FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Mousavi, K Zare, H Wang, AHJ Sartorelli, V AF Mousavi, Kambiz Zare, Hossein Wang, A. Hongjun Sartorelli, Vittorio TI Polycomb Protein Ezh1 Promotes RNA Polymerase II Elongation SO MOLECULAR CELL LA English DT Article ID EMBRYONIC STEM-CELLS; GROUP GENE; TARGET GENES; DIFFERENTIATION; EXPRESSION; CHROMATIN; PLURIPOTENCY; METHYLATION; MECHANISMS; NETWORK AB Polycomb group (PcG) proteins initiate the formation of repressed chromatin domains and regulate developmental gene expression. A mammalian PcG protein, enhancer of zeste homolog 2 (Ezh2), triggers transcriptional repression by catalyzing the addition of methyl groups onto lysine 27 of histone H3 (H3K27me2/3). This action facilitates the binding of other PcG proteins to chromatin for purposes of transcriptional silencing. Interestingly, there exists a paralog of Ezh2, termed Ezh1, whose primary function remains unclear. Here, we provide evidence for genome-wide association of Ezh1 complex with active epigenetic mark (H3K4me3), RNA polymerase II (Pol II), and mRNA production. Ezh1 depletion reduced global Pol II occupancy within gene bodies and resulted in delayed transcriptional activation during differentiation of skeletal muscle cells. Conversely, overexpression of wild-type Ezh1 led to premature gene activation and rescued Pol II occupancy defects in Ezh1-depleted cells. Collectively, these findings reveal a role for a PcG complex in promoting mRNA transcription. C1 [Mousavi, Kambiz; Zare, Hossein; Wang, A. Hongjun; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Rockville, MD 20852 USA. RP Sartorelli, V (reprint author), NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, 50 South Dr, Rockville, MD 20852 USA. EM sartorev@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH); NIH FX We thank Mr. Gustavo Gutierrez-Cruz of NIAMS Genome Facility for assistance with sequencing and Drs. T. Jenuwein, S.H. Orkin, and R. Margueron for providing the plasmids and Ezh1 antibody used in this study. This work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) and the NIH Director's Challenge Award on "Epigenomic Regulation of Mammalian Development and Differentiation." NR 25 TC 72 Z9 73 U1 2 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 27 PY 2012 VL 45 IS 2 BP 255 EP 262 DI 10.1016/j.molcel.2011.11.019 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 885EQ UT WOS:000299761700013 PM 22196887 ER PT J AU Fouchier, RAM Garcia-Sastre, A Kawaoka, Y Barclay, WS Bouvier, NM Brown, IH Capua, I Chen, H Compans, RW Couch, RB Cox, NJ Doherty, PC Donis, RO Feldmann, H Guan, Y Katz, J Klenk, HD Kobinger, G Liu, JH Liu, XF Lowen, A Metten-Leiter, TC Osterhaus, ADME Palese, P Peiris, JSM Perez, DR Richt, JA Schultz-Cherry, S Steel, J Subbarao, K Swayne, DE Takimoto, T Tashiro, M Taubenberger, JK Thomas, PG Tripp, RA Tumpey, TM Webby, RJ Webster, RG AF Fouchier, Ron A. M. Garcia-Sastre, Adolfo Kawaoka, Yoshihiro Barclay, Wendy S. Bouvier, Nicole M. Brown, Ian H. Capua, Ilaria Chen, Hualan Compans, Richard W. Couch, Robert B. Cox, Nancy J. Doherty, Peter C. Donis, Ruben O. Feldmann, Heinz Guan, Yi Katz, Jaqueline Klenk, H. D. Kobinger, Gary Liu, Jinhua Liu, Xiufan Lowen, Anice Metten-Leiter, Thomas C. Osterhaus, Albert D. M. E. Palese, Peter Peiris, J. S. Malik Perez, Daniel R. Richt, Juergen A. Schultz-Cherry, Stacey Steel, John Subbarao, Kanta Swayne, David E. Takimoto, Toru Tashiro, Masato Taubenberger, Jeffery K. Thomas, Paul G. Tripp, Ralph A. Tumpey, Terrence M. Webby, Richard J. Webster, Robert G. TI Pause on Avian Flu Transmission Research SO SCIENCE LA English DT Letter C1 [Fouchier, Ron A. M.; Osterhaus, Albert D. M. E.] Erasmus MC, Dept Virol, NL-3015 GE Rotterdam, Netherlands. [Bouvier, Nicole M.] Mt Sinai Sch Med, Dept Microbiol, Sch Med, New York, NY 10029 USA. [Kawaoka, Yoshihiro] Univ Wisconsin, Dept Pathobiol Sci, Sch Vet Med, Madison, WI 53711 USA. [Barclay, Wendy S.] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England. [Bouvier, Nicole M.] Mt Sinai Sch Med, Div Infect Dis, Sch Med, New York, NY 10029 USA. [Brown, Ian H.] Anim Hlth & Vet Labs Agcy, Dept Virol, Addlestone KT15, Surrey, England. [Capua, Ilaria] Ist Zooprofilatt Sperimentale Venezie, I-35020 Padua, Italy. [Chen, Hualan] CAAS, Harbin Vet Res Inst, Harbin 150001, Peoples R China. [Compans, Richard W.] Emory Univ, Sch Med, Influenza Pathogenesis & Immunol Res Ctr, Atlanta, GA 30322 USA. [Couch, Robert B.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Donis, Ruben O.] Ctr Dis Control & Prevent, Influenza Div, Mol Virol & Vaccines Branch, Atlanta, GA 30333 USA. [Doherty, Peter C.] St Jude Childrens Hosp, Dept Immunol, Memphis, TN 38105 USA. [Feldmann, Heinz] NIAID, Virol Lab, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. [Guan, Yi] Univ Hong Kong, State Key Lab Emerging Infect Dis, Hong Kong, Hong Kong, Peoples R China. [Katz, Jaqueline] Ctr Dis Control & Prevent, Immunol & Pathogenesis Branch, Influenza Div, Atlanta, GA 30333 USA. [Klenk, H. D.] Inst Virol, D-35043 Marburg, Germany. [Kobinger, Gary] Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB R3E 3R2, Canada. [Liu, Jinhua] China Agr Univ, Dept Preventat Vet Med, Beijing 100094, Peoples R China. [Liu, Xiufan] Yangzhou Univ, Anim Infect Dis Lab, Sch Vet Med, Yangzhou 225009, Jiangsu, Peoples R China. [Lowen, Anice] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Metten-Leiter, Thomas C.] Friedrich Loeffler Inst, D-17493 Greifswald, Germany. [Palese, Peter] Mt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA. [Peiris, J. S. Malik] Univ Hong Kong, Dept Microbiol, Pokfulam, Hong Kong, Peoples R China. [Peiris, J. S. Malik] Univ Hong Kong, HKU Pasteur Res Ctr, Pokfulam, Hong Kong, Peoples R China. [Perez, Daniel R.] Univ Maryland, Dept Vet Med, College Pk, MD 20742 USA. [Richt, Juergen A.] Kansas State Univ, Coll Vet Med, Manhattan, KS 66506 USA. [Schultz-Cherry, Stacey] St Jude Childrens Hosp, Dept Infect Dis, Memphis, TN 38105 USA. [Steel, John] Emory Univ, Dept Microbiol & Immunol, Sch Med, Atlanta, GA 30322 USA. [Subbarao, Kanta] NIAID, Emerging Resp Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Swayne, David E.] ARS, SE Poultry Res Lab, USDA, Athens, GA 30605 USA. [Takimoto, Toru] Univ Rochester, Med Ctr, Dept Microbiol & Immunol, Rochester, NY 14642 USA. [Tashiro, Masato] Natl Inst Infect Dis, Influenza Virus Res Ctr, Tokyo 208001, Japan. [Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Lab Infect Dis, NIH, Bethesda, MD 20892 USA. [Thomas, Paul G.] St Jude Childrens Hosp, Dept Immunol, Memphis, TN 38105 USA. [Tripp, Ralph A.] Univ Georgia, Dept Infect Dis, Coll Vet Med, Athens, GA 30602 USA. [Tumpey, Terrence M.] Ctr Dis Control & Prevent, Influenza Div, Atlanta, GA 30333 USA. [Webster, Robert G.] St Jude Childrens Hosp, Dept Infect Dis, Div Virol, Memphis, TN 38105 USA. RP Fouchier, RAM (reprint author), Erasmus MC, Dept Virol, 3000CA Rotterdam, NL-3015 GE Rotterdam, Netherlands. EM r.fouchier@erasmusmc.nl RI Doherty, Peter Charles/C-4185-2013; Compans, Richard/I-4087-2013; Brown, Ian/E-1119-2011; APHA, Staff publications/E-6082-2010; Fouchier, Ron/A-1911-2014; OI Bouvier, Nicole/0000-0002-4530-2841; Doherty, Peter Charles/0000-0002-5028-3489; Osterhaus, Albert/0000-0002-6074-1172; Palese, Peter/0000-0002-0337-5823; Garcia-Sastre, Adolfo/0000-0002-6551-1827; Perez, Daniel/0000-0002-6569-5689; Compans, Richard/0000-0003-2360-335X; Fouchier, Ron/0000-0001-8095-2869; Tripp, Ralph/0000-0002-2924-9956; Thomas, Paul G./0000-0001-7955-0256 FU Intramural NIH HHS [Z01 AI000986-01] NR 0 TC 35 Z9 38 U1 1 U2 29 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 27 PY 2012 VL 335 IS 6067 BP 400 EP 401 DI 10.1126/science.1219412 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 881FG UT WOS:000299466800019 PM 22282787 ER PT J AU Brown, JC Huedo-Medina, TB Pescatello, LS Ryan, SM Pescatello, SM Moker, E LaCroix, JM Ferrer, RA Johnson, BT AF Brown, Justin C. Huedo-Medina, Tania B. Pescatello, Linda S. Ryan, Stacey M. Pescatello, Shannon M. Moker, Emily LaCroix, Jessica M. Ferrer, Rebecca A. Johnson, Blair T. TI The Efficacy of Exercise in Reducing Depressive Symptoms among Cancer Survivors: A Meta-Analysis SO PLOS ONE LA English DT Article ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; POPULATION-BASED COHORT; BREAST-CANCER; PHYSICAL-ACTIVITY; REHABILITATION PROGRAM; ADJUVANT CHEMOTHERAPY; AEROBIC EXERCISE; PUBLICATION BIAS; META-REGRESSION AB Introduction: The purpose of this meta-analysis was to examine the efficacy of exercise to reduce depressive symptoms among cancer survivors. In addition, we examined the extent to which exercise dose and clinical characteristics of cancer survivors influence the relationship between exercise and reductions in depressive symptoms. Methods: We conducted a systematic search identifying randomized controlled trials of exercise interventions among adult cancer survivors, examining depressive symptoms as an outcome. We calculated effect sizes for each study and performed weighted multiple regression moderator analysis. Results: We identified 40 exercise interventions including 2,929 cancer survivors. Diverse groups of cancer survivors were examined in seven exercise interventions; breast cancer survivors were examined in 26; prostate cancer, leukemia, and lymphoma were examined in two; and colorectal cancer in one. Cancer survivors who completed an exercise intervention reduced depression more than controls, d(+) = 20.13 (95% CI: -0.26, -0.01). Increases in weekly volume of aerobic exercise reduced depressive symptoms in dose-response fashion (beta = -0.24, p = 0.03), a pattern evident only in higher quality trials. Exercise reduced depressive symptoms most when exercise sessions were supervised (beta = -0.26, p = 0.01) and when cancer survivors were between 47-62 yr (beta = 0.27, p = 0.01). Conclusion: Exercise training provides a small overall reduction in depressive symptoms among cancer survivors but one that increased in dose-response fashion with weekly volume of aerobic exercise in high quality trials. Depressive symptoms were reduced to the greatest degree among breast cancer survivors, among cancer survivors aged between 47-62 yr, or when exercise sessions were supervised. C1 [Brown, Justin C.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Brown, Justin C.] Univ Penn, Perelman Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Huedo-Medina, Tania B.; Pescatello, Linda S.; Moker, Emily; LaCroix, Jessica M.; Johnson, Blair T.] Univ Connecticut, Ctr Hlth Intervent & Prevent, Storrs, CT USA. [Ryan, Stacey M.] Univ Texas MD Anderson Canc Ctr, Dept Phys Therapy, Houston, TX 77030 USA. [Pescatello, Shannon M.] Western New England Coll, Dept Psychol, Springfield, MA USA. [Ferrer, Rebecca A.] NCI, Rockville, MD USA. RP Brown, JC (reprint author), Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. EM brownjus@mail.med.upenn.edu FU University of Connecticut Research Advisory Council Foundation [433527] FX Funding was provided by the University of Connecticut Research Advisory Council Foundation grant no. 433527 (PIs: Blair T. Johnson and Linda S. Pescatello). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 91 TC 93 Z9 95 U1 2 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 27 PY 2012 VL 7 IS 1 AR e30955 DI 10.1371/journal.pone.0030955 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 911GB UT WOS:000301704200049 ER PT J AU Gamaleddin, I Zvonok, A Makriyannis, A Goldberg, SR Le Foll, B AF Gamaleddin, Islam Zvonok, Alexander Makriyannis, Alexandros Goldberg, Steven R. Le Foll, Bernard TI Effects of a Selective Cannabinoid CB2 Agonist and Antagonist on Intravenous Nicotine Self Administration and Reinstatement of Nicotine Seeking SO PLOS ONE LA English DT Article ID RECEPTOR ANTAGONIST; ENDOCANNABINOID SYSTEM; NEUROPATHIC PAIN; HUMAN BRAIN; RATS; ACTIVATION; MICE; INHIBITION; ADDICTION; BEHAVIOR AB Over the last decade there have been significant advances in the discovery and understanding of the cannabinoid system along with the development of pharmacologic tools that modulate its function. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications on our understanding of the neurobiological mechanisms underlying nicotine dependence. Two types of cannabinoid receptors (CB1 and CB2) have been identified. CB1 receptors are expressed in the brain and modulate drug taking and drug seeking for various drugs of abuse, including nicotine. CB2 receptors have been recently identified in the brain and have been proposed to play a functional role in mental disorders and drug addiction. Our objective was to explore the role of CB2 receptors on intravenous nicotine self administration under two schedules of reinforcement (fixed and progressive ratio) and on nicotine seeking induced by nicotine priming or by nicotine associated cues. For this, we evaluated the effects of various doses of the selective CB2 antagonist AM630 (1.25 to 5 mg/kg) and CB2 agonist AM1241 (1 to 10 mg/kg) on these behavioral responses in rats. Different groups of male Long Evans rats were trained to lever press for nicotine at a unit dose of 30 mu g/kg/infusion. Subsequently, animals were randomized using a Latin-square design and injected with either AM1241 or AM630 using a counterbalanced within subject design. Administration of the CB2 ligands did not affect either nicotinetaking nicotine-seeking behavior. Our results do not support the involvement of CB2 receptors in nicotine-taking or nicotine-seeking behavior. C1 [Gamaleddin, Islam; Le Foll, Bernard] Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON, Canada. [Le Foll, Bernard] Univ Toronto, Inst Med Sci, Dept Family & Community Med, Toronto, ON M5S 1A1, Canada. [Le Foll, Bernard] Univ Toronto, Inst Med Sci, Dept Psychiat, Toronto, ON M5S 1A1, Canada. [Le Foll, Bernard] Univ Toronto, Inst Med Sci, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A1, Canada. [Gamaleddin, Islam; Le Foll, Bernard] Ctr Addict & Mental Hlth, Addict Program, Toronto, ON, Canada. [Goldberg, Steven R.] Natl Inst Drug Abuse, US Dept HHS, Intramural Res Program, NIH, Baltimore, MD USA. [Zvonok, Alexander; Makriyannis, Alexandros] Northeastern Univ, Ctr Drug Discovery, Bouve Coll Hlth Sci, Boston, MA 02115 USA. RP Gamaleddin, I (reprint author), Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON, Canada. EM bernard_lefoll@camh.net RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 FU Canadian Tobacco Control Research Initiative [73776 45000 0802]; Egyptian Ministry of Higher Education - Ain Shams University; Centre for Addiction and Mental Health CAMH; CFI - LOF [940707]; NIDA, NIH, DHHS FX This research was supported by a student grant from Canadian Tobacco Control Research Initiative (Grant # 73776 45000 0802) by the Egyptian Ministry of Higher Education - Ain Shams University, by the Centre for Addiction and Mental Health CAMH, CFI - LOF # 940707 and by the Intramural Research Program of NIDA, NIH, DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 29 Z9 29 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 26 PY 2012 VL 7 IS 1 AR e29900 DI 10.1371/journal.pone.0029900 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 911FX UT WOS:000301703800006 PM 22291896 ER PT J AU Park, C Hwang, IY Sinha, RK Kamenyeva, O Davis, MD Kehrl, JH AF Park, Chung Hwang, Il-Young Sinha, Rajesh K. Kamenyeva, Olena Davis, Michael D. Kehrl, John H. TI Lymph node B lymphocyte trafficking is constrained by anatomy and highly dependent upon chemoattractant desensitization SO BLOOD LA English DT Article ID T-LYMPHOCYTES; CHEMOKINE RECEPTOR; DENDRITIC CELLS; IN-VIVO; MIGRATION; ORGANS; ENTRY; EXPRESSION; EGRESS; MICROENVIRONMENTS AB B lymphocyte recirculation through lymph nodes (LNs) requires crossing endothelial barriers and chemoattractant-triggered cell migration. Here we show how LN anatomy and chemoattractant receptor signaling organize B lymphocyte LN trafficking. Blood-borne B cells predominately used CCR7 signaling to adhere to high endothelial venules (HEVs). New B cell emigrants slowly transited the HEV perivenule space, and thereafter localized nearby, avoiding the follicle. Eventually, the newly arrived B cells entered the basal portion of the follicle gradually populating it. In contrast, newly arriving activated B cells rapidly crossed HEVs and migrated toward the lymph node follicle. During their LN residency, recirculating B cells reacquired their sphingosine-1 phospate receptor 1 (S1P1) receptors and markedly attenuated their sensitivity to chemokines. Eventually, the B cells exited the LN follicle by entering the cortical lymphatics or returning to the paracortical cords. Upon entering the lymph, the B cells lost their polarity, down-regulated their S1P1 receptors, and subsequently strongly up-regulated their sensitivity to chemokines. These results are summarized in a model of homeostatic trafficking of B cells through LNs. (Blood. 2012;119(4):978-989) C1 [Park, Chung; Hwang, Il-Young; Sinha, Rajesh K.; Kamenyeva, Olena; Davis, Michael D.; Kehrl, John H.] NIAID, Cell Mol Immunol Sect B, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Kehrl, JH (reprint author), NIAID, Cell Mol Immunol Sect B, Immunoregulat Lab, NIH, Bldg 10,Rm 11B08,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov OI Kehrl, John/0000-0002-6526-159X FU National Institutes of Health (National Institute of Allergy and Infectious Diseases [NIAID]) FX This research was supported by the Intramural Research Program of the National Institutes of Health (National Institute of Allergy and Infectious Diseases [NIAID]). NR 42 TC 27 Z9 27 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 26 PY 2012 VL 119 IS 4 BP 978 EP 989 DI 10.1182/blood-2011-06-364273 PG 12 WC Hematology SC Hematology GA 886NI UT WOS:000299860700012 PM 22039261 ER PT J AU Sjoberg, J Halthur, C Kristinsson, SY Landgren, O Nygell, UA Dickman, PW Bjorkholm, M AF Sjoberg, Jan Halthur, Cat Kristinsson, Sigurdur Y. Landgren, Ola Nygell, Ulla Axdorph Dickman, Paul W. Bjorkholm, Magnus TI Progress in Hodgkin lymphoma: a population-based study on patients diagnosed in Sweden from 1973-2009 SO BLOOD LA English DT Article ID NATIONAL CARE PROGRAM; COLLABORATIVE BRITISH COHORT; SWEDISH CANCER REGISTER; HIGH-DOSE CHEMOTHERAPY; LONG-TERM SURVIVORS; RANDOMIZED-TRIAL; COMBINATION CHEMOTHERAPY; CELL TRANSPLANTATION; PROGNOSTIC-FACTORS; RELATIVE SURVIVAL AB In recent decades, attention has focused on reducing long-term, treatment-related morbidity and mortality in Hodgkin lymphoma (HL). In the present study, we looked for trends in relative survival for all patients diagnosed with HL in Sweden from 1973-2009 (N = 6949; 3985 men and 2964 women; median age, 45 years) and followed up for death until the end of 2010. Patients were categorized into 6 age groups and 5 calendar periods (19731979, 1980-1986, 1987-1994, 1994-2000, and 2001-2009). Relative survival improved in all age groups, with the greatest improvement in patients 51-65 years of age (P < .0005). A plateau in relative survival was observed in patients below 65 years of age during the last calendar period, suggesting a reduced long-term, treatment-related mortality. The 10-year relative survival for patients diagnosed in 2000-2009 was 0.95, 0.96, 0.93, 0.80, and 0.44 for the age groups 0-18, 19-35, 36-50, 51-65, and 66-80, respectively. Therefore, despite progress, age at diagnosis remains an important prognostic factor (P < .0005). Advances in therapy for patients with limited and advanced-stage HL have contributed to an increasing cure rate. In addition, our findings support that long-term mortality of HL therapy has decreased. Elderly HL patients still do poorly, and targeted treatment options associated with fewer side effects will advance the clinical HL field. (Blood. 2012; 119(4):990-996) C1 [Sjoberg, Jan; Kristinsson, Sigurdur Y.; Landgren, Ola; Nygell, Ulla Axdorph; Bjorkholm, Magnus] Karolinska Univ Hosp Solna, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. [Halthur, Cat; Dickman, Paul W.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Landgren, Ola] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bjorkholm, M (reprint author), Karolinska Univ Hosp Solna, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. EM magnus.bjorkholm@karolinska.se RI Dickman, Paul/B-4572-2013; Kristinsson, Sigurdur /M-2910-2015; OI Dickman, Paul/0000-0002-5788-3380; Kristinsson, Sigurdur /0000-0002-4964-7476; Halthur, Cat/0000-0003-4146-2810 FU Swedish Cancer Society [CAN 2009/1203]; Stockholm County Council; Karolinska Institutet [SLL 20090201]; Karolinska Institutet Foundations [2009Fobi0072] FX This work was supported by the Swedish Cancer Society (CAN 2009/1203), the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet (SLL 20090201), and the Karolinska Institutet Foundations (2009Fobi0072). NR 51 TC 27 Z9 29 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 26 PY 2012 VL 119 IS 4 BP 990 EP 996 DI 10.1182/blood-2010-08-302604 PG 7 WC Hematology SC Hematology GA 886NI UT WOS:000299860700013 PM 22147892 ER PT J AU LeGrand, J Park, ES Wang, HY Gupta, S Owens, JD Nelson, PJ DuBois, W Bair, T Janz, S Mushinski, JF AF LeGrand, Jason Park, Eun Sung Wang, Hongyang Gupta, Shalu Owens, James D. Nelson, Patrick J. DuBois, Wendy Bair, Thomas Janz, Siegfried Mushinski, J. Frederic TI Global gene expression profiling in mouse plasma cell tumor precursor and bystander cells reveals potential intervention targets for plasma cell neoplasia SO BLOOD LA English DT Article ID PRECEDES MULTIPLE-MYELOMA; GROWTH-FACTOR; MONOCLONAL GAMMOPATHY; BREAST-CANCER; B-CELL; UNDETERMINED SIGNIFICANCE; HEPATOCELLULAR-CARCINOMA; OSTEOPONTIN EXPRESSION; SUPPRESSOR GENE; C-MYC AB Tumor progression usually proceeds through several sequential stages, any of which could be targets for interrupting the progression process if one understood these steps at the molecular level. We extracted nascent plasma cell tumor (PCT) cells from within inflammatory oil granulomas (OG) isolated from IP pristane-injected BALB/c.iMyc(E mu) mice at 5 different time points during tumor progression. We used laser capture microdissection to collect incipient PCT cells and analyzed their global gene expression on Affymetrix Mouse Genome 430A microarrays. Two independent studies were performed with different sets of mice. Analysis of the expression data used ANOVA and Bayesian estimation of temporal regulation. Genetic pathway analysis was performed using Meta Core (Gene Go) and IPA (Ingenuity). The gene expression profiles of PCT samples and those of undissected OG samples from adjacent sections showed that different genes and pathways were mobilized in the tumor cells during tumor progression, corn-pared with their stroma. Our analysis implicated several genetic pathways in PCT progression, including biphasic (up-and then down-regulation) of the Spp1/osteopontin-dependent network and up-regulation of mRNA translation/protein synthesis. The latter led to a biologic validation study that showed that the AMPK-activating diabetes drug, metformin, was a potent specific PCT inhibitor in vitro. (Blood. 2012;119(4)1018-1028) C1 [Janz, Siegfried] Univ Iowa, Dept Pathol, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA. [LeGrand, Jason; Park, Eun Sung; Wang, Hongyang; Gupta, Shalu; Owens, James D.; Nelson, Patrick J.; DuBois, Wendy; Mushinski, J. Frederic] NCI, Mol Genet Sect, Lab Canc Biol & Genet, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Bair, Thomas; Janz, Siegfried] Univ Iowa, Holden Comprehens Canc Ctr, Iowa City, IA 52242 USA. RP Janz, S (reprint author), Univ Iowa, Dept Pathol, Roy J & Lucille A Carver Coll Med, 500 Newton Rd,1030 ML, Iowa City, IA 52242 USA. EM siegfried-janz@uiowa.edu; mushinsj@gmail.com FU National Institutes of Health; Multiple Myeloma Research and International Waldenstrom's Macroglobulinemia Foundations [R01CA151354]; National Cancer Institute (NCI) FX This work was supported in part by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute (NCI). This work was also supported, in part, by research awards from the Multiple Myeloma Research and International Waldenstrom's Macroglobulinemia Foundations (Si.) and R01CA151354 from the NCI (Si.). NR 50 TC 4 Z9 5 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 26 PY 2012 VL 119 IS 4 BP 1018 EP 1028 DI 10.1182/blood-2011-06-363887 PG 11 WC Hematology SC Hematology GA 886NI UT WOS:000299860700016 PM 22147894 ER PT J AU Cheruku, P Plaza, A Lauro, G Keffer, J Lloyd, JR Bifulco, G Bewley, CA AF Cheruku, Pradeep Plaza, Alberto Lauro, Gianluigi Keffer, Jessica Lloyd, John R. Bifulco, Giuseppe Bewley, Carole A. TI Discovery and Synthesis of Namalide Reveals a New Anabaenopeptin Scaffold and Peptidase inhibitor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SPONGE THEONELLA SP; CYCLIC-PEPTIDES; BIOACTIVE COMPOUNDS; CARBOXYPEPTIDASE-A; CYANOBACTERIA; METABOLITES; MIRABILIS; PRODUCT; POTENT AB The discovery, structure elucidation, and solid-phase synthesis of namalide, a marine natural product, are described. Namalide is a cyclic tetrapeptide; its macrocycle is formed by only three amino acids, with an exocyclic ureido phenylalanine moiety at its C-terminus. The absolute configuration of namalide was established, and analogs were generated through Fmoc-based solid phase peptide synthesis. We found that only natural namalide and not its analogs containing L-Lys or L-allo-Ile inhibited carboxypeptidase A at submicromolar concentrations. In parallel, an inverse virtual screening approach aimed at identifying protein targets of namalide selected carboxypeptidase A as the third highest scoring hit. Namalide represents a new anabaenopeptin-type scaffold, and its protease inhibitory activity demonstrates that the 13-membered macrolactam can exhibit similar activity as the more common hexapeptides. C1 [Lauro, Gianluigi; Bifulco, Giuseppe] Univ Salerno, Dipartimento Sci Farmaceut & Biomed, I-84084 Salerno, Italy. [Cheruku, Pradeep; Plaza, Alberto; Keffer, Jessica; Lloyd, John R.; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bifulco, G (reprint author), Univ Salerno, Dipartimento Sci Farmaceut & Biomed, Via Ponte Don Melillo, I-84084 Salerno, Italy. EM bifulco@unisa.it; caroleb@mail.nih.gov RI Cheruku, Pradeep/A-2176-2012; Bifulco, Giuseppe/A-5413-2011; OI Bifulco, Giuseppe/0000-0002-1788-5170; Keffer, Jessica/0000-0002-0302-3588 FU NIH (NIDDK); FARB (University of Salerno) FX This work was supported by the NIH Intramural Research Program (NIDDK) and FARB (University of Salerno). NR 34 TC 8 Z9 8 U1 3 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JAN 26 PY 2012 VL 55 IS 2 BP 735 EP 742 DI 10.1021/jm201238p PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 881BC UT WOS:000299453300017 PM 22168797 ER PT J AU Ombrello, MJ Remmers, EF Sun, GP Freeman, AF Datta, S Torabi-Parizi, P Subramanian, N Bunney, TD Baxendale, RW Martins, MS Romberg, N Komarow, H Aksentijevich, I Kim, HS Ho, J Cruse, G Jung, MY Gilfillan, AM Metcalfe, DD Nelson, C O'Brien, M Wisch, L Stone, K Douek, DC Gandhi, C Wanderer, AA Lee, H Nelson, SF Shianna, KV Cirulli, ET Goldstein, DB Long, EO Moir, S Meffre, E Holland, SM Kastner, DL Katan, M Hoffman, HM Milner, JD AF Ombrello, Michael J. Remmers, Elaine F. Sun, Guangping Freeman, Alexandra F. Datta, Shrimati Torabi-Parizi, Parizad Subramanian, Naeha Bunney, Tom D. Baxendale, Rhona W. Martins, Marta S. Romberg, Neil Komarow, Hirsh Aksentijevich, Ivona Kim, Hun Sik Ho, Jason Cruse, Glenn Jung, Mi-Yeon Gilfillan, Alasdair M. Metcalfe, Dean D. Nelson, Celeste O'Brien, Michelle Wisch, Laura Stone, Kelly Douek, Daniel C. Gandhi, Chhavi Wanderer, Alan A. Lee, Hane Nelson, Stanley F. Shianna, Kevin V. Cirulli, Elizabeth T. Goldstein, David B. Long, Eric O. Moir, Susan Meffre, Eric Holland, Steven M. Kastner, Daniel L. Katan, Matilda Hoffman, Hal M. Milner, Joshua D. TI Cold Urticaria, Immunodeficiency, and Autoimmunity Related to PLCG2 Deletions SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COMMON VARIABLE IMMUNODEFICIENCY; ANTIBODY-DEFICIENCY SYNDROME; B-CELL RECEPTOR; PHOSPHOLIPASE C-GAMMA-2; GENE; MUTATIONS; PROTEIN; ENTEROPATHY; ACTIVATION; SIGNALS AB Background Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance. Methods We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays. Genetic studies included linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing. Results Cold urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, the presence of antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA and circulating natural killer cells and class-switched memory B cells were reduced. Linkage analysis showed a 7-Mb candidate interval on chromosome 16q in one family, overlapping by 3.5 Mb a disease-associated haplotype in a smaller family. This interval includes PLCG2, encoding phospholipase C gamma(2) (PLC gamma(2)), a signaling molecule expressed in B cells, natural killer cells, and mast cells. Sequencing of complementary DNA revealed heterozygous transcripts lacking exon 19 in two families and lacking exons 20 through 22 in a third family. Genomic sequencing identified three distinct in-frame deletions that cosegregated with disease. These deletions, located within a region encoding an autoinhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37 degrees C but enhanced signaling at subphysiologic temperatures. Conclusions Genomic deletions in PLCG2 cause gain of PLC gamma(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function. (Funded by the National Institutes of Health Intramural Research Programs and others.) C1 [Sun, Guangping; Datta, Shrimati; Komarow, Hirsh; Cruse, Glenn; Jung, Mi-Yeon; Gilfillan, Alasdair M.; Metcalfe, Dean D.; Nelson, Celeste; O'Brien, Michelle; Wisch, Laura; Stone, Kelly; Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Ombrello, Michael J.; Remmers, Elaine F.; Aksentijevich, Ivona; Kastner, Daniel L.] NHGRI, Inflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. [Freeman, Alexandra F.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Torabi-Parizi, Parizad; Subramanian, Naeha] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Kim, Hun Sik; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. [Ho, Jason; Moir, Susan] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Douek, Daniel C.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Torabi-Parizi, Parizad] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Bunney, Tom D.; Baxendale, Rhona W.; Martins, Marta S.; Katan, Matilda] UCL, Dept Struct & Mol Biol, Div Biosci, London WC1E 6BT, England. [Romberg, Neil; Meffre, Eric] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [Kim, Hun Sik] Univ Ulsan, Grad Sch, Med Res Ctr, Dept Med, Ulsan 680749, South Korea. [Gandhi, Chhavi; Hoffman, Hal M.] Univ Calif San Diego, Dept Pediat & Med, Div Allergy Immunol & Rheumatol, San Diego, CA 92103 USA. [Hoffman, Hal M.] Rady Childrens Hosp San Diego, San Diego, CA USA. [Hoffman, Hal M.] Ludwig Inst Canc Res, San Diego, CA USA. [Wanderer, Alan A.] Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. [Lee, Hane; Nelson, Stanley F.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. [Shianna, Kevin V.; Cirulli, Elizabeth T.; Goldstein, David B.] Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC USA. RP Milner, JD (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jdmilner@niaid.nih.gov RI Nelson, Stanley/D-4771-2009; Cruse, Glenn/B-4597-2012; Long, Eric/G-5475-2011; Martins, Marta/A-9905-2013 OI Long, Eric/0000-0002-7793-3728; Martins, Marta/0000-0003-0429-9380 FU National Human Genome Research Institute; National Institute of Allergy and Infectious Diseases (NIAID) [AI061093, AI071087, AI082713]; National Institute of Arthritis and Musculoskeletal and Skin Diseases; University of California, San Diego (UCSD) Department of Pediatrics; National Institutes of Health [T32 AI07469]; UCSD Clinical Translational Research Institute [UL1RR031980] FX Supported by the Intramural Research Programs of the National Human Genome Research Institute, the National Institute of Allergy and Infectious Diseases (NIAID), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases; grants from NIAID (AI061093, AI071087, and AI082713, to Dr. Meffre); the University of California, San Diego (UCSD) Department of Pediatrics; a National Institutes of Health training grant (T32 AI07469); and the UCSD Clinical Translational Research Institute, which has funding from awards issued by the National Center for Research Resources (UL1RR031980, to Dr. Hoffman). NR 40 TC 118 Z9 120 U1 1 U2 23 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 26 PY 2012 VL 366 IS 4 BP 330 EP 338 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 881EQ UT WOS:000299464100004 PM 22236196 ER PT J AU Ou, W Delisle, J Jacques, J Shih, J Price, G Kuhn, JH Wang, V Verthelyi, D Kaplan, G Wilson, CA AF Ou, Wu Delisle, Josie Jacques, Jerome Shih, Joanna Price, Graeme Kuhn, Jens H. Wang, Vivian Verthelyi, Daniela Kaplan, Gerardo Wilson, Carolyn A. TI Induction of ebolavirus cross-species immunity using retrovirus-like particles bearing the Ebola virus glycoprotein lacking the mucin-like domain SO VIROLOGY JOURNAL LA English DT Article DE Ebola; Ebolavirus; Envelope glycoprotein; Filovirus; Mucin-like domain; Retrovirus; Virus-like particles; DNA vaccine ID DNA VACCINES; PROTECTIVE EFFICACY; NONHUMAN-PRIMATES; PROTEINS CD55; INSECT CELLS; INFECTION; EPITOPES; IMMUNOGENICITY; IMMUNIZATION; RESPONSES AB Background: The genus Ebolavirus includes five distinct viruses. Four of these viruses cause hemorrhagic fever in humans. Currently there are no licensed vaccines for any of them; however, several vaccines are under development. Ebola virus envelope glycoprotein (GP(1,2)) is highly immunogenic, but antibodies frequently arise against its least conserved mucin-like domain (MLD). We hypothesized that immunization with MLD-deleted GP(1,2) (GP Delta MLD) would induce cross-species immunity by making more conserved regions accessible to the immune system. Methods: To test this hypothesis, mice were immunized with retrovirus-like particles (retroVLPs) bearing Ebola virus GP Delta MLD, DNA plasmids (plasmo-retroVLP) that can produce such retroVLPs in vivo, or plasmo-retroVLP followed by retroVLPs. Results: Cross-species neutralizing antibody and GP(1,2)-specific cellular immune responses were successfully induced. Conclusion: Our findings suggest that GP Delta MLD presented through retroVLPs may provide a strategy for development of a vaccine against multiple ebolaviruses. Similar vaccination strategies may be adopted for other viruses whose envelope proteins contain highly variable regions that may mask more conserved domains from the immune system. C1 [Ou, Wu; Delisle, Josie; Price, Graeme; Wilson, Carolyn A.] US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. [Jacques, Jerome; Kaplan, Gerardo] US FDA, Ctr Biol Evaluat & Res, Div Emerging & Transfus Transmitted Dis, Bethesda, MD 20892 USA. [Shih, Joanna] NCI, Biometr Res Branch, Rockville, MD USA. [Kuhn, Jens H.] NIAID, NIH, Integrated Res Facil Ft Detrick, Frederick, MD USA. [Wang, Vivian; Verthelyi, Daniela] US FDA, Ctr Drug Evaluat & Review, Div Therapeut Prot, Off Biotechnol Prod, Bethesda, MD 20892 USA. RP Wilson, CA (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Bldg 29B,Room 5NN22,8800 Rockville Pike, Bethesda, MD 20892 USA. EM carolyn.wilson@fda.hhs.gov RI Kuhn, Jens H./B-7615-2011 OI Kuhn, Jens H./0000-0002-7800-6045 FU Biomedical Advanced Research and Development Authority (BARDA); NIAID [HHSN272200200016I] FX We thank Julia Misplon and Chia-Yun Lo for their advice and input into the design of some of the immunologic evaluations performed in these studies. This research was partially supported by an inter-agency agreement with the Biomedical Advanced Research and Development Authority (BARDA). In addition, we thank Ronald Rabin and Andrew Byrnes for their critical review of the manuscript.; JHK performed this work as an employee of Tunnell Consulting, Inc., a subcontractor to Battelle Memorial Institute under its prime contract with NIAID, under Contract No. HHSN272200200016I. NR 55 TC 6 Z9 7 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD JAN 25 PY 2012 VL 9 AR 32 DI 10.1186/1743-422X-9-32 PG 13 WC Virology SC Virology GA 950NE UT WOS:000304655200001 PM 22273269 ER PT J AU Belarbi, K Jopson, T Tweedie, D Arellano, C Luo, WM Greig, NH Rosi, S AF Belarbi, Karim Jopson, Timothy Tweedie, David Arellano, Carla Luo, Weiming Greig, Nigel H. Rosi, Susanna TI TNF-alpha protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Arc; Hippocampus; Immediate-early gene; Inflammation; Learning and memory; Tumor necrosis factor-a ID NECROSIS-FACTOR-ALPHA; LONG-TERM POTENTIATION; EARLY GENE ARC; ALZHEIMERS-DISEASE; MESSENGER-RNA; DENTATE GYRUS; NEURODEGENERATIVE DISEASES; PERISPINAL ETANERCEPT; SYNAPTIC-TRANSMISSION; RECEPTOR TRAFFICKING AB Background: Chronic neuroinflammation is a hallmark of several neurological disorders associated with cognitive loss. Activated microglia and secreted factors such as tumor necrosis factor (TNF)-alpha are key mediators of neuroinflammation and may contribute to neuronal dysfunction. Our study was aimed to evaluate the therapeutic potential of a novel analog of thalidomide, 3,6'-dithiothalidomide (DT), an agent with anti-TNF-alpha activity, in a model of chronic neuroinflammation. Methods: Lipopolysaccharide or artificial cerebrospinal fluid was infused into the fourth ventricle of three-month-old rats for 28 days. Starting on day 29, animals received daily intraperitoneal injections of DT (56 mg/kg/day) or vehicle for 14 days. Thereafter, cognitive function was assessed by novel object recognition, novel place recognition and Morris water maze, and animals were euthanized 25 min following water maze probe test evaluation. Results: Chronic LPS-infusion was characterized by increased gene expression of the proinflammatory cytokines TNF-alpha and IL-1 beta in the hippocampus. Treatment with DT normalized TNF-alpha levels back to control levels but not IL-1 beta. Treatment with DT attenuated the expression of TLR2, TLR4, IRAK1 and Hmgb1, all genes involved in the TLR-mediated signaling pathway associated with classical microglia activation. However DT did not impact the numbers of MHC Class II immunoreactive cells. Chronic neuroinflammation impaired novel place recognition, spatial learning and memory function; but it did not impact novel object recognition. Importantly, treatment with DT restored cognitive function in LPS-infused animals and normalized the fraction of hippocampal neurons expressing the plasticity-related immediate-early gene Arc. Conclusion: Our data demonstrate that the TNF-alpha synthesis inhibitor DT can significantly reverse hippocampus-dependent cognitive deficits induced by chronic neuroinflammation. These results suggest that TNF-alpha is a critical mediator of chronic neuroinflammation-induced neuronal dysfunction and cognitive impairment and targeting its synthesis could provide an effective therapeutic approach to several human neurodegenerative diseases. C1 [Belarbi, Karim; Jopson, Timothy; Arellano, Carla; Rosi, Susanna] Univ Calif San Francisco, Brain & Spinal Injury Ctr, San Francisco, CA 94143 USA. [Belarbi, Karim; Jopson, Timothy; Arellano, Carla; Rosi, Susanna] Univ Calif San Francisco, Dept Phys Therapy Rehabil Sci, San Francisco, CA 94143 USA. [Belarbi, Karim; Jopson, Timothy; Arellano, Carla; Rosi, Susanna] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Tweedie, David; Luo, Weiming; Greig, Nigel H.