WOS:000325987300018 ER PT J AU Woo, D Deka, R Falcone, GJ Flaherty, ML Haverbusch, M Martini, SR Greenberg, SM Ayres, AM Sauerbeck, L Kissela, BM Kleindorfer, DO Moomaw, CJ Anderson, CD Broderick, JP Rosand, J Langefeld, CD Woo, JG AF Woo, Daniel Deka, Ranjan Falcone, Guido J. Flaherty, Matthew L. Haverbusch, Mary Martini, Sharyl R. Greenberg, Steven M. Ayres, Alison M. Sauerbeck, Laura Kissela, Brett M. Kleindorfer, Dawn O. Moomaw, Charles J. Anderson, Christopher D. Broderick, Joseph P. Rosand, Jonathan Langefeld, Carl D. Woo, Jessica G. TI Apolipoprotein E, Statins, and Risk of Intracerebral Hemorrhage SO STROKE LA English DT Article DE apolipoprotein E; epidemiology; genetics; hydroxymethylgutaryl-CoA reductase inhibitors; intracerebral hemorrhage; pharmacogenomics ID SPORADIC ALZHEIMERS-DISEASE; CORONARY-ARTERY-DISEASE; AMYLOID ANGIOPATHY; CHOLESTEROL LEVELS; SERUM-CHOLESTEROL; STROKE; ALLELE; HYPERCHOLESTEROLEMIA; POLYMORPHISMS; POPULATION AB Background and Purpose Apolipoprotein E (ApoE) genotypes have been associated with lobar intracerebral hemorrhage (ICH). Although statins have been associated with an increased risk of ICH, meta-analyses have not consistently shown a statin-induced risk of ICH. Here, we test whether hypercholesterolemia (HC) and ApoE polymorphisms affect the risk of ICH by statin use. Methods The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study is a prospective, demographically matched case-control study of ICH. A similar study of ICH, Genetic Risks for Medication-Related Hemorrhagic Stroke (GOCHA), was used as a replication cohort. Subjects were classified as normocholesterolemia, HC without statin use, and HC with statin use. Statistical comparisons were performed using Fisher exact test, (2) tests, and the Breslow-Day test. Results The discovery cohort consisted of 558 ICH cases and 1444 controls, and the replication cohort consisted of 1020 ICH cases and 382 controls. The association of lower risk for HC was not attenuated by statin use. Statin use was observed to confer a higher risk for lobar ICH in those carrying ApoE4/E4 and ApoE2/E4 genotypes in both discovery and replication cohorts, and a test for interaction showed a trend towards significance (P=0.11 for statin and ApoE4/E4). Conclusions Statin use does not seem to attenuate the association of HC with decreased risk for nonlobar ICH. Our data support a gene-by-drug effect for lobar ICH, but larger sample sizes are needed to confirm the association before any clinical change is warranted. Clinical Trial Registration URL: http://clinicaltrials.gov. Unique identifier: NCT00930280. C1 [Woo, Daniel; Flaherty, Matthew L.; Haverbusch, Mary; Martini, Sharyl R.; Sauerbeck, Laura; Kissela, Brett M.; Kleindorfer, Dawn O.; Moomaw, Charles J.; Broderick, Joseph P.] Univ Cincinnati, Dept Neurol, Cincinnati, OH 45267 USA. [Deka, Ranjan] Univ Cincinnati, Dept Environm Hlth, Cincinnati, OH 45267 USA. [Falcone, Guido J.; Anderson, Christopher D.; Rosand, Jonathan] Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Falcone, Guido J.; Greenberg, Steven M.; Ayres, Alison M.; Anderson, Christopher D.; Rosand, Jonathan] Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA. [Falcone, Guido J.; Anderson, Christopher D.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Falcone, Guido J.; Anderson, Christopher D.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Falcone, Guido J.; Anderson, Christopher D.; Rosand, Jonathan] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Langefeld, Carl D.] Wake Forest Univ, Dept Biostat Sci, Winston Salem, NC 27109 USA. [Woo, Jessica G.] Cincinnati Childrens Hosp Med Ctr, Div Biostat & Epidemiol