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Rosi, Susanna] Univ Calif San Francisco, San Francisco Gen Hosp, Brain & Spinal Injury Ctr, San Francisco, CA 94110 USA. RP Rosi, S (reprint author), Univ Calif San Francisco, Brain & Spinal Injury Ctr, San Francisco, CA 94143 USA. EM rosis@ptrehab.ucsf.edu RI belarbi, karim/G-4467-2013; OI belarbi, karim/0000-0002-0027-1172 FU Alzheimer's Association [NIRG-08-90589, IIRG-11-202064]; National Institute on Aging, National Institutes of Health FX The authors thank Jinghua Yao for her valuable help in processing brain tissues. This work was supported by the Alzheimer's Association grants NIRG-08-90589 (SR) and IIRG-11-202064 (SR), and the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 77 TC 67 Z9 71 U1 3 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD JAN 25 PY 2012 VL 9 AR 23 DI 10.1186/1742-2094-9-23 PG 13 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 917IB UT WOS:000302165800001 PM 22277195 ER PT J AU Leblanc, P Hasenkrug, K Ward, A Myers, L Messer, RJ Alais, S Timmes, A Priola, S AF Leblanc, Pascal Hasenkrug, Kim Ward, Anne Myers, Lara Messer, Ronald J. Alais, Sandrine Timmes, Andrew Priola, Sue TI Co-Infection with the Friend Retrovirus and Mouse Scrapie Does Not Alter Prion Disease Pathogenesis in Susceptible Mice SO PLOS ONE LA English DT Article ID FOLLICULAR DENDRITIC CELLS; MURINE LEUKEMIA-VIRUS; IN-VITRO; INFECTION; NEUROINVASION; REPLICATION; SPLEEN; EXPRESSION; PROTEIN; RELEASE AB Prion diseases are fatal, transmissible neurodegenerative diseases of the central nervous system. An abnormally protease-resistant and insoluble form (PrPSc) of the normally soluble protease-sensitive host prion protein (PrPC) is the major component of the infectious prion. During the course of prion disease, PrPSc accumulates primarily in the lymphoreticular and central nervous systems. Recent studies have shown that co-infection of prion-infected fibroblast cells with the Moloney murine leukemia virus (Mo-MuLV) strongly enhanced the release and spread of scrapie infectivity in cell culture, suggesting that retroviral coinfection might significantly influence prion spread and disease incubation times in vivo. We now show that another retrovirus, the murine leukemia virus Friend (F-MuLV), also enhanced the release and spread of scrapie infectivity in cell culture. However, peripheral co-infection of mice with both Friend virus and the mouse scrapie strain 22L did not alter scrapie disease incubation times, the levels of PrPSc in the brain or spleen, or the distribution of pathological lesions in the brain. Thus, retroviral co-infection does not necessarily alter prion disease pathogenesis in vivo, most likely because of different cell-specific sites of replication for scrapie and F-MuLV. C1 [Leblanc, Pascal; Alais, Sandrine] Univ Lyon, Lyon, France. [Leblanc, Pascal; Alais, Sandrine] INSERM, U758, Lab Virol Humaine, F-69008 Lyon, France. [Leblanc, Pascal] UMR5239, Lab Biol Mol Cellule, Lyon, France. [Leblanc, Pascal; Alais, Sandrine] Ecole Normale Super Lyon, F-69364 Lyon, France. [Hasenkrug, Kim; Ward, Anne; Myers, Lara; Messer, Ronald J.; Timmes, Andrew; Priola, Sue] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Leblanc, P (reprint author), Univ Lyon, Lyon, France. EM spriola@niaid.nih.gov FU National Institutes of Health's Institute of Allergy and Infectious Diseases; CNRS; INSERM FX This research was supported by the Intramural Research Program of the National Institutes of Health's Institute of Allergy and Infectious Diseases (S. Priola and K. Hasenkrug) and by CNRS and INSERM (P. Leblanc). The funders had no role in study design, data collection and analysis, or preparation of the manuscript. Clearance to publish was obtained from the Intramural Research Program of the National Institutes of Health, Institute of Allergy and Infectious Diseases. NR 40 TC 1 Z9 1 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 25 PY 2012 VL 7 IS 1 AR e30872 DI 10.1371/journal.pone.0030872 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 910ME UT WOS:000301640600063 PM 22295118 ER PT J AU Oleinikov, AV Voronkova, VV Frye, IT Amos, E Morrison, R Fried, M Duffy, PE AF Oleinikov, Andrew V. Voronkova, Valentina V. Frye, Isaac Tyler Amos, Emily Morrison, Robert Fried, Michal Duffy, Patrick E. TI A Plasma Survey Using 38 PfEMP1 Domains Reveals Frequent Recognition of the Plasmodium falciparum Antigen VAR2CSA among Young Tanzanian Children SO PLOS ONE LA English DT Article ID ERYTHROCYTE-MEMBRANE PROTEIN-1; INTERCELLULAR-ADHESION MOLECULE-1; INFECTED ERYTHROCYTES; IMMUNOGLOBULIN-G; SEVERE MALARIA; VAR GENES; DIFFERENTIAL EXPRESSION; HUMAN PLACENTA; ANTIBODIES; CYTOADHERENCE AB PfEMP1 proteins comprise a family of variant antigens that appear on the surface of P. falciparum-infected erythrocytes and bind to multiple host receptors. Using a mammalian expression system and BioPlex technology, we developed an array of 24 protein constructs representing 38 PfEMP1 domains for high throughput analyses of receptor binding as well as total and functional antibody responses. We analyzed the reactivity of 561 plasma samples from 378 young Tanzanian children followed up to maximum 192 weeks of life in a longitudinal birth cohort. Surprisingly, reactivity to the DBL5 domain of VAR2CSA, a pregnancy malaria vaccine candidate, was most common, and the prevalence of reactivity was stable throughout early childhood. Reactivity to all other PfEMP1 constructs increased with age. Antibodies to the DBL2 beta C2(PF11_0521) domain, measured as plasma reactivity or plasma inhibition of ICAM1 binding, predicted reduced risk of hospitalization for severe or moderately severe malaria. These data suggest a role for VAR2CSA in childhood malaria and implicate DBL2 beta C2(PF11_0521) in protective immunity. C1 [Oleinikov, Andrew V.; Voronkova, Valentina V.; Frye, Isaac Tyler; Amos, Emily; Morrison, Robert; Fried, Michal; Duffy, Patrick E.] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Fried, Michal; Duffy, Patrick E.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Fried, Michal; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. RP Oleinikov, AV (reprint author), Seattle Biomed Res Inst, 4 Nickerson St, Seattle, WA 98109 USA. EM andrew.oleinikov@seattlebiomed.org FU National Institutes of Health [1R21AI064503, 1R01AI092120, RO1AI52059]; Foundation of the National Institutes of Health through the Grand Challenges in Global Health initiative [29202] FX The work was supported by National Institutes of Health (http://www.nih.gov) grants 1R21AI064503 and 1R01AI092120 to AVO, RO1AI52059 to PED, and funded in part by the Foundation of the National Institutes of Health through the Grand Challenges in Global Health initiative (http://www.grandchallenges.org/Pages/default.aspx) Grant No. 29202 to PED. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 17 Z9 17 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 25 PY 2012 VL 7 IS 1 AR e31011 DI 10.1371/journal.pone.0031011 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 910ME UT WOS:000301640600068 PM 22295123 ER PT J AU Nussinov, R Ma, BY AF Nussinov, Ruth Ma, Buyong TI Protein dynamics and conformational selection in bidirectional signal transduction SO BMC BIOLOGY LA English DT Editorial Material ID EPH; UBIQUITIN AB Protein conformational dynamics simultaneously allow promiscuity and specificity in binding. The multiple conformations of the free EphA4 ligand-binding domain observed in two new EphA4 crystal structures provide a unique insight into the conformational dynamics of EphA4 and its signaling pathways. The heterogeneous ensemble and loop dynamics explain how the EphA4 receptor is able to bind multiple A-and B-ephrin ligands and small molecules via conformational selection, which helps to fine-tune cellular signal response in both receptor and ligand cells. C1 [Nussinov, Ruth; Ma, Buyong] NCI Frederick, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI Frederick, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU Intramural NIH HHS; PHS HHS [HHSN261200800001E] NR 13 TC 31 Z9 31 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD JAN 25 PY 2012 VL 10 AR 2 DI 10.1186/1741-7007-10-2 PG 5 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 886CC UT WOS:000299827500001 PM 22277130 ER PT J AU Bolton, KL Chenevix-Trench, G Goh, C Sadetzki, S Ramus, SJ Karlan, BY Lambrechts, D Despierre, E Barrowdale, D McGuffog, L Healey, S Easton, DF Sinilnikova, O Benitez, J Garcia, MJ Neuhausen, S Gail, MH Hartge, P Peock, S Frost, D Evans, G Eeles, R Godwin, AK Daly, MB Kwong, A Ma, ESK Lazaro, C Blanco, I Montagna, M D'Andrea, E Nicoletto, MO Johnatty, SE Kruger, S Jensen, A Hogdall, E Goode, EL Fridley, BL Loud, JT Greene, MH Mai, PL Chetrit, A Lubin, F Hirsh-Yechezkel, G Glendon, G Andrulis, IL Toland, AE Senter, L Gore, ME Gourley, C Michie, CO Song, HL Tyrer, J Whittemore, AS McGuire, V Sieh, W Kristoffersson, U Olsson, H Borg, A Levine, DA Steele, L Beattie, MS Chan, S Nussbaum, RL Moysich, KB Gross, J Cass, I Walsh, C Li, AJ Leuchter, R Gordon, O Garcia-Closas, M Gayther, SA Chanock, SJ Antoniou, AC Pharoah, PDP AF Bolton, Kelly L. Chenevix-Trench, Georgia Goh, Cindy Sadetzki, Siegal Ramus, Susan J. Karlan, Beth Y. Lambrechts, Diether Despierre, Evelyn Barrowdale, Daniel McGuffog, Lesley Healey, Sue Easton, Douglas F. Sinilnikova, Olga Benitez, Javier Garcia, Maria J. Neuhausen, Susan Gail, Mitchell H. Hartge, Patricia Peock, Susan Frost, Debra Evans, Gareth Eeles, Rosalind Godwin, Andrew K. Daly, Mary B. Kwong, Ava Ma, Edmond S. K. Lazaro, Conxi Blanco, Ignacio Montagna, Marco D'Andrea, Emma Nicoletto, Maria Ornella Johnatty, Sharon E. Krueger, Susanne Jensen, Allan Hogdall, Estrid Goode, Ellen L. Fridley, Brooke L. Loud, Jennifer T. Greene, Mark H. Mai, Phuong L. Chetrit, Angela Lubin, Flora Hirsh-Yechezkel, Galit Glendon, Gord Andrulis, Irene L. Toland, Amanda E. Senter, Leigha Gore, Martin E. Gourley, Charlie Michie, Caroline O. Song, Honglin Tyrer, Jonathan Whittemore, Alice S. McGuire, Valerie Sieh, Weiva Kristoffersson, Ulf Olsson, Hakan Borg, Ake Levine, Douglas A. Steele, Linda Beattie, Mary S. Chan, Salina Nussbaum, Robert L. Moysich, Kirsten B. Gross, Jenny Cass, Ilana Walsh, Christine Li, Andrew J. Leuchter, Ronald Gordon, Ora Garcia-Closas, Montserrat Gayther, Simon A. Chanock, Stephen J. Antoniou, Antonis C. Pharoah, Paul D. P. CA EMBRACE KConFab Investigators Canc Genome Atlas Res Network TI Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BREAST-CANCER; PROGESTERONE-RECEPTOR; SUSCEPTIBILITY GENE; LOW-GRADE; CARCINOMA; CARRIERS; NONSENSE; RISK; POLYMERASE; CONSORTIUM AB Context Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. Objective To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. Design, Setting, and Participants A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n=909) or BRCA2 (n=304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). Main Outcome Measure Five-year overall mortality. Results The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P<.001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P<.001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P<.001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P<.001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity=.003). Conclusion Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis. JAMA. 2012;307(4):382-390 C1 [Song, Honglin; Tyrer, Jonathan; Pharoah, Paul D. P.] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Canc Res United Kingdom, Cambridge CB1 8RN, England. [Song, Honglin; Tyrer, Jonathan; Pharoah, Paul D. P.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Bolton, Kelly L.; Gail, Mitchell H.; Hartge, Patricia; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bolton, Kelly L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Chenevix-Trench, Georgia; Healey, Sue; Johnatty, Sharon E.] Univ Queensland, Royal Brisbane Hosp, Queensland Inst Med Res, Herston, Qld, Australia. [Goh, Cindy] Addenbrookes Hosp, Cambridge, England. [Sadetzki, Siegal; Chetrit, Angela; Lubin, Flora; Hirsh-Yechezkel, Galit] Chaim Sheba Med Ctr, Gertner Inst Epidemiol & Hlth Policy Res, IL-52621 Tel Hashomer, Israel. [Sadetzki, Siegal] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Ramus, Susan J.; Gayther, Simon A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Karlan, Beth Y.; Gross, Jenny; Cass, Ilana; Walsh, Christine; Li, Andrew J.; Leuchter, Ronald; Gordon, Ora] Cedars Sinai Med Ctr, Womens Canc Program, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Lambrechts, Diether] Univ Leuven, VIB Vesalius Res Ctr, Louvain, Belgium. [Despierre, Evelyn] Univ Leuven, Univ Hosp Leuven, Dept Obstet & Gynaecol, Louvain, Belgium. [Barrowdale, Daniel; McGuffog, Lesley; Easton, Douglas F.; Peock, Susan; Frost, Debra; Antoniou, Antonis C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Sinilnikova, Olga] Hosp Civils Lyon, Ctr Leon Berard, Unit Genet Predisposit Common Canc, Lyon, France. [Sinilnikova, Olga] Univ Lyon 1, INSERM, CNRS, Canc Res Ctr Lyon,U0152,UMR5286, F-69365 Lyon, France. [Garcia, Maria J.] Human Genet Grp, Madrid, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Madrid, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr, Genotyping Unit, Madrid, Spain. [Benitez, Javier; Garcia, Maria J.] CIBERER, Madrid, Spain. [Neuhausen, Susan; Steele, Linda] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Evans, Gareth] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, England. [Eeles, Rosalind] Inst Canc Res, Oncogenet Team, Sutton, Surrey, England. [Eeles, Rosalind] Royal Marsden NHS Fdn Trust, Sutton, Surrey, England. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, MO USA. [Daly, Mary B.] Fox Chase Canc Ctr, Dept Clin Genet, Philadelphia, PA 19111 USA. [Kwong, Ava; Ma, Edmond S. K.] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China. [Ma, Edmond S. K.] Hong Kong Sanat & Hosp, Div Mol Pathol, Hong Kong, Hong Kong, Peoples R China. [Kwong, Ava] Univ Hong Kong, Queen Mary Hosp, Div Breast Surg, Hong Kong, Hong Kong, Peoples R China. [Lazaro, Conxi; Blanco, Ignacio] LHospitalet, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain. [Montagna, Marco] Ist Oncol Veneto IRCCS, Immunol & Mol Oncol Unit, Padua, Italy. [Nicoletto, Maria Ornella] Ist Oncol Veneto IRCCS, Med Oncol Unit 1, Padua, Italy. [D'Andrea, Emma] Ist Oncol Veneto IOV IRCCS, Dept Oncol & Surg Sci, Padua, Italy. [Krueger, Susanne; Jensen, Allan; Hogdall, Estrid] Univ Copenhagen, Rigshosp, Dept Virus Hormones & Canc, Danish Canc Soc, DK-2100 Copenhagen, Denmark. [Krueger, Susanne; Jensen, Allan; Hogdall, Estrid] Univ Copenhagen, Rigshosp, Dept Gynecol, DK-2100 Copenhagen, Denmark. [Goode, Ellen L.; Fridley, Brooke L.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Loud, Jennifer T.; Greene, Mark H.; Mai, Phuong L.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Glendon, Gord; Andrulis, Irene L.] Canc Care Ontario, Ontario Canc Genet Network, Toronto, ON, Canada. [Andrulis, Irene L.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Toland, Amanda E.] Ohio State Univ, Comprehens Canc Ctr, Dept Internal Med & Mol Virol, Columbus, OH 43210 USA. [Toland, Amanda E.] Ohio State Univ, Comprehens Canc Ctr, Dept Immunol, Columbus, OH 43210 USA. [Toland, Amanda E.] Ohio State Univ, Comprehens Canc Ctr, Dept Med Genet, Columbus, OH 43210 USA. [Senter, Leigha] Ohio State Univ, Comprehens Canc Ctr, Dept Internal Med, Clin Canc Genet Program, Columbus, OH 43210 USA. [Gore, Martin E.] Royal Marsden Hosp, Gynecol Oncol Unit, London SW3 6JJ, England. [Gourley, Charlie; Michie, Caroline O.] Univ Edinburgh, Canc Res Ctr, Inst Genet & Mol Med, Western Gen Hosp, Edinburgh, Midlothian, Scotland. [Whittemore, Alice S.; McGuire, Valerie; Sieh, Weiva] Stanford Univ, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. [Olsson, Hakan; Borg, Ake] Lund Univ, Dept Oncol, Lund, Sweden. [Kristoffersson, Ulf] Univ & Reg Lab Skane, Dept Clin Genet, Lund, Sweden. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Beattie, Mary S.; Chan, Salina; Nussbaum, Robert L.] Univ Calif San Francisco, Canc Risk Program, San Francisco, CA 94143 USA. [Beattie, Mary S.; Nussbaum, Robert L.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Garcia-Closas, Montserrat] Breakthrough Breast Canc Res Ctr, London, England. [Garcia-Closas, Montserrat] Inst Canc Res, Epidemiol Sect, London SW3 6JB, England. [Garcia-Closas, Montserrat] Inst Canc Res, Genet Sect, London SW3 6JB, England. RP Pharoah, PDP (reprint author), Univ Cambridge, Strangeways Res Lab, Dept Oncol, Canc Res United Kingdom, Worts Causeway, Cambridge CB1 8RN, England. EM paul.pharoah@srl.cam.ac.uk RI Saunders, Christobel/H-5779-2014; Lester, Jenny/B-5933-2012; Toland, Amanda/E-4202-2011; montagna, marco/E-2225-2012; Verdrengh, Evelien/H-4571-2012; D'Andrea, Emma/B-4374-2013; Kwong, Ava/D-8005-2013; Andrulis, Irene/E-7267-2013; Blanco, Ignacio/D-2565-2013; Whittemore, Alice/F-9925-2014; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; Garcia, Maria/G-1361-2016; Johnatty, Sharon/R-8890-2016; OI Saunders, Christobel/0000-0003-2281-9829; montagna, marco/0000-0002-4929-2150; Kwong, Ava/0000-0002-6968-9489; Blanco, Ignacio/0000-0002-7414-7481; Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; Garcia, Maria/0000-0002-2236-9912; Johnatty, Sharon/0000-0002-7888-1966; Barrowdale, Daniel/0000-0003-1661-3939; Eeles, Rosalind/0000-0002-3698-6241; Kjaer, Susanne/0000-0002-8347-1398; Ramus, Susan/0000-0003-0005-7798; Evans, Gareth/0000-0002-8482-5784 FU TetraLogic; Pfizer; Merck; Millennium; Roche; Schering-Plough; Merck Sharpe Dohme; Chugia; GlaxoSmithKline; PharmaMar; AstraZeneca; Cyclacel; Complete Genomics Inc.; Cancer Research UK [C490/A10119, C490/A10124, C1287/A10118, C1287/A11990, C5047/A8385]; Edinburgh Experimental Cancer Medicine Center [223175, HEALTH-F2-2009-223175]; European Community; Fondo de Investigacion Sanitaria [PS09/01094, PI081120]; Fundacion Mutua Madrilena [AP-8101-2010]; National Cancer Institute; DCEG from the Melville Trust for the Care and Cure of Cancer; National Institutes of Health; Nationaal Kankerplan-Actie 29' of Belgium; NHMRC of Australia; National Breast Cancer Foundation of Australia; Cancer Australia [628333]; Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; Cancer Foundation of Western Australia; Scottish Funding Council; Scottish Chief Scientist's Office; Manchester NIHR Biomedical Research Center; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Mermaid 1 project; Danish Cancer Society; Ministero dell'Istruzione, dell'Universita e della Ricerca; Ministero della Salute [RFPS 2006-5-341353, ACC2/R6.9]; Israeli Cancer Association; Helen Diller Family Comprehensive Cancer Center at University of California San Francisco; Avon Foundation; Hong Kong Hereditary Breast Cancer Family Registry; Dr Ellen Li Charitable Foundation; National Cancer Institute [NO2-CP-11019-50, N02-CP-65504]; Westat, Inc, Rockville, MD; Asociacion Espanola Contra el Cancer; Carlos III Health Institute; Catalan Health Institute [ISCIIIRETIC RD06/0020/1051, PI10/01422, PI10/31488, 2009SGR290]; Autonomous Government of Catalonia; American Cancer Society [SIOP-06-258-06-COUN]; Instituto de Salud Carlos III; [CA 74415]; [CA 61126-03]; [R01-CA 61107]; [R01-CA 122443]; [P50 CA 136393]; [P01 CA 130818]; [2P50 CA 058207] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Easton reported serving on the board of Genome Canada SIAC. Dr Godwin reported receiving consultancy fees from TetraLogic and Pfizer and grants from Merck, TetraLogic, and Millennium. Dr Gourley reported receiving consultancy fees from Roche, Schering-Plough, Merck Sharpe Dohme, Chugia, GlaxoSmithKline, and PharmaMar; receiving grants from AstraZeneca, GlaxoSmithKline, and Cyclacel; serving as a board member for Roche, Schering-Plough, and Chugai; receiving payment for lectures and educational presentations from Chugai and Merck Sharpe Dohme; and receiving compensation for travel expenses from Schering-Plough, Chugai, PharmaMar, Roche, and Boehringer Ingelheim. Dr Olsson reported receiving payment for lectures from NovoNordisk. Dr Nussbaum reported serving on the board and receiving consultancy fees and stock from Complete Genomics Inc. No other authors reported any disclosures.; This work was supported by grants C490/A10119, C490/A10124, C1287/A10118, C1287/A11990, C5047/A8385 from Cancer Research UK; grants 223175, HEALTH-F2-2009-223175 from the Edinburgh Experimental Cancer Medicine Center, the European Community's Seventh Framework Program; grants PS09/01094 and PI081120 from the Fondo de Investigacion Sanitaria; grant AP-8101-2010 from the Fundacion Mutua Madrilena; grants CA 74415, CA 61126-03, R01-CA 61107, R01-CA 122443, P50 CA 136393, P01 CA 130818, 2P50 CA 058207, and the Intramural Research Program of the National Cancer Institute, DCEG from the Melville Trust for the Care and Cure of Cancer, National Institutes of Health; the Nationaal Kankerplan-Actie 29' of Belgium; the NHMRC of Australia; the National Breast Cancer Foundation of Australia, Cancer Australia (628333); the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; the Cancer Foundation of Western Australia; the Scottish Funding Council; the Scottish Chief Scientist's Office; the Manchester NIHR Biomedical Research Center; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Mermaid 1 project; the Danish Cancer Society; Ministero dell'Istruzione, dell'Universita e della Ricerca and Ministero della Salute ("Progetto Tumori Femminili" and RFPS 2006-5-341353, ACC2/R6.9"); the Israeli Cancer Association; the Helen Diller Family Comprehensive Cancer Center at University of California San Francisco; the Avon Foundation; The Hong Kong Hereditary Breast Cancer Family Registry and the Dr Ellen Li Charitable Foundation; and service grants NO2-CP-11019-50 and N02-CP-65504 (with Westat, Inc, Rockville, MD) through the National Cancer Institute; Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; and grants ISCIIIRETIC RD06/0020/1051, PI10/01422, PI10/31488, and 2009SGR290 from the Catalan Health Institute and Autonomous Government of Catalonia. Dr Karlan is supported by funding (grant SIOP-06-258-06-COUN) from the American Cancer Society, Clinical Research Professorship. Dr Garcia is the recipient of a Miguel Servet contract from the Instituto de Salud Carlos III. Dr Antoniou is a Cancer Research UK Senior Cancer Research Fellow. NR 37 TC 164 Z9 172 U1 4 U2 35 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 25 PY 2012 VL 307 IS 4 BP 382 EP 390 DI 10.1001/jama.2012.20 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 881EP UT WOS:000299464000024 PM 22274685 ER PT J AU Bevans, M Sternberg, EM AF Bevans, Margaret Sternberg, Esther M. TI Caregiving Burden, Stress, and Health Effects Among Family Caregivers of Adult Cancer Patients SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID STEM-CELL TRANSPLANTATION; MARROW-TRANSPLANTATION; SWEAT PATCHES; EXPERIENCE; WOMEN; DYSREGULATION; DEPRESSION; CORTISOL; RISK; PATHOPHYSIOLOGY AB Unlike professional caregivers such as physicians and nurses, informal caregivers, typically family members or friends, provide care to individuals with a variety of conditions including advanced age, dementia, and cancer. This experience is commonly perceived as a chronic stressor, and caregivers often experience negative psychological, behavioral, and physiological effects on their daily lives and health. In this report, we describe the experience of a 53-year-old woman who is the sole caregiver for her husband, who has acute myelogenous leukemia and was undergoing allogeneic hematopoietic stem cell transplantation. During his intense and unpredictable course, the caregiver's burden is complex and complicated by multiple competing priorities. Because caregivers are often faced with multiple concurrent stressful events and extended, unrelenting stress, they may experience negative health effects, mediated in part by immune and autonomic dysregulation. Physicians and their interdisciplinary teams are presented daily with individuals providing such care and have opportunity to intervene. This report describes a case that exemplifies caregiving burden and discusses the importance of identifying caregivers at risk of negative health outcomes and intervening to attenuate the stress associated with the caregiving experience. JAMA. 2012;307(4):398-403 C1 [Bevans, Margaret] NIMH, Neuroendocrine Immunol & Behav Sect, NIH, Ctr Clin, Bethesda, MD 20892 USA. [Bevans, Margaret] US PHS, Nursing & Patient Care Serv, Hlth Clin Ctr, Bethesda, MD USA. RP Bevans, M (reprint author), NIMH, Neuroendocrine Immunol & Behav Sect, NIH, Ctr Clin, 10 Ctr Dr,Room 2B13,MSC 1151, Bethesda, MD 20892 USA. EM mbevans@cc.nih.gov FU NIH Clinical Center FX The authors would like to acknowledge the family featured in the case study and for providing permission to publish their story. We also thank Leslie Wehrlen, RN, BSN, OCN; Alyson Ross, RN, MS; Stephen Klagholz, BS, Gwenyth Wallen, RN, PhD; and Clare Hastings, RN, PhD, FAAN, at the NIH Clinical Center for their support of this program of research and help with the manuscript, none of whom received compensation beyond their regular salaries. NR 52 TC 74 Z9 76 U1 4 U2 34 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 25 PY 2012 VL 307 IS 4 BP 398 EP 403 DI 10.1001/jama.2012.29 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 881EP UT WOS:000299464000026 PM 22274687 ER PT J AU Dilts, DM Rosenblum, D Trochim, WM AF Dilts, David M. Rosenblum, Daniel Trochim, William M. TI A Virtual National Laboratory for Reengineering Clinical Translational Science SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID DRUG DEVELOPMENT; TRIAL DEVELOPMENT; NIH ROADMAP; INNOVATION AB Clinical research is burdened by inefficiencies and complexities, with a poor record of trial completion, none of which is desirable. The Clinical and Translational Science Award (CTSA) Consortium, including more than 60 clinical research institutions, supports a unified national effort to become, in effect, a virtual national laboratory designed to identify, implement, evaluate, and extend process improvements across all parts of clinical research, from conception to completion. If adequately supported by academic health centers, industry, and funding agencies, the Consortium could become a test bed for improvements that can dramatically reduce wasteful complexity, thus increasing the likelihood of clinical trial completion. C1 [Rosenblum, Daniel] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. [Dilts, David M.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. [Trochim, William M.] Cornell Univ, Ithaca, NY 14853 USA. RP Rosenblum, D (reprint author), NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. EM rosenblumd@mail.nih.gov FU NIH/NCRR Institutional CTSA; NIH [1 UL1 RR024996, UL1 RR024139, UL13 RR025975] FX Funding: NIH/NCRR Institutional CTSA and the NIH: 1 UL1 RR024996 (Oregon Clinical and Translational Research Institute), 1 UL1 RR024996 (Clinical and Translational Science Center at Weill Cornell Medical College), and UL1 RR024139 and UL13 RR025975 (Yale Center for Clinical Investigation). NR 22 TC 10 Z9 10 U1 1 U2 10 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JAN 25 PY 2012 VL 4 IS 118 AR 118cm2 DI 10.1126/scitranslmed.3002951 PG 4 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 882CR UT WOS:000299539500002 PM 22277966 ER PT J AU Chan, CC Moser, JM Dyer, KD Percopo, CM Rosenberg, HF AF Chan, Calvin C. Moser, Jennifer M. Dyer, Kimberly D. Percopo, Caroline M. Rosenberg, Helene F. TI Genetic diversity of human RNase 8 SO BMC GENOMICS LA English DT Article DE ribonuclease; polymorphism ID RIBONUCLEASE-A SUPERFAMILY; ANTIMICROBIAL PEPTIDES; MESSENGER-RNA; HOST-DEFENSE; HUMAN SKIN; EVOLUTION; SELECTION; PROTEIN; EXPRESSION; SEQUENCE AB Background: Ribonuclease 8 is a member of the RNase A family of secretory ribonucleases; orthologs of this gene have been found only in primate genomes. RNase 8 is a divergent paralog of RNase 7, which is lysine-enriched, highly conserved, has prominent antimicrobial activity, and is expressed in both normal and diseased skin; in contrast, the physiologic function of RNase 8 remains uncertain. Here, we examine the genetic diversity of human RNase 8, a subject of significant interest given the existence of functional pseudogenes (coding sequences that are otherwise intact but with mutations in elements crucial for ribonucleolytic activity) in non-human primate genomes. Results: RNase 8 expression was detected in adult human lung, spleen and testis tissue by quantitative reverse-transcription PCR. Only two single-nucleotide polymorphisms and four unique alleles were identified within the RNase 8 coding sequence; nucleotide sequence diversity (pi = 0.00122 +/- 0.00009 per site) was unremarkable for a human nuclear gene. We isolated transcripts encoding RNase 8 via rapid amplification of cDNA ends (RACE) and RT-PCR which included a distal potential translational start site followed by sequence encoding an additional 30 amino acids that are conserved in the genomes of several higher primates. The distal translational start site is functional and promotes RNase 8 synthesis in transfected COS-7 cells. Conclusions: These results suggest that RNase 8 may diverge considerably from typical RNase A family ribonucleases and may likewise exhibit unique function. This finding prompts a reconsideration of what we have previously termed functional pseudogenes, as RNase 8 may be responding to constraints that promote significant functional divergence from the canonical structure and enzymatic activity characteristic of the RNase A family. C1 [Chan, Calvin C.; Moser, Jennifer M.; Dyer, Kimberly D.; Percopo, Caroline M.; Rosenberg, Helene F.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C215,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU NIAID-DIR [Z01-AI00942] FX We thank Dr. Todd Wilson, Ms. Daly Cantave, and Dr. Dean Metcalfe for use of the LAD/NIAID 09-I-0049 normal volunteer blood donor protocol. This work was supported by NIAID-DIR funding (Z01-AI00942). NR 33 TC 3 Z9 4 U1 3 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JAN 24 PY 2012 VL 13 AR 40 DI 10.1186/1471-2164-13-40 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 907SW UT WOS:000301439400001 PM 22272736 ER PT J AU Zeeberg, BR Reinhold, W Snajder, R Thallinger, GG Weinstein, JN Kohn, KW Pommier, Y AF Zeeberg, Barry R. Reinhold, William Snajder, Rene Thallinger, Gerhard G. Weinstein, John N. Kohn, Kurt W. Pommier, Yves TI Functional Categories Associated with Clusters of Genes That Are Co-Expressed across the NCI-60 Cancer Cell Lines SO PLOS ONE LA English DT Article ID MICROARRAY DATA; DIFFERENTIAL COEXPRESSION; MOLECULAR PHARMACOLOGY; EXPRESSION PROFILES; ONTOLOGY; DATABASE; TOOL; RESOURCE; GOMINER AB Background: The NCI-60 is a panel of 60 diverse human cancer cell lines used by the U.S. National Cancer Institute to screen compounds for anticancer activity. In the current study, gene expression levels from five platforms were integrated to yield a single composite transcriptome profile. The comprehensive and reliable nature of that dataset allows us to study gene co-expression across cancer cell lines. Methodology/Principal Findings: Hierarchical clustering revealed numerous clusters of genes in which the genes co-vary across the NCI-60. To determine functional categorization associated with each cluster, we used the Gene Ontology (GO) Consortium database and the GoMiner tool. GO maps genes to hierarchically-organized biological process categories. GoMiner can leverage GO to perform ontological analyses of gene expression studies, generating a list of significant functional categories. Conclusions/Significance: GoMiner analysis revealed many clusters of coregulated genes that are associated with functional groupings of GO biological process categories. Notably, those categories arising from coherent co-expression groupings reflect cancer-related themes such as adhesion, cell migration, RNA splicing, immune response and signal transduction. Thus, these clusters demonstrate transcriptional coregulation of functionally-related genes. C1 [Zeeberg, Barry R.; Reinhold, William; Weinstein, John N.; Kohn, Kurt W.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Snajder, Rene; Thallinger, Gerhard G.] Graz Univ Technol, Inst Genom & Bioinformat, A-8010 Graz, Austria. RP Zeeberg, BR (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM zeebergb@mail.nih.gov OI Thallinger, Gerhard G./0000-0002-2864-5404 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research, Research; Austrian Ministry of Science and Research, GEN-AU FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Research and the Austrian Ministry of Science and Research, GEN-AU project Bioinformatics Integration Network. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 7 Z9 7 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 24 PY 2012 VL 7 IS 1 AR e30317 DI 10.1371/journal.pone.0030317 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 910LV UT WOS:000301639600012 PM 22291933 ER PT J AU Behra, M Gallardo, VE Bradsher, J Torrado, A Elkahloun, A Idol, J Sheehy, J Zonies, S Xu, L Shaw, KM Satou, C Higashijima, SI Weinstein, BM Burgess, SM AF Behra, Martine Gallardo, Viviana E. Bradsher, John Torrado, Aranza Elkahloun, Abdel Idol, Jennifer Sheehy, Jessica Zonies, Seth Xu, Lisha Shaw, Kenna M. Satou, Chie Higashijima, Shin-ichi Weinstein, Brant M. Burgess, Shawn M. TI Transcriptional signature of accessory cells in the lateral line, using the Tnk1bp1:EGFP transgenic zebrafish line SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article DE Regeneration; hair cells; progenitor cells; lateral line; zebrafish; supporting cells; accessory cells; microarrays; Tnk1bp1 ID HAIR-CELLS; SYSTEM; GENE; REGENERATION; PROLIFERATION; TANKYRASE-1; NEUROMASTS; EXPRESSION; FISH AB Background: Because of the structural and molecular similarities between the two systems, the lateral line, a fish and amphibian specific sensory organ, has been widely used in zebrafish as a model to study the development/biology of neuroepithelia of the inner ear. Both organs have hair cells, which are the mechanoreceptor cells, and supporting cells providing other functions to the epithelium. In most vertebrates (excluding mammals), supporting cells comprise a pool of progenitors that replace damaged or dead hair cells. However, the lack of regenerative capacity in mammals is the single leading cause for acquired hearing disorders in humans. Results: In an effort to understand the regenerative process of hair cells in fish, we characterized and cloned an egfp transgenic stable fish line that trapped tnks1bp1, a highly conserved gene that has been implicated in the maintenance of telomeres' length. We then used this Tg(tnks1bp1:EGFP) line in a FACsorting strategy combined with microarrays to identify new molecular markers for supporting cells. Conclusions: We present a Tg(tnks1bp1: EGFP) stable transgenic line, which we used to establish a transcriptional profile of supporting cells in the zebrafish lateral line. Therefore we are providing a new set of markers specific for supporting cells as well as candidates for functional analysis of this important cell type. This will prove to be a valuable tool for the study of regeneration in the lateral line of zebrafish in particular and for regeneration of neuroepithelia in general. C1 [Behra, Martine; Gallardo, Viviana E.; Elkahloun, Abdel; Idol, Jennifer; Sheehy, Jessica; Zonies, Seth; Xu, Lisha; Burgess, Shawn M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Shaw, Kenna M.; Weinstein, Brant M.] NICHHD, Bethesda, MD 20892 USA. [Behra, Martine; Bradsher, John; Torrado, Aranza] Univ Puerto Rico, Sch Med, Dept Anat & Neurobiol, San Juan, PR 00936 USA. [Satou, Chie; Higashijima, Shin-ichi] Natl Inst Nat Sci, Okazaki Inst Integrat Biol, Okazaki, Aichi 4448787, Japan. [Shaw, Kenna M.] NCI, Bethesda, MD 20892 USA. RP Behra, M (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM martine.behra@upr.edu OI Burgess, Shawn/0000-0003-1147-0596 FU National Human Genome Research Institute (NHGRI); National Institute of Child Health and Human Development (NICHD); National Institute of Deafness and other communication disorders (NIDCD) [4 R00 DC009443-02] FX We thank Jizhou Yan for helping to improve the FAC sorting methods. We thank the people in the FACsorting and microarray cores of NHGRI. We thank T. Oka for excellent fish husbandry, Dr. B. Feldman and his lab for the use of the confocal microscope. This research was supported by the Intramural Research Program of the National Human Genome Research Institute (NHGRI, MB, VE, AE, JI, JI, SZ and SB), and of the National Institute of Child Health and Human Development (NICHD, KS and BW) and by a K99/R00 grant #4 R00 DC009443-02 from the National Institute of Deafness and other communication disorders (NIDCD, MB/SB). NR 28 TC 9 Z9 9 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD JAN 24 PY 2012 VL 12 AR 6 DI 10.1186/1471-213X-12-6 PG 14 WC Developmental Biology SC Developmental Biology GA 907PL UT WOS:000301429700001 PM 22273551 ER PT J AU Capone, R Jang, H Kotler, SA Kagan, BL Nussinov, R Lal, R AF Capone, Ricardo Jang, Hyunbum Kotler, Samuel A. Kagan, Bruce L. Nussinov, Ruth Lal, Ratnesh TI Probing Structural Features of Alzheimer's Amyloid-beta Pores in Bilayers Using Site-Specific Amino Acid Substitutions SO BIOCHEMISTRY LA English DT Article ID RAPID CELLULAR DEGENERATION; PLANAR LIPID-BILAYERS; ION CHANNELS; SECONDARY STRUCTURE; CALCIUM-CHANNELS; PEPTIDE CHANNELS; NEURONAL DEATH; GRAMICIDIN-A; DISEASE; MEMBRANES AB A current hypothesis for the pathology of Alzheimer's disease (AD) proposes that amyloid-beta (A beta) peptides induce uncontrolled, neurotoxic ion flux across cellular membranes. The mechanism of ion flux is not fully understood because no experiment-based A beta channel structures at atomic resolution are currently available (only a few polymorphic states have been predicted by computational models). Structural models and experimental evidence lend support to the view that the A beta channel is an assembly of loosely associated mobile beta-sheet subunits. Here, using planar lipid bilayers and molecular dynamics (MD) simulations, we show that amino acid substitutions can be used to infer which residues are essential for channel structure. We created two A beta(1-42) peptides with point mutations: F19P and F20C. The substitution of Phe19 with Pro inhibited channel conductance. MD simulation suggests a collapsed pore of F19P channels at the lower bilayer leaflet. The kinks at the Pro residues in the pore-lining beta-strands induce blockage of the solvated pore by the N-termini of the chains. The cysteine mutant is capable of forming channels, and the conductance behavior of F20C channels is similar to that of the wild type. Overall, the mutational analysis of the channel activity performed in this work tests the proposition that the channels consist of a beta-sheet rich organization, with the charged/polar central strand containing the mutation sites lining the pore, and the C-terminal strands facing the hydrophobic lipid tails. A detailed understanding of channel formation and its structure should aid studies of drug design aiming to control unregulated A beta-dependent ion fluxes. C1 [Jang, Hyunbum; Nussinov, Ruth] SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Natl Canc Inst Frederick, Frederick, MD 21702 USA. [Capone, Ricardo; Kotler, Samuel A.; Lal, Ratnesh] Univ Calif San Diego, Dept Bioengn, Dept Mech & Aerosp Engn, La Jolla, CA 92093 USA. [Capone, Ricardo; Kotler, Samuel A.; Lal, Ratnesh] Univ Calif San Diego, Mat Sci Program, La Jolla, CA 92093 USA. [Kagan, Bruce L.] Univ Calif Los Angeles, Dept Psychiat, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Nussinov, Ruth] Tel Aviv Univ, Dept Human Mol Genet & Biochem, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Natl Canc Inst Frederick, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov; rlal@ucsd.edu RI Capone, Ricardo/D-1943-2010 OI Capone, Ricardo/0000-0002-7327-9837 FU National Institutes of Health (National Institute on Aging) [AG028709]; National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the National Institutes of Health (National Institute on Aging Grant AG028709 to R.L.). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health (NIH), under Contract HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 71 TC 32 Z9 32 U1 2 U2 28 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 24 PY 2012 VL 51 IS 3 BP 776 EP 785 DI 10.1021/bi2017427 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 879YD UT WOS:000299367900007 PM 22242635 ER PT J AU Fox, CS Muntner, P Chen, AY Alexander, KP Roe, MT Wiviott, SD AF Fox, Caroline S. Muntner, Paul Chen, Anita Y. Alexander, Karen P. Roe, Matthew T. Wiviott, Stephen D. TI Short-Term Outcomes of Acute Myocardial Infarction in Patients With Acute Kidney Injury A Report From the National Cardiovascular Data Registry SO CIRCULATION LA English DT Article DE acute kidney injury; kidney; mortality; myocardial infarction ID ACUTE-RENAL-FAILURE; ACUTE CORONARY TREATMENT; TIMI RISK SCORE; SERUM CREATININE; CARDIAC-SURGERY; MORTALITY; INCREASES; NETWORK; ASSOCIATION; DYSFUNCTION AB Background-Acute kidney injury (AKI) is a risk factor for long-term adverse outcomes, including acute myocardial infarction and death. However, the relationship between severity of AKI and in-hospital outcomes in the setting of acute myocardial infarction has not been well documented. Methods and Results-The study population (n = 59 970) was drawn from the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry-Get With the Guidelines (GWTG), a nationwide sample of myocardial infarction patients admitted to 383 hospitals in the United States between July 2008 and September 2009. AKI was defined using absolute changes in serum creatinine (SCr; peak SCr minus admission SCr) and categorized as no AKI (SCr change, <0.3 mg/dL), mild AKI (SCr change, 0.3-<0.5 mg/dL), moderate AKI (SCr change, 0.5-<1.0 mg/dL), and severe AKI (SCr change, >= 1.0 mg/dL). Overall, 16.1% had AKI, including 6.5% with mild AKI, 5.6% with moderate AKI, and 4.0% with severe AKI. In-hospital mortality rates for those with mild, moderate, and severe AKI were 6.6%, 14.2%, and 31.8% compared with 2.1% in those without AKI. The odds ratios for in-hospital death were 2.4 (95% confidence interval, 2.0-2.7), 4.5 (95% confidence interval, 3.9-5.1), and 12.6 (95% confidence interval, 11.1-14.3) for mild, moderate, and severe AKI compared with those without AKI. Although patients with AKI were less likely to undergo early invasive care or to receive antiplatelet therapies, rates of major bleeding ranged from 8.4% (no AKI) to 32.7% (severe AKI). Conclusion-AKI is common and associated with mortality and bleeding, underscoring the importance of efforts to identify risk factors and to prevent AKI in acute myocardial infarction care. (Circulation. 2012; 125: 497-504.) C1 [Fox, Caroline S.] NHLBIs Framingham Heart Study, Div Intramural Res, NHLBI, Framingham, MA 01702 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.; Wiviott, Stephen D.] Harvard Univ, Sch Med, Boston, MA USA. [Muntner, Paul] Univ Alabama, Dept Epidemiol, Birmingham, AL USA. [Chen, Anita Y.; Alexander, Karen P.; Roe, Matthew T.] Duke Clin Res Inst, Durham, NC USA. [Wiviott, Stephen D.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBIs Framingham Heart Study, Div Intramural Res, NHLBI, 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU ACTION Registry-GWTG is an initiative of the American College of Cardiology Foundation; American Heart Association; BristolMyers Squibb/Sanofi Pharmaceuticals; Eli Lilly; Novartis; Merck-Schering Plough; American College of Cardiology; Glaxo Smith Kline; KAI Pharmaceuticals; Sanofi-Aventis; AstraZeneca; Daiichi Sankyo; Arena FX The ACTION Registry-GWTG is an initiative of the American College of Cardiology Foundation and the American Heart Association with partnering support from the Society of Chest Pain Centers, the American College of Emergency Physicians, and the Society of Hospital Medicine. The registry is sponsored in part by the BristolMyers Squibb/Sanofi Pharmaceuticals Partnership.; Dr Roe has received research funding from Eli Lilly, Novartis, Merck-Schering Plough, Bristol-Myers Squibb, American College of Cardiology, and American Heart Association, as well as consulting fees or honoraria from Glaxo Smith Kline, KAI Pharmaceuticals, Novartis, Eli Lilly, Bristol-Myers Squibb, Sanofi-Aventis, and AstraZeneca. Dr Wiviott has received research funding from Daiichi Sankyo, Eli Lilly, and Schering-Plough; consulting fees from AstraZeneca, Bristol-Myers Squibb, Sanofi-Aventis, and Arena; and honoraria from Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Schering-Plough, Merck, The Medicine Company, and Bayer. The other authors report no conflicts. The ACTION Registry-GTWG is administered by the American College of Cardiology Foundation and is sponsored by Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Genentech, and Schering-Plough Corp. NR 24 TC 45 Z9 56 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 24 PY 2012 VL 125 IS 3 BP 497 EP U99 DI 10.1161/CIRCULATIONAHA.111.039909 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 891YL UT WOS:000300252800017 PM 22179533 ER PT J AU Phelps, L Fox, BA Marincola, FM AF Phelps, Lisa Fox, Bernard A. Marincola, Francesco M. TI Supporting the advancement of science: Open access publishing and the role of mandates SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material AB In December 2011 the United States House of Representatives introduced a new bill, the Research Works Act (H. R. 3699), which if passed could threaten the public's access to US government funded research. In a digital age when professional and lay parties alike look more and more to the online environment to keep up to date with developments in their fields, does this bill serve the best interests of the community? Those in support of the Research Works Act argue that government open access mandates undermine peer-review and take intellectual property from publishers without compensation, however journals like Journal of Translational Medicine show that this is not the case. Journal of Translational Medicine in affiliation with the Society for Immunotherapy of Cancer demonstrates how private and public organisations can work together for the advancement of science. C1 [Phelps, Lisa] BioMed Cent, London WC1X 8HB, England. [Fox, Bernard A.] Providence Portland Med Ctr, Providence Canc Ctr, Earle A Chiles Res Inst, Robert W Franz Res Ctr, Portland, OR USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Marincola, Francesco M.] NIH, Bethesda, MD 20892 USA. RP Phelps, L (reprint author), BioMed Cent, 236 Grays Inn Rd,Floor 6, London WC1X 8HB, England. EM lisa.phelps@biomedcentral.com NR 7 TC 2 Z9 2 U1 0 U2 26 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JAN 24 PY 2012 VL 10 AR 13 DI 10.1186/1479-5876-10-13 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 893IB UT WOS:000300348500001 PM 22272665 ER PT J AU Cui, CY Childress, V Piao, Y Michel, M Johnson, AA Kunisada, M Ko, MSH Kaestner, KH Marmorstein, AD Schlessinger, D AF Cui, Chang-Yi Childress, Victoria Piao, Yulan Michel, Marc Johnson, Adiv A. Kunisada, Makoto Ko, Minoru S. H. Kaestner, Klaus H. Marmorstein, Alan D. Schlessinger, David TI Forkhead transcription factor FoxA1 regulates sweat secretion through Bestrophin 2 anion channel and Na-K-Cl cotransporter 1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ectodysplasin; idiopathic-acquired generalized anhidrosis; cystic fibrosis ID HUMAN ECCRINE SWEAT; GLANDS; FAMILY; MEMBRANE; MUTATION; PROTEIN; MOUSE; CELLS; HCO3 AB Body temperature is maintained in a narrow range in mammals, primarily controlled by sweating. In humans, the dynamic thermoregulatory organ, comprised of 2-4 million sweat glands distributed over the body, can secrete up to 4 L of sweat per day, thereby making it possible to withstand high temperatures and endure prolonged physical stress (e.g., long-distance running). The genetic basis for sweat gland function, however, is largely unknown. We find that the forkhead transcription factor, FoxA1, is required to generate mouse sweating capacity. Despite continued sweat gland morphogenesis, ablation of FoxA1 in mice results in absolute anihidrosis (lack of sweating). This inability to sweat is accompanied by down-regulation of the Na-K-Cl cotransporter 1 (Nkcc1) and the Ca2+-activated anion channel Bestrophin 2 (Best2), as well as glycoprotein accumulation in gland lumens and ducts. Furthermore, Best2-deficient mice display comparable anhidrosis and glycoprotein accumulation. These findings link earlier observations that both sodium/potassium/chloride exchange and Ca2+ are required for sweat production. FoxA1 is inferred to regulate two corresponding features of sweat secretion. One feature, via Best2, catalyzes a bicarbonate gradient that could help to drive calcium-associated ionic transport; the other, requiring Nkcc1, facilitates monovalent ion exchange into sweat. These mechanistic components can be pharmaceutical targets to defend against hyperthermia and alleviate defective thermoregulation in the elderly, and may provide a model relevant to more complex secretory processes. C1 [Cui, Chang-Yi; Childress, Victoria; Piao, Yulan; Michel, Marc; Ko, Minoru S. H.; Schlessinger, David] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Johnson, Adiv A.; Marmorstein, Alan D.] Univ Arizona, Dept Ophthalmol & Vis Sci, Tucson, AZ 85719 USA. [Kunisada, Makoto] Kobe Univ, Div Dermatol, Dept Internal Related, Grad Sch Med, Kobe, Hyogo 650, Japan. [Kaestner, Klaus H.] Univ Penn, Sch Med, Dept Genet, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. RP Cui, CY (reprint author), NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. EM cuic@mail.nih.gov; schlessingerd@mail.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU National Institute on Aging; NIH [EY13160]; Research to Prevent Blindness; [R01 DK055342] FX The authors thank Yaohui Chen, Ramaiah Nagaraja, and Steven Sollott for helpful discussions and collaborative interactions. This work was supported by the Intramural Research Program of the National Institute on Aging; Grant NIH EY13160 and an unrestricted grant to the Department of Ophthalmology and Vision Science at the University of Arizona from Research to Prevent Blindness (to A.D.M.); and Grant R01 DK055342 (to K.H.K.). NR 30 TC 26 Z9 26 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 24 PY 2012 VL 109 IS 4 BP 1199 EP 1203 DI 10.1073/pnas.1117213109 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 880NA UT WOS:000299412600044 PM 22223659 ER PT J AU Madigan, CA Cheng, TY Layre, E Young, DC McConnell, MJ Debono, CA Murry, JP Wei, JR Barry, CE Rodriguez, GM Matsunaga, I Rubin, EJ Moody, DB AF Madigan, Cressida A. Cheng, Tan-Yun Layre, Emilie Young, David C. McConnell, Matthew J. Debono, C. Anthony Murry, Jeffrey P. Wei, Jun-Rong Barry, Clifton E., III Rodriguez, G. Marcela Matsunaga, Isamu Rubin, Eric J. Moody, D. Branch TI Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IRON ACQUISITION; GENE-CLUSTER; INFECTIONS; MACROPHAGES; GROWTH AB To measure molecular changes underlying pathogen adaptation, we generated a searchable dataset of more than 12,000 mass spectrometry events, corresponding to lipids and small molecules that constitute a lipidome for Mycobacterium tuberculosis. Iron is essential for M. tuberculosis survival, and the organism imports this metal using mycobactin and carboxymycobactin siderophores. Detection of an unexpected siderophore variant and deletions of genes for iron scavenging has led to a revised mycobactin biosynthesis model. An organism-wide search of the M. tuberculosis database for hypothetical compounds predicted by this model led to the discovery of two families of previously unknown lipids, designated monodeoxymycobactins and monodeoxycarboxymycobactins. These molecules suggest a revised biosynthetic model that alters the substrates and order of action of enzymes through the mycobactin biosynthetic pathway. We tested this model genetically by solving M. tuberculosis lipidomes after deletion of the iron-dependent regulator (ideR), mycobactin synthase B (mbtB), or mycobactin synthase G (mbtG). These studies show that deoxymycobactins are actively regulated during iron starvation, and also define essential roles of MbtG in converting deoxymycobactins to mycobactin and in promoting M. tuberculosis growth. Thus, lipidomics is an efficient discovery tool that informs genetic relationships, leading to a revised general model for the biosynthesis of these virulence-conferring siderophores. C1 [Murry, Jeffrey P.; Wei, Jun-Rong; Rubin, Eric J.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Barry, Clifton E., III] NIAID, TB Res Sect, Bethesda, MD 20892 USA. [Rodriguez, G. Marcela] Univ Med & Dent New Jersey, Publ Hlth Res Inst Ctr, Newark, NJ 07103 USA. [Rodriguez, G. Marcela] Univ Med & Dent New Jersey, Dept Med, Newark, NJ 07103 USA. [Matsunaga, Isamu] Kyoto Univ, Inst Virus Res, Dept Viral Oncol, Lab Cell Regulat, Kyoto 6068507, Japan. [Madigan, Cressida A.; Cheng, Tan-Yun; Layre, Emilie; Young, David C.; McConnell, Matthew J.; Debono, C. Anthony; Moody, D. Branch] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. RP Moody, DB (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. EM bmoody@rics.bwh.harvard.edu RI Barry, III, Clifton/H-3839-2012; OI Rubin, Eric/0000-0001-5120-962X; Murry, Jeffrey/0000-0002-3716-1460 FU National Institute of Allergy and Infectious Diseases [U19 AI076217, R01 AI071155, AR048632, R01 AI071881]; Intramural Research Program; Mark and Lisa Schwartz Foundation; National Science Foundation FX This work was supported by National Institute of Allergy and Infectious Diseases Grants U19 AI076217, R01 AI071155, and AR048632 (to D.B.M.), Grant R01 AI071881 (to E.J.R.), the Intramural Research Program (C.E.B.), the Mark and Lisa Schwartz Foundation (to D.B.M. and E.J.R.), and the National Science Foundation (to C.A.M.). NR 28 TC 34 Z9 34 U1 0 U2 22 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 24 PY 2012 VL 109 IS 4 BP 1257 EP 1262 DI 10.1073/pnas.1109958109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 880NA UT WOS:000299412600054 PM 22232695 ER PT J AU Periasamy, S Joo, HS Duong, AC Bach, THL Tan, VY Chatterjee, SS Cheung, GYC Otto, M AF Periasamy, Saravanan Joo, Hwang-Soo Duong, Anthony C. Bach, Thanh-Huy L. Tan, Vee Y. Chatterjee, Som S. Cheung, Gordon Y. C. Otto, Michael TI How Staphylococcus aureus biofilms develop their characteristic structure SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID QUORUM-SENSING SYSTEM; PSEUDOMONAS-AERUGINOSA; BACILLUS-SUBTILIS; EPIDERMIDIS; AGR; INFECTIONS; SURFACTANT; MATURATION; PEPTIDES; PATHOGEN AB Biofilms cause significant problems in the environment and during the treatment of infections. However, the molecular mechanisms underlying biofilm formation are poorly understood. There is a particular lack of knowledge about biofilm maturation processes, such as biofilm structuring and detachment, which are deemed crucial for the maintenance of biofilm viability and the dissemination of cells from a biofilm. Here, we identify the phenol-soluble modulin (PSM) surfactant peptides as key biofilm structuring factors in the premier biofilm-forming pathogen Staphylococcus aureus. We provide evidence that all known PSM classes participate in structuring and detachment processes. Specifically, absence of PSMs in isogenic S. aureus psm deletion mutants led to strongly impaired formation of biofilm channels, abolishment of the characteristic waves of biofilm detachment and regrowth, and loss of control of biofilm expansion. In contrast, induced expression of psm loci in preformed biofilms promoted those processes. Furthermore, PSMs facilitated dissemination from an infected catheter in a mouse model of biofilm-associated infection. Moreover, formation of the biofilm structure was linked to strongly variable, quorum sensing-controlled PSM expression in biofilm microenvironments, whereas overall PSM production remained constant to ascertain biofilm homeostasis. Our study describes a mechanism of biofilm structuring in molecular detail, and the general principle (i.e., quorum-sensing controlled expression of surfactants) seems to be conserved in several bacteria, despite the divergence of the respective biofilm-structuring surfactants. These findings provide a deeper understanding of biofilm development processes, which represents an important basis for strategies to interfere with biofilm formation in the environment and human disease. C1 [Periasamy, Saravanan; Joo, Hwang-Soo; Duong, Anthony C.; Bach, Thanh-Huy L.; Tan, Vee Y.; Chatterjee, Som S.; Cheung, Gordon Y. C.; Otto, Michael] NIAID, NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov RI Cheung, Yiu Chong /K-3565-2012; OI JOO, HWANG-SOO/0000-0003-4668-3225; Otto, Michael/0000-0002-2222-4115 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 26 TC 136 Z9 140 U1 4 U2 64 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 24 PY 2012 VL 109 IS 4 BP 1281 EP 1286 DI 10.1073/pnas.1115006109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 880NA UT WOS:000299412600058 PM 22232686 ER PT J AU Rao, JS Kim, HW Kellom, M Greenstein, D Chen, M Kraft, AD Harry, GJ Rapoport, SI Basselin, M AF Rao, Jagadeesh Sridhara Kim, Hyung-Wook Kellom, Matthew Greenstein, Dede Chen, Mei Kraft, Andrew David Harry, Gaylia Jean Rapoport, Stanley Isaac Basselin, Mireille TI Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in brain of HIV-1 transgenic rats (vol 8, pg 101, 2011) SO JOURNAL OF NEUROINFLAMMATION LA English DT Correction AB Correction to Rao J S, Kim H W, Kellom M, Greenstein D, Chen M, Kraft A D, Harry G J, Rapoport S I, Basselin M. Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in brain of HIV-1 transgenic rats. Journal of Neuroinflammation 8:101. C1 [Rao, Jagadeesh Sridhara; Kim, Hyung-Wook; Kellom, Matthew; Chen, Mei; Rapoport, Stanley Isaac; Basselin, Mireille] NIA, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. [Greenstein, Dede] NIMH, NIH, Bethesda, MD 20892 USA. [Kraft, Andrew David; Harry, Gaylia Jean] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, NIH, Durham, NC 27709 USA. RP Rao, JS (reprint author), NIA, Brain Physiol & Metab Sect, 9000 Rockville Pike,Bldg 9,1S-126, Bethesda, MD 20892 USA. EM jrao@mail.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD JAN 23 PY 2012 VL 9 AR 19 DI 10.1186/1742-2094-9-19 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 917HY UT WOS:000302165300001 ER PT J AU Ryabov, Y Clore, GM Schwieters, CD AF Ryabov, Yaroslav Clore, G. Marius Schwieters, Charles D. TI Coupling between internal dynamics and rotational diffusion in the presence of exchange between discrete molecular conformations SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID MODEL-FREE APPROACH; MAGNETIC-RESONANCE RELAXATION; BODY STOCHASTIC APPROACH; NMR RELAXATION; ELLIPSOIDAL MOLECULES; INTERDOMAIN MOBILITY; MOTIONS; MACROMOLECULES; PROTEINS; MOVEMENT AB We present a general formalism for the computation of orientation correlation functions involving a molecular system undergoing rotational diffusion in the presence of transitions between discrete conformational states. In this formalism, there are no proscriptions on the time scales of conformational rearrangement relative to that for rotational diffusion, and the rotational diffusion tensors of the different states can be completely arbitrary. Although closed-form results are limited to the frequency domain, this is generally useful for many spectroscopic observables as the result allows the computation of the spectral density function. We specialize the results for the computation of the frequency-domain correlation function associated with the NMR relaxation.[doi:10.1063/1.3675602] C1 [Ryabov, Yaroslav; Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Schwieters, CD (reprint author), NIH, Div Computat Biosci, Ctr Informat Technol, Bldg 12A, Bethesda, MD 20892 USA. EM charles.schwieters@nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU NIH of CIT; NIDDK; Office of the Director of the NIH FX The authors thank Attila Szabo and Alexander Berezhkovskii for many stimulating discussions and encouragement. This work was supported by the NIH Intramural Research Programs of CIT (C. D. S.) and NIDDK (G. M. C.) and by the AIDS Targeted Antiviral Program of the Office of the Director of the NIH (G.M.C.). NR 24 TC 16 Z9 16 U1 2 U2 20 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD JAN 21 PY 2012 VL 136 IS 3 AR 034108 DI 10.1063/1.3675602 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 880EN UT WOS:000299387700010 PM 22280745 ER PT J AU Coovadia, HM Brown, ER Fowler, MG Chipato, T Moodley, D Manji, K Musoke, P Stranix-Chibanda, L Chetty, V Fawzi, W Nakabiito, C Msweli, L Kisenge, R Guay, L Mwatha, A Lynn, DJ Eshleman, SH Richardson, P George, K Andrew, P Mofenson, LM Zwerski, S Maldonado, Y AF Coovadia, Hoosen M. Brown, Elizabeth R. Fowler, Mary Glenn Chipato, Tsungai Moodley, Dhayendre Manji, Karim Musoke, Philippa Stranix-Chibanda, Lynda Chetty, Vani Fawzi, Wafaie Nakabiito, Clemensia Msweli, Lindiwe Kisenge, Roderick Guay, Laura Mwatha, Anthony Lynn, Diana J. Eshleman, Susan H. Richardson, Paul George, Kathleen Andrew, Philip Mofenson, Lynne M. Zwerski, Sheryl Maldonado, Yvonne CA HPTN 046 Protocol Team TI Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial SO LANCET LA English DT Article ID RESOURCE-LIMITED SETTINGS; TO-CHILD; ANTIRETROVIRAL DRUGS; DOSE NEVIRAPINE; FREE SURVIVAL; ZIDOVUDINE; PROPHYLAXIS; LAMIVUDINE; MORTALITY; PREGNANCY AB Background Nevirapine given once-daily for the first 6, 14, or 28 weeks of life to infants exposed to HIV-1 via breastfeeding reduces transmission through this route compared with single-dose nevirapine at birth or neonatally. We aimed to assess incremental safety and efficacy of extension of such prophylaxis to 6 months. Methods In our phase 3, randomised, double-blind, placebo-controlled HPTN 046 trial, we assessed the incremental benefit of extension of once-daily infant nevirapine from age 6 weeks to 6 months. We enrolled breastfeeding infants born to mothers with HIV-1 in four African countries within 7 days of birth. Following receipt of nevirapine from birth to 6 weeks, infants without HIV infection were randomly allocated (by use of a computer-generated permuted block algorithm with random block sizes and stratified by site and maternal antiretroviral treatment status) to receive extended nevirapine prophylaxis or placebo until 6 months or until breastfeeding cessation, whichever came first. The primary efficacy endpoint was HIV-1 infection in infants at 6 months and safety endpoints were adverse reactions in both groups. We used Kaplan-Meier analyses to compare differences in the primary outcome between groups. This study is registered with ClinicalTrials.gov, number NCT00074412. Findings Between June 19, 2008, and March 12, 2010, we randomly allocated 1527 infants (762 nevirapine and 765 placebo); five of whom had HIV-1 infection at randomisation and were excluded from the primary analyses. In Kaplan-Meier analysis, 1.1% (95% CI 0.3-1.8) of infants who received extended nevirapine developed HIV-1 between 6 weeks and 6 months compared with 2.4% (1.3-3.6) of controls (difference 1.3%, 95% CI 0-2.6), equating to a 54% reduction in transmission (p=0.049). However, mortality (1.2% for nevirapine vs 1.1% for placebo; p=0.81) and combined HIV infection and mortality rates (2.3% vs 3.2%; p=0.27) did not differ between groups at 6 months. 125 (16%) of 758 infants given extended nevirapine and 116 (15%) of 761 controls had serious adverse events, but frequency of adverse events, serious adverse events, and deaths did not differ significantly between treatment groups. Interpretation Nevirapine prophylaxis can safely be used to provide protection from mother-to-child transmission of HIV-1 via breastfeeding for infants up to 6 months of age. C1 [Coovadia, Hoosen M.] Univ Witwatersrand, Maternal Adolescent & Child Hlth MatCH, Johannesburg, South Africa. [Coovadia, Hoosen M.] Univ Kwazulu Natal, Nelson Mandela Sch Med, Durban, South Africa. [Brown, Elizabeth R.; Mwatha, Anthony; Lynn, Diana J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Fowler, Mary Glenn; Eshleman, Susan H.; Richardson, Paul] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Chipato, Tsungai; Stranix-Chibanda, Lynda] Univ Zimbabwe, Coll Med, Harare, Zimbabwe. [Moodley, Dhayendre; Chetty, Vani; Msweli, Lindiwe] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Ctr AIDS Programme Res S Africa CAPRISA, Durban, South Africa. [Manji, Karim; Kisenge, Roderick] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Musoke, Philippa; Nakabiito, Clemensia] Makerere Univ Johns Hopkins Univ Res Collaborat, Kampala, Uganda. [Fawzi, Wafaie] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Guay, Laura] George Washington Univ, Sch Publ Hlth, Washington, DC USA. [Guay, Laura] George Washington Univ, Hlth Serv, Washington, DC USA. [George, Kathleen; Andrew, Philip] Family Hlth Int, Res Triangle Pk, NC 27709 USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD USA. [Zwerski, Sheryl] NIAID, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Maldonado, Yvonne] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Coovadia, HM (reprint author), Maternal Adolescent & Child Hlth MatCH, 155 Juniper Rd, ZA-4091 Durban, South Africa. EM hcoovadia@match.org.za RI Brown, Elizabeth/A-8984-2008; OI Mofenson, Lynne/0000-0002-2818-9808 FU US National Institutes of Health (NIH); US National Institutes of Health (NIH) through the HPTN [046]; US National Institutes of Health (NIH) through the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group; National Institute of Allergy and Infectious Diseases (NIAID) [U01AI46749, U01AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); NICHD FX US National Institutes of Health.; The HIV Prevention Trials Network (HPTN) 046 study was funded by the US National Institutes of Health (NIH), initially through the HPTN and later through the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group. The HPTN (U01AI46749) has been funded by the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Drug Abuse (NIDA), and National Institute of Mental Health (NIMH). The IMPAACT Group (U01AI068632) has been funded by NIAID, NICHD, and NIMH. The study products were provided for free by Boehringer-Ingelheim. We thank the mothers and their children who participated in the study; the HPTN 046 study coordinators, counsellors, clinicians, pharmacists, data quality and laboratory staff, and those responsible for recruitment and retention for their dedication and hard work on site; Thomas R Fleming (University of Washington/Fred Hutchinson Cancer Research Center) for his contributions to study design and his strong support throughout study conduct; Scharla Estep (NIAID protocol pharmacist) for her help on pharmaceutical matters; and Avinash Shetty (Wake Forest University Health Sciences) for his contribution to study development and safety data review. NR 23 TC 56 Z9 56 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JAN 21 PY 2012 VL 379 IS 9812 BP 221 EP 228 DI 10.1016/S0140-6736(11)61653-X PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 879FW UT WOS:000299316100036 PM 22196945 ER PT J AU Mulholland, N Xu, Y Sugiyama, H Zhao, KJ AF Mulholland, Niveen Xu, Yan Sugiyama, Hiroshi Zhao, Keji TI SWI/SNF-mediated chromatin remodeling induces Z-DNA formation on a nucleosome SO CELL AND BIOSCIENCE LA English DT Article ID SEQUENCES; REVEALS; BRG1 AB Background: Z-DNA is a higher-energy, left-handed form of the double helix. A primary function of Z-DNA formation is to facilitate transcriptional initiation and activation. Sequences favoring Z-DNA formation are frequently located in promoter regions and Z-DNA is stabilized by torsional strain resulting from negative supercoiling, such as that generated by an actively transcribing polymerase or by a nucleosome remodeling event. We previously have shown that activation of the CSF1 gene by a chromatin remodeling event in the promoter results in Z-DNA formation at TG repeats within the promoter. Results: We show that remodeling of a mononucleosome by the human SWI/SNF complex results in Z-DNA formation when the DNA within the mononucleosome contains Z-DNA favoring sequence. Nuclease accessibility patterns of nucleosome core particle consisting of Z-DNA are quite different from counterpart nucleosomes containing classic B-DNA. Z-nucleosomes represent a novel mononucleosome structure. Conclusions: We present evidence that Z-DNA can form on nucleosomes though previous observations indicate the occlusion of nucleosome formation from Z-DNA. C1 [Mulholland, Niveen; Zhao, Keji] NHLBI, Syst Biol Ctr, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Xu, Yan; Sugiyama, Hiroshi] Kyoto Univ, Dept Chem, Grad Sch Sci, Kyoto 606, Japan. RP Zhao, KJ (reprint author), NHLBI, Syst Biol Ctr, Div Intramural Res, NIH, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov RI Sugiyama, Hiroshi/C-7687-2011; OI Xu, Yan/0000-0003-0379-8866 FU National Heart Lung and Blood Institute of the National Institutes of Health FX The authors would like to thank Drs. Sam John and Hua-Ying Fan for critical review of the manuscript. This work was funded by intramural research grant from the National Heart Lung and Blood Institute of the National Institutes of Health. NR 15 TC 8 Z9 9 U1 2 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD JAN 20 PY 2012 VL 2 AR 3 DI 10.1186/2045-3701-2-3 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982QZ UT WOS:000307061800001 PM 22264354 ER PT J AU Malempati, S Weigel, B Ingle, AM Ahern, CH Carroll, JM Roberts, CT Reid, JM Schmechel, S Voss, SD Cho, SY Chen, HX Krailo, MD Adamson, PC Blaney, SM AF Malempati, Suman Weigel, Brenda Ingle, Ashish M. Ahern, Charlotte H. Carroll, Julie M. Roberts, Charles T. Reid, Joel M. Schmechel, Stephen Voss, Stephan D. Cho, Steven Y. Chen, Helen X. Krailo, Mark D. Adamson, Peter C. Blaney, Susan M. TI Phase I/II Trial and Pharmacokinetic Study of Cixutumumab in Pediatric Patients With Refractory Solid Tumors and Ewing Sarcoma: A Report From the Children's Oncology Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID FACTOR-I-RECEPTOR; GROWTH-FACTOR RECEPTOR; MONOCLONAL-ANTIBODY; ANTITUMOR-ACTIVITY; CLINICAL-TRIALS; DOWN-REGULATION; BREAST-CANCER; FACTOR SYSTEM; WILMS-TUMOR; INSULIN AB Purpose A phase I/II study of cixutumumab (IMC-A12) in children with refractory solid tumors was conducted. This study was designed to assess the toxicities, pharmacokinetics, and pharmacodynamics of cixutumumab in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma (ES). Patients and Methods Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1-hour intravenous infusion once per week. Two dose levels-6 and 9 mg/kg-were evaluated using a standard three-plus-three cohort design. Patients with refractory ES were treated in an expanded phase II cohort at each dose level. Results Forty-seven eligible patients with a median age of 15 years (range, 4 to 28 years) were enrolled. Twelve patients were treated in the dose-finding phase. Hematologic and nonhematologic toxicities were generally mild and infrequent. Dose-limiting toxicities included grade 4 thrombocytopenia at 6 mg/kg and grade 3 dehydration at 9 mg/kg. Mean trough concentration (+/- standard deviation) at 9 mg/kg was 106 +/- 57 mu g/mL, which exceeded the effective trough concentration of 60 mu g/mL observed in xenograft models. Three patients with ES had confirmed partial responses: one of 10 at 6 mg/kg and two of 20 at 9 mg/kg. Serum insulin-like growth factor I (IGF-I) levels consistently increased after one dose of cixutumumab. Tumor IGF-I receptor expression by immunohistochemistry did not correlate with response in patients with ES. Conclusion Cixutumumab is well tolerated in children with refractory solid tumors. The recommended phase II dose is 9 mg/kg. Limited single-agent activity of cixutumumab was seen in ES. C1 [Malempati, Suman] Oregon Hlth & Sci Univ, Dept Pediat, CDRC P, Portland, OR 97239 USA. [Carroll, Julie M.; Roberts, Charles T.] Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Weigel, Brenda; Schmechel, Stephen] Univ Minnesota, Minneapolis, MN USA. [Ingle, Ashish M.; Krailo, Mark D.] Childrens Oncol Grp Operat Ctr, Arcadia, CA USA. [Ahern, Charlotte H.; Blaney, Susan M.] Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. [Reid, Joel M.] Mayo Clin & Mayo Fdn, Rochester, MN USA. [Voss, Stephan D.] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Cho, Steven Y.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Chen, Helen X.] NCI, Rockville, MD USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Malempati, S (reprint author), Oregon Hlth & Sci Univ, Dept Pediat, CDRC P, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM malempat@ohsu.edu OI Roberts, Charles/0000-0003-1756-5772 FU National Cancer Institute [U01 CA97452, U10 CA98543]; General Clinical Research Center [M01-RR00188-46] FX Supported by National Cancer Institute Grants No. U01 CA97452 and U10 CA98543 and General Clinical Research Center Grant No. M01-RR00188-46. NR 38 TC 68 Z9 70 U1 0 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2012 VL 30 IS 3 BP 256 EP 262 DI 10.1200/JCO.2011.37.4355 PG 7 WC Oncology SC Oncology GA 923LG UT WOS:000302620200012 PM 22184397 ER PT J AU Zhu, WZ Petrashevskaya, N Ren, SX Zhao, AZ Chakir, K Gao, EH Chuprun, JK Wang, YB Talan, M Dorn, GW Lakatta, EG Koch, WJ Feldman, AM Xiao, RP AF Zhu, Weizhong Petrashevskaya, Natalia Ren, Shuxun Zhao, Aizhi Chakir, Khalid Gao, Erhe Chuprun, J. Kurt Wang, Yibin Talan, Mark Dorn, Gerald W., III Lakatta, Edward G. Koch, Walter J. Feldman, Arthur M. Xiao, Rui-Ping TI G(i)-Biased beta(2)AR Signaling Links GRK2 Upregulation to Heart Failure SO CIRCULATION RESEARCH LA English DT Article DE beta(2)-adrenergic receptor; G protein-coupled receptor kinase; heart failure; hypertrophy ID ADRENERGIC-RECEPTOR KINASE; MOUSE CARDIAC MYOCYTES; FAILING HUMAN HEART; GENE-TARGETED MICE; G-PROTEIN; BETA(2)-ADRENERGIC RECEPTOR; CARDIOVASCULAR-DISEASE; DILATED CARDIOMYOPATHY; PRESSURE-OVERLOAD; BETA-ARRESTINS AB Rationale: Phosphorylation of beta(2)-adrenergic receptor (beta(2)AR) by a family of serine/threonine kinases known as G protein-coupled receptor kinase (GRK) and protein kinase A (PKA) is a critical determinant of cardiac function. Upregulation of G protein-coupled receptor kinase 2 (GRK2) is a well-established causal factor of heart failure, but the underlying mechanism is poorly understood. Objective: We sought to determine the relative contribution of PKA- and GRK-mediated phosphorylation of beta(2)AR to the receptor coupling to G(i) signaling that attenuates cardiac reserve and contributes to the pathogenesis of heart failure in response to pressure overload. Methods and Results: Overexpression of GRK2 led to a G(i)-dependent decrease of contractile response to beta AR stimulation in cultured mouse cardiomyocytes and in vivo. Importantly, cardiac-specific transgenic overexpression of a mutant beta(2)AR lacking PKA phosphorylation sites (PKA-TG) but not the wild-type beta(2)AR (WT-TG) or a mutant beta(2)AR lacking GRK sites (GRK-TG) led to exaggerated cardiac response to pressure overload, as manifested by markedly exacerbated cardiac maladaptive remodeling and failure and early mortality. Furthermore, inhibition of G(i) signaling with pertussis toxin restores cardiac function in heart failure associated with increased beta(2)AR to G(i) coupling induced by removing PKA phosphorylation of the receptor and in GRK2 transgenic mice, indicating that enhanced phosphorylation of beta(2)AR by GRK and resultant increase in G(i)-biased beta(2)AR signaling play an important role in the development of heart failure. Conclusions: Our data show that enhanced beta(2)AR phosphorylation by GRK, in addition to PKA, leads the receptor to G(i)-biased signaling, which, in turn, contributes to the pathogenesis of heart failure, marking G(i)-biased beta(2)AR signaling as a primary event linking upregulation of GRK to cardiac maladaptive remodeling, failure and cardiodepression. (Circ Res. 2012;110:265-274.) C1 [Xiao, Rui-Ping] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. [Zhu, Weizhong; Petrashevskaya, Natalia; Zhao, Aizhi; Chakir, Khalid; Talan, Mark; Lakatta, Edward G.; Xiao, Rui-Ping] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Zhu, Weizhong; Gao, Erhe; Chuprun, J. Kurt; Koch, Walter J.] Thomas Jefferson Univ, Ctr Translat Med, Philadelphia, PA 19107 USA. [Ren, Shuxun; Wang, Yibin] Univ Calif Los Angeles, Dept Anesthesiol, Div Mol Med, Los Angeles, CA 90024 USA. [Dorn, Gerald W., III] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Zhu, Weizhong; Feldman, Arthur M.] Temple Univ, Dept Physiol, Sch Med, Philadelphia, PA 19107 USA. [Xiao, Rui-Ping] Peking Univ, Ctr Life Sci, Beijing 100871, Peoples R China. RP Xiao, RP (reprint author), Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. EM Weizhong.Zhu@Temple.edu; Xiaor@pku.edu.cn OI Wang, Yibin/0000-0003-0852-0767 FU National Institutes of Health, National Institute on Aging; National Basic Research Program of China [2012CB518000]; National Natural Science Foundation of China [81070674, 81130073]; National Institutes of Health [R37 HL061690, R01 HL56205, P01 HL091799] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (W.Z.Z., K. C., E. G. L., M. T., N.P., A.Z.Z., and R. P. X.); by the National Basic Research Program of China (2012CB518000) and National Natural Science Foundation of China (81070674 and 81130073) (R. P. X.); and by National Institutes of Health grants R37 HL061690 and R01 HL56205 (W.J.K.) and P01 HL091799 (W.J.K. and A.M.F.). NR 54 TC 24 Z9 28 U1 2 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JAN 20 PY 2012 VL 110 IS 2 BP 265 EP + DI 10.1161/CIRCRESAHA.111.253260 PG 20 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 880UH UT WOS:000299432600010 PM 22179058 ER PT J AU Gonzalez, RG Lev, MH Goldmacher, GV Smith, WS Payabvash, S Harris, GJ Halpern, EF Koroshetz, WJ Camargo, ECS Dillon, WP Furie, KL AF Gonzalez, R. Gilberto Lev, Michael H. Goldmacher, Gregory V. Smith, Wade S. Payabvash, Seyedmehdi Harris, Gordon J. Halpern, Elkan F. Koroshetz, Walter J. Camargo, Erica C. S. Dillon, William P. Furie, Karen L. TI Improved Outcome Prediction Using CT Angiography in Addition to Standard Ischemic Stroke Assessment: Results from the STOPStroke Study SO PLOS ONE LA English DT Article ID TISSUE-PLASMINOGEN ACTIVATOR; COMPUTED-TOMOGRAPHY; DIAGNOSTIC-APPROACH; IMAGING SCALE; SCORE; INFARCTION; MISMATCH; TRIAL; SCANS; RISK AB Purpose: To improve ischemic stroke outcome prediction using imaging information from a prospective cohort who received admission CT angiography (CTA). Methods: In a prospectively designed study, 649 stroke patients diagnosed with acute ischemic stroke had admission NIH stroke scale scores, noncontrast CT (NCCT), CTA, and 6-month outcome assessed using the modified Rankin scale (mRS) scores. Poor outcome was defined as mRS>2. Strokes were classified as "major'' by the (1) Alberta Stroke Program Early CT Score (ASPECTS+) if NCCT ASPECTS was <= 7; (2) Boston Acute Stroke Imaging Scale (BASIS+) if they were ASPECTS+ or CTA showed occlusion of the distal internal carotid, proximal middle cerebral, or basilar arteries; and (3) NIHSS for scores>10. Results: Of 649 patients, 253 (39.0%) had poor outcomes. NIHSS, BASIS, and age, but not ASPECTS, were independent predictors of outcome. BASIS and NIHSS had similar sensitivities, both superior to ASPECTS (p<0.0001). Combining NIHSS with BASIS was highly predictive: 77.6% (114/147) classified as NIHSS>10/BASIS+ had poor outcomes, versus 21.5% (77/358) with NIHSS <= 10/BASIS- (p<0.0001), regardless of treatment. The odds ratios for poor outcome is 12.6 (95% CI: 7.9 to 20.0) in patients who are NIHSS>10/BASIS+ compared to patients who are NIHSS <= 10/BASIS-; the odds ratio is 5.4 (95% CI: 3.5 to 8.5) when compared to patients who are only NIHSS>10 or BASIS+. Conclusions: BASIS and NIHSS are independent outcome predictors. Their combination is stronger than either instrument alone in predicting outcomes. The findings suggest that CTA is a significant clinical tool in routine acute stroke assessment. C1 [Gonzalez, R. Gilberto; Lev, Michael H.; Goldmacher, Gregory V.; Payabvash, Seyedmehdi; Harris, Gordon J.; Halpern, Elkan F.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Gonzalez, R. Gilberto; Lev, Michael H.; Goldmacher, Gregory V.; Payabvash, Seyedmehdi; Harris, Gordon J.; Halpern, Elkan F.; Camargo, Erica C. S.; Furie, Karen L.] Harvard Univ, Sch Med, Boston, MA USA. [Smith, Wade S.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Halpern, Elkan F.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Koroshetz, Walter J.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Camargo, Erica C. S.; Furie, Karen L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Dillon, William P.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. RP Gonzalez, RG (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM rggonzalez@partners.org FU National Institute of Health Agency for Health Care Policy and Research (AHCPR) [R01 HS11392-01A1]; GE Healthcare FX This work was supported by the National Institute of Health Agency for Health Care Policy and Research (AHCPR), R01 HS11392-01A1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Michael H. Lev has read the journal's policy and has the following conflicts: He receives research support from GE Healthcare, and is Consultant to Co-Axia, GE Healthcare, and Millennium Pharmaceuticals. Otherwise, the other authors have declared that no competing interests exist. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. NR 28 TC 21 Z9 21 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2012 VL 7 IS 1 AR e30352 DI 10.1371/journal.pone.0030352 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 909MH UT WOS:000301568100037 PM 22276182 ER PT J AU Srihirun, S Sriwantana, T Unchern, S Kittikool, D Noulsri, E Pattanapanyasat, K Fucharoen, S Piknova, B Schechter, AN Sibmooh, N AF Srihirun, Sirada Sriwantana, Thanaporn Unchern, Supeenun Kittikool, Dusadee Noulsri, Egarit Pattanapanyasat, Kovit Fucharoen, Suthat Piknova, Barbora Schechter, Alan N. Sibmooh, Nathawut TI Platelet Inhibition by Nitrite Is Dependent on Erythrocytes and Deoxygenation SO PLOS ONE LA English DT Article ID RED-BLOOD-CELLS; OXIDE SYNTHASE; CYTOPLASMIC DOMAIN; SMOOTH-MUSCLE; IN-VIVO; HEMOGLOBIN; NO; AGGREGATION; REDUCTION; DEOXYHEMOGLOBIN AB Background: Nitrite is a nitric oxide (NO) metabolite in tissues and blood, which can be converted to NO under hypoxia to facilitate tissue perfusion. Although nitrite is known to cause vasodilation following its reduction to NO, the effect of nitrite on platelet activity remains unclear. In this study, the effect of nitrite and nitrite+erythrocytes, with and without deoxygenation, on platelet activity was investigated. Methodology/Finding: Platelet aggregation was studied in platelet-rich plasma (PRP) and PRP+erythrocytes by turbidimetric and impedance aggregometry, respectively. In PRP, DEANONOate inhibited platelet aggregation induced by ADP while nitrite had no effect on platelets. In PRP+erythrocytes, the inhibitory effect of DEANONOate on platelets decreased whereas nitrite at physiologic concentration (0.1 mu M) inhibited platelet aggregation and ATP release. The effect of nitrite+erythrocytes on platelets was abrogated by C-PTIO (a membrane-impermeable NO scavenger), suggesting an NO-mediated action. Furthermore, deoxygenation enhanced the effect of nitrite as observed from a decrease of P-selectin expression and increase of the cGMP levels in platelets. The ADP-induced platelet aggregation in whole blood showed inverse correlations with the nitrite levels in whole blood and erythrocytes. Conclusion: Nitrite alone at physiological levels has no effect on platelets in plasma. Nitrite in the presence of erythrocytes inhibits platelets through its reduction to NO, which is promoted by deoxygenation. Nitrite may have role in modulating platelet activity in the circulation, especially during hypoxia. C1 [Srihirun, Sirada; Sriwantana, Thanaporn; Unchern, Supeenun; Kittikool, Dusadee; Sibmooh, Nathawut] Mahidol Univ, Fac Sci, Dept Pharmacol, Bangkok 10400, Thailand. [Noulsri, Egarit; Pattanapanyasat, Kovit] Mahidol Univ, Siriraj Hosp, Fac Med, Off Res & Dev, Bangkok 10700, Thailand. [Fucharoen, Suthat] Mahidol Univ, Thalassemia Res Ctr, Inst Sci & Technol Res & Dev, Nakhon Pathom, Thailand. [Piknova, Barbora; Schechter, Alan N.] NIDDK, Mol Med Branch, NIH, Bethesda, MD USA. RP Srihirun, S (reprint author), Mahidol Univ, Fac Sci, Dept Pharmacol, Bangkok 10400, Thailand. EM scnsm@mahidol.ac.th OI Schechter, Alan N/0000-0002-5235-9408; Noulsri, Egarit/0000-0002-8557-8631 FU Institute for the Promotion of Teaching of Science and Technology; Office of the Higher Education Commission; Mahidol University under the National Research Universities Initiative; Thailand Research Fund; National Institute of Diabetes, and Digestive, and Kidney Diseases FX This research was supported by grants from the Institute for the Promotion of Teaching of Science and Technology, the Office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative, the Thailand Research Fund - Senior Research Scholar, and the intramural program of the National Institute of Diabetes, and Digestive, and Kidney Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 40 Z9 41 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2012 VL 7 IS 1 AR e30380 DI 10.1371/journal.pone.0030380 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 909MH UT WOS:000301568100041 PM 22276188 ER PT J AU Barsotti, AM Beckerman, R Laptenko, O Huppi, K Caplen, NJ Prives, C AF Barsotti, Anthony M. Beckerman, Rachel Laptenko, Oleg Huppi, Konrad Caplen, Natasha J. Prives, Carol TI p53-dependent Induction of PVT1 and miR-1204 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-CYCLE ARREST; WILD-TYPE P53; P53-MEDIATED APOPTOSIS; C-MYC; GENE-EXPRESSION; NONCODING RNA; BREAST-CANCER; G(2) ARREST; DNA-DAMAGE; STEM-CELLS AB p53 is a tumor suppressor protein that acts as a transcription factor to regulate (either positively or negatively) a plethora of downstream target genes. Although its ability to induce protein coding genes is well documented, recent studies have implicated p53 in the regulation of non-coding RNAs, including both microRNAs (e.g. miR-34a) and long non-coding RNAs (e.g. lincRNA-p21). We have identified the non-protein coding locus PVT1 as a p53-inducible target gene. PVT1, a very large (>300 kb) locus located downstream of c-myc on chromosome 8q24, produces a wide variety of spliced non-coding RNAs as well as a cluster of six annotated microRNAs: miR-1204, miR-1205, miR-1206, miR-1207-5p, miR-1207-3p, and miR-1208. Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and luciferase assays reveal that p53 binds and activates a canonical response element within the vicinity of miR-1204. Consistently, we demonstrate the p53-dependent induction of endogenous PVT1 transcripts and consequent upregulation of mature miR-1204. Finally, we have shown that ectopic expression of miR-1204 leads to increased p53 levels and causes cell death in a partially p53-dependent manner. C1 [Barsotti, Anthony M.; Beckerman, Rachel; Laptenko, Oleg; Prives, Carol] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Huppi, Konrad; Caplen, Natasha J.] NCI, Gene Silencing Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Prives, C (reprint author), Columbia Univ, Dept Biol Sci, 1212 Amsterdam Ave, New York, NY 10027 USA. EM clp3@columbia.edu RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 FU National Institutes of Health [CA77742]; (Center for Cancer Research, NCI) of the National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grant CA77742 and the Intramural Research Program (Center for Cancer Research, NCI) of the National Institutes of Health. NR 55 TC 50 Z9 51 U1 4 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 20 PY 2012 VL 287 IS 4 BP 2509 EP 2519 DI 10.1074/jbc.M111.322875 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 892NG UT WOS:000300292300025 PM 22110125 ER PT J AU Park, JH Johansson, HE Aoki, H Huang, BX Kim, HY Ganoza, MC Park, MH AF Park, Jong-Hwan Johansson, Hans E. Aoki, Hiroyuki Huang, Bill X. Kim, Hee-Yong Ganoza, M. Clelia Park, Myung Hee TI Post-translational Modification by beta-Lysylation Is Required for Activity of Escherichia coli Elongation Factor P (EF-P) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PEPTIDE-BOND SYNTHESIS; SYNTHESIS INITIATION-FACTORS; PROTEIN-SYNTHESIS; CRYSTAL-STRUCTURE; SACCHAROMYCES-CEREVISIAE; TRANSLATION ELONGATION; HYPUSINE MODIFICATION; BACILLUS-SUBTILIS; GENE-PRODUCT; EXPRESSION AB Bacterial elongation factor P (EF-P) is the ortholog of archaeal and eukaryotic initiation factor 5A (eIF5A). EF-P shares sequence homology and crystal structure with eIF5A, but unlike eIF5A, EF-P does not undergo hypusine modification. Recently, two bacterial genes, yjeA and yjeK, encoding truncated homologs of class II lysyl-tRNA synthetase and of lysine-2,3-aminomutase, respectively, have been implicated in the modification of EF-P to convert a specific lysine to a hypothetical beta-lysyl-lysine. Here we present biochemical evidence for beta-lysyl-lysine modification in Escherichia coli EF-P and for its role in EF-P activity by characterizing native and recombinant EF-P proteins for their modification status and activity in vitro. Mass spectrometric analyses confirmed the lysyl modification at lysine 34 in native and recombinant EF-P proteins. The beta-lysyl-lysine isopeptide was identified in the exhaustive Pronase digests of native EF-P and recombinant EF-P isolated from E. coli coexpressing EF-P, YjeA, and YjeK but not in the digests of proteins derived from the vectors encoding EF-P alone or EF-P together with YjeA, indicating that both enzymes, YjeA and YjeK, are required for beta-lysylation of EF-P. Endogenous EF-P as well as the recombinant EF-P preparation containing beta-lysyl-EF-P stimulated N-formyl-methionyl-puromycin synthesis similar to 4-fold over the preparations containing unmodified EF-P and/or alpha-lysyl-EF-P. The mutant lacking the modification site lysine (K34A) was inactive. This is the first report of biochemical evidence for the beta-lysylation of EF-P in vivo and the requirement for this modification for the activity of EF-P. C1 [Johansson, Hans E.] Biosearch Technol Inc, Novato, CA 94949 USA. [Park, Jong-Hwan; Park, Myung Hee] NIDCR, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. [Huang, Bill X.; Kim, Hee-Yong] NIAAA, Lab Mol Signaling, NIH, Bethesda, MD 20892 USA. [Aoki, Hiroyuki; Ganoza, M. Clelia] Univ Toronto, Banting & Best Dept Med Res, Toronto, ON M5G 1L6, Canada. RP Johansson, HE (reprint author), Biosearch Technol Inc, 81 Digital Dr, Novato, CA 94949 USA. EM hjohansson@biosearchtech.com; mhpark@nih.gov FU NIDCR; NIAAA, National Institutes of Health; Carl Trygger Foundation FX This work was supported, in whole or in part, by the Intramural Research Program of NIDCR and NIAAA, National Institutes of Health. This work was also supported in part by a grant from the Carl Trygger Foundation (to H. E. J.). NR 44 TC 26 Z9 29 U1 2 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 20 PY 2012 VL 287 IS 4 BP 2579 EP 2590 DI 10.1074/jbc.M111.309633 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 892NG UT WOS:000300292300031 PM 22128152 ER PT J AU Yu, FS Wang, ZF Tchantchou, F Chiu, CT Zhang, YM Chuang, DM AF Yu, Fengshan Wang, Zhifei Tchantchou, Flaubert Chiu, Chi-Tso Zhang, Yumin Chuang, De-Maw TI Lithium Ameliorates Neurodegeneration, Suppresses Neuroinflammation, and Improves Behavioral Performance in a Mouse Model of Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE GSK-3/beta; lithium; neuroinflammation; neuroprotection; traumatic brain injury ID GLYCOGEN-SYNTHASE KINASE-3; FOCAL CEREBRAL-ISCHEMIA; SPINAL-CORD-INJURY; BARRIER BREAKDOWN; NEURONAL SURVIVAL; BIPOLAR DISORDER; RAT MODEL; CYCLOOXYGENASE-2; MICE; INHIBITION AB Although traumatic brain injury (TBI) is recognized as one of the leading causes of death from trauma to the central nervous system (CNS), no known treatment effectively mitigates its effects. Lithium, a primary drug for the treatment of bipolar disorder, has been known to have neuroprotective effects in various neurodegenerative conditions such as stroke. Until this study, however, it has not been investigated as a post-insult treatment for TBI. To evaluate whether lithium could have beneficial effects following TBI, lithium at a dose of 1.5 mEq/kg was administered after injury. Assessed at 3 days and 3 weeks post-injury using hematoxylin and eosin staining, lithium treatment was found to reduce lesion volume. Lithium at doses of 2.0 and 3.0 mEq/kg also significantly reduced lesion volume at 3 days after injury, and the therapeutic window was at least 3 h post-injury. TBI-induced neuronal death, microglial activation, and cyclooxygenase-2 induction were all attenuated by lithium at 3 days after injury. In addition, lithium treatment reduced TBI-induced matrix metalloproteinase-9 expression and preserved the integrity of the blood brain barrier. As for behavioral outcomes, lithium treatment reduced anxiety-like behavior in an open-field test, and improved short- and long-term motor coordination in rotarod and beam-walk tests. Lithium robustly increased serine phosphorylation of glycogen synthase kinase-3 beta (GSK-3 beta), suggesting that the underlying mechanisms responsible for lithium's protective effects are triggered by increasing phosphorylation of this kinase and thereby inhibiting its activity. Our results support the notion that lithium has heretofore unrecognized capacity to mitigate the neurodegenerative effects and improve functional outcomes in TBI. C1 [Yu, Fengshan; Wang, Zhifei; Chiu, Chi-Tso; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Yu, Fengshan; Zhang, Yumin; Chuang, De-Maw] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Yu, Fengshan; Tchantchou, Flaubert; Zhang, Yumin] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, 10 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. EM yzhang@usuhs.mil; chuang@mail.nih.gov RI Wang, Zhifei/I-2787-2013 FU Department of Defense in the Center for Neuroscience and Regenerative Medicine; Blast Lethality Injury and Research Program; National Institute of Mental Health, National Institutes of Health (NIMH-NIH) FX Support for this work included funding from the Department of Defense in the Center for Neuroscience and Regenerative Medicine, the Blast Lethality Injury and Research Program, and the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (NIMH-NIH). The authors wish to gratefully acknowledge the editorial assistance of Dr. Elizabeth Sherman, Ioline Henter, and Peter Leeds of the NIMH. We are also grateful to Dr. Oz Malkesman, Laura Tucker, and Dr. Amanda Fu from the Center for Neuroscience and Regenerative Medicine for help with behavioral tests and CCI surgery. NR 59 TC 39 Z9 40 U1 0 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JAN 20 PY 2012 VL 29 IS 2 BP 362 EP 374 DI 10.1089/neu.2011.1942 PG 13 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 885SO UT WOS:000299801300015 PM 21895523 ER PT J AU Ludek, OR Marquez, VE AF Ludek, Olaf R. Marquez, Victor E. TI Synthesis of Conformationally North-Locked Pyrimidine Nucleosides Built on an Oxabicyclo[3.1.0]hexane Scaffold SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID STEREOSELECTIVE-SYNTHESIS; CARBOCYCLIC NUCLEOSIDES; ALKOXIDE PRECOORDINATION; BAFILOMYCIN A(1); CYCLOPROPANATION; PECTENOTOXIN-2; HYDROGENATION; DERIVATIVES; PRECURSOR; ADENOSINE AB Beginning with a known 3-oxabicyclo[3.1.0]-hexane scaffold (I), the relocation of the fused cyclopropane ring bond and the shifting of the oxygen atom to an alternative location engendered a new 2-oxabicyclo[3.1.0]hexane template (II) that mimics more closely the tetrahydrofuran ring of conventional nucleosides. The synthesis of this new class of locked nucleosides involved a novel approach that required the isocyanate II (B = NCO) with a hydroxyl-protected scaffold as a pivotal intermediate that was obtained in 11 steps from a known dihydrofuran precursor. The completion of the nucleobases was successfully achieved by quenching the isocyanate with the lithium salts of the corresponding acrylic amides that led to the uracil and thymidine precursors in a single step. Ring closure of these intermediates led to the target, locked nucleosides. The anti-HIV activity of 29 (uridine analogue), 31 (thymidine analogue), and 34 (cytidine analogue) was explored in human osteosarcoma (Has) cells or modified HOS cells (HOS-313) expressing the herpes simplex virus 1 thymidine kinase (HSV-1 TK). Only the cytidine analogue showed moderate activity in HOS-313 cells, which means that the compounds are not good substrates for the cellular kinases. C1 [Ludek, Olaf R.; Marquez, Victor E.] NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Marquez, VE (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM marquezv@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We express our gratitude to Drs. Stephen H. Hughes and B. Christie Vu of the HIV Drug Resistant Program at NCI for the biological testing. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 33 TC 5 Z9 5 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD JAN 20 PY 2012 VL 77 IS 2 BP 815 EP 824 DI 10.1021/jo201716c PG 10 WC Chemistry, Organic SC Chemistry GA 878EN UT WOS:000299238400001 PM 22026578 ER PT J AU Rigaux, P Killoran, KE Qiu, ZJ Rosenberg, HF AF Rigaux, Peter Killoran, Kristin E. Qiu, Zhijun Rosenberg, Helene F. TI Depletion of alveolar macrophages prolongs survival in response to acute pneumovirus infection SO VIROLOGY LA English DT Article DE Inflammation; Cytokines; Respiratory virus; Infection ID RESPIRATORY-SYNCYTIAL-VIRUS; INTERFERON-GAMMA; PNEUMONIA VIRUS; LUNG INFECTION; INFLAMMATORY PROTEIN-1-ALPHA; MICE PVM; IN-VIVO; BRONCHIOLITIS; DISEASE; INFANTS AB Alveolar macrophages are immunoregulatory effector cells that interact directly with respiratory virus pathogens in vivo. We examined the role of alveolar macrophages in acute infection with pneumonia virus of mice (PVM), a rodent pneumovirus that replicates the clinical sequelae of severe human respiratory syncytial virus disease. We show that PVM replicates in primary mouse macrophage culture, releasing infectious virions and proinflammatory cytokines. Alveolar macrophages isolated from PVM-infected mice express activation markers Clec43 and CD86, cytokines TNF alpha, IL-1, IL-6, and numerous CC and CXC chemokines. Alveolar macrophage depletion prior to PVM infection results in small but statistically significant increases in virus recovery but paradoxically prolonged survival. In parallel, macrophage depleted PVM-infected mice exhibit enhanced NK cell recruitment and increased production of IFN gamma by NM, CD4(+) and CD8(+) T cells. These results suggest a protective, immunomodulatory role for IFN gamma, as overproduction secondary to macrophage depletion may promote survival despite increased virus recovery. Published by Elsevier Inc. C1 [Rigaux, Peter; Killoran, Kristin E.; Qiu, Zhijun; Rosenberg, Helene F.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C215, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU NIAID Division of Intramural Research [A1000943] FX The authors are grateful to Ms. Caroline M. Percopo for her expert training in intratracheal inoculation techniques, to Dr. Alfonso Gozalo and the staff of the 14BS animal facility for the care of the mice used in these experiments, and to Mr. Stanislaw Gabryszewski, Dr. Tolga Barker, and Dr. Kimberly Dyer for critical reading of the manuscript. The studies carried out in our laboratory are supported by funding from the NIAID Division of Intramural Research, #A1000943. NR 52 TC 9 Z9 9 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 20 PY 2012 VL 422 IS 2 BP 338 EP 345 DI 10.1016/j.virol.2011.10.031 PG 8 WC Virology SC Virology GA 885CK UT WOS:000299755900019 PM 22129848 ER PT J AU Sanders-Beer, BE Eschricht, M Seifried, J Hirsch, VM Allan, JS Norley, S AF Sanders-Beer, Brigitte E. Eschricht, Magdalena Seifried, Janna Hirsch, Vanessa M. Allan, Jonathan S. Norley, Stephen TI Characterization of a monoclonal anti-capsid antibody that cross-reacts with three major primate lentivirus lineages SO VIROLOGY LA English DT Article DE AG3.0; Epitope; Gag; Capsid; p24; p27; Human immunodeficiency virus; Simian immunodeficiency virus ID SIMIAN-IMMUNODEFICIENCY-VIRUS; AFRICAN-GREEN MONKEYS; COLOBUS PILIOCOLOBUS-BADIUS; DEFICIENCY SYNDROME AIDS; GAG PROTEIN; MOLECULAR CHARACTERIZATION; GENETIC DIVERSITY; CYCLOPHILIN-A; CAPTURE ASSAY; POSTTRANSLATIONAL MODIFICATIONS AB Mouse monoclonal antibodies with varying specificities against the Gag capsid of simian and human immunodeficiency virus (SIV/HIV) were generated by immunizing mice with whole inactivated SIVagmTYO-1. Monoclonal antibody AG3.0 showed the broadest reactivity recognizing the Gag capsid protein (p24-27) and Gag precursors p38, p55, and p150 of HIV-1, HIV-2, SIVmac, and SIVagm. Using overlapping peptides, the AG3.0 epitope was mapped in capsid to a sequence (SPRTLNA) conserved among HIV-1, HIV-2, SIVrcm, SIVsm/mac, and SIVagm related viruses. Because of its broad cross-reactivity, AG3.0 was used to develop an antigen capture assay with a lower detection limit of 100 pg/ml HIV-1 Gag p24. Interestingly, AG3.0 was found to have a faster binding on/off rate for SIVagmVer and SIVmac Gag than for SIVagmSab Gag, possibly due to differences outside the SPRTLNA motif. In addition, the ribonucleic acid (RNA) coding for AG3.0 was sequenced to facilitate the development of humanized monoclonal antibodies. (C) 2011 Elsevier Inc. All rights reserved. C1 [Sanders-Beer, Brigitte E.] BIOQUAL Inc, Rockville, MD 20850 USA. [Eschricht, Magdalena; Seifried, Janna; Norley, Stephen] Robert Koch Inst, D-13353 Berlin, Germany. [Hirsch, Vanessa M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Allan, Jonathan S.] Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX 78227 USA. RP Sanders-Beer, BE (reprint author), BIOQUAL Inc, 9600 Med Ctr Dr, Rockville, MD 20850 USA. EM bsanders@bioqual.com; eschrichtm@rki.de; seifriedj@rki.de; vhirsch@niaid.nih.gov; jpatters@sfbr.org; norleys@rki.de FU NIH [AI-28273, AI-41396] FX This paper is dedicated to the memory of Jonathan S. Allan who generated and initially characterized the AG3.0 monoclonal antibody in his laboratory. We thank Evelyn M. Whitehead, Manuela Schutze, and Nicole Norley for their excellent technical assistance. We would also like to thank Phyllis Kanki and Soulemayne M'Boup for the HIV-2 serum, and the U.S. Air Force Wilford Hall AIDS program for the HIV-1 serum. This work was funded in part from NIH grants AI-28273 and AI-41396 to JSA. NR 81 TC 5 Z9 5 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 20 PY 2012 VL 422 IS 2 BP 402 EP 412 DI 10.1016/j.virol.2011.11.003 PG 11 WC Virology SC Virology GA 885CK UT WOS:000299755900026 PM 22153299 ER PT J AU Kessler, JD Kahle, KT Sun, TT Meerbrey, KL Schlabach, MR Schmitt, EM Skinner, SO Xu, QK Li, MZ Hartman, ZC Rao, M Yu, P Dominguez-Vidana, R Liang, AC Solimini, NL Bernardi, RJ Yu, B Hsu, T Golding, I Luo, J Osborne, CK Creighton, CJ Hilsenbeck, SG Schiff, R Shaw, CA Elledge, SJ Westbrook, TF AF Kessler, Jessica D. Kahle, Kristopher T. Sun, Tingting Meerbrey, Kristen L. Schlabach, Michael R. Schmitt, Earlene M. Skinner, Samuel O. Xu, Qikai Li, Mamie Z. Hartman, Zachary C. Rao, Mitchell Yu, Peng Dominguez-Vidana, Rocio Liang, Anthony C. Solimini, Nicole L. Bernardi, Ronald J. Yu, Bing Hsu, Tiffany Golding, Ido Luo, Ji Osborne, C. Kent Creighton, Chad J. Hilsenbeck, Susan G. Schiff, Rachel Shaw, Chad A. Elledge, Stephen J. Westbrook, Thomas F. TI A SUMOylation-Dependent Transcriptional Subprogram Is Required for Myc-Driven Tumorigenesis SO SCIENCE LA English DT Article ID NEGATIVE BREAST-CANCER; C-MYC; EXPRESSION SIGNATURE; THERAPY; P53; METASTASIS; TRANSACTIVATION; ACTIVATION; INHIBITION; ADDICTION AB Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we used a genome-wide RNA interference screen to search for Myc-synthetic lethal genes and uncovered a role for the SUMO-activating enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Inactivation of SAE2 leads to mitotic catastrophe and cell death upon Myc hyperactivation. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent Myc switchers (SMS genes) is required for mitotic spindle function and to support the Myc oncogenic program. SAE2 is required for growth of Myc-dependent tumors in mice, and gene expression analyses of Myc-high human breast cancers suggest that low SAE1 and SAE2 abundance in the tumors correlates with longer metastasis-free survival of the patients. Thus, inhibition of SUMOylation may merit investigation as a possible therapy for Myc-driven human cancers. C1 [Kahle, Kristopher T.; Schlabach, Michael R.; Xu, Qikai; Li, Mamie Z.; Liang, Anthony C.; Solimini, Nicole L.; Elledge, Stephen J.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Brigham & Womens Hosp,Div Genet,Dept Genet, Boston, MA 02115 USA. [Kessler, Jessica D.; Sun, Tingting; Meerbrey, Kristen L.; Schmitt, Earlene M.; Skinner, Samuel O.; Dominguez-Vidana, Rocio; Hsu, Tiffany; Golding, Ido; Westbrook, Thomas F.] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Kessler, Jessica D.; Meerbrey, Kristen L.; Schmitt, Earlene M.; Rao, Mitchell; Yu, Peng; Dominguez-Vidana, Rocio; Hsu, Tiffany; Shaw, Chad A.; Westbrook, Thomas F.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Kahle, Kristopher T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Skinner, Samuel O.; Golding, Ido] Univ Illinois, Dept Phys, Urbana, IL 61801 USA. [Hartman, Zachary C.] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. [Bernardi, Ronald J.; Westbrook, Thomas F.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Yu, Bing; Luo, Ji] NCI, Med Oncol Branch, Ctr Drive, Bethesda, MD 20892 USA. [Osborne, C. Kent; Creighton, Chad J.; Hilsenbeck, Susan G.; Schiff, Rachel; Westbrook, Thomas F.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Osborne, C. Kent; Hilsenbeck, Susan G.; Schiff, Rachel] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Osborne, C. Kent; Schiff, Rachel] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Osborne, C. Kent; Schiff, Rachel] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Creighton, Chad J.; Hilsenbeck, Susan G.] Baylor Coll Med, Div Biostat, Houston, TX 77030 USA. RP Elledge, SJ (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Brigham & Womens Hosp,Div Genet,Dept Genet, Boston, MA 02115 USA. EM selledge@genetics.med.harvard.edu; thomasw@bcm.edu RI Dominguez-Vidana, Rocio/A-1153-2009; OI Dominguez-Vidana, Rocio/0000-0003-3855-5178; Shaw, Chad/0000-0001-7267-5398 FU NIH [T32HD05520/T32CA090221-09, R01GM082837, CA149196]; U.S. Department of Defense [W81XWH-10-1-0354]; Human Frontier Science Program [RGY70/2008]; Welch Foundation [Q-1759]; NSF [082265]; Susan G. Komen for the Cure [KG090355]; CPRIT [RP120583]; Specialized Program of Research Excellence developmental grant [P50 CA058183]; SU2C-American Association for Cancer Research; U.S. Army [W81XWH0410197] FX We thank C. Bland for critical comments on the manuscript and T. Mitchell, W. Choi, S. Songyang, and the BCM C-BASS and CCSC Cores for reagents and technical assistance. J.D.K and K. L. M. are supported by NIH training grants T32HD05520/T32CA090221-09 and U.S. Department of Defense predoctoral fellowship W81XWH-10-1-0354, respectively. The Golding lab is supported by NIH grant R01GM082837, Human Frontier Science Program grant RGY70/2008, Welch Foundation grant Q-1759, and NSF grant 082265 (PFC: Center for the Physics of Living Cells). This work was supported by a Susan G. Komen for the Cure grant (KG090355), CPRIT grant (RP120583), and NIH grant (CA149196) to T. F. W., Specialized Program of Research Excellence developmental grant (P50 CA058183) to T. F. W., SU2C-American Association for Cancer Research Breast Cancer program grant to R. S. and C.K.O., and U.S. Army Innovator Award (W81XWH0410197) to S.J.E. S.J.E. is an Investigator with the Howard Hughes Medical Institute. T. F. W. is a scholar of The V Foundation and The Mary Kay Ash Foundation for Cancer Research. Gene Expression data are deposited in GEO (accession no. GSE34055). NR 39 TC 143 Z9 146 U1 3 U2 23 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 20 PY 2012 VL 335 IS 6066 BP 348 EP 353 DI 10.1126/science.1212728 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 878RE UT WOS:000299273400051 PM 22157079 ER PT J AU Cheng, YZ Kwon, DY Arai, AL Mucci, D Kassis, JA AF Cheng, Yuzhong Kwon, Deborah Y. Arai, Allison L. Mucci, Diane Kassis, Judith A. TI P-Element Homing Is Facilitated by engrailed Polycomb-Group Response Elements in Drosophila melanogaster SO PLOS ONE LA English DT Article ID ENHANCER-PROMOTER COMMUNICATION; GENE DISRUPTION PROJECT; TRANSPOSABLE ELEMENT; BITHORAX COMPLEX; EXPRESSION; REGION; TRANSCRIPTION; CHROMOSOME; CHROMATIN; PROTEINS AB P-element vectors are commonly used to make transgenic Drosophila and generally insert in the genome in a nonselective manner. However, when specific fragments of regulatory DNA from a few Drosophila genes are incorporated into P-transposons, they cause the vectors to be inserted near the gene from which the DNA fragment was derived. This is called P-element homing. We mapped the minimal DNA fragment that could mediate homing to the engrailed/invected region of the genome. A 1.6 kb fragment of engrailed regulatory DNA that contains two Polycomb-group response elements (PREs) was sufficient for homing. We made flies that contain a 1.5kb deletion of engrailed DNA (en(Delta 1.5)) in situ, including the PREs and the majority of the fragment that mediates homing. Remarkably, homing still occurs onto the en(Delta 1.5) chromosome. In addition to homing to en, P[en] inserts near Polycomb group target genes at an increased frequency compared to P[EPgy2], a vector used to generate 18,214 insertions for the Drosophila gene disruption project. We suggest that homing is mediated by interactions between multiple proteins bound to the homing fragment and proteins bound to multiple areas of the engrailed/invected chromatin domain. Chromatin structure may also play a role in homing. C1 [Cheng, Yuzhong; Kwon, Deborah Y.; Arai, Allison L.; Kassis, Judith A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Mucci, Diane] US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Cheng, YZ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM jkassis@mail.nih.gov OI Kassis, Judith/0000-0001-9268-3213 FU National Institutes of Health, National Institute of Child Health and Human Development (NIH, NICHD); Cystic Fibrosis Foundation FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Child Health and Human Development (NIH, NICHD). Diane Mucci was supported by a grant from the Cystic Fibrosis Foundation. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 35 TC 9 Z9 9 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 19 PY 2012 VL 7 IS 1 AR e30437 DI 10.1371/journal.pone.0030437 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 907YS UT WOS:000301457200062 PM 22276200 ER PT J AU Starr, T Child, R Wehrly, TD Hansen, B Hwang, S Lopez-Otin, C Virgin, HW Celli, J AF Starr, Tregei Child, Robert Wehrly, Tara D. Hansen, Bryan Hwang, Seungmin Lopez-Otin, Carlos Virgin, Herbert W. Celli, Jean TI Selective Subversion of Autophagy Complexes Facilitates Completion of the Brucella Intracellular Cycle SO CELL HOST & MICROBE LA English DT Article ID ENDOPLASMIC-RETICULUM; PHOSPHATIDYLINOSITOL 3-KINASE; BECLIN 1; LEGIONELLA-PNEUMOPHILA; FRANCISELLA-TULARENSIS; CONTAINING VACUOLE; HOST-CELLS; MACROPHAGES; REPLICATION; MATURATION AB Autophagy is a cellular degradation process that can capture and eliminate intracellular microbes by delivering them to lysosomes for destruction. However, pathogens have evolved mechanisms to subvert this process. The intracellular bacterium Brucella abortus ensures its survival by forming the Brucella-containing vacuole (BCV), which traffics from the endocytic compartment to the endoplasmic reticulum (ER), where the bacterium proliferates. We show that Brucella replication in the ER is followed by BCV conversion into a compartment with autophagic features (aBCV). While Brucella trafficking to the ER was unaffected in autophagy-deficient cells, aBCV formation required the autophagy-initiation proteins ULK1, Beclin 1, and ATG14L and PI3-kinase activity. However, aBCV formation was independent of the autophagy-elongation proteins ATG5, ATG16L1, ATG4B, ATG7, and LC3B. Furthermore, aBCVs were required to complete the intracellular Brucella lifecycle and for cell-to-cell spreading, demonstrating that Brucella selectively co-opts autophagy-initiation complexes to subvert host clearance and promote infection. C1 [Starr, Tregei; Child, Robert; Wehrly, Tara D.; Celli, Jean] NIAID, Lab Intracellular Parasites, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Hansen, Bryan] NIAID, Electron Microscopy Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Hwang, Seungmin; Virgin, Herbert W.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Hwang, Seungmin; Virgin, Herbert W.] Washington Univ, Sch Med, Midw Reg Ctr Excellence Biodef & Emerging Infect, St Louis, MO 63110 USA. [Lopez-Otin, Carlos] Univ Oviedo, Inst Univ Oncol, Fac Med, Dept Bioquim & Biol Mol, E-33006 Oviedo, Spain. RP Celli, J (reprint author), NIAID, Lab Intracellular Parasites, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM jcelli@niaid.nih.gov RI Lopez-Otin, Carlos/C-6657-2013; OI Lopez-Otin, Carlos/0000-0001-6964-1904; Hwang, Seungmin/0000-0003-0846-5462 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases [U54 AI057160]; Ministry of Science and Innovation, Spain; Botin Foundation FX We are grateful to Zijiang Zhao for his assistance in providing bone marrow from ATG5flox/flox and ATG5flox/flox-lyz-Cre mice, and to George Banting, Joyce Karlinsey, Tamotsu Yoshimori, Ed Miao, and Leigh Knodler for providing reagents and helpful suggestions. We thank Bob Heinzen and Leigh Knodler for critical reading of the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, by grant U54 AI057160 to H.W.V., and by the Ministry of Science and Innovation, Spain, FP7 (Microenvimet) and the Botin Foundation to C.L.-O. NR 53 TC 122 Z9 127 U1 2 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD JAN 19 PY 2012 VL 11 IS 1 BP 33 EP 45 DI 10.1016/j.chom.2011.12.002 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 885EB UT WOS:000299760200006 PM 22264511 ER PT J AU Compton, AA Hirsch, VM Emerman, M AF Compton, Alex A. Hirsch, Vanessa M. Emerman, Michael TI The Host Restriction Factor APOBEC3G and Retroviral Vif Protein Coevolve due to Ongoing Genetic Conflict SO CELL HOST & MICROBE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; AFRICAN-GREEN MONKEY; VIRION INFECTIVITY FACTOR; NONHUMAN PRIMATE HOSTS; AIDS; REPLICATION; SIV; MORTALITY; EVOLUTION; PATTERNS AB APOBEC3G (A3G) is a host cytidine deaminase that inhibits retroviruses. HIV and related primate lentiviruses encode Vif, which counteracts A3G by inducing its degradation. This Vif-mediated A3G inhibition is species specific, suggesting that the A3G-Vif interaction has evolved as primate lentiviruses have adapted to their hosts. We examined the evolutionary dynamics of the A3G-Vif interaction within four African green monkey (AGM) subspecies, which are each naturally infected with a distinct simian immunodeficiency virus (SIV). We identified single amino acid changes within A3G in two AGM subspecies that render it resistant to Vif proteins, except for Vif from the viruses that naturally infect these subspecies. Moreover, experimental infection of AGMs shows that Vif can rapidly adapt to these arising Vif-resistant A3G genotypes. These data suggest that despite being generally nonpathogenic in its natural host, SIV infection selects for Vif-resistant forms of A3G in AGM populations, driving Vif counterevolution and functional divergence. C1 [Compton, Alex A.; Emerman, Michael] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. [Compton, Alex A.; Emerman, Michael] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. [Compton, Alex A.] Univ Washington, Mol & Cellular Biol Grad Program, Seattle, WA 98195 USA. [Hirsch, Vanessa M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Emerman, M (reprint author), Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. EM memerman@fhcrc.org OI Compton, Alex/0000-0002-7508-4953 FU NIH [R01-AI30937, T32AI083203]; National Science Foundation FX We are grateful to the following investigators and their staff for providing invaluable samples: M. Muller-Trutwin (AGM PBMC), C. Apetrei (AGM PBMC), and N. Freimer and A. Jasinska (AGM DNA). We thank S. Whitted (National Institutes of Health, NIH) and W. Switzer (Centers for Disease Control and Prevention, CDC) for preparing AGM samples for inspection and shipment. We thank the NIH Nonhuman Primate Research Resource for providing the V038 and AG23 AGM cells and SIVagm.Gri+ plasma. We thank E. Matsen, V. Minin, and C. Carlson for helpful discussions on phylogenetics and population genetics. We thank H. Malik, M. Levine, M. Metzger, and members of the Emerman lab for critical reading of the manuscript. A.A.C. and M.E. designed the experiments. A.A.C. performed the experiments. V.M.H. provided AGM PBMC, SIV+ AGM plasma samples and guidance on experimental design. A.A.C. and M.E. wrote the paper. This work was supported by NIH R01-AI30937 (to M.E.), a National Science Foundation Graduate Research Fellowship (to A.A.C.), and an NIH Training Grant in Viral Pathogenesis T32AI083203 (to A.A.C.). NR 32 TC 47 Z9 47 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD JAN 19 PY 2012 VL 11 IS 1 BP 91 EP 98 DI 10.1016/j.chom.2011.11.010 PG 8 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 885EB UT WOS:000299760200011 PM 22264516 ER PT J AU Bressler, NM Beck, RW Ferris, FL AF Bressler, Neil M. Beck, Roy W. Ferris, Frederick L. TI Panretinal Photocoagulation for Diabetic Retinopathy REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID COMPLICATIONS C1 [Bressler, Neil M.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Beck, Roy W.] Jaeb Ctr Hlth Res, Tampa, FL USA. [Ferris, Frederick L.] NEI, Bethesda, MD 20892 USA. RP Bressler, NM (reprint author), Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. EM ferrisf@nei.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 19 PY 2012 VL 366 IS 3 BP 278 EP 279 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 877RZ UT WOS:000299201400021 ER PT J AU Lozier, J AF Lozier, Jay TI More on Hemophilia A Induced by Ipilimumab SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Lozier, J (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM lozierjn@cc.nih.gov NR 2 TC 2 Z9 2 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 19 PY 2012 VL 366 IS 3 BP 280 EP 281 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 877RZ UT WOS:000299201400025 PM 22256820 ER PT J AU Majounie, E Abramzon, Y Renton, AE Perry, R Bassett, SS Pletnikova, O Troncoso, JC Hardy, J Singleton, AB Traynor, BJ AF Majounie, Elisa Abramzon, Yevgeniya Renton, Alan E. Perry, Rodney Bassett, Susan S. Pletnikova, Olga Troncoso, Juan C. Hardy, John Singleton, Andrew B. Traynor, Bryan J. TI Repeat Expansion in C9ORF72 in Alzheimer's Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Majounie, Elisa; Abramzon, Yevgeniya; Renton, Alan E.; Singleton, Andrew B.; Traynor, Bryan J.] NIA, Bethesda, MD 20892 USA. [Perry, Rodney] Univ Alabama, Birmingham, AL USA. [Bassett, Susan S.; Pletnikova, Olga; Troncoso, Juan C.] Johns Hopkins Univ, Baltimore, MD USA. [Hardy, John] UCL, Inst Neurol, London, England. RP Majounie, E (reprint author), NIA, Bethesda, MD 20892 USA. EM traynorb@mail.nih.gov RI Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009; Traynor, Bryan/G-5690-2010 FU Intramural NIH HHS [ZIA AG000934-04]; Medical Research Council [, G0701075]; NIA NIH HHS [P50 AG005146, P50AG05146, Z01 AG000949]; Parkinson's UK [G-0907]; Wellcome Trust NR 6 TC 91 Z9 95 U1 0 U2 11 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 19 PY 2012 VL 366 IS 3 BP 283 EP 284 DI 10.1056/NEJMc1113592 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 877RZ UT WOS:000299201400028 PM 22216764 ER PT J AU Mullen, AR Wheaton, WW Jin, ES Chen, PH Sullivan, LB Cheng, T Yang, YF Linehan, WM Chandel, NS DeBerardinis, RJ AF Mullen, Andrew R. Wheaton, William W. Jin, Eunsook S. Chen, Pei-Hsuan Sullivan, Lucas B. Cheng, Tzuling Yang, Youfeng Linehan, W. Marston Chandel, Navdeep S. DeBerardinis, Ralph J. TI Reductive carboxylation supports growth in tumour cells with defective mitochondria SO NATURE LA English DT Article ID GLUTAMINE-METABOLISM; CANCER; DEHYDROGENASE; GENE; PARAGANGLIOMA; MUTATIONS; LIVER; LINE; FLUX; ROS AB Mitochondrial metabolism provides precursors to build macromolecules in growing cancer cells(1,2). In normally functioning tumour cell mitochondria, oxidative metabolism of glucose- and glutamine-derived carbon produces citrate and acetyl-coenzyme A for lipid synthesis, which is required for tumorigenesis(3). Yet some tumours harbour mutations in the citric acid cycle (CAC) or electron transport chain (ETC) that disable normal oxidative mitochondrial function(4-7), and it is unknown how cells from such tumours generate precursors for macromolecular synthesis. Here we show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. This pathway uses mitochondrial and cytosolic isoforms of NADP(+)/NADPH-dependent isocitrate dehydrogenase, and subsequent metabolism of glutamine-derived citrate provides both the acetylcoenzyme A for lipid synthesis and the four-carbon intermediates needed to produce the remaining CAC metabolites and related macromolecular precursors. This reductive, glutamine-dependent pathway is the dominant mode of metabolism in rapidly growing malignant cells containing mutations in complex I or complex III of the ETC, in patient-derived renal carcinoma cells with mutations in fumarate hydratase, and in cells with normal mitochondria subjected to acute pharmacological ETC inhibition. Our findings reveal the novel induction of a versatile glutamine-dependent pathway that reverses many of the reactions of the canonical CAC, supports tumour cell growth, and explains how cells generate pools of CAC intermediates in the face of impaired mitochondrial metabolism. C1 [Mullen, Andrew R.; Chen, Pei-Hsuan; Cheng, Tzuling; DeBerardinis, Ralph J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Wheaton, William W.; Sullivan, Lucas B.; Chandel, Navdeep S.] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Wheaton, William W.; Sullivan, Lucas B.; Chandel, Navdeep S.] Northwestern Univ, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Jin, Eunsook S.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Jin, Eunsook S.] Univ Texas SW Med Ctr Dallas, Adv Imaging Res Ctr, Dallas, TX 75390 USA. [Yang, Youfeng; Linehan, W. Marston] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [DeBerardinis, Ralph J.] Univ Texas SW Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA. [DeBerardinis, Ralph J.] Univ Texas SW Med Ctr Dallas, Harold C Simmons Comprehens Canc Ctr, Dallas, TX 75235 USA. RP DeBerardinis, RJ (reprint author), Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. EM nav@northwestern.edu; ralph.deberardinis@utsouthwestern.edu FU NIH [K08DK072565, R01CA157996, R01CA123067, DK078933, RR02584, 5T32GM083831, T32CA009560, T32GM008061]; Cancer Prevention and Research Institute of Texas (CPRIT) [HIRP100437]; Robert A. Welch Foundation [I1733]; LUNGevity Foundation; Consortium of Independent Lung Health Organizations; NIH, National Cancer Institute Center for Cancer Research FX K. Uyeda and members of the DeBerardinis and Chandel laboratories provided critical assessment of the data, and J. Sudderth and C. Yang provided experimental assistance. We thank C. Moraes and I. F. M. de Coo for the WT 143B and CYTB 143B cell lines, I. E. Scheffler for CCL16-B2 cells and T. Yagi for CCL16-NDI1 cells. This work was supported by grants to R. J. D. from the NIH (K08DK072565 and R01CA157996), the Cancer Prevention and Research Institute of Texas (CPRIT, HIRP100437) and the Robert A. Welch Foundation (I1733); to N.S.C. from the NIH (R01CA123067), the LUNGevity Foundation and a Consortium of Independent Lung Health Organizations convened by Respiratory Health Association of Metropolitan Chicago; and to E. S. J. by an NIH grant (DK078933). The work was also supported by the Intramural Research Program of the NIH, National Cancer Institute Center for Cancer Research and by NIH grant RR02584. NIH training grants supported A. R. M. (5T32GM083831), W. W. W. (T32CA009560) and L. B. S. (T32GM008061). T. C. was supported by a CPRIT training grant. NR 26 TC 307 Z9 310 U1 7 U2 78 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 19 PY 2012 VL 481 IS 7381 BP 385 EP U171 DI 10.1038/nature10642 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 877VK UT WOS:000299210600047 ER PT J AU O'Brien, EP Brooks, BR Thirumalai, D AF O'Brien, Edward P. Brooks, Bernard R. Thirumalai, D. TI Effects of pH on Proteins: Predictions for Ensemble and Single-Molecule Pulling Experiments SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ENERGY LANDSCAPE ROUGHNESS; GLOBULAR-PROTEINS; CHYMOTRYPSIN INHIBITOR-2; DEPENDENT PROPERTIES; DENATURED STATES; TITRATION CURVES; PK(A) VALUES; KINETICS; SPECTROSCOPY; SIMULATIONS AB Protein conformations change among distinct thermodynamic states as solution conditions (temperature, denaturants, pH) are altered or when they are subjected to mechanical forces. A quantitative description of the changes in the relative stabilities of the various thermodynamic states is needed to interpret and predict experimental outcomes. We provide a framework based on the Molecular Transfer Model (MTM) to account for pH effects on the properties of globular proteins. The MTM utilizes the partition function of a protein calculated from molecular simulations at one set of solution conditions to predict protein properties at another set of solution conditions. To take pH effects into account, we utilized experimentally measured pK(a) values in the native and unfolded states to calculate the free energy of transferring a protein from a reference pH to the pH of interest. We validate our approach by demonstrating that the native-state stability as a function of pH is accurately predicted for chymotrypsin inhibitor 2 (CI2) and protein G. We use the MTM to predict the response of CI2 and protein G subjected to a constant force (f) and varying pH. The phase diagrams of CI2 and protein G as a function off and pH are dramatically different and reflect the underlying pH-dependent stability changes in the absence of force. The calculated equilibrium free energy profiles as functions of the end-to-end distance of the two proteins show that, at various pH values, CI2 unfolds via an intermediate when subjected to f. The locations of the two transition states move toward the more unstable state as f is changed, which is in accord with the Hammond-Leffler postulate. In sharp contrast, force-induced unfolding of protein G occurs in a single step. Remarkably, the location of the transition state with respect to the folded state is independent off, which suggests that protein G is mechanically brittle. The MTM provides a natural framework for predicting the outcomes of ensemble and single-molecule experiments for a wide range of solution conditions. C1 [O'Brien, Edward P.; Thirumalai, D.] Univ Maryland, Inst Phys Sci & Technol, Biophys Program, College Pk, MD 20742 USA. [O'Brien, Edward P.; Thirumalai, D.] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [O'Brien, Edward P.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Thirumalai, D (reprint author), Univ Maryland, Inst Phys Sci & Technol, Biophys Program, College Pk, MD 20742 USA. EM thirum@umd.edu RI O'Brien, Edward/C-3587-2015 FU National Science Foundation (NSF) [09-14033]; National Institutes of Health (NIH) [GM089685] FX We are grateful to Changbong Hyeon and Greg Morrison for useful discussions. E.P.O. thanks Professor D. Wayne Bolen for suggesting the use of the Henderson-Hasselbach equation to estimate group transfer free energies upon a change in pH. This work was supported in part by grants from the National Science Foundation (NSF; 09-14033) and National Institutes of Health (NIH; GM089685) to D.T. and an NIH Graduate Partnerships Program (GPP) Biophysics Fellowship and NSF postdoctoral fellowship to E.P.O. In this study we utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD (http://biowulf.nih.gov). NR 62 TC 11 Z9 12 U1 2 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JAN 18 PY 2012 VL 134 IS 2 BP 979 EP 987 DI 10.1021/ja206557y PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 903AC UT WOS:000301084300054 PM 22148729 ER PT J AU Raab, JR Chiu, J Zhu, JC Katzman, S Kurukuti, S Wade, PA Haussler, D Kamakaka, RT AF Raab, Jesse R. Chiu, Jonathan Zhu, Jingchun Katzman, Sol Kurukuti, Sreenivasulu Wade, Paul A. Haussler, David Kamakaka, Rohinton T. TI Human tRNA genes function as chromatin insulators SO EMBO JOURNAL LA English DT Article DE chromatin; chromosome conformation capture; human; insulator; tRNA ID POLYMERASE-III TRANSCRIPTION; BETA-GLOBIN INSULATOR; ENHANCER-BLOCKING ACTIVITY; GENOME-WIDE LOCALIZATION; SACCHAROMYCES-CEREVISIAE; FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; POL-II; HETEROCHROMATIN BARRIERS; CHROMOSOME CONFORMATION AB Insulators help separate active chromatin domains from silenced ones. In yeast, gene promoters act as insulators to block the spread of Sir and HP1 mediated silencing while in metazoans most insulators are multipartite autonomous entities. tDNAs are repetitive sequences dispersed throughout the human genome and we now show that some of these tDNAs can function as insulators in human cells. Using computational methods, we identified putative human tDNA insulators. Using silencer blocking, transgene protection and repressor blocking assays we show that some of these tDNA-containing fragments can function as barrier insulators in human cells. We find that these elements also have the ability to block enhancers from activating RNA pol II transcribed promoters. Characterization of a putative tDNA insulator in human cells reveals that the site possesses chromatin signatures similar to those observed at other better-characterized eukaryotic insulators. Enhanced 4C analysis demonstrates that the tDNA insulator makes long-range chromatin contacts with other tDNAs and ETC sites but not with intervening or flanking RNA pol II transcribed genes. The EMBO Journal (2012) 31, 330-350. doi:10.1038/emboj.2011.406; Published online 15 November 2011 C1 [Raab, Jesse R.; Chiu, Jonathan; Katzman, Sol; Kamakaka, Rohinton T.] Univ Calif Santa Cruz, Dept MCD Biol, Santa Cruz, CA 95064 USA. [Zhu, Jingchun; Haussler, David] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Kurukuti, Sreenivasulu] Univ Hyderabad, Sch Life Sci, Dept Anim Sci, Hyderabad 500134, Andhra Pradesh, India. [Wade, Paul A.] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC USA. RP Kamakaka, RT (reprint author), Univ Calif Santa Cruz, Dept MCD Biol, 249 Sinsheimer Labs,1156 High St, Santa Cruz, CA 95064 USA. EM rohinton@ucsc.edu OI Raab, Jesse/0000-0001-6387-8994 FU NIH [GM078068]; University of California Cancer Research coordinating committee [T32-GM008646]; UC [2008-16] FX We would like to thank Adam West, Mike Bulger and Frederique Magdinier for protocols and advice during the course of this research. We would like to thank Gary Felsenfeld, Nigel Bunnett, Robin Allshire, Kristin Scott, Michael Carey, Claudius Vincenz and Naoko Tanese for plasmids and reagents. We would also like to acknowledge the technical help of Serdar Kasakyan. This work was supported by a grant from the NIH (GM078068) and the University of California Cancer Research coordinating committee to RTK and (T32-GM008646, and the GREAT Training Program of the UC System wide Biotechnology Research and Education Program, grant # 2008-16) to JR. Integrated DNA technologies synthesized the wild-type and mutant 1.2kb fragment analysed in Supplementary Figure S4. NR 151 TC 41 Z9 41 U1 2 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 18 PY 2012 VL 31 IS 2 BP 330 EP 350 DI 10.1038/emboj.2011.406 PG 21 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 888ZQ UT WOS:000300043700010 PM 22085927 ER PT J AU Adoro, S McCaughtry, T Erman, B Alag, A Van Laethem, F Park, JH Tai, XG Kimura, M Wang, L Grinberg, A Kubo, M Bosselut, R Love, P Singer, A AF Adoro, Stanley McCaughtry, Thomas Erman, Batu Alag, Amala Van Laethem, Francois Park, Jung-Hyun Tai, Xuguang Kimura, Motoko Wang, Lie Grinberg, Alex Kubo, Masato Bosselut, Remy Love, Paul Singer, Alfred TI Coreceptor gene imprinting governs thymocyte lineage fate SO EMBO JOURNAL LA English DT Article DE coreceptor; lineage fate; Runx3; ThPOK; thymocyte development ID T-CELL DEVELOPMENT; LYMPHOCYTE DEVELOPMENT; TRANSCRIPTION FACTORS; POSITIVE SELECTION; TRANSGENIC MICE; CD8 EXPRESSION; RUNX PROTEINS; REGULATES CD4; B-CELLS; DIFFERENTIATION AB Immature thymocytes are bipotential cells that are signalled during positive selection to become either helper- or cytotoxic-lineage T cells. By tracking expression of lineage determining transcription factors during positive selection, we now report that the Cd8 coreceptor gene locus co-opts any coreceptor protein encoded within it to induce thymocytes to express the cytotoxic-lineage factor Runx3 and to adopt the cytotoxic-lineage fate, findings we refer to as 'coreceptor gene imprinting'. Specifically, encoding CD4 proteins in the endogenous Cd8 gene locus caused major histocompatibility complex class II-specific thymocytes to express Runx3 during positive selection and to differentiate into CD4(+) cytotoxic-lineage T cells. Our findings further indicate that coreceptor gene imprinting derives from the dynamic regulation of specific cis Cd8 gene enhancer elements by positive selection signals in the thymus. Thus, for coreceptor-dependent thymocytes, lineage fate is determined by Cd4 and Cd8 coreceptor gene loci and not by the specificity of T-cell antigen receptor/coreceptor signalling. This study identifies coreceptor gene imprinting as a critical determinant of lineage fate determination in the thymus. The EMBO Journal (2012) 31, 366-377. doi:10.1038/emboj.2011.388; Published online 28 October 2011 C1 [Adoro, Stanley; McCaughtry, Thomas; Alag, Amala; Van Laethem, Francois; Park, Jung-Hyun; Tai, Xuguang; Kimura, Motoko; Singer, Alfred] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Adoro, Stanley] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. [Erman, Batu] Sabanci Univ, Fac Engn & Nat Sci, Biol Sci & Bioengn Program, Istanbul, Turkey. [Wang, Lie; Bosselut, Remy] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. [Grinberg, Alex; Love, Paul] NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. [Kubo, Masato] Tokyo Univ Sci, Div Biotechnol, Res Inst Biol Sci, Chiba, Japan. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM singera@nih.gov RI Park, Jung Hyun /B-5712-2015 OI Park, Jung Hyun /0000-0002-9547-9055 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We are grateful to D Littman for the Runx3d(YFP) reporter mice; W Ellmeier for enhancer reporter elements; N Taylor and R Hodes for critical reading of the manuscript; S Sharrow, A Adams, and L Granger for expert flow cytometry; M Catalfamo for assistance with re-directed cytotoxicity assays; and N Taylor for helpful discussions and support throughout the course of this study. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 42 TC 10 Z9 10 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 18 PY 2012 VL 31 IS 2 BP 366 EP 377 DI 10.1038/emboj.2011.388 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 888ZQ UT WOS:000300043700012 PM 22036949 ER PT J AU Monach, PA Kumpers, P Lukasz, A Tomasson, G Specks, U Stone, JH Cuthbertson, D Krischer, J Carette, S Ding, LN Hoffman, GS Ikle, D Kallenberg, CGM Khalidi, NA Langford, CA Seo, P St Clair, EW Spiera, R Tchao, N Ytterberg, SR Haubitz, M Merkel, PA AF Monach, Paul A. Kuempers, Philipp Lukasz, Alexander Tomasson, Gunnar Specks, Ulrich Stone, John H. Cuthbertson, David Krischer, Jeffrey Carette, Simon Ding, Linna Hoffman, Gary S. Ikle, David Kallenberg, Cees G. M. Khalidi, Nader A. Langford, Carol A. Seo, Philip St Clair, E. William Spiera, Robert Tchao, Nadia Ytterberg, Steven R. Haubitz, Marion Merkel, Peter A. TI Circulating Angiopoietin-2 as a Biomarker in ANCA-Associated Vasculitis SO PLOS ONE LA English DT Article ID SOLUBLE ADHESION MOLECULES; ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; TIE-2 LIGAND ANGIOPOIETIN-2; CRITICALLY-ILL PATIENTS; C-REACTIVE PROTEIN; WEGENERS-GRANULOMATOSIS; E-SELECTIN; FOLLOW-UP; SYSTEMIC VASCULITIS; DISEASE-ACTIVITY AB The endothelial-specific Angiopoietin-Tie2 ligand-receptor system is an important regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to Tie2 receptor renders the endothelial barrier responsive to pro-inflammatory cytokines. We previously showed that circulating Ang-2 correlated with disease severity in a small cohort of critically ill patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. The current study reassessed Ang-2 as a biomarker of disease activity and relapse in AAV. Circulating Ang-2 was measured in 162 patients with severe AAV (BVAS/WG >= 3, with or without glomerulonephritis) in a clinical trial. Ang-2 levels during active AAV were compared to levels in the same patients during remission (BVAS/WG = 0). Levels in clinical subsets of AAV were compared, and association with future disease course was assessed. Ang-2 levels were elevated in severe disease (median 3.0 ng/ml, interquartile range 1.9-4.4) compared to healthy controls (1.2, 0.9-1.5). However, they did not reliably decline with successful treatment (median 2.6 ng/ml, interquartile range 1.9-3.8, median change -0.1). Ang-2 correlated weakly with BVAS/WG score (r = 0.17), moderately with markers of systemic inflammation (r = 0.25-0.41), and inversely with renal function (r = -0.36). Levels were higher in patients with glomerulonephritis, but levels adjusted for renal dysfunction were no different in patients with or without glomerulonephritis. Levels were higher in patients with newly diagnosed AAV and lower in patients in whom treatment had recently been started. Ang-2 levels during active disease did not predict response to treatment, and Ang-2 levels in remission did not predict time to flare. Thus, Ang-2 appears to have limited practical value in AAV as a biomarker of disease activity at time of measurement or for predicting future activity. C1 [Monach, Paul A.; Tomasson, Gunnar; Merkel, Peter A.] Boston Univ, Rheumatol Sect, Dept Med, Sch Med,Vasculitis Ctr, Boston, MA 02215 USA. [Kuempers, Philipp; Lukasz, Alexander; Haubitz, Marion] Hannover Med Sch, Dept Hypertens & Nephrol, D-3000 Hannover, Germany. [Kuempers, Philipp] Univ Hosp Munster, Div Gen Internal Med Nephrol & Rheumatol, Dept Med, Munster, Germany. [Specks, Ulrich] Mayo Clin Coll Med, Div Pulm & Crit Care Med, Rochester, MN USA. [Stone, John H.] Massachusetts Gen Hosp, Rheumatol Unit, Boston, MA 02114 USA. [Cuthbertson, David; Krischer, Jeffrey] Univ S Florida, Coll Med, Dept Pediat, Tampa, FL 33612 USA. [Carette, Simon] Univ Toronto, Div Rheumatol, Toronto, ON, Canada. [Ding, Linna] NIAID, Bethesda, MD 20892 USA. [Hoffman, Gary S.; Langford, Carol A.] Cleveland Clin, Ctr Vasculitis Care & Res, Cleveland, OH 44106 USA. [Ikle, David] Rho, Fed Syst Div, Chapel Hill, NC USA. [Kallenberg, Cees G. M.] Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, Groningen, Netherlands. [Khalidi, Nader A.] McMaster Univ, Div Rheumatol, Hamilton, ON, Canada. [Seo, Philip] Johns Hopkins Univ, Div Rheumatol, Baltimore, MD USA. [St Clair, E. William] Duke Univ, Div Rheumatol & Immunol, Durham, NC USA. [Spiera, Robert] Hosp Special Surg, Div Rheumatol, New York, NY 10021 USA. [Tchao, Nadia] Immune Tolerance Network, San Francisco, CA USA. [Ytterberg, Steven R.] Mayo Clin Coll Med, Div Rheumatol, Rochester, MN USA. RP Monach, PA (reprint author), Boston Univ, Rheumatol Sect, Dept Med, Sch Med,Vasculitis Ctr, Boston, MA 02215 USA. EM pmonach@bu.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [U54AR057319, RC1 AR058303, P60 AR047785]; National Center for Research Resources [U54 RR019497]; National Institute of Neurological Disorders and Stroke [NS064808]; Office of Rare Diseases Research; NIH [N01 AI15416, M01 RR00533, K24 AR02224]; National Institute of Allergy and Infectious Diseases; Juvenile Diabetes Research Foundation; National Center for Research Resources (NCRR) [RR024150-01, RR025005, K24 AR049185, K23 AR052820]; Boston University [RR 025771]; Arthritis Foundation FX This work was sponsored by the Vasculitis Clinical Research Consortium which has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54AR057319, RC1 AR058303, and P60 AR047785), the National Center for Research Resources (U54 RR019497), the National Institute of Neurological Disorders and Stroke (NS064808), and the Office of Rare Diseases Research. The Rituximab in ANCA-Associated Vasculitis (RAVE) trial was performed with the support of the Immune Tolerance Network (NIH Contract #N01 AI15416), an international clinical research consortium supported by the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Research Foundation. Genentech and Biogen Idec provided the study medications and partial funding of the clinical trial. For this ancillary study, Genentech had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. At the Mayo Clinic and Foundation, the trial was supported by a Clinical and Translational Science Award from the National Center for Research Resources (NCRR) (RR024150-01); at Johns Hopkins University, by grants from the NCRR (RR025005) and career development awards (K24 AR049185 to Dr. Stone, and K23 AR052820 to Dr. Seo); and at Boston University, by a Clinical and Translational Science Award (RR 025771), grants from the National Institutes of Health (M01 RR00533) and a career development award (K24 AR02224 to Dr. Merkel). Dr. Monach was also supported by an Arthritis Investigator Award from the Arthritis Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 5 Z9 5 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 18 PY 2012 VL 7 IS 1 AR e30197 DI 10.1371/journal.pone.0030197 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 885IH UT WOS:000299771900048 PM 22279570 ER PT J AU Toda, K Sugase-Miyamoto, Y Mizuhiki, T Inaba, K Richmond, BJ Shidara, M AF Toda, Koji Sugase-Miyamoto, Yasuko Mizuhiki, Takashi Inaba, Kiyonori Richmond, Barry J. Shidara, Munetaka TI Differential Encoding of Factors Influencing Predicted Reward Value in Monkey Rostral Anterior Cingulate Cortex SO PLOS ONE LA English DT Article ID PRIMATE FRONTAL-CORTEX; ORBITOFRONTAL CORTEX; PREFRONTAL CORTEX; NEURONAL SIGNALS; DOPAMINE NEURONS; MACAQUE MONKEY; RHESUS-MONKEY; CONNECTIONS; AMYGDALA; MOTIVATION AB Background: The value of a predicted reward can be estimated based on the conjunction of both the intrinsic reward value and the length of time to obtain it. The question we addressed is how the two aspects, reward size and proximity to reward, influence the responses of neurons in rostral anterior cingulate cortex (rACC), a brain region thought to play an important role in reward processing. Methods and Findings: We recorded from single neurons while two monkeys performed a multi-trial reward schedule task. The monkeys performed 1-4 sequential color discrimination trials to obtain a reward of 1-3 liquid drops. There were two task conditions, a valid cue condition, where the number of trials and reward amount were associated with visual cues, and a random cue condition, where the cue was picked from the cue set at random. In the valid cue condition, the neuronal firing is strongly modulated by the predicted reward proximity during the trials. Information about the predicted reward amount is almost absent at those times. In substantial subpopulations, the neuronal responses decreased or increased gradually through schedule progress to the predicted outcome. These two gradually modulating signals could be used to calculate the effect of time on the perception of reward value. In the random cue condition, little information about the reward proximity or reward amount is encoded during the course of the trial before reward delivery, but when the reward is actually delivered the responses reflect both the reward proximity and reward amount. Conclusions: Our results suggest that the rACC neurons encode information about reward proximity and amount in a manner that is dependent on utility of reward information. The manner in which the information is represented could be used in the moment-to-moment calculation of the effect of time and amount on predicted outcome value. C1 [Toda, Koji; Mizuhiki, Takashi; Inaba, Kiyonori; Shidara, Munetaka] Univ Tsukuba, Doctoral Program Kansei Behav & Brain Sci, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki, Japan. [Sugase-Miyamoto, Yasuko] Natl Inst Adv Ind Sci & Technol, Human Technol Res Inst, Tsukuba, Ibaraki, Japan. [Mizuhiki, Takashi; Shidara, Munetaka] Univ Tsukuba, Fac Med, Tsukuba, Ibaraki, Japan. [Richmond, Barry J.] NIMH, Neuropsychol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Toda, K (reprint author), Univ Tsukuba, Doctoral Program Kansei Behav & Brain Sci, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki, Japan. EM mshidara@md.tsukuba.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan [17022052]; 21st Century COE; AIST/Japan; US National Institute of Mental Health FX The work was supported by Grant-in-Aid for JSPS Fellows (KT), Grant-in-Aid for Scientific Research on Priority Areas -System study on higher-order brain functions-from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant No. 17022052 to MS), and 21st Century COE Program (MS) and AIST/Japan (YS). BJR is supported by the Intramural Research Program of the US National Institute of Mental Health. The authors thank JSPS for providing travel support for BJR in Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 7 Z9 7 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 18 PY 2012 VL 7 IS 1 AR e30190 DI 10.1371/journal.pone.0030190 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 885IH UT WOS:000299771900047 PM 22279569 ER PT J AU Xiang, TX Li, LL Yin, XD Yuan, CF Tan, C Su, XW Xiong, L Putti, TC Oberst, M Kelly, K Ren, GS Tao, Q AF Xiang, Tingxiu Li, Lili Yin, Xuedong Yuan, Chenfu Tan, Cui Su, Xianwei Xiong, Lei Putti, Thomas C. Oberst, Michael Kelly, Kathleen Ren, Guosheng Tao, Qian TI The Ubiquitin Peptidase UCHL1 Induces G0/G1 Cell Cycle Arrest and Apoptosis Through Stabilizing p53 and Is Frequently Silenced in Breast Cancer SO PLOS ONE LA English DT Article ID CANDIDATE TUMOR-SUPPRESSOR; TERMINAL HYDROLASE L1; DNA METHYLATION; PROMOTER METHYLATION; MULTIPLE CARCINOMAS; PROTEASOME PATHWAY; GENE; ESOPHAGEAL; DISEASE; NASOPHARYNGEAL AB Background: Breast cancer (BrCa) is a complex disease driven by aberrant gene alterations and environmental factors. Recent studies reveal that abnormal epigenetic gene regulation also plays an important role in its pathogenesis. Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is a tumor suppressor silenced by promoter methylation in multiple cancers, but its role and alterations in breast tumorigenesis remain unclear. Methodology/Principal Findings: We found that UCHL1 was frequently downregulated or silenced in breast cancer cell lines and tumor tissues, but readily expressed in normal breast tissues and mammary epithelial cells. Promoter methylation of UCHL1 was detected in 9 of 10 breast cancer cell lines (90%) and 53 of 66 (80%) primary tumors, but rarely in normal breast tissues, which was statistically correlated with advanced clinical stage and progesterone receptor status. Pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. Ectopic expression of UCHL1 significantly suppressed the colony formation and proliferation of breast tumor cells, through inducing G0/G1 cell cycle arrest and apoptosis. Subcellular localization study showed that UCHL1 increased cytoplasmic abundance of p53. We further found that UCHL1 induced p53 accumulation and reduced MDM2 protein level, and subsequently upregulated the expression of p21, as well as cleavage of caspase3 and PARP, but not in catalytic mutant UCHL1 C90S-expressed cells. Conclusions/Significance: UCHL1 exerts its tumor suppressive functions by inducing G0/G1cell cycle arrest and apoptosis in breast tumorigenesis, requiring its deubiquitinase activity. Its frequent silencing by promoter CpG methylation may serve as a potential tumor marker for breast cancer. C1 [Xiang, Tingxiu; Yin, Xuedong; Yuan, Chenfu; Tan, Cui; Ren, Guosheng; Tao, Qian] Chongqing Med Univ, Affiliated Hosp 1, Mol Oncol & Epigenet Lab, Chongqing, Peoples R China. [Li, Lili; Su, Xianwei; Xiong, Lei; Tao, Qian] Chinese Univ Hong Kong, CUHK Shenzhen Res Inst, Li Ka Shing Inst Hlth Sci,Canc Epigenet Lab, Dept Clin Oncol,Sir YK Pao Ctr Canc, Hong Kong, Hong Kong, Peoples R China. [Putti, Thomas C.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pathol, Singapore 117595, Singapore. [Oberst, Michael; Kelly, Kathleen] NCI, Signal Transduct Sect, NIH, Bethesda, MD 20892 USA. RP Ren, GS (reprint author), Chongqing Med Univ, Affiliated Hosp 1, Mol Oncol & Epigenet Lab, Chongqing, Peoples R China. EM rgs726@163.com; qtao@clo.cuhk.edu.hk FU Chongqing Health Bureau; National Natural Science Foundation of China [31171243, 81072148, 81172582]; Shenzhen Science Fund for Distinguished Young Scholars [JC201005270328A] FX This study was supported by the Chongqing Health Bureau grant, National Natural Science Foundation of China (#31171243, 81072148 and 81172582) and Shenzhen Science Fund for Distinguished Young Scholars (#JC201005270328A). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 40 Z9 45 U1 0 U2 9 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 JAN 18 PY 2012 VL 7 IS 1 AR e29783 DI 10.1371/journal.pone.0029783 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 885IH UT WOS:000299771900023 PM 22279545 ER PT J AU Volkow, ND Wang, GJ Tomasi, D Kollins, SH Wigal, TL Newcorn, JH Telang, FW Fowler, JS Logan, J Wong, CT Swanson, JM AF Volkow, Nora D. Wang, Gene-Jack Tomasi, Dardo Kollins, Scott H. Wigal, Tim L. Newcorn, Jeffrey H. Telang, Frank W. Fowler, Joanna S. Logan, Jean Wong, Christopher T. Swanson, James M. TI Methylphenidate-Elicited Dopamine Increases in Ventral Striatum Are Associated with Long-Term Symptom Improvement in Adults with Attention Deficit Hyperactivity Disorder SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DEFICIT/HYPERACTIVITY DISORDER; HUMAN BRAIN; EXTRACELLULAR DOPAMINE; ORAL METHYLPHENIDATE; PREFRONTAL CORTEX; EMISSION-TOMOGRAPHY; C-11 RACLOPRIDE; RATING-SCALES; PART II; ADHD AB Stimulant medications, such as methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and [(11)C]raclopride (D(2)/D(3) receptor radioligand sensitive to competition with endogenous dopamine). Clinical responses were assessed using the Conners' Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous methylphenidate significantly increased dopamine in striatum (assessed as decreases in D(2)/D(3) receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response. C1 [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. [Volkow, Nora D.; Tomasi, Dardo; Telang, Frank W.; Wong, Christopher T.] Natl Inst Alcohol Abuse & Alcoholism, Lab Neuroimaging, Bethesda, MD 20892 USA. [Wang, Gene-Jack; Fowler, Joanna S.; Logan, Jean] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Wang, Gene-Jack; Fowler, Joanna S.; Logan, Jean] Brookhaven Natl Lab, Dept Chem, Upton, NY 11973 USA. [Kollins, Scott H.; Swanson, James M.] Duke Univ, Dept Psychiat, Durham, NC 27710 USA. [Wigal, Tim L.] Univ Calif Irvine, Child Dev Ctr, Irvine, CA 92612 USA. [Newcorn, Jeffrey H.] Mt Sinai Med Ctr, Dept Psychiat, New York, NY 10029 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, 6001 Execut Blvd,Room 5274, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov RI Kollins, Scott/G-2965-2012; Tomasi, Dardo/J-2127-2015; OI Newcorn, Jeffrey /0000-0001-8993-9337 FU National Institutes of Health (National Institute on Alcoholism and Alcohol Abuse); National Institute of Mental Health [R01MH66961]; U.S. Department of Energy/Office of Biological and Environmental Research [DE-AC02-76CH00016] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute on Alcoholism and Alcohol Abuse), National Institute of Mental Health Grant R01MH66961 (G.-J.W.), with infrastructure support from U.S. Department of Energy/Office of Biological and Environmental Research Grant DE-AC02-76CH00016. We thank the following: David Schlyer and Michael Schueller for cyclotron operations; Donald Warner, David Alexoff, and Paul Vaska for PET operations; Richard Ferrieri, Colleen Shea, Youwen Xu, Lisa Muench, and Payton King for radiotracer preparation and analysis, Karen Apelskog-Torres for study protocol preparation; Millard Jayne, Joseph English, Allan Chrisman, Barbara Hubbard, and Pauline Carter for patient care; and Ruben Baler and Denise Pintello for editorial assistance. This paper was presented at the Society of Nuclear Medicine in 2011. NR 60 TC 62 Z9 64 U1 4 U2 21 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 18 PY 2012 VL 32 IS 3 BP 841 EP 849 DI 10.1523/JNEUROSCI.4461-11.2012 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 879JG UT WOS:000299324900009 PM 22262882 ER PT J AU Luan, HJ Diao, FQ Peabody, NC White, BH AF Luan, Haojiang Diao, Fengqiu Peabody, Nathan C. White, Benjamin H. TI Command and Compensation in a Neuromodulatory Decision Network SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ECDYSIS-TRIGGERING HORMONE; CENTRAL PATTERN GENERATORS; ECLOSION HORMONE; WING EXPANSION; INSECT ECDYSIS; NEURONAL CONTROL; ACTION SELECTION; MANDUCA-SEXTA; NEURAL BASIS; DROSOPHILA AB The neural circuits that mediate behavioral choices must not only weigh internal demands and environmental circumstances, but also select and implement specific actions, including associated visceral or neuroendocrine functions. Coordinating these multiple processes suggests considerable complexity. As a consequence, even circuits that support simple behavioral decisions remain poorly understood. Here we show that the environmentally sensitive wing expansion decision of adult fruit flies is coordinated by a single pair of neuromodulatory neurons with command-like function. Targeted suppression of these neurons using the Split Gal4 system abrogates the fly's ability to expand its wings in the face of environmental challenges, while stimulating them forces expansion by coordinately activating both motor and neuroendocrine outputs. The arbitration and implementation of the wing expansion decision by this neuronal pair may illustrate a general strategy by which neuromodulatory neurons orchestrate behavior. Interestingly, the decision network exhibits a plasticity that is unmasked under conducive environmental conditions in flies lacking the function of the command-like neuromodulatory neurons. Such flies can often expand their wings using a motor program distinct from that of wild-type animals and controls. This compensatory program may be the vestige of an ancestral, environmentally insensitive program used for wing expansion that existed before the evolution of the environmentally adaptive program currently used by Drosophila and other cyclorrhaphan flies. C1 [Luan, Haojiang; Diao, Fengqiu; Peabody, Nathan C.; White, Benjamin H.] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP White, BH (reprint author), NIMH, Mol Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM benjaminwhite@mail.nih.gov FU National Institute of Mental Health [1ZIA-MH-002800-07] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health (Project 1ZIA-MH-002800-07). We thank Kevin HoWan, Sarrah Ben-Achour, and Michael Syme for technical assistance in generating and characterizing the enhancer-trap hemidriver lines. We thank Aaron Hsueh and Willi Honnegger for the anti-pburs antibody, Deborah Hursh for UAS-hid flies, and Grace Gray for critical comments on the manuscript. We would also like to express our profound gratitude to the late Howard Nash whose encouragement, generous advice, and thoughtful comments were invaluable throughout. NR 59 TC 10 Z9 10 U1 0 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 18 PY 2012 VL 32 IS 3 BP 880 EP 889 DI 10.1523/JNEUROSCI.3707-11.2012 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 879JG UT WOS:000299324900013 PM 22262886 ER PT J AU Badea, TC Williams, J Smallwood, P Shi, M Motajo, O Nathans, J AF Badea, Tudor Constantin Williams, John Smallwood, Philip Shi, Melody Motajo, Oluwaseyi Nathans, Jeremy TI Combinatorial Expression of Brn3 Transcription Factors in Somatosensory Neurons: Genetic and Morphologic Analysis SO JOURNAL OF NEUROSCIENCE LA English DT Article ID RETINAL GANGLION-CELLS; PRIMARY SENSORY NEURONS; DORSAL-ROOT GANGLION; TRIGEMINAL GANGLION; BRN-3A DEFICIENCY; RECEPTOR EXPRESSION; MOUSE; DIFFERENTIATION; DISTINCT; MECHANORECEPTORS AB The three members of the Brn3 family of POU-domain transcription factors (Brn3a/Pou4f1, Brn3b/Pou4f2, and Brn3c/Pou4f3) are expressed in overlapping subsets of visual, auditory/vestibular, and somatosensory neurons. Using unmarked Brn3-null alleles and Brn3 conditional alleles in which gene loss is coupled to expression of an alkaline phosphatase reporter, together with sparse Cre-mediated recombination, we describe the following: (1) the overlapping patterns of Brn3 gene expression in somatosensory neurons; (2) the manner in which these patterns correlate with molecular markers, peripheral afferent arbor morphologies, and dorsal horn projections; and (3) the consequences for these neurons of deleting individual Brn3 genes in the mouse. We observe broad expression of Brn3a among DRG neurons, but subtype-restricted expression of Brn3b and Brn3c. We also observe a nearly complete loss of hair follicle-associated sensory endings among Brn3a(-/-) neurons. Together with earlier analyses of Brn3 gene expression patterns in the retina and inner ear, these experiments suggest a deep functional similarity among primary somatosensory neurons, spiral and vestibular ganglion neurons, and retinal ganglion cells. This work also demonstrates the utility of sparse genetically directed labeling for visualizing individual somatosensory afferent arbors and for defining cell-autonomous mutant phenotypes. C1 [Badea, Tudor Constantin; Shi, Melody; Motajo, Oluwaseyi] NEI, NIH, Bethesda, MD 20892 USA. [Badea, Tudor Constantin; Williams, John; Smallwood, Philip; Nathans, Jeremy] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Nathans, Jeremy] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Nathans, Jeremy] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Williams, John; Smallwood, Philip; Nathans, Jeremy] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. RP Badea, TC (reprint author), NEI, NIH, Bldg 6, Bethesda, MD 20892 USA. EM badeatc@mail.nih.gov; jnathans@jhmi.edu FU Howard Hughes Medical Institute; National Institutes of Health FX This work was supported by the Howard Hughes Medical Institute and the National Institutes of Health. We thank Rocky Cheung, Sumit Kumar, and Yanshu Wang for help with histology and immunostaining; and Xinzhong Dong, David Ginty, Qin Liu, and Ting Guo for helpful discussions and/or comments on this manuscript. NR 62 TC 27 Z9 27 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 18 PY 2012 VL 32 IS 3 BP 995 EP 1007 DI 10.1523/JNEUROSCI.4755-11.2012 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 879JG UT WOS:000299324900025 PM 22262898 ER PT J AU Yang, HD Shew, WL Roy, R Plenz, D AF Yang, Hongdian Shew, Woodrow L. Roy, Rajarshi Plenz, Dietmar TI Maximal Variability of Phase Synchrony in Cortical Networks with Neuronal Avalanches SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SELF-ORGANIZED CRITICALITY; IN-VITRO; EPILEPTIFORM ACTIVITY; COMPLEX NETWORKS; CELL ASSEMBLIES; NEURAL-NETWORKS; CORTEX; NEOCORTEX; OSCILLATIONS; MECHANISMS AB Ongoing interactionsamongcortical neurons often manifest as network-level synchrony. Understanding the spatiotemporal dynamics of such spontaneous synchrony is important because it may (1) influence network response to input, (2) shape activity-dependent microcircuit structure, and (3) reveal fundamental network properties, such as an imbalance of excitation (E) and inhibition (I). Here we delineate the spatiotemporal character of spontaneous synchrony in rat cortex slice cultures and a computational model over a range of different E-I conditions including disfacilitated (antagonized AMPA, NMDA receptors), unperturbed, and disinhibited (antagonized GABA(A) receptors). Local field potential was recorded with multielectrode arrays during spontaneous burst activity. Synchrony among neuronal groups was quantified based on phase-locking among recording sites. As network excitability was increased from low to high, we discovered three phenomena at an intermediate excitability level: (1) onset of synchrony, (2) maximized variability of synchrony, and (3) neuronal avalanches. Our computational model predicted that these three features occur when the network operates near a unique balanced E-I condition called "criticality." These results were invariant to changes in the measurement spatial extent, spatial resolution, and frequency bands. Our findings indicate that moderate average synchrony, which is required to avoid pathology, occurs over a limited range of E-I conditions and emerges together with maximally variable synchrony. If variable synchrony is detrimental to cortical function, this is a cost paid for moderate average synchrony. However, if variable synchrony is beneficial, then by operating near criticality the cortex may doubly benefit from moderate mean and maximized variability of synchrony. C1 [Yang, Hongdian; Shew, Woodrow L.; Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Lab Syst Neurosci, Bethesda, MD 20892 USA. [Yang, Hongdian] Univ Maryland, Biophys Program, College Pk, MD 20742 USA. [Roy, Rajarshi] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. RP Plenz, D (reprint author), NIMH, Sect Crit Brain Dynam, Lab Syst Neurosci, Bethesda, MD 20892 USA. EM plenzd@mail.nih.gov RI Yang, Hongdian/D-1450-2015; OI Shew, Woodrow/0000-0003-0679-1766; Roy, Rajarshi/0000-0002-2381-829X FU National Institute of Mental Health; Department of Defense Multidisciplinary University Research Initiative [ONR N000140710734] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health. R.R. acknowledges support from Department of Defense Multidisciplinary University Research Initiative Grant ONR N000140710734 to the University of Maryland. We thank Craig Stewart for help preparing the cultures and Dr. Shan Yu for helpful discussions. NR 65 TC 56 Z9 57 U1 1 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 18 PY 2012 VL 32 IS 3 BP 1061 EP 1072 DI 10.1523/JNEUROSCI.2771-11.2012 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 879JG UT WOS:000299324900031 PM 22262904 ER PT J AU Feng, S Ekong, UD Lobritto, SJ Demetris, AJ Roberts, JP Rosenthal, P Alonso, EM Philogene, MC Ikle, D Poole, KM Bridges, ND Turka, LA Tchao, NK AF Feng, Sandy Ekong, Udeme D. Lobritto, Steven J. Demetris, Anthony J. Roberts, John P. Rosenthal, Philip Alonso, Estella M. Philogene, Mary C. Ikle, David Poole, Katharine M. Bridges, Nancy D. Turka, Laurence A. Tchao, Nadia K. TI Complete Immunosuppression Withdrawal and Subsequent Allograft Function Among Pediatric Recipients of Parental Living Donor Liver Transplants SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ORGAN-TRANSPLANTATION; OPERATIONAL TOLERANCE; REJECTION; ANTIBODY; CELL; CHIMERISM AB Context Although life-saving, liver transplantation burdens children with lifelong immunosuppression and substantial potential for morbidity and mortality. Objective To establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients. Design, Setting, and Patients Prospective, multicenter, open-label, single-group pilot trial conducted in 20 stable pediatric recipients (11 male; 55%) of parental living donor liver transplants for diseases other than viral hepatitis or an autoimmune disease who underwent immunosuppression withdrawal. Their median age was 6.9 months (interquartile range [IQR], 5.5-9.1 months) at transplant and 8 years 6 months (IQR, 6 years 5 months to 10 years 9 months) at study enrollment. Additional entry requirements included stable allograft function while taking a single immunosuppressive drug and no evidence of acute or chronic rejection or significant fibrosis on liver biopsy. Gradual immunosuppression withdrawal over a minimum of 36 weeks was instituted at 1 of 3 transplant centers between June 5, 2006, and November 18, 2009. Recipients were followed up for a median of 32.9 months (IQR, 1.0-49.9 months). Main Outcome Measures The primary end point was the proportion of operationally tolerant patients, defined as patients who remained off immunosuppression therapy for at least 1 year with normal graft function. Secondary clinical end points included the durability of operational tolerance, and the incidence, timing, severity, and reversibility of rejection. Results Of 20 pediatric patients, 12 (60%; 95% CI, 36.1%-80.9%) met the primary end point, maintaining normal allograft function for a median of 35.7 months (IQR, 28.1-39.7 months) after discontinuing immunosuppression therapy. Follow-up biopsies obtained more than 2 years after completing withdrawal showed no significant change compared with baseline biopsies. Eight patients did not meet the primary end point secondary to an exclusion criteria violation (n=1), acute rejection (n=2), or indeterminate rejection (n=5). Seven patients were treated with increased or reinitiation of immunosuppression therapy; all returned to baseline allograft function. Patients with operational tolerance compared with patients without operational tolerance initiated immunosuppression withdrawal later after transplantation (median of 100.6 months [IQR, 71.8-123.5] vs 73.0 months [IQR, 57.6-74.9], respectively; P=.03), had less portal inflammation (91.7% [95% CI, 61.5%-99.8%] vs 42.9% [95% CI, 9.9%-81.6%] with no inflammation; P=.04), and had lower total C4d scores on the screening liver biopsy (median of 6.1 [IQR, 5.1-9.3] vs 12.5 [IQR, 9.3-16.8]; P=.03). Conclusion In this pilot study, 60% of pediatric recipients of parental living donor liver transplants remained off immunosuppression therapy for at least 1 year with normal graft function and stable allograft histology. JAMA. 2012;307(3):283-293 C1 [Feng, Sandy; Roberts, John P.; Rosenthal, Philip] Univ Calif San Francisco, Dept Surg, Div Transplantat, San Francisco, CA 94113 USA. [Rosenthal, Philip] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94113 USA. [Tchao, Nadia K.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94113 USA. [Ekong, Udeme D.; Alonso, Estella M.] Childrens Mem Hosp, Dept Pediat, Chicago, IL 60614 USA. [Ekong, Udeme D.; Alonso, Estella M.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Lobritto, Steven J.] Columbia Univ, Dept Pediat, Morgan Stanley Childrens Hosp, Med Ctr, New York, NY 10027 USA. [Lobritto, Steven J.] Columbia Univ, Dept Surg, Morgan Stanley Childrens Hosp, Med Ctr, New York, NY 10027 USA. [Demetris, Anthony J.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. [Philogene, Mary C.; Turka, Laurence A.; Tchao, Nadia K.] Immune Tolerance Network, Bethesda, MD USA. [Turka, Laurence A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA. [Ikle, David; Poole, Katharine M.] Rho, Chapel Hill, NC USA. [Bridges, Nancy D.] NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. RP Feng, S (reprint author), Univ Calif San Francisco, Dept Surg, Div Transplantat, 505 Parnasus Ave,POB 0780, San Francisco, CA 94113 USA. EM sandy.feng@ucsfmedctr.org FU Novartis/DCL Laboratory; Bristol-Myers Squibb; National Institutes of Health/National Center for Research Resources [UL1 RR024131] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Demetris reported that he has received fees as a consultant for pathology services related to clinical trials of immunosuppression drugs in adult de novo liver transplant recipients from Novartis/DCL Laboratory and Bristol-Myers Squibb; and is a co-inventor of Omnyx Digital Pathology Solution, a joint venture between the University of Pittsburgh Medical Center and General Electric to create a complete digital pathology solution. Dr Turka reported that he owns stock in and has a family member employed by Novartis. No other disclosures were reported.; The Immune Tolerance Network, an international clinical research consortium founded by the National Institutes of Health, funded the study. This study also was supported by grant UL1 RR024131 from the National Institutes of Health/National Center for Research Resources awarded to the University of California, San Francisco, Clinical & Translational Science Institute. NR 30 TC 122 Z9 132 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 18 PY 2012 VL 307 IS 3 BP 283 EP 293 DI 10.1001/jama.2011.2014 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 877EY UT WOS:000299161200024 PM 22253395 ER PT J AU Dougherty, EJ Guo, C Simons, SS Chow, CC AF Dougherty, Edward J. Guo, Chunhua Simons, S. Stoney, Jr. Chow, Carson C. TI Deducing the Temporal Order of Cofactor Function in Ligand-Regulated Gene Transcription: Theory and Experimental Verification SO PLOS ONE LA English DT Article ID NUCLEAR RECEPTOR COREGULATORS; GLUCOCORTICOID-RECEPTOR; INDUCTION PROPERTIES; EXPRESSION; BINDING; TRANSACTIVATION; COACTIVATOR; AGONIST; MODULATION; COMPLEXES AB Cofactors are intimately involved in steroid-regulated gene expression. Two critical questions are (1) the steps at which cofactors exert their biological activities and (2) the nature of that activity. Here we show that a new mathematical theory of steroid hormone action can be used to deduce the kinetic properties and reaction sequence position for the functioning of any two cofactors relative to a concentration limiting step (CLS) and to each other. The predictions of the theory, which can be applied using graphical methods similar to those of enzyme kinetics, are validated by obtaining internally consistent data for pair-wise analyses of three cofactors (TIF2, sSMRT, and NCoR) in U2OS cells. The analysis of TIF2 and sSMRT actions on GR-induction of an endogenous gene gave results identical to those with an exogenous reporter. Thus new tools to determine previously unobtainable information about the nature and position of cofactor action in any process displaying first-order Hill plot kinetics are now available. C1 [Dougherty, Edward J.; Guo, Chunhua; Simons, S. Stoney, Jr.] NIDDK, Steroid Hormones Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Chow, Carson C.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. RP Dougherty, EJ (reprint author), NIDDK, Steroid Hormones Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. EM steroids@helix.nih.gov; carsonc@niddk.nih.gov RI Chow, Carson/A-7970-2009; Guo, Chunhua/N-2586-2014; OI Dougherty, Edward/0000-0001-7664-9779 FU NIH/NIDDK FX Funding was provided by the Intramural Research Program of the NIH/NIDDK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 9 Z9 9 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 17 PY 2012 VL 7 IS 1 AR e30225 DI 10.1371/journal.pone.0030225 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 907XU UT WOS:000301454400091 PM 22272313 ER PT J AU Goldin, E Zheng, W Motabar, O Southall, N Choi, JH Marugan, J Austin, CP Sidransky, E AF Goldin, Ehud Zheng, Wei Motabar, Omid Southall, Noel Choi, Jae Hyuk Marugan, Juan Austin, Christopher P. Sidransky, Ellen TI High Throughput Screening for Small Molecule Therapy for Gaucher Disease Using Patient Tissue as the Source of Mutant Glucocerebrosidase SO PLOS ONE LA English DT Article ID ACID BETA-GLUCOSIDASE; ISOFAGOMINE INCREASES; MIGLUSTAT; MUTATION; TYPE-1 AB Gaucher disease (GD), the most common lysosomal storage disorder, results from the inherited deficiency of the lysosomal enzyme glucocerebrosidase (GCase). Previously, wildtype GCase was used for high throughput screening (HTS) of large collections of compounds to identify small molecule chaperones that could be developed as new therapies for GD. However, the compounds identified from HTS usually showed reduced potency later in confirmatory cell-based assays. An alternate strategy is to perform HTS on mutant enzyme to identify different lead compounds, including those enhancing mutant enzyme activities. We developed a new screening assay using enzyme extract prepared from the spleen of a patient with Gaucher disease with genotype N370S/N370S. In tissue extracts, GCase is in a more native physiological environment, and is present with the native activator saposin C and other potential cofactors. Using this assay, we screened a library of 250,000 compounds and identified novel modulators of mutant GCase including 14 new lead inhibitors and 30 lead activators. The activities of some of the primary hits were confirmed in subsequent cell-based assays using patient-derived fibroblasts. These results suggest that primary screening assays using enzyme extracted from tissues is an alternative approach to identify high quality, physiologically relevant lead compounds for drug development. C1 [Goldin, Ehud; Motabar, Omid; Choi, Jae Hyuk; Sidransky, Ellen] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Zheng, Wei; Motabar, Omid; Southall, Noel; Choi, Jae Hyuk; Marugan, Juan; Austin, Christopher P.] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. RP Goldin, E (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM goldine@mail.nih.gov RI Southall, Noel/H-8991-2012; OI Southall, Noel/0000-0003-4500-880X; Zheng, Wei/0000-0003-1034-0757 FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research; National Human Genome Research Institute; National Institutes of Health FX This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Programs of the National Human Genome Research Institute and National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 27 Z9 27 U1 5 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 17 PY 2012 VL 7 IS 1 AR e29861 DI 10.1371/journal.pone.0029861 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 907XU UT WOS:000301454400033 PM 22272254 ER PT J AU Monti, DA Mitchell, E Bazzan, AJ Littman, S Zabrecky, G Yeo, CJ Pillai, MV Newberg, AB Deshmukh, S Levine, M AF Monti, Daniel A. Mitchell, Edith Bazzan, Anthony J. Littman, Susan Zabrecky, George Yeo, Charles J. Pillai, Madhaven V. Newberg, Andrew B. Deshmukh, Sandeep Levine, Mark TI Phase I Evaluation of Intravenous Ascorbic Acid in Combination with Gemcitabine and Erlotinib in Patients with Metastatic Pancreatic Cancer SO PLOS ONE LA English DT Article ID RECOMMENDED DIETARY ALLOWANCE; VITAMIN-C PHARMACOKINETICS; TERMINAL HUMAN CANCER; III TRIAL; SUPPLEMENTAL ASCORBATE; SUPPORTIVE TREATMENT; HYDROGEN-PEROXIDE; SURVIVAL TIMES; ANTIOXIDANTS; THERAPY AB Background: Preclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy. Methods and Findings: 14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of disease or treatment with gemcitabine or erlotinib. Applying RECIST 1.0 criteria, seven of the nine subjects had stable disease while the other two had progressive disease. Conclusions: These initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients. This, combined with the observed response to treatment, suggests the need for a phase II study of longer duration. C1 [Monti, Daniel A.; Bazzan, Anthony J.; Zabrecky, George; Newberg, Andrew B.] Thomas Jefferson Univ, Myrna Brind Ctr Integrat Med, Philadelphia, PA 19107 USA. [Mitchell, Edith; Littman, Susan; Pillai, Madhaven V.] Thomas Jefferson Univ, Dept Med Oncol, Philadelphia, PA 19107 USA. [Yeo, Charles J.] Thomas Jefferson Univ, Dept Surg, Philadelphia, PA 19107 USA. [Yeo, Charles J.] Thomas Jefferson Univ, Jefferson Pancreas Biliary & Related Canc Ctr, Philadelphia, PA 19107 USA. [Deshmukh, Sandeep] Thomas Jefferson Univ, Dept Radiol, Philadelphia, PA 19107 USA. [Levine, Mark] NIDDK, Mol & Clin Nutr Sect, NIH, Bethesda, MD USA. RP Monti, DA (reprint author), Thomas Jefferson Univ, Myrna Brind Ctr Integrat Med, Philadelphia, PA 19107 USA. EM MarkL@mail.nih.gov OI Newberg, Andrew/0000-0001-8230-1752 FU NIDDK, NIH [ZIA DK053212-05] FX This research was supported by a gift from the Marcus Foundation. M. L. was supported by the Intramural Research Program, NIDDK, NIH (ZIA DK053212-05). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 53 Z9 54 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 17 PY 2012 VL 7 IS 1 AR e29794 DI 10.1371/journal.pone.0029794 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 907XU UT WOS:000301454400027 PM 22272248 ER PT J AU Vathipadiekal, V Saxena, D Mok, SC Hauschka, PV Ozbun, L Birrer, MJ AF Vathipadiekal, Vinod Saxena, Deepa Mok, Samuel C. Hauschka, Peter V. Ozbun, Laurent Birrer, Michael J. TI Identification of a Potential Ovarian Cancer Stem Cell Gene Expression Profile from Advanced Stage Papillary Serous Ovarian Cancer SO PLOS ONE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; DRUG EFFLUX CAPACITY; SIDE POPULATION; HEMATOPOIETIC STEM; INITIATING CELLS; SOLID TUMORS; SURVIVAL; PHENOTYPE; NOTCH; CARCINOMA AB Identification of gene expression profiles of cancer stem cells may have significant implications in the understanding of tumor biology and for the design of novel treatments targeted toward these cells. Here we report a potential ovarian cancer stem cell gene expression profile from isolated side population of fresh ascites obtained from women with high-grade advanced stage papillary serous ovarian adenocarcinoma. Affymetrix U133 Plus 2.0 microarrays were used to interrogate the differentially expressed genes between side population (SP) and main population (MP), and the results were analyzed by paired T-test using BRB-ArrayTools. We identified 138 up-regulated and 302 down-regulated genes that were differentially expressed between all 10 SP/MP pairs. Microarray data was validated using qRT-PCR and17/19 (89.5%) genes showed robust correlations between microarray and qRT-PCR expression data. The Pathway Studio analysis identified several genes involved in cell survival, differentiation, proliferation, and apoptosis which are unique to SP cells and a mechanism for the activation of Notch signaling is identified. To validate these findings, we have identified and isolated SP cells enriched for cancer stem cells from human ovarian cancer cell lines. The SP populations were having a higher colony forming efficiency in comparison to its MP counterpart and also capable of sustained expansion and differentiation in to SP and MP phenotypes. 50,000 SP cells produced tumor in nude mice whereas the same number of MP cells failed to give any tumor at 8 weeks after injection. The SP cells demonstrated a dose dependent sensitivity to specific c-secretase inhibitors implicating the role of Notch signaling pathway in SP cell survival. Further the generated SP gene list was found to be enriched in recurrent ovarian cancer tumors. C1 [Vathipadiekal, Vinod; Birrer, Michael J.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Saxena, Deepa; Hauschka, Peter V.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Orthopaed Surg, Boston, MA USA. [Mok, Samuel C.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Ozbun, Laurent] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Vathipadiekal, V (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. EM mbirrer@partners.org OI Vathipadiekal, Vinod/0000-0002-8181-6890 FU National Institutes of the Health [5R01CA142832-02 216288 2009A051746, 1RC4CA156551-01 217168 2010A053125]; National Cancer Institute; CDMRP-DOD [W81XWH-06-1-0422, W81XWH-09-1-0292]; Susan G. Komen for the Cure [BCTR 0600935]; Orthopaedic Surgery Foundation, Children's Hospital Boston FX This work was supported in part by grants from National Institutes of the Health (5R01CA142832-02 216288 2009A051746, 1RC4CA156551-01 217168 2010A053125 and an Intramural Research Program of the National Cancer Institute) to MJB. PVH and DS were supported by grants from the CDMRP-DOD (W81XWH-06-1-0422 and W81XWH-09-1-0292), Susan G. Komen for the Cure (BCTR 0600935), and the Orthopaedic Surgery Foundation, Children's Hospital Boston. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 65 TC 43 Z9 44 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 17 PY 2012 VL 7 IS 1 AR e29079 DI 10.1371/journal.pone.0029079 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 907XU UT WOS:000301454400006 PM 22272227 ER PT J AU Phinney, KW Bedner, M Tai, SSC Vamathevan, VV Sander, LC Sharpless, KE Wise, SA Yen, JH Schleicher, RL Chaudhary-Webb, M Pfeiffer, CM Betz, JM Coates, PM Picciano, MF AF Phinney, Karen W. Bedner, Mary Tai, Susan S. -C. Vamathevan, Veronica V. Sander, Lane C. Sharpless, Katherine E. Wise, Stephen A. Yen, James H. Schleicher, Rosemary L. Chaudhary-Webb, Madhulika Pfeiffer, Christine M. Betz, Joseph M. Coates, Paul M. Picciano, Mary Frances TI Development and Certification of a Standard Reference Material for Vitamin D Metabolites in Human Serum SO ANALYTICAL CHEMISTRY LA English DT Article ID TANDEM MASS-SPECTROMETRY; 25-HYDROXYVITAMIN D-3; CIRCULATING 25-HYDROXYVITAMIN-D; CANCER-RISK; ASSAYS; PREVENTION; ACCURACY AB The National Institute of Standards and Technology (NIST), in collaboration with the National Institutes of Health's Office of Dietary Supplements (NIH-ODS), has developed a Standard Reference Material (SRM) for the determination of 25-hydroxyvitamin D [25(OH)D] in serum. SRM 972 Vitamin D in Human Serum consists of four serum pools with different levels of vitamin D metabolites and has certified and reference values for 25 (OH)D-2, 25(OH)D-3, and 3-epi-25(OH)D-3. Value assignment of this SRM was accomplished using a combination of three isotope-dilution mass spectrometry approaches, with measurements performed at NIST and at the Centers for Disease Control and Prevention (CDC). Chromatographic resolution of the 3-epimer of 25(OH)D-3 proved to be essential for accurate determination of the metabolites. C1 [Phinney, Karen W.; Bedner, Mary; Tai, Susan S. -C.; Vamathevan, Veronica V.; Sander, Lane C.; Sharpless, Katherine E.; Wise, Stephen A.] Natl Inst Stand & Technol, Div Analyt Chem, Gaithersburg, MD 20899 USA. [Yen, James H.] Natl Inst Stand & Technol, Stat Engn Div, Gaithersburg, MD 20899 USA. [Schleicher, Rosemary L.; Chaudhary-Webb, Madhulika; Pfeiffer, Christine M.] Ctr Dis Control & Prevent, Div Sci Lab, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. [Betz, Joseph M.; Coates, Paul M.; Picciano, Mary Frances] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Phinney, KW (reprint author), Natl Inst Stand & Technol, Div Analyt Chem, Gaithersburg, MD 20899 USA. EM karen.phinney@nist.gov OI Sharpless, Katherine/0000-0001-6569-198X FU National Institutes of Health, Office of Dietary Supplements FX The authors wish to thank Graham Carter and Donald Wiebe for helpful discussions during the development of SRM 972. Partial funding for this work was provided by the National Institutes of Health, Office of Dietary Supplements. NR 31 TC 57 Z9 58 U1 0 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD JAN 17 PY 2012 VL 84 IS 2 BP 956 EP 962 DI 10.1021/ac202047n PG 7 WC Chemistry, Analytical SC Chemistry GA 876UY UT WOS:000299134400034 PM 22141317 ER PT J AU Maltsev, AS Grishaev, A Bax, A AF Maltsev, Alexander S. Grishaev, Alexander Bax, Ad TI Monomeric alpha-Synuclein Binds Congo Red Micelles in a Disordered Manner SO BIOCHEMISTRY LA English DT Article ID AMYLOID-SPECIFIC DYE; X-RAY-SCATTERING; NMR-SPECTROSCOPY; CHEMICAL-EXCHANGE; FIBRIL FORMATION; RELAXATION DISPERSION; SECONDARY STRUCTURE; TIME-SCALE; PROTEIN; AGGREGATION AB The histological dye Congo Red (CR) previously has been shown to inhibit alpha-synuclein (aS) fibrillation, but the mode of this inhibition remained unclear. Because of favorable exchange kinetics, interaction between CR and aS lends itself to a detailed nuclear magnetic resonance study, and relaxation dispersion measurements yield the bound fraction and time scales for the interaction of aS with CR. We find that at pH 6, CR exists as a micelle, and at a CR:aS molar ratio of similar to 1, only a small fraction of aS (similar to 2%) is bound to these micelles. Rapid exchange (k(ex) similar to 3000 s(-1)) between the free and CR-bound states broadens and strongly attenuates resonances of aS by two processes: a magnetic field-dependent contribution, caused by the chemical shift difference between the two states, and a nearly field-independent contribution caused by slower tumbling of aS bound to the CR micelle. The salt dependence of the interaction suggests a predominantly electrostatic mechanism for the 60 N-terminal residues, while the weaker interaction between residues 61-100 and CR is mostly hydrophobic. Chemical shift and transferred NOE data indicate that aS becomes slightly more helical but remains largely disordered when bound to CR. Results indicate that inhibition of fibril formation does not result from binding of CR to free aS and, therefore, must result from interaction of aS fibrils or protofibrils with CR micelles. C1 [Maltsev, Alexander S.; Grishaev, Alexander; Bax, Ad] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, 5 Mem Dr, Bethesda, MD 20892 USA. EM bax@nih.gov RI Maltsev, Alexander/A-8175-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); Office of the Director, NIH; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-ENG-38] FX This work was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), and the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH.; We acknowledge use of the shared scattering beamline resource allocated under the PUP-77 agreement between the National Cancer Institute and the Argonne National Laboratory and thank Dr. Soenke Seifert (Argonne National Laboratory) for his support of the SAXS experiments and Drs. Jinfa Ying and James L. Baber for support of the NMR measurements. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under Contract W-31-109-ENG-38. NR 52 TC 19 Z9 19 U1 0 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 17 PY 2012 VL 51 IS 2 BP 631 EP 642 DI 10.1021/bi201435d PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 876VJ UT WOS:000299135500007 PM 22242826 ER PT J AU Pistolesi, S Tjandra, N AF Pistolesi, Sara Tjandra, Nico TI Temperature Dependence of Molecular Interactions Involved in Defining Stability of Glutamine Binding Protein and Its Complex with L-Glutamine SO BIOCHEMISTRY LA English DT Article ID NUCLEAR MAGNETIC-RESONANCE; CALMODULIN-PEPTIDE COMPLEX; N-15 NMR RELAXATION; MODEL-FREE APPROACH; BACKBONE DYNAMICS; ESCHERICHIA-COLI; CONFORMATIONAL ENTROPY; ORDER PARAMETERS; SPIN RELAXATION; HEAT-CAPACITY AB The temperature dependence of dynamic parameters derived from nuclear magnetic resonance (NMR) relaxation data is related to conformational entropy of the system under study. This provides information such as macromolecules stability and thermodynamics of ligand binding. We studied the temperature dependence of NMR order parameter of glutamine binding protein (GlnBP), a periplasmic binding protein (PBP) highly specific to L-glutamine associated with its ABC transporter, with the goal of elucidating the dynamical differences between the respective ligand bound and free forms. We found that the protein ligand interaction, which is stabilized at higher temperature, has a striking effect on the stability of the hydrophobic core of the large domain of GlnBP. Moreover, in contrast to what was found for less specific PBPs, the decreasing backbone motion of the hinge region at increasing temperature supports the idea that the likelihood that GlnBP can adopt a ligand free closed conformation in solution diminishes at higher temperatures. Our results support the induced-fit model as mode of action for GlnBP. In addition, we found that the backbones of residues involved in a salt bridge do not necessarily become more rigid as the temperature rises as it was previously suggested [Vinther, J. M., et al. (2011) J. Am. Chem. Soc., 133, 271-278]. Our results show that for this to happen these residues have to also directly interact with a region of the protein that is becoming more rigid as the temperature increases. C1 [Pistolesi, Sara; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov FU NIH, NHLBI FX This work was supported by the Intramural Research Program of the NIH, NHLBI. NR 46 TC 4 Z9 4 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 17 PY 2012 VL 51 IS 2 BP 643 EP 652 DI 10.1021/bi201494h PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 876VJ UT WOS:000299135500008 PM 22206385 ER PT J AU Creager, MA Belkin, M Bluth, EI Casey, DE Chaturvedi, S Dake, MD Fleg, JL Hirsch, AT Jaff, MR Kern, JA Malenka, DJ Martin, ET Mohler, ER Murphy, T Olin, JW Regensteiner, JG Rosenwasser, RH Sheehan, P Stewart, KJ Treat-Jacobson, D Upchurch, GR White, CJ Ziffer, JA AF Creager, Mark A. Belkin, Michael Bluth, Edward I. Casey, Donald E., Jr. Chaturvedi, Seemant Dake, Michael D. Fleg, Jerome L. Hirsch, Alan T. Jaff, Michael R. Kern, John A. Malenka, David J. Martin, Edward T. Mohler, Emile R., III Murphy, Timothy Olin, Jeffrey W. Regensteiner, Judith G. Rosenwasser, Robert H. Sheehan, Peter Stewart, Kerry J. Treat-Jacobson, Diane Upchurch, Gilbert R., Jr. White, Christopher J. Ziffer, Jack A. CA Amer Assoc Cardiovasc Pulm Rehabil Amer Acad Neurology Amer Assoc Neurological Surg Amer Diabet Assoc Soc Atherosclerosis Imaging Preven Soc Cardiovasc Computed Tomography Soc Cardiovasc Magnetic Resonance Vasc Dis Fdn TI 2012 ACCF/AHA/ACR/SCAI/SIR/STS/SVM/SVN/SVS Key Data Elements and Definitions for Peripheral Atherosclerotic Vascular Disease A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Clinical Data Standards for Peripheral Atherosclerotic Vascular Disease) SO CIRCULATION LA English DT Article DE AHA Scientific Statements; clinical outcomes; peripheral atherosclerotic vascular disease; registries ID RENAL-ARTERY STENOSIS; CAROTID-ENDARTERECTOMY; ISCHEMIC-STROKE; MANAGEMENT; OUTCOMES; REVASCULARIZATION; RATIONALE; TRIAL; ANGIOGRAPHY; GUIDELINES C1 [Belkin, Michael; Upchurch, Gilbert R., Jr.] Soc Vasc Surg, Chicago, IL USA. [Bluth, Edward I.] Amer Coll Radiol, Reston, VA USA. [Casey, Donald E., Jr.] Amer Coll Physicians, Philadelphia, PA USA. [Chaturvedi, Seemant] Amer Acad Neurol, St Paul, MN USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD USA. [Jaff, Michael R.] Vasc Dis Fdn, Vienna, VA USA. [Kern, John A.] Soc Thorac Surg, Chicago, IL USA. [Martin, Edward T.] Soc Cardiovasc Magnet Resonance, Mt Royal, NJ USA. [Mohler, Emile R., III] Soc Atherosclerosis Imaging & Prevent, Potomac, MD USA. [Murphy, Timothy] Soc Intervent Radiol, Fairfax, VA USA. [Regensteiner, Judith G.] Soc Vasc Med, Deerfield, IL USA. [Rosenwasser, Robert H.] Amer Assoc Neurol Surg, Rolling Meadows, IL USA. [Sheehan, Peter] Amer Diabet Assoc, Alexandria, VA USA. [Stewart, Kerry J.] Amer Assoc Cardiovasc & Pulm Rehabil, Chicago, IL USA. [Treat-Jacobson, Diane] Soc Vasc Nursing, Beverly, MA USA. [White, Christopher J.] Soc Cardiovasc Angiog & Intervent, Washington, DC USA. [Ziffer, Jack A.] Soc Cardiovasc Computed Tomog, Vienna, VA USA. ACCF AHA Task Force Clin Data Stand, Kansas City, KS USA. RI White, Christopher/J-6686-2012; Bluth, Edward/A-8613-2011 OI White, Christopher/0000-0001-8618-7539; NR 29 TC 17 Z9 20 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JAN 17 PY 2012 VL 125 IS 2 BP 395 EP 467 DI 10.1161/CIR.0b013e31823299a1 PG 73 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 879HZ UT WOS:000299321600031 ER PT J AU Yan, JS Mihaylov, V Xu, XH Brzostowski, JA Li, HY Liu, LH Veenstra, TD Parent, CA Jin, T AF Yan, Jianshe Mihaylov, Vassil Xu, Xuehua Brzostowski, Joseph A. Li, Hongyan Liu, Lunhua Veenstra, Timothy D. Parent, Carole A. Jin, Tian TI A G beta gamma Effector, ElmoE, Transduces GPCR Signaling to the Actin Network during Chemotaxis SO DEVELOPMENTAL CELL LA English DT Article ID PROTEIN-MEDIATED ACTIVATION; HETEROTRIMERIC G-PROTEIN; DICTYOSTELIUM-DISCOIDEUM; NEUTROPHIL CHEMOTAXIS; ADENYLYL-CYCLASE; LEADING-EDGE; LIVING CELLS; MYOSIN-II; RECEPTOR; COMPLEX AB Activation of G protein-coupled receptors (GPCRs) leads to the dissociation of heterotrimeric G-proteins into G alpha and G beta gamma subunits, which go on to regulate various effectors involved in a panoply of cellular responses. During chemotaxis, G beta gamma subunits regulate actin assembly and migration, but the protein(s) linking G beta gamma to the actin cytoskeleton remains unknown. Here, we identified a G beta gamma effector, ElmoE in Dictyostelium, and demonstrated that it is required for GPCR-mediated chemotaxis. Remarkably, ElmoE associates with G beta gamma and Dock-like proteins to activate the small GTPase Rac, in a GPCR-dependent manner, and also associates with Arp2/3 complex and F-actin. Thus, ElmoE serves as a link between chemoattractant GPCRs, G-proteins and the actin cytoskeleton. The pathway, consisting of GPCR, G beta gamma, Elmo/Dock, Rac, and Arp2/3, spatially guides the growth of dendritic actin networks in pseudopods of eukaryotic cells during chemotaxis. C1 [Yan, Jianshe; Xu, Xuehua; Li, Hongyan; Jin, Tian] NIAID, Chemotaxis Signal Sect, NIH, Rockville, MD 20852 USA. [Brzostowski, Joseph A.] NIAID, Lab Immunogenet Imaging Facil, NIH, Rockville, MD 20852 USA. [Mihaylov, Vassil; Liu, Lunhua; Parent, Carole A.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick, Frederick, MD 21702 USA. RP Jin, T (reprint author), NIAID, Chemotaxis Signal Sect, NIH, Rockville, MD 20852 USA. EM tjin@niaid.nih.gov FU NIAID/NIH; NCI/NIH FX This study was supported by NIAID/NIH and NCI/NIH intramural funds. We thank the members of the Jin lab, and P. Kriebel of the Parent lab. We thank Dicty Stock Center for providing rasC-&rasG- strain and plasmids pDV-CYFP-CTAP, pDM314, pDXA-GST, pDXA-GFPABD120, and GFP-Arp2/pBIG; A. Muller-Taubenberger for the Delta limE-RFP plasmid; M. Dubin and W. Nellen for the vector pDbsrXP6xMYC; F. Rivero for GFP-Racs; M. Zhao at NIAID; and S. Shu and X. Liu at NHLBI/NIH for their technical assistance. We thank X. Xiang for critical comments. NR 51 TC 35 Z9 37 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD JAN 17 PY 2012 VL 22 IS 1 BP 92 EP 103 DI 10.1016/j.devcel.2011.11.007 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 879XI UT WOS:000299365800012 PM 22264729 ER PT J AU Beverly, LJ Lockwood, WW Shah, PP Erdjument-Bromage, H Varmus, H AF Beverly, Levi J. Lockwood, William W. Shah, Parag P. Erdjument-Bromage, Hediye Varmus, Harold TI Ubiquitination, localization, and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE apoptosis; PLIC; BH3 ID BCL-2 FAMILY; CELL-DEATH; PLASMA-MEMBRANE; PROTEASOME; SURVIVAL; LEUKEMOGENESIS; DEGRADATION; MECHANISMS; RESISTANCE; AUTOPHAGY AB We have previously shown that all six members of the anti-apoptotic BCL2 gene family can cooperate with (myelocytomatosis oncogene) MYC in a mouse model of leukemia, but three of them are significantly less potent contributors to leukemogenicity than the other three. The protein encoded by one of these less potent genes, BCL2L10/BCLb, was recently shown to vary dramatically in many primary human cancers by immunohistochemistry, and the protein levels were inversely correlated with survival in patients with several cancer types. We examined BCLb mRNA in a panel of human cancer cell lines and did not observe the extensive variation in mRNA that would be required to explain the vast differences in protein levels. We found that the levels of BCLb protein diminish quickly after inhibition of protein synthesis with cycloheximide, so we searched for interacting proteins that might affect posttranslational stability of BCLb. Using a variety of approaches, including immunoaffinity and mass spectrometry, we identified a protein, Ubiquilin1 (Ubqln), that specifically interacts with BCLb, and not with other anti-apoptotic BCL2-like proteins. Ubqln stabilizes BCLb protein, while also promoting monoubiquitination on multiple lysine residues and relocation to the cytosol. Furthermore, primary lung adencarcinomas have more Ubqln mRNA than normal adjacent lung tissue, and higher Ubqln mRNA levels are associated with shorter survival of lung cancer patients, suggesting that potentiation of the anti-apoptotic potential of BCLb through regulation of its stability by Ubqln may be an important factor in tumor progression. C1 [Beverly, Levi J.; Lockwood, William W.; Varmus, Harold] NHGRI, Canc Biol & Genet Sect, Canc Genet Branch, Bethesda, MD 20892 USA. [Erdjument-Bromage, Hediye] NCI, NIH, Bethesda, MD 20892 USA. [Varmus, Harold] Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 USA. [Beverly, Levi J.; Shah, Parag P.] Univ Louisville, Div Hematol & Oncol, James Graham Brown Canc Ctr, Dept Med, Louisville, KY 40202 USA. [Beverly, Levi J.; Lockwood, William W.; Varmus, Harold] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA. RP Beverly, LJ (reprint author), NHGRI, Canc Biol & Genet Sect, Canc Genet Branch, Bethesda, MD 20892 USA. EM Levi.Beverly@Louisville.edu; Harold.Varmus@nih.gov FU NIH [P01 2P01CA094060-06A1]; NCI; NCI Cancer Center [P30 CA08748]; James Graham Brown Cancer Center; Kosair Pediatric Cancer Research Fund FX We thank former members of the Varmus laboratory at Memorial Sloan-Kettering Cancer Center, especially G Sanchez, A Giannakou, R DeMatteo, and MA Melnick, for expert handling of the mouse colony, including genotyping. We thank current members of the Varmus laboratory at the National Institutes of Health (NIH), D O'Mard, J Idol, and S-Q Lee-Lin for technical support and A Unni for critical reading of manuscript and scientific discussions. We thank investigators that deposited plasmids at Addgene. We thank Laura Fabrizio for help with sample preparation for mass spectrometry. Funding for this project was provided, in part, by NIH P01 2P01CA094060-06A1 (to H.V.) and by intramural NCI funds. This work was also supported by NCI Cancer Center support Grant P30 CA08748 to Microchemistry and Proteomics Core Lab (H.E.-B.) and by funds from the James Graham Brown Cancer Center and the Kosair Pediatric Cancer Research Fund (L.J.B.). NR 43 TC 25 Z9 25 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 17 PY 2012 VL 109 IS 3 BP 119 EP 126 DI 10.1073/pnas.1119167109 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 877CK UT WOS:000299154000003 PM 22233804 ER PT J AU Musselman, CA Ramirez, J Sims, JK Mansfield, RE Oliver, SS Denu, JM Mackay, JP Wade, PA Hagman, J Kutateladze, TG AF Musselman, Catherine A. Ramirez, Julita Sims, Jennifer K. Mansfield, Robyn E. Oliver, Samuel S. Denu, John M. Mackay, Joel P. Wade, Paul A. Hagman, James Kutateladze, Tatiana G. TI Bivalent recognition of nucleosomes by the tandem PHD fingers of the CHD4 ATPase is required for CHD4-mediated repression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene repression; epigenetics; histone; posttranslational modifications ID HISTONE H3 TAIL; REMODELING COMPLEX; DNA-DAMAGE; CHROMODOMAIN; DEACETYLASE; BINDING; DERMATOMYOSITIS; AUTOANTIGEN; MECHANISM; PROTEINS AB CHD(4) is a catalytic subunit of the NuRD (nucleosome remodeling and deacetylase) complex essential in transcriptional regulation, chromatin assembly and DNA damage repair. CHD4 contains tandem plant homeodomain (PHD) fingers connected by a short linker, the biological function of which remains unclear. Here we explore the combinatorial action of the CHD4 PHD1/2 fingers and detail the molecular basis for their association with chromatin. We found that PHD1/2 targets nucleosomes in a multivalent manner, concomitantly engaging two histone H3 tails. This robust synergistic interaction displaces HP1 gamma from pericentric sites, inducing changes in chromatin structure and leading to the dispersion of the heterochromatic mark H3K9me3. We demonstrate that recognition of the histone H3 tails by the PHD fingers is required for repressive activity of the CHD4/NuRD complex. Together, our data elucidate the molecular mechanism of multivalent association of the PHD fingers with chromatin and reveal their critical role in the regulation of CHD4 functions. C1 [Musselman, Catherine A.; Kutateladze, Tatiana G.] Univ Colorado Denver Sch Med, Dept Pharmacol, Aurora, CO 80045 USA. [Ramirez, Julita; Hagman, James] Natl Jewish Hlth, Integrated Dept Immunol, Denver, CO 80206 USA. [Sims, Jennifer K.; Wade, Paul A.] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Mansfield, Robyn E.; Mackay, Joel P.] Univ Sydney, Sch Mol Biosci, Sydney, NSW 2006, Australia. [Oliver, Samuel S.; Denu, John M.] Univ Wisconsin, Dept Biomol Chem, Madison, WI 53706 USA. RP Kutateladze, TG (reprint author), Univ Colorado Denver Sch Med, Dept Pharmacol, Aurora, CO 80045 USA. EM Tatiana.Kutateladze@UCDenver.edu OI Mackay, Joel/0000-0001-7508-8033 FU National Institutes of Health (NIH) [GM096863, CA113472, R01 AI054661, AI081878, T32 AI07405]; Cancer League of Colorado; National Institute of Environmental Health Sciences, NIH [Z01ES101765]; Rocky Mountain Chapter of the Arthritis Foundation; NIH National Research Service (NHLBI) [F32HL096399] FX We thank F. Davrazou, J. Scorgie, and B. Hirsch for help with the experiments and discussions; G. Blobel for the CHD4 cDNA plasmid; and K. Luger for the histone H3 and H4 plasmids. This research is supported by grants from the National Institutes of Health (NIH) (GM096863 and CA113472) and the Cancer League of Colorado to T. G. K. and NIH Grants R01 AI054661 and AI081878 to J. H. This work is also supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH (Z01ES101765 to P. W.). J. R. was supported by a generous grant from the Rocky Mountain Chapter of the Arthritis Foundation and NIH Postdoctoral Training Grant T32 AI07405. C. A. M. is an NIH National Research Service Award postdoctoral fellow (NHLBI, F32HL096399). NR 31 TC 50 Z9 51 U1 0 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 17 PY 2012 VL 109 IS 3 BP 787 EP 792 DI 10.1073/pnas.1113655109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 877CK UT WOS:000299154000034 PM 22215588 ER PT J AU Ling, BMT Bharathy, N Chung, TK Kok, WK Li, S Tan, YH Rao, VK Gopinadhan, S Sartorelli, V Walsh, MJ Taneja, R AF Ling, Belinda Mei Tze Bharathy, Narendra Chung, Teng-Kai Kok, Wai Kay Li, Side Tan, Yong Hua Rao, Vinay Kumar Gopinadhan, Suma Sartorelli, Vittorio Walsh, Martin J. Taneja, Reshma TI Lysine methyltransferase G9a methylates the transcription factor MyoD and regulates skeletal muscle differentiation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HISTONE METHYLTRANSFERASE; MYOGENESIS; PCAF; DEACETYLASES; ACETYLATION; ACTIVATION; COMPLEXES; PROGRAM; ROLES; P300 AB Skeletal muscle cells have served as a paradigm for understanding mechanisms leading to cellular differentiation. The proliferation and differentiation of muscle precursor cells require the concerted activity of myogenic regulatory factors including MyoD. In addition, chromatin modifiers mediate dynamic modifications of histone tails that are vital to reprogramming cells toward terminal differentiation. Here, we provide evidence for a unique dimension to epigenetic regulation of skeletal myogenesis. We demonstrate that the lysine methyltransferase G9a is dynamically expressed in myoblasts and impedes differentiation in a methyltransferase activity-dependent manner. In addition to mediating histone H3 lysine-9 di-methylation (H3K9me2) on MyoD target promoters, endogenous G9a interacts with MyoD in precursor cells and directly methylates it at lysine 104 (K104) to constrain its transcriptional activity. Mutation of K104 renders MyoD refractory to inhibition by G9a and enhances its myogenic activity. Interestingly, MyoD methylation is critical for G9a-mediated inhibition of myogenesis. These findings provide evidence of an unanticipated role for methyltransferases in cellular differentiation states by direct posttranslational modification of a transcription factor. C1 [Ling, Belinda Mei Tze; Bharathy, Narendra; Chung, Teng-Kai; Kok, Wai Kay; Tan, Yong Hua; Rao, Vinay Kumar; Gopinadhan, Suma; Taneja, Reshma] Natl Univ Singapore, Dept Physiol, Singapore 117597, Singapore. [Li, Side; Walsh, Martin J.] Mt Sinai Sch Med, Dept Struct & Chem Biol, New York, NY 10029 USA. [Li, Side; Walsh, Martin J.] Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA. [Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, Bethesda, MD 20892 USA. RP Taneja, R (reprint author), Natl Univ Singapore, Dept Physiol, Singapore 117597, Singapore. EM phsrt@nus.edu.sg FU National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health; National Medical Research Council; Agency for Science, Technology, and Research Singapore Stem Cell Consortium FX We thank D. Sassoon and G. Pavlath for reagents. V.S. is supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health. This work was supported by grants from the National Medical Research Council, and Agency for Science, Technology, and Research Singapore Stem Cell Consortium (to R.T.). NR 29 TC 55 Z9 63 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 17 PY 2012 VL 109 IS 3 BP 841 EP 846 DI 10.1073/pnas.1111628109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 877CK UT WOS:000299154000043 PM 22215600 ER PT J AU Rivollier, A He, JP Kole, A Valatas, V Kelsall, BL AF Rivollier, Aymeric He, Jianping Kole, Abhisake Valatas, Vassilis Kelsall, Brian L. TI Inflammation switches the differentiation program of Ly6C(hi) monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID INTESTINAL LAMINA PROPRIA; REGULATORY T-CELLS; IN-VIVO DEPLETION; RETINOIC-ACID; IMMUNE-RESPONSES; PEYERS PATCH; CD103(+); SUBSETS; MICE; COLITIS AB Dendritic cells (DCs) and macrophages (MPs) are important for immunological homeostasis in the colon. We found that F4/80(hi)CX3CR1(hi) (CD11b(+)CD103(-)) cells account for 80% of mouse colonic lamina propria MHC-IIhi cells. Both CD11c(+) and CD11c(-) cells within this population were identified as MPs based on multiple criteria, including an MP transcriptome revealed by microarray analysis. These MPs constitutively released high levels of IL-10 at least partially in response to the microbiota via an MyD88-independent mechanism. In contrast, cells expressing low to intermediate levels of F4/80 and CX3CR1 were identified as DCs based on phenotypic and functional analysis and comprise three separate CD11c(hi) cell populations: CD103(+)CX3CR1(-)CD11b(-) DCs, CD103(+)CX3CR1(-)CD11b(+) DCs, and CD103(-)CX3CR1(int)CD11b(+) DCs. In noninflammatory conditions, Ly6C(hi) monocytes (MOs) differentiated primarily into CD11c(+) but not CD11c(-) MPs. In contrast, during colitis, Ly6C(hi) MOs massively invaded the colon and differentiated into proinflammatory CD103(-)CX3CR1(int)CD11b(+) DCs, which produced high levels of IL-12, IL-23, iNOS, and TNF. These findings demonstrate the dual capacity of Ly6C(hi) blood MOs to differentiate into either regulatory MPs or inflammatory DCs in the colon and that the balance of these immunologically antagonistic cell types is dictated by microenvironmental conditions. C1 [Rivollier, Aymeric; He, Jianping; Kole, Abhisake; Valatas, Vassilis; Kelsall, Brian L.] NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Kelsall, BL (reprint author), NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. EM bkelsall@niaid.nih.gov FU Division of Intramural Research, NIAID FX This work was supported by the Division of Intramural Research, NIAID. NR 56 TC 220 Z9 220 U1 4 U2 18 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JAN 16 PY 2012 VL 209 IS 1 BP 139 EP 155 DI 10.1084/jem.20101387 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 885ZO UT WOS:000299820200012 PM 22231304 ER PT J AU Yang, D Postnikov, YV Li, Y Tewary, P de la Rosa, G Wei, F Klinman, D Gioannini, T Weiss, JP Furusawa, T Bustin, M Oppenheim, JJ AF Yang, De Postnikov, Yuri V. Li, Yana Tewary, Poonam de la Rosa, Gonzalo Wei, Feng Klinman, Dennis Gioannini, Theresa Weiss, Jerrold P. Furusawa, Takashi Bustin, Michael Oppenheim, Joost J. TI High-mobility group nucleosome-binding protein 1 acts as an alarmin and is critical for lipopolysaccharide-induced immune responses SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TOLL-LIKE RECEPTOR-4; GROUP BOX-1 PROTEIN; DENDRITIC CELLS; HMGN PROTEINS; ACTIVATION; MICE; ADJUVANT; PATHWAY; TOLL-LIKE-RECEPTOR-4; DIFFERENTIATION AB Alarmins are endogenous mediators capable of promoting the recruitment and activation of antigen-presenting cells (APCs), including dendritic cells (DCs), that can potentially alert host defense against danger signals. However, the relevance of alarmins to the induction of adaptive immune responses remains to be demonstrated. In this study, we report the identification of HMGN1 (high-mobility group nucleosome-binding protein 1) as a novel alarmin and demonstrate that it contributes to the induction of antigen-specific immune responses. HMGN1 induced DC maturation via TLR4 (Toll-like receptor 4), recruitment of APCs at sites of injection, and activation of NF-kappa B and multiple mitogen-activated protein kinases in DCs. HMGN1 promoted antigen-specific immune response upon co-administration with antigens, and Hmgn1(-/-) mice developed greatly reduced antigen-specific antibody and T cell responses when immunized with antigens in the presence of lipopolysaccharide (LPS). The impaired ability of Hmgn1(-/-) mice to mount antigen-specific immune responses was accompanied by both deficient DC recruitment at sites of immunization and reduced production of inflammatory cytokines. Bone marrow chimera experiments revealed that HMGN1 derived from nonleukocytes was critical for the induction of antigen-specific antibody and T cell responses. Thus, extracellular HMGN1 acts as a novel alarmin critical for LPS-induced development of innate and adaptive immune responses. C1 [Yang, De] NCI, Basic Res Program, Sci Applicat & Int Corp Frederick Inc, Frederick, MD 21702 USA. [Yang, De; Li, Yana; Tewary, Poonam; de la Rosa, Gonzalo; Wei, Feng; Oppenheim, Joost J.] NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Klinman, Dennis] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Postnikov, Yuri V.; Furusawa, Takashi; Bustin, Michael] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gioannini, Theresa; Weiss, Jerrold P.] Univ Iowa, Dept Internal Med, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA. RP Yang, D (reprint author), NCI, Basic Res Program, Sci Applicat & Int Corp Frederick Inc, Frederick, MD 21702 USA. EM yangd@mail.nih.gov; oppenhei@ncifcrf.gov RI Wei, Feng/E-2806-2015; Bustin, Michael/G-6155-2015 OI Wei, Feng/0000-0002-4797-449X; FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Center for Cancer Research, National Cancer Institute, National Institutes of Health; National Key Basic Research Program of China [2012CB932503] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. This work was also supported in part by a grant (2012CB932503) from the National Key Basic Research Program of China. NR 43 TC 43 Z9 44 U1 2 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JAN 16 PY 2012 VL 209 IS 1 BP 157 EP 171 DI 10.1084/jem.20101354 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 885ZO UT WOS:000299820200013 PM 22184635 ER PT J AU Berman, BD Horovitz, SG Venkataraman, G Hallett, M AF Berman, Brian D. Horovitz, Silvina G. Venkataraman, Gaurav Hallett, Mark TI Self-modulation of primary motor cortex activity with motor and motor imagery tasks using real-time fMRI-based neurofeedback SO NEUROIMAGE LA English DT Article DE Real-time functional MRI; Neurofeedback; Finger tapping; Motor imagery; Primary motor cortex; Electromyography ID IMAGINED HAND MOVEMENTS; BRAIN ACTIVATION; FUNCTIONAL MRI; EXECUTION; INHIBITION; NETWORK; LOBE; AREA AB Advances in fMRI data acquisition and processing have made it possible to analyze brain activity as rapidly as the images are acquired allowing this information to be fed back to subjects in the scanner. The ability of subjects to learn to volitionally control localized brain activity within motor cortex using such real-time fMRI-based neurofeedback (NF) is actively being investigated as it may have clinical implications for motor rehabilitation after central nervous system injury and brain-computer interfaces. We investigated the ability of fifteen healthy volunteers to use NF to modulate brain activity within the primary motor cortex (M1) during a finger tapping and tapping imagery task. The M1 hand area ROI (ROI(m)) was functionally localized during finger tapping and a visual representation of BOLD signal changes within the ROI(m) fed back to the subject in the scanner. Surface EMG was used to assess motor output during tapping and ensure no motor activity was present during motor imagery task. Subjects quickly learned to modulate brain activity within their ROI(m) during the finger-tapping task, which could be dissociated from the magnitude of the tapping, but did not show a significant increase within the ROI(m) during the hand motor imagery task at the group level despite strongly activating a network consistent with the performance of motor imagery. The inability of subjects to modulate M1 proper with motor imagery may reflect an inherent difficulty in activating synapses in this area, with or without NF, since such activation may lead to M1 neuronal output and obligatory muscle activity. Future real-time fMRI-based NF investigations involving motor cortex may benefit from focusing attention on cortical regions other than M1 for feedback training or alternative feedback strategies such as measures of functional connectivity within the motor system. (C) 2011 Elsevier Inc. All rights reserved. C1 [Berman, Brian D.] Univ Colorado, Dept Neurol, Denver, CO USA. [Berman, Brian D.; Horovitz, Silvina G.; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Venkataraman, Gaurav] Reed Coll, Portland, OR 97202 USA. RP Berman, BD (reprint author), Univ Colorado Denver, Dept Neurol, 12631 E 17th Ave,Mail Stop B-185, Aurora, CO 80045 USA. EM brian.berman@ucdenver.edu FU NINDS/NIH FX The Intramural Research Program of the NINDS/NIH supported this research. We are grateful to Jerzy Bodurka for his help in setting up the real-time fMRI functionality used in this study. NR 38 TC 28 Z9 31 U1 0 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 16 PY 2012 VL 59 IS 2 BP 917 EP 925 DI 10.1016/j.neuroimage.2011.07.035 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 864AY UT WOS:000298210600007 PM 21803163 ER PT J AU Sati, P Silva, AC van Gelderen, P Gaitan, MI Wohler, JE Jacobson, S Duyn, JH Reich, DS AF Sati, Pascal Silva, Afonso C. van Gelderen, Peter Gaitan, Maria I. Wohler, Jillian E. Jacobson, Steven Duyn, Jeff H. Reich, Daniel S. TI In vivo quantification of T-2* anisotropy in white matter fibers in marmoset monkeys SO NEUROIMAGE LA English DT Article DE Anisotropic R-2* relaxation rate; White matter fiber orientation; Myelin; High-field imaging; Nonhuman primate brain ID NMR RELAXATION-TIMES; HUMAN BRAIN; OCCIPITAL LOBE; T-2 RELAXATION; IRON CONTENT; 7.0 T; MRI; CONTRAST; ORIENTATION; TISSUE AB T-2*-weighted MRI at high field is a promising approach for studying noninvasively the tissue structure and composition of the brain. However, the biophysical origin of T-2* contrast, especially in white matter, remains poorly understood. Recent work has shown that R-2* (= 1/T-2*) may depend on the tissue's orientation relative to the static magnetic field (B-0) and suggested that this dependence could be attributed to local anisotropy in the magnetic properties of brain tissue. In the present work, we analyzed high-resolution, multi-gradient-echo images of in vivo marmoset brains at 7 T, and compared them with ex vivo diffusion tensor images, to show that R-2* relaxation in white matter is highly sensitive to the fiber orientation relative to the main field. We directly demonstrate this orientation dependence by performing in vivo multi-gradient-echo experiments in two orthogonal brain positions, uncovering a nearly 50% change in the R-2* relaxation rate constant of the optic radiations. We attribute this substantial R-2* anisotropy to local subvoxel susceptibility effects arising from the highly ordered and anisotropic structure of the myelin sheath. Published by Elsevier Inc. C1 [Sati, Pascal; Gaitan, Maria I.; Reich, Daniel S.] NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Silva, Afonso C.] NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [van Gelderen, Peter; Duyn, Jeff H.] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Wohler, Jillian E.; Jacobson, Steven] NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Sati, P (reprint author), NINDS, Translat Neuroradiol Unit, Neuroimmunol Branch, NIH, 9000 Rockville Pike,Bldg 10-5C205, Bethesda, MD 20892 USA. EM satip@ninds.nih.gov RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 FU NINDS FX We thank Dr. Hellmut Merkle for designing the 5-element receive coil used in this study, Dr. Frank Q. Ye for helping with the DTI acquisition, Colin D. Shea for support with MIPAV and JIST software, Xianfeng (Lisa) Zhang for animal preparation, and Dr. Luca Massacesi for insightful discussions. We also thank the Intramural Research Program of NINDS for support. NR 49 TC 30 Z9 30 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 16 PY 2012 VL 59 IS 2 BP 979 EP 985 DI 10.1016/j.neuroimage.2011.08.064 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 864AY UT WOS:000298210600014 PM 21906687 ER PT J AU Smith, SM Bandettini, PA Miller, KL Behrens, TEJ Friston, KJ David, O Liu, T Woolrich, MW Nichols, TE AF Smith, S. M. Bandettini, P. A. Miller, K. L. Behrens, T. E. J. Friston, K. J. David, O. Liu, T. Woolrich, M. W. Nichols, T. E. TI The danger of systematic bias in group-level FMRI-lag-based causality estimation SO NEUROIMAGE LA English DT Article DE Granger causality; FMRI; Haemodynamic lag AB Schippers, Renken and Keysers (NeuroImage, 2011) present a simulation of multi-subject lag-based causality estimation. We fully agree that single-subject evaluations (e.g., Smith et al., 2011) need to be revisited in the context of multi-subject studies, and Schippers' paper is a good example, including detailed multi-level simulation and cross-subject statistical modelling. The authors conclude that "the average chance to find a significant Granger causality effect when no actual influence is present in the data stays well below the p-level imposed on the second level statistics" and that "when the analyses reveal a significant directed influence, this direction was accurate in the vast majority of the cases". Unfortunately, we believe that the general meaning that may be taken from these statements is not supported by the paper's results, as there may in reality be a systematic (group-average) difference in haemodynamic delay between two brain areas. While many statements in the paper (e.g., the final two sentences) do refer to this problem, we fear that the overriding message that many readers may take from the paper could cause misunderstanding. (C) 2011 Elsevier Inc. All rights reserved. C1 [Smith, S. M.; Miller, K. L.; Behrens, T. E. J.; Woolrich, M. W.; Nichols, T. E.] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford Ctr Funct MRI Brain FMRIB, Oxford OX1 2JD, England. [Bandettini, P. A.] NIMH, Funct MRI Core Facil, Bethesda, MD 20892 USA. [Behrens, T. E. J.; Friston, K. J.] UCL, Wellcome Trust Ctr Neuroimaging, London, England. [David, O.] Grenoble Inst Neurosci, F-38700 La Tronche, France. [Liu, T.] UCSD, Ctr Funct Magnet Resonance Imaging, La Jolla, CA USA. [Woolrich, M. W.] Oxford Ctr Human Brain Act OHBA, Dept Psychiat, Oxford, England. [Nichols, T. E.] Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England. [Nichols, T. E.] Univ Warwick, Warwick Mfg Grp, Coventry CV4 7AL, W Midlands, England. RP Smith, SM (reprint author), Univ Oxford, Nuffield Dept Clin Neurosci, Oxford Ctr Funct MRI Brain FMRIB, Oxford OX1 2JD, England. EM steve@fmrib.ox.ac.uk RI David, Olivier/A-6068-2009; Bandettini, Peter/F-5871-2012; Friston, Karl/D-9230-2011; OI David, Olivier/0000-0003-0776-0216; Friston, Karl/0000-0001-7984-8909; Nichols, Thomas/0000-0002-4516-5103; Miller, Karla/0000-0002-2511-3189; Smith, Stephen/0000-0001-8166-069X FU Medical Research Council [G0700399, G0900908]; Wellcome Trust [088130, 091593] NR 5 TC 20 Z9 21 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 16 PY 2012 VL 59 IS 2 BP 1228 EP 1229 DI 10.1016/j.neuroimage.2011.08.015 PG 2 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 864AY UT WOS:000298210600044 PM 21867760 ER PT J AU Berman, BD Horovitz, SG Morel, B Hallett, M AF Berman, Brian D. Horovitz, Silvina G. Morel, Brent Hallett, Mark TI Neural correlates of blink suppression and the buildup of a natural bodily urge SO NEUROIMAGE LA English DT Article DE Eye blinking; Urge suppression; fMRI; Electrooculography ID EVENT-RELATED FMRI; EYE BLINKING; TOURETTE-SYNDROME; PREFRONTAL CORTEX; FUNCTIONAL MRI; RESPONSE-INHIBITION; BRAIN ACTIVATION; INSULAR CORTEX; TIC GENERATION; MOTOR AB Neuroimaging studies have elucidated some of the underlying physiology of spontaneous and voluntary eye blinking: however, the neural networks involved in eye blink suppression remain poorly understood. Here we investigated blink suppression by analyzing fMRI data in a block design and event-related manner, and employed a novel hypothetical time-varying neural response model to detect brain activations associated with the buildup of urge. Blinks were found to activate visual cortices while our block design analysis revealed activations limited to the middle occipital gyri and deactivations in medial occipital, posterior cingulate and precuneus areas. Our model for urge, however, revealed a widespread network of activations including right greater than left insular cortex, right ventrolateral prefrontal cortex, middle cingulate cortex, and bilateral temporo-parietal cortices, primary and secondary face motor regions, and visual cortices. Subsequent inspection of BOLD time-series in an extensive ROI analysis showed that activity in the bilateral insular cortex, right ventrolateral prefrontal cortex, and bilateral STG and MTG showed strong correlations with our hypothetical model for urge suggesting these areas play a prominent role in the buildup of urge. The involvement of the insular cortex in particular, along with its function in interoceptive processing, helps support a key role for this structure in the buildup of urge during blink suppression. The right ventrolateral prefrontal cortex findings in conjunction with its known involvement in inhibitory control suggest a role for this structure in maintaining volitional suppression of an increasing sense of urge. The consistency of our urge model findings with prior studies investigating the suppression of blinking and other bodily urges, thoughts, and behaviors suggests that a similar investigative approach may have utility in fMRI studies of disorders associated with abnormal urge suppression such as Tourette syndrome and obsessive-compulsive disorder. (C) 2011 Elsevier Inc. All rights reserved. C1 [Berman, Brian D.] Univ Colorado Denver, Dept Neurol, Denver, CO USA. [Morel, Brent] Emory Univ, Atlanta, GA 30322 USA. [Berman, Brian D.; Horovitz, Silvina G.; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Berman, BD (reprint author), Univ Colorado Denver, Dept Neurol, 12631 E 17th Ave,Mail Stop 13-185, Aurora, CO 80045 USA. EM brian.berman@ucdenver.edu FU Intramural NIH HHS [Z99 NS999999] NR 51 TC 16 Z9 16 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 16 PY 2012 VL 59 IS 2 BP 1441 EP 1450 DI 10.1016/j.neuroimage.2011.08.050 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 864AY UT WOS:000298210600063 PM 21906689 ER PT J AU Yu, X Glen, D Wang, SM Dodd, S Hirano, Y Saad, Z Reynolds, R Silva, AC Koretsky, AP AF Yu, Xin Glen, Daniel Wang, Shumin Dodd, Stephen Hirano, Yoshiyuki Saad, Ziad Reynolds, Richard Silva, Afonso C. Koretsky, Alan P. TI Direct imaging of macrovascular and microvascular contributions to BOLD fMRI in layers IV-V of the rat whisker-barrel cortex SO NEUROIMAGE LA English DT Article DE Spatial specificity; BOLD; Rat; Somatosensory cortex; Whisker barrel ID CEREBRAL-BLOOD-FLOW; SPIN-ECHO FMRI; FUNCTIONAL MRI; NEURONAL-ACTIVITY; HUMAN BRAIN; SOMATOSENSORY STIMULATION; SENSORY STIMULATION; SIGNAL CHANGES; GRADIENT-ECHO; LAMINAR SPECIFICITY AB The spatiotemporal characteristics of the hemodynamic response to increased neural activity were investigated at the level of individual intracortical vessels using BOLD-fMRI in a well-established rodent model of somatosensory stimulation at 11.7 T. Functional maps of the rat barrel cortex were obtained at 150 x 150 x 500 mu m spatial resolution every 200 ms. The high spatial resolution allowed separation of active voxels into those containing intracortical macro vessels, mainly vein/venules (referred to as macrovasculature), and those enriched with arteries/capillaries and small venules (referred to as microvasculature) since the macro vessel can be readily mapped due to the fast T2* decay of blood at 11.7 T. The earliest BOLD response was observed within layers IV-V by 0.8s following stimulation and encompassed mainly the voxels containing the microvasculature and some confined macrovasculature voxels. By 1.2 s, the BOLD signal propagated to the macrovasculature voxels where the peak BOLD signal was 2-3 times higher than that of the microvasculature voxels. The BOLD response propagated in individual venules/veins far from neuronal sources at later times. This was also observed in layers IV-V of the barrel cortex after specific stimulation of separated whisker rows. These results directly visualized that the earliest hemodynamic changes to increased neural activity occur mainly in the microvasculature and spread toward the macrovasculature. However, at peak response, the BOLD signal is dominated by penetrating venules even at layers IV-V of the cortex. (C) 2011 Elsevier Inc. All rights reserved. C1 [Yu, Xin; Wang, Shumin; Dodd, Stephen; Hirano, Yoshiyuki; Silva, Afonso C.; Koretsky, Alan P.] NINDS, LFMI, NIH, Bethesda, MD 20892 USA. [Glen, Daniel; Saad, Ziad; Reynolds, Richard] NIMH, NIH, Bethesda, MD 20892 USA. RP Koretsky, AP (reprint author), NINDS, LFMI, NIH, Bldg 10,Rm B1D728,10 Ctr Dr, Bethesda, MD 20892 USA. EM koretskya@ninds.nih.gov RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU NIH, NINDS FX This research was supported by the Intramural Research Program of the NIH, NINDS. We thank Ms. Nadia Bouraoud and Ms. Kathryn Sharer for their technical support. NR 60 TC 38 Z9 38 U1 0 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 16 PY 2012 VL 59 IS 2 BP 1451 EP 1460 DI 10.1016/j.neuroimage.2011.08.001 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 864AY UT WOS:000298210600064 PM 21851857 ER PT J AU Michaelides, M Thanos, PK Kim, R Cho, J Ananth, M Wang, GJ Volkow, ND AF Michaelides, Michael Thanos, Panayotis K. Kim, Ronald Cho, Jacob Ananth, Mala Wang, Gene-Jack Volkow, Nora D. TI PET imaging predicts future body weight and cocaine preference SO NEUROIMAGE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; RECEPTORS; IMPULSIVITY; ADDICTION; OBESITY; BRAIN; FOOD AB Deficits in dopamine D2/D3 receptor (D2R/D3R) binding availability using PET imaging have been reported in obese humans and rodents. Similar deficits have been reported in cocaine-addicts and cocaine-exposed primates. We found that D2R/D3R binding availability negatively correlated with measures of body weight at the time of scan (ventral striatum), at 1 (ventral striatum) and 2 months (dorsal and ventral striatum) post scan in rats. Cocaine preference was negatively correlated with D2R/D3R binding availability 2 months (ventral striatum) post scan. Our findings suggest that inherent deficits in striatal D2R/D3R signaling are related to obesity and drug addiction susceptibility and that ventral and dorsal striatum serve dissociable roles in maintaining weight gain and cocaine preference. Measuring D2R/D3R binding availability provides a way for assessing susceptibility to weight gain and cocaine abuse in rodents and given the translational nature of PET imaging, potentially primates and humans. Published by Elsevier Inc. C1 [Michaelides, Michael; Thanos, Panayotis K.; Kim, Ronald; Cho, Jacob; Ananth, Mala; Wang, Gene-Jack] Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol Lab, Upton, NY 11973 USA. [Michaelides, Michael; Thanos, Panayotis K.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11790 USA. [Thanos, Panayotis K.] SUNY Stony Brook, Dept Neurosci, Stony Brook, NY 11790 USA. [Thanos, Panayotis K.; Volkow, Nora D.] Natl Inst Alcohol Abuse & Alcoholism, Lab Neurobnaging, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Thanos, PK (reprint author), Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol Lab, Bldg 490, Upton, NY 11973 USA. EM thanos@bnl.gov RI Michaelides, Michael/K-4736-2013 OI Michaelides, Michael/0000-0003-0398-4917 FU NIAAA [AM 1034, AA07574, AA07611]; SBU FX This work was supported by the NIAAA (AM 1034, AA07574, and AA07611) and a graduate teaching fellowship from SBU to MM. We thank Millard C. Jayne and Colleen Shea for PET tracer synthesis and scheduling as well as Brenda Anderson and John Robinson for helpful comments on the manuscript as part of the dissertation of MM. NR 13 TC 24 Z9 24 U1 1 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 16 PY 2012 VL 59 IS 2 BP 1508 EP 1513 DI 10.1016/j.neuroimage.2011.08.028 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 864AY UT WOS:000298210600071 PM 21889993 ER PT J AU Vidi, PA Chandramouly, G Gray, M Wang, L Liu, E Kim, JJ Roukos, V Bissell, MJ Moghe, PV Lelievre, SA AF Vidi, Pierre-Alexandre Chandramouly, Gurushankar Gray, Matthew Wang, Lei Liu, Er Kim, Joseph J. Roukos, Vassilis Bissell, Mina J. Moghe, Prabhas V. Lelievre, Sophie A. TI Interconnected contribution of tissue morphogenesis and the nuclear protein NuMA to the DNA damage response SO JOURNAL OF CELL SCIENCE LA English DT Article DE Tissue architecture; Basal polarity; Nuclear mitotic apparatus protein; DNA double-strand break; Chromatin; Three-dimensional cell culture ID DOUBLE-STRAND BREAKS; MAMMARY EPITHELIAL-CELLS; EXTRACELLULAR-MATRIX; 3-DIMENSIONAL CULTURE; CANCER DEVELOPMENT; RECIPROCAL INTERACTIONS; MALIGNANT PHENOTYPE; SIGNALING PATHWAYS; IN-VIVO; REPAIR AB Epithelial tissue morphogenesis is accompanied by the formation of a polarity axis a feature of tissue architecture that is initiated by the binding of integrins to the basement membrane. Polarity plays a crucial role in tissue homeostasis, preserving differentiation, cell survival and resistance to chemotherapeutic drugs among others. An important aspect in the maintenance of tissue homeostasis is genome integrity. As normal tissues frequently experience DNA double-strand breaks (DSBs), we asked how tissue architecture might participate in the DNA damage response. Using 3D culture models that mimic mammary glandular morphogenesis and tumor formation, we show that DSB repair activity is higher in basally polarized tissues, regardless of the malignant status of cells, and is controlled by hemidesmosomal integrin signaling. In the absence of glandular morphogenesis, in 2D flat monolayer cultures, basal polarity does not affect DNA repair activity but enhances H2AX phosphorylation, an early chromatin response to DNA damage. The nuclear mitotic apparatus protein 1 (NuMA), which controls breast glandular morphogenesis by acting on the organization of chromatin, displays a polarity-dependent pattern and redistributes in the cell nucleus of basally polarized cells upon the induction of DSBs. This is shown using high-content analysis of nuclear morphometric descriptors. Furthermore, silencing NuMA impairs H2AX phosphorylation thus, tissue polarity and NuMA cooperate to maintain genome integrity. C1 [Vidi, Pierre-Alexandre; Chandramouly, Gurushankar; Gray, Matthew; Wang, Lei; Lelievre, Sophie A.] Purdue Univ, Dept Basic Med Sci, W Lafayette, IN 47907 USA. [Liu, Er; Kim, Joseph J.; Moghe, Prabhas V.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. [Roukos, Vassilis] NCI, NIH, Bethesda, MD 20892 USA. [Bissell, Mina J.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. [Lelievre, Sophie A.] Purdue Univ, Ctr Canc Res, W Lafayette, IN 47907 USA. RP Vidi, PA (reprint author), Purdue Univ, Dept Basic Med Sci, W Lafayette, IN 47907 USA. EM pvidi@purdue.edu; Lelievre@purdue.edu RI Roukos, Vassilis/K-6248-2012; Liu, Er/H-8441-2012; OI Liu, Er/0000-0001-7858-1333; Vidi, Pierre-Alexandre/0000-0002-9117-8896 FU National Institutes of Health [R01CA112017, P41EB001046]; Bay Area Physical Sciences-Oncology Center, University of California, Berkeley, California [R37CA064786, U54CA126552, R01CA057621, U54CA112970, U01CA143233, U54CA143836]; U.S. Department of Energy, Office of Biological and Environmental Research and Low Dose Radiation [DE-AC02-05CH1123]; US Department of Defense [W81XWH0810736]; Novartis Foundation; Swiss National Science Foundation [PBNEA-116967]; NIH; National Cancer Institute; Purdue University Center for Cancer Research FX This work was funded by the National Institutes of Health [grant numbers R01CA112017 to SAL., P41EB001046 NIBIB-funded RESBIO (Integrated Technology Resource for Polymeric Biomaterials) to P.V.M.]; the Bay Area Physical Sciences-Oncology Center, University of California, Berkeley, California [grant numbers R37CA064786, U54CA126552, R01CA057621, U54CA112970, U01CA143233 and U54CA143836 to M.J.B.]; the U.S. Department of Energy, Office of Biological and Environmental Research and Low Dose Radiation Program (contract no. DE-AC02-05CH1123 to M.J.B.); the US Department of Defense [grant number W81XWH0810736 to M.J.B.]; and postdoctoral fellowships from the Novartis Foundation and the Swiss National Science Foundation [grant number PBNEA-116967 to PAY.]. This research was also supported in part by the Intramural Research Program of the NIH, the National Cancer Institute and the Purdue University Center for Cancer Research. Deposited in PMC for release after 12 months. NR 62 TC 11 Z9 11 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JAN 15 PY 2012 VL 125 IS 2 BP 350 EP 361 DI 10.1242/jcs.089177 PG 12 WC Cell Biology SC Cell Biology GA 909GM UT WOS:000301551000011 PM 22331358 ER PT J AU Bergmann, JH Jakubsche, JN Martins, NM Kagansky, A Nakano, M Kimura, H Kelly, DA Turner, BM Masumoto, H Larionov, V Earnshaw, WC AF Bergmann, Jan H. Jakubsche, Julia N. Martins, Nuno M. Kagansky, Alexander Nakano, Megumi Kimura, Hiroshi Kelly, David A. Turner, Bryan M. Masumoto, Hiroshi Larionov, Vladimir Earnshaw, William C. TI Epigenetic engineering: histone H3K9 acetylation is compatible with kinetochore structure and function SO JOURNAL OF CELL SCIENCE LA English DT Article DE Centromere; CENP-A; Chromatin; Epigenetics; Human artificial chromosome; Kinetochore ID ALPHA-SATELLITE DNA; HUMAN CENTROMERIC CHROMATIN; HUMAN ARTIFICIAL CHROMOSOME; CENP-A NUCLEOSOMES; MICROTUBULE INTERFACE; PROTEINS; TRANSCRIPTION; DISTINCT; PLATE; HETEROCHROMATIN AB Human kinetochores are transcriptionally active, producing very low levels of transcripts of the underlying alpha-satellite DNA. However, it is not known whether kinetochores can tolerate acetylated chromatin and the levels of transcription that are characteristic of housekeeping genes, or whether kinetochore-associated 'centrochromatin', despite being transcribed at a low level, is essentially a form of repressive chromatin. Here, we have engineered two types of acetylated chromatin within the centromere of a synthetic human artificial chromosome. Tethering a minimal NF-kappa B p65 activation domain within kinetochore-associated chromatin produced chromatin with high levels of histone H3 acetylated on lysine 9 (H3K9ac) and an similar to 10-fold elevation in transcript levels, but had no substantial effect on kinetochore assembly or function. By contrast, tethering the herpes virus VP16 activation domain produced similar modifications in the chromatin but resulted in an similar to 150-fold elevation in transcripts, approaching the level of transcription of an endogenous housekeeping gene. This rapidly inactivated kinetochores, causing a loss of assembled CENP-A and blocking further CENP-A assembly. Our data reveal that functional centromeres in vivo show a remarkable plasticity kinetochores tolerate profound changes to their chromatin environment, but appear to be critically sensitive to the level of centromeric transcription. C1 [Bergmann, Jan H.; Jakubsche, Julia N.; Martins, Nuno M.; Kagansky, Alexander; Kelly, David A.; Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. [Nakano, Megumi; Masumoto, Hiroshi] Kazusa DNA Res Inst, Dept Human Genome Res, Lab Cell Engn, Chiba 2920818, Japan. [Kimura, Hiroshi] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan. [Turner, Bryan M.] Univ Birmingham, Coll Med & Dent Sci, Chromatin & Gene Express Grp, Birmingham B15 2TT, W Midlands, England. [Larionov, Vladimir] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Earnshaw, WC (reprint author), Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Kings Bldg,Mayfield Rd, Edinburgh EH9 3JR, Midlothian, Scotland. EM bill.earnshaw@ed.ac.uk RI Kagansky, Alexander/B-3137-2011; OI Kagansky, Alexander/0000-0002-6219-6892; Martins, Nuno/0000-0003-3953-9313 FU Wellcome Trust [080458, 073915, 092076]; National Institutes of Health, the National Cancer Institute, the Center for Cancer Research; Ministry of Education, Sports, Culture, Sports, Science and Technology (MEXT) [23247030]; Genome Network; MEXT of Japan [22370063] FX J.H.B. was funded by a PhD studentship from The Wellcome Trust [grant number 080458]. This work was supported by the intramural research program of the National Institutes of Health, the National Cancer Institute, the Center for Cancer Research to V.L.; a grant-in-aid from the Ministry of Education, Sports, Culture, Sports, Science and Technology (MEXT) [grant number 23247030 to H.M.]; and the Genome Network project and grants-in-aid from the MEXT of Japan [grant number 22370063 to H.K.]. Work in the W.C.E. lab is funded by The Wellcome Trust, of which he is a Principal Research Fellow [grant number 073915]. The Wellcome Trust Centre for Cell Biology is supported by grant number 092076. Deposited in PMC for release after 6 months. NR 54 TC 39 Z9 39 U1 5 U2 13 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JAN 15 PY 2012 VL 125 IS 2 BP 411 EP 421 DI 10.1242/jcs.090639 PG 11 WC Cell Biology SC Cell Biology GA 909GM UT WOS:000301551000016 PM 22331359 ER PT J AU Richardson, ED Price, DK Figg, WD AF Richardson, Emily D. Price, Douglas K. Figg, William D. TI Significant addition to treatment options for bone metastasis in prostate cancer SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE prostate cancer; bone metastasis; denosumab; bisphosphonates; osteonecrosis of the jaw ID BREAST-CANCER; ZOLEDRONIC ACID; DENOSUMAB AB Pathologic fractures, spinal compression and pain take a great toll on the healthcare costs and well-being of men with prostate cancer metastatic to the bone. For almost 10 years, the only drug proven to prevent these skeletal-related adverse events was the bisphosphonate zoledronic acid. In a study published by Fizazi et al. in The Lancet, the monoclonal antibody to RANKL, denosumab, is shown to be superior to zoledronic acid in the prevention of these events. The only notable adverse event more frequent in either arm was increased hypocalcemia in the denosumab arm. There was a greater frequency of osteonecrosis of the jaw in the denosumab treatment group that did not reach statistical significance, but is of great concern. While further analysis is needed to determine the value of denosumab in preventing adverse events and improving quality of life, this new therapy is a significant addition to the treatment of men living with metastatic prostate cancer. C1 [Figg, William D.] NCI, Clin Pharmacol Sect, Med Oncol Branch, Bethesda, MD 20892 USA. [Richardson, Emily D.; Price, Douglas K.] NCI, Mol Pharmacol Sect, Med Oncol Branch, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Sect, Med Oncol Branch, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 13 TC 1 Z9 1 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JAN 15 PY 2012 VL 13 IS 2 BP 69 EP 70 DI 10.4161/cbt.13.2.18441 PG 2 WC Oncology SC Oncology GA 893LP UT WOS:000300357700002 PM 22336908 ER PT J AU Yubero-Lahoz, S Ayestas, MA Blough, BE Partilla, JS Rothman, RB de la Torre, R Baumann, MH AF Yubero-Lahoz, Samanta Ayestas, Mario A., Jr. Blough, Bruce E. Partilla, John S. Rothman, Richard B. de la Torre, Rafael Baumann, Michael H. TI Effects of MDMA and related analogs on plasma 5-HT: Relevance to 5-HT transporters in blood and brain SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Blood; Brain; MDMA; Microdialysis; Platelet; 5-HT (serotonin); SERT (serotonin transporter) ID PULMONARY ARTERIAL-HYPERTENSION; PLATELET SEROTONIN TRANSPORTER; BIOGENIC-AMINE TRANSPORTERS; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; DOPAMINE; RELEASE; NOREPINEPHRINE; NEUROTOXICITY; ECSTASY; SYSTEM AB (+/-)-3,4-Methylenedioxymethamphetamine (MDMA) is an illicit drug that evokes transporter-mediated release of serotonin (5-HT) in the brain. 5-HT transporter (SERT) proteins are also expressed in non-neural tissues (e.g., blood), and evidence suggests that MDMA targets platelet SERT to increase plasma 5-HT. Here we tested two hypotheses related to the effects of MDMA on circulating 5-HT. First, to determine if MDMA metabolites might contribute to actions of the drug in vivo, we used in vitro microdialysis in rat blood specimens to examine the effects of MDMA and its metabolites on plasma 5-HT. Second, to determine whether effects of MDMA on plasma 5-HT might be used as an index of central SERT activity, we carried out in vivo microdialysis in blood and brain after intravenous MDMA administration. The in vitro results show that test drugs evoke dose-related increases in plasma 5-HT ranging from two- to sevenfold above baseline, with MDMA and its metabolite, (+/-)-3,4-methylenedioxyamphetamine (MDA), producing the largest effects. The ability of MDMA and related analogs to elevate plasma 5-HT is correlated with their potency as SERT substrates in rat brain synaptosomes. The in vivo results reveal that MDMA causes concurrent increases in extracellular 5-HT in blood and brain, but there are substantial individual differences in responsiveness to the drug. Collectively, our findings indicate that MDMA and its metabolites increase plasma 5-HT by a SERT-dependent mechanism, and suggest the possibility that measures of evoked 5-HT release in blood may reflect central SERT activity. Published by Elsevier B.V. C1 [Ayestas, Mario A., Jr.; Partilla, John S.; Rothman, Richard B.; Baumann, Michael H.] NIDA, Translat Pharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Yubero-Lahoz, Samanta; de la Torre, Rafael] IMIM Hosp Mar Res Inst, Human Pharmacol & Clin Neurosci Res Grp, Neurosci Res Program, Barcelona, Spain. [Yubero-Lahoz, Samanta; de la Torre, Rafael] Univ Pompeu Fabra CEXS UPF, Barcelona, Spain. [Blough, Bruce E.] Res Triangle Inst, Ctr Organ & Med Chem, Res Triangle Pk, NC 27709 USA. RP Baumann, MH (reprint author), NIDA, Translat Pharmacol Sect, Intramural Res Program, NIH, 333 Cassell Dr,Suite 4500, Baltimore, MD 21224 USA. EM mbaumann@mail.nih.gov FU IMIM-Hospital del Mar, Barcelona, Spain; DIUE de la Generalitat de Catalunya [2009 SGR 718]; National Institute on Drug Abuse [5R01BA017987-01]; Intramural Research Program [1R01 DA017987] FX This research was generously supported by intramural funding of the Neurosciences Research Program, IMIM-Hospital del Mar, Barcelona, Spain, DIUE de la Generalitat de Catalunya (2009 SGR 718) and by grants from the National Institute on Drug Abuse, 5R01BA017987-01 and Intramural Research Program [Grant 1R01 DA017987]. NR 37 TC 13 Z9 14 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JAN 15 PY 2012 VL 674 IS 2-3 BP 337 EP 344 DI 10.1016/j.ejphar.2011.10.033 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 891EM UT WOS:000300200000035 PM 22079770 ER PT J AU Li, HY Zhang, Y Wang, HB Zheng, XG Chen, XG AF Li, Hongyan Zhang, Yi Wang, Hongbo Zheng, Xuguang Chen, Xiaoguang TI Nicousamide blocks the effects of advanced glycation end products on renal cells SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE Nicousamide; AGE (Advanced glycation end products); TGF-beta 1 (Transforming growth factor-beta 1); CTGF (Connective tissue growth factor); MMPs (Matrix metalloproteinase) ID TISSUE GROWTH-FACTOR; RAT MESANGIAL CELLS; DIABETIC-NEPHROPATHY; EXTRACELLULAR-MATRIX; MAILLARD REACTION; FACTOR-BETA; IN-VITRO; COMPLICATIONS; PROGRESSION; EXPRESSION AB Advanced glycation end products (AGE) are key factors in the pathogenesis of diabetic nephropathy. AGE can stimulate the expressions of fibrogenic transforming growth factor (TGF-beta 1) and connective tissue growth factor (CTGF), which in turn induce renal hypertrophy, sclerosis and functional failure. The purpose of this study was to examine nicousamide, a novel coumarin aspirin derivative, in the treatment of diabetic nephropathy using a renal mesangial and tubular epithelia cell model. RT-PCR and ELISA analyses showed that nicousamide inhibited AGE-induced TGF-beta 1 and CTGF. Nicousamide blocked AGE-induced G1-arrest in mesangial cells and tubular epithelia by flow cytometry. Suppression of matrix metalloproteinase activity by AGE was restored by nicousamide. This study supports that nicousamide retards diabetic nephropathy by blocking the effects of AGE on renal cells. (C) 2011 Elsevier B.V. All rights reserved. C1 [Li, Hongyan; Zhang, Yi; Wang, Hongbo; Zheng, Xuguang; Chen, Xiaoguang] Chinese Acad Med Sci, Dept Pharmacol, Inst Mat Med, Beijing 100050, Peoples R China. [Li, Hongyan; Zhang, Yi; Wang, Hongbo; Zheng, Xuguang; Chen, Xiaoguang] Peking Union Med Coll, Beijing 100050, Peoples R China. [Li, Hongyan] NIDDK, NIH, Bethesda, MD USA. RP Chen, XG (reprint author), Chinese Acad Med Sci, Dept Pharmacol, Inst Mat Med, 1 Xian Nong Tan St, Beijing 100050, Peoples R China. EM lhy2116@gmail.com; hsccat@imm.ac.cn; Hongbowang1980@gmail.com; zhengxg@gmail.com; chxg@imm.ac.cn FU National Program on Key Basic Research Project of China (973 Program) [2004CB518900]; National Natural Science Foundation of China [30672493] FX We appreciate sustentation funds of National Program on Key Basic Research Project of China (973 Program, 2004CB518900) and National Natural Science Foundation of China (No. 30672493). We also greatly appreciate Michael Epsey (NIDDK/NIH) for his kind help in writing in English. NR 44 TC 6 Z9 6 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 EI 1879-0712 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JAN 15 PY 2012 VL 674 IS 2-3 BP 455 EP 459 DI 10.1016/j.ejphar.2011.06.056 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 891EM UT WOS:000300200000052 PM 21763303 ER PT J AU Aitken, ML Limaye, A Pottinger, P Whimbey, E Goss, CH Tonelli, MR Cangelosi, GA Dirac, MA Olivier, KN Brown-Elliott, BA McNulty, S Wallace, RJ AF Aitken, Moira L. Limaye, Ajit Pottinger, Paul Whimbey, Estella Goss, Christopher H. Tonelli, Mark R. Cangelosi, Gerard A. Dirac, M. Ashworth Olivier, Kenneth N. Brown-Elliott, Barbara A. McNulty, Steven Wallace, Richard J., Jr. TI Respiratory Outbreak of Mycobacterium abscessus Subspecies massiliense in a Lung Transplant and Cystic Fibrosis Center SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter ID TRANSMISSION; INFECTIONS C1 [Aitken, Moira L.; Limaye, Ajit; Pottinger, Paul; Whimbey, Estella; Goss, Christopher H.; Tonelli, Mark R.] Univ Washington, Seattle, WA 98195 USA. [Cangelosi, Gerard A.; Dirac, M. Ashworth] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Olivier, Kenneth N.] NIAID, Bethesda, MD 20892 USA. [Brown-Elliott, Barbara A.; McNulty, Steven; Wallace, Richard J., Jr.] Univ Texas Hlth Sci Ctr, Tyler, TX USA. RP Aitken, ML (reprint author), Univ Washington, Seattle, WA 98195 USA. NR 12 TC 112 Z9 114 U1 0 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JAN 15 PY 2012 VL 185 IS 2 BP 231 EP 232 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 879EC UT WOS:000299311500024 PM 22246710 ER PT J AU Kim, MK Lee, HS Kim, S Cho, SY Roth, BL Chong, Y Choo, H AF Kim, Mi Kyoung Lee, Hyo Seon Kim, Sora Cho, Suh Young Roth, Bryan L. Chong, Youhoon Choo, Hyunah TI 4-Aminoethylpiperazinyl aryl ketones with 5-HT1A/5-HT7 selectivity SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Serotonergic receptor; 5-HT1AR; 5-HT7R; Selectivity; 4-Aminoethylpiperazinyl aryl ketones ID SITE-DIRECTED MUTAGENESIS; RECEPTOR; 5-HT7; PHARMACOLOGY; INVOLVEMENT; DERIVATIVES; ANTAGONISM; DEPRESSION; AFFINITY; AGONIST AB The well-known 5-HT1A/5-HT7 selectivity issue was tackled by a new series of 4-aminoethylpiperazinyl aryl ketones (1a-1l) specifically designed to distinguish the two hydrophobic sites centered at the anchoring salt bridge. The 4-aminoethylpiperazinyl aryl ketones showed a wide spectrum of activity and selectivity for the 5-HT receptors depending on the type of the hydrophobic groups attached at the aryl piperazinyl ketone scaffold. Docking study of the most active compounds against 5-HT7R and 5-HT1AR revealed that both receptors have two hydrophobic pockets around the anchoring salt bridge. These two binding sites are perpendicular to each other in 5-HT7R but parallel in 5-HT1AR, and this observation is well matched with the previous report which claimed that 5-HT7R affinity arises from bent conformation of the bound ligand whereas an extended one is best suited for 5-HT1AR selectivity. Also, as these pockets have different size and shape, inhibitory activity as well as selectivity of the 4-aminoethylpiperazinyl aryl ketones against 5-HT7R and 5-HT1AR seemed to be determined by combination of two hydrophobic substituents attached at both ends of the title compounds. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Kim, Mi Kyoung; Lee, Hyo Seon; Cho, Suh Young; Chong, Youhoon] Konkuk Univ, Dept Biosci & Biotechnol, Bio Mol Informat Ctr, Seoul 143701, South Korea. [Lee, Hyo Seon; Kim, Sora; Choo, Hyunah] Korea Inst Sci & Technol, Neuromed Ctr, Seoul 136791, South Korea. [Roth, Bryan L.] Univ N Carolina, Sch Med, Div Med Chem & Nat Prod,Dept Pharmacol, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Chapel Hill, NC 27599 USA. RP Chong, Y (reprint author), Korea Inst Sci & Technol, Life Hlth Div, POB 131, Seoul 130650, South Korea. EM chongy@konkuk.ac.kr; hchoo@kist.re.kr RI Roth, Bryan/F-3928-2010 FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2011-0005041, 2009-0093824]; Priority Research Centers through the National Research Foundation of Korea (NRF); Korea Rural Development Administration [PJ007982] FX This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0005041) and Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0093824), and by a grant from Next Generation Bio-Green 21 PJ007982 (Korea Rural Development Administration). NR 28 TC 9 Z9 9 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JAN 15 PY 2012 VL 20 IS 2 SI SI BP 1139 EP 1148 DI 10.1016/j.bmc.2011.11.005 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 881ON UT WOS:000299496100064 PM 22196512 ER PT J AU Sorensen, AG Emblem, KE Polaskova, P Jennings, D Kim, H Ancukiewicz, M Wang, MY Wen, PY Ivy, P Batchelor, TT Jain, RK AF Sorensen, A. Gregory Emblem, Kyrre E. Polaskova, Pavlina Jennings, Dominique Kim, Heisoog Ancukiewicz, Marek Wang, Meiyun Wen, Patrick Y. Ivy, Percy Batchelor, Tracy T. Jain, Rakesh K. TI Increased Survival of Glioblastoma Patients Who Respond to Antiangiogenic Therapy with Elevated Blood Perfusion SO CANCER RESEARCH LA English DT Article ID VASCULAR NORMALIZATION; RECURRENT GLIOBLASTOMA; TUMOR VASCULATURE; KINASE INHIBITOR; CEDIRANIB; CANCER; EDEMA; BEVACIZUMAB AB The abnormal vasculature of the tumor microenvironment supports progression and resistance to treatment. Judicious application of antiangiogenic therapy may normalize the structure and function of the tumor vasculature, promoting improved blood perfusion. However, direct clinical evidence is lacking for improvements in blood perfusion after antiangiogenic therapy. In this study, we used MRI to assess tumor blood perfusion in 30 recurrent glioblastoma patients who were undergoing treatment with cediranib, a pan-VEGF receptor tyrosine kinase inhibitor. Tumor blood perfusion increased durably for more than 1 month in 7 of 30 patients, in whom it was associated with longer survival. Together, our findings offer direct clinical evidence in support of the hypothesis that vascular normalization can increase tumor perfusion and help improve patient survival. Cancer Res; 72(2); 402-7. (C)2011 AACR. C1 [Sorensen, A. Gregory; Emblem, Kyrre E.; Polaskova, Pavlina; Jennings, Dominique; Kim, Heisoog; Wang, Meiyun] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ancukiewicz, Marek; Batchelor, Tracy T.; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Charlestown, MA 02129 USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Wen, Patrick Y.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wen, Patrick Y.] Harvard Univ, Sch Med, Boston, MA USA. [Ivy, Percy] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Emblem, Kyrre E.] Oslo Univ Hosp, Intervent Ctr, Oslo, Norway. [Kim, Heisoog] MIT, Dept Nucl Sci & Engn, Cambridge, MA 02139 USA. RP Emblem, KE (reprint author), Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM sorensen@nmr.mgh.harvard.edu; kyrre@nmr.mgh.harvard.edu RI Emblem, Kyrre/H-6691-2012 OI Emblem, Kyrre/0000-0002-6580-9519 FU NCI/NIH [R21CA117079, R01CA129371, K24CA125440]; NIH [S10RR023401, S10RR019307, S10RR019254, S10RR023043, S10RR021110, R01CA137254, 5R01NS060918, UL1 RR025758]; NCI [P01CA80124]; Saic-Frederick Inc. [26XS263]; Norwegian Research Council [191088/V50]; Harvard Catalyst grant [M01-RR-01066]; Merck; Sanofi-Aventis; Genentech; Novartis; Medimmune; AstraZeneca; Amgen; Vascular Biogenics; Genzyme; Millennium; Pfizer; Dyax; Roche FX This work was supported by NCI/NIH R21CA117079, R01CA129371, and K24CA125440 (T.T. Batchelor); NIH S10RR023401, S10RR019307, S10RR019254, S10RR023043, S10RR021110, R01CA137254, and 5R01NS060918 (A.A. Sorensen); NCI P01CA80124 (R.K. Jain); Saic-Frederick Inc. grant 26XS263 (T.T. Batchelor); Norwegian Research Council grant 191088/V50 (K.E. Emblem); Harvard Catalyst grant M01-RR-01066 (T.T. Batchelor, A.G. Sorensen, and R.K. Jain); and NIH Award UL1 RR025758 (T.T. Batchelor, A.G. Sorensen, and R.K. Jain).; P.Y. Wen received research support from Merck, Sanofi-Aventis, Genentech, Novartis, Medimmune, AstraZeneca, Amgen, Vascular Biogenics, and Genzyme; T.T. Batchelor received support from Millennium, AstraZeneca, and Pfizer; and R.K. Jain received support from Dyax, MedImmune, and Roche. No potential conflicts of interest were disclosed by other authors. NR 20 TC 118 Z9 122 U1 3 U2 18 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2012 VL 72 IS 2 BP 402 EP 407 DI 10.1158/0008-5472.CAN-11-2464 PG 6 WC Oncology SC Oncology GA 879HW UT WOS:000299321300004 PM 22127927 ER PT J AU Webster, BR Lu, ZP Sack, MN Scott, I AF Webster, Bradley R. Lu, Zhongping Sack, Michael N. Scott, Iain TI The role of sirtuins in modulating redox stressors SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE SIRT1; SIRT3; Sirtuins; Mitochondria; Redox stress; Resveratrol; Metabolism; Free radicals ID FATTY-ACID OXIDATION; SMALL-MOLECULE ACTIVATORS; INDUCIBLE FACTOR 1-ALPHA; NITRIC-OXIDE SYNTHASE; CEREVISIAE LIFE-SPAN; CALORIE RESTRICTION; SACCHAROMYCES-CEREVISIAE; MITOCHONDRIAL-FUNCTION; LYSINE ACETYLATION; TUMOR-SUPPRESSOR AB For much of the time since their discovery, the sirtuin family of deacetylase enzymes has been associated with extension of life span. This longevity-promoting capacity in numerous model systems has enabled the sirtuins to gain "celebrity status" in the field of aging research. However, the mechanisms underpinning these changes remain incompletely defined. A general phenotype long associated with aging is the dysregulation of biological systems, which partly occurs via the accumulation of damage over time. One of the major sources of this damage is oxidative stress, which can harm both biological structures and the mechanisms with which they are repaired. It is now becoming clear that the beneficial life-span effects of sirtuins, along with many of their other functions, are closely linked to their ability to regulate systems that control the redox environment. Here we investigate the links between sirtuins and their oxidative/redox environment and review the control mechanisms that are regulated by the activity of sirtuin deacetylase proteins. Published by Elsevier Inc. C1 [Webster, Bradley R.; Lu, Zhongping; Sack, Michael N.; Scott, Iain] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Scott, I (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM scotti@nhlbi.nih.gov FU Division of Intramural Research of the NHLBI FX All the authors are funded by the Division of Intramural Research of the NHLBI. NR 127 TC 40 Z9 43 U1 1 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JAN 15 PY 2012 VL 52 IS 2 BP 281 EP 290 DI 10.1016/j.freeradbiomed.2011.10.484 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 878IB UT WOS:000299247600005 PM 22085655 ER PT J AU Zhou, H Zhang, F Chen, SH Zhang, D Wilson, B Hong, JS Gao, HM AF Zhou, Hui Zhang, Feng Chen, Shih-Heng Zhang, Dan Wilson, Belinda Hong, Jau-shyong Gao, Hui-Ming TI Rotenone activates phagocyte NADPH oxidase by binding to its membrane subunit gp91(phox) SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Rotenone; Macrophages; NADPH oxidase; gp91(phox); Superoxide; PHOX; NOX2; Rac1; Free radicals ID OXYGEN SPECIES PRODUCTION; SODIUM DODECYL-SULFATE; CELL-FREE SYSTEM; PARKINSONS-DISEASE; DOPAMINERGIC-NEURONS; SUPEROXIDE-PRODUCTION; CYTOSOLIC COMPONENTS; INDUCED DEGENERATION; PESTICIDE EXPOSURE; RESPIRATORY BURST AB Rotenone, a widely used pesticide, reproduces parkinsonism in rodents and associates with increased risk for Parkinson disease. We previously reported that rotenone increased superoxide production by stimulating the microglial phagocyte NADPH oxidase (PHOX). This study identified a novel mechanism by which rotenone activates PHOX. Ligand-binding assay revealed that rotenone directly bound to membrane gp91(phox), the catalytic subunit of PHOX; such binding was inhibited by diphenyleneiodonium, a PHOX inhibitor with a binding site on gp91(phox). Functional studies showed that both membrane and cytosolic subunits were required for rotenone-induced superoxide production in cell-free systems, intact phagocytes, and COS7 cells transfected with membrane subunits (gp91(phox)/p22(phox)) and cytosolic subunits (p67(phox) and p47(phox)). Rotenone-elicited extracellular superoxide release in p47(phox)-deficient macrophages suggested that rotenone enabled activation of PHOX through a p47(phox)-independent mechanism. Increased membrane translocation of p67(phox), elevated binding of p67(phox) to rotenone-treated membrane fractions, and coimmunoprecipitation of p67(phox) and gp91(phox) in rotenone-treated wild-type and p47(phox)-deficient macrophages indicated that p67(phox) played a critical role in rotenone-induced PHOX activation via its direct interaction with gp91(phox). Rac1, a Rho-like small GTPase, enhanced p67(phox)-gp91(phox) interaction; Rac1 inhibition decreased rotenone-elicited superoxide release. In conclusion, rotenone directly interacted with gp91(phox); such an interaction triggered membrane translocation of p67(phox), leading to PHOX activation and superoxide production. Published by Elsevier Inc. C1 [Zhou, Hui; Zhang, Feng; Chen, Shih-Heng; Zhang, Dan; Wilson, Belinda; Hong, Jau-shyong; Gao, Hui-Ming] NIEHS, Neuropharmacol Sect, Lab Toxicol & Pharmacol, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Gao, HM (reprint author), NIEHS, Neuropharmacol Sect, Lab Toxicol & Pharmacol, NIH,Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM gao2@niehs.nih.gov RI gao, huiming/C-8454-2012 FU National Institutes of Health, the National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences. We thank Jeff Tucker for his assistance in collecting confocal imaging data and Anthony Lockhart for his assistance with animal colony management and maintenance of the timed pregnant mice. NR 62 TC 22 Z9 26 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JAN 15 PY 2012 VL 52 IS 2 BP 303 EP 313 DI 10.1016/j.freeradbiomed.2011.10.488 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 878IB UT WOS:000299247600008 PM 22094225 ER PT J AU Mao, M Sudhahar, V Ansenberger-Fricano, K Fernandes, DC Tanaka, LY Fukai, T Laurindo, FRM Mason, RP Vasquez-Vivar, J Minshall, RD Stadler, K Bonini, MG AF Mao, Mao Sudhahar, Varadarajan Ansenberger-Fricano, Kristine Fernandes, Denise C. Tanaka, Leonardo Y. Fukai, Tohru Laurindo, Francisco R. M. Mason, Ronald P. Vasquez-Vivar, Jeannette Minshall, Richard D. Stadler, Krisztian Bonini, Marcelo G. TI Nitroglycerin drives endothelial nitric oxide synthase activation via the phosphatidylinositol 3-kinase/protein kinase B pathway SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Nitroglycerin; Glyceryl trinitrate; PI3K; Akt; eNOS; Nitric oxide; Free radicals ID MITOCHONDRIAL ALDEHYDE DEHYDROGENASE; GLUTATHIONE-S-TRANSFERASE; INDUCED OXIDATIVE STRESS; NITRATE TOLERANCE; DEPENDENT VASODILATION; VASCULAR DYSFUNCTION; TREATMENT PROTECTS; CORONARY-ARTERIES; HEART-FAILURE; L-ARGININE AB Nitroglycerin (GIN) has been clinically used to treat angina pectoris and acute heart episodes for over 100 years. The effects of GTN have long been recognized and active research has contributed to the unraveling of numerous metabolic routes capable of converting GIN to the potent vasoactive messenger nitric oxide. Recently, the mechanism by which minute doses of GIN elicit robust pharmacological responses was revisited and eNOS activation was implicated as an important route mediating vasodilation induced by low GTN doses (1-50 nM). Here, we demonstrate that at such concentrations the pharmacologic effects of nitroglycerin are largely dependent on the phosphatidylinositol 3-kinase, Akt/PKB, and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signal transduction axis. Furthermore, we demonstrate that nitroglycerin-dependent accumulation of 3,4,5-InsP(3), probably because of inhibition of PTEN, is important for eNOS activation, conferring a mechanistic basis for GIN pharmacological action at pharmacologically relevant doses. (C) 2011 Elsevier Inc. All rights reserved. C1 [Mao, Mao; Sudhahar, Varadarajan; Ansenberger-Fricano, Kristine; Fukai, Tohru; Bonini, Marcelo G.] Univ Illinois, Coll Med, Cardiol Sect, Chicago, IL 60612 USA. [Mao, Mao; Sudhahar, Varadarajan; Ansenberger-Fricano, Kristine; Fukai, Tohru; Bonini, Marcelo G.] Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA. [Fernandes, Denise C.; Tanaka, Leonardo Y.; Laurindo, Francisco R. M.] Univ Sao Paulo, Sch Med, Vasc Biol Lab, Heart Inst InCor, Sao Paulo, Brazil. [Mason, Ronald P.; Stadler, Krisztian; Bonini, Marcelo G.] NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. [Vasquez-Vivar, Jeannette] Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. [Minshall, Richard D.] Univ Illinois, Dept Anesthesiol, Chicago, IL 60612 USA. RP Bonini, MG (reprint author), Univ Illinois, Coll Med, Cardiol Sect, Chicago, IL 60612 USA. EM mbonini@uic.edu RI Fernandes, Denise/K-2267-2012; Mao, Mao/E-3783-2013; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013; Tanaka, Leonardo/H-9832-2013; Laurindo, Francisco/J-6575-2015 OI Fernandes, Denise/0000-0002-5056-5734; Mao, Mao/0000-0003-1524-8853; FU National Institute of Environmental Health Sciences Division of Intramural Research, an American Heart Association [09SDG2250933]; National Heart Lung and Blood [R01 HL070187]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo; Conselho Nacional de Pesquisa de Desenvolvimento Cientifico e Tecnologico FX The authors are indebted to Drs. Asrar Malik and Xiaopei Gao for the generous gifts of PI3Kp110 gamma-knockout mice and mouse endothelial cells. We thank Dr. Ann Motten for the careful review of the manuscript. These studies were supported in part by the National Institute of Environmental Health Sciences Division of Intramural Research, an American Heart Association Scientist Development grant (09SDG2250933 to M.G.B.), and a National Heart Lung and Blood grant (R01 HL070187 to T.F.). The authors also thank the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo and Conselho Nacional de Pesquisa de Desenvolvimento Cientifico e Tecnologico for financial support to F.R.M.L. NR 40 TC 11 Z9 11 U1 0 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JAN 15 PY 2012 VL 52 IS 2 BP 427 EP 435 DI 10.1016/j.freeradbiomed.2011.09.020 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 878IB UT WOS:000299247600020 PM 22037515 ER PT J AU Scarbrough, PM Mapuskar, KA Mattson, DM Gius, D Watson, WH Spitz, DR AF Scarbrough, Peter M. Mapuskar, Kranti A. Mattson, David M. Gius, David Watson, Walter H. Spitz, Douglas R. TI Simultaneous inhibition of glutathione- and thioredoxin-dependent metabolism is necessary to potentiate 17AAG-induced cancer cell killing via oxidative stress SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Glutathione; Thioredoxin; 2-Deoxyglucose; Auranofin; Thioredoxin reductase; Free radicals ID GLUCOSE DEPRIVATION; H2O2 MEDIATE; TUMOR-CELLS; 2-DEOXY-D-GLUCOSE; CYTOTOXICITY; ANTIOXIDANT; PROGRESSION; SUPEROXIDE; RESISTANCE; APOPTOSIS AB 17-Allylamino-17-demethoxygeldanamycin (17AAG) is an experimental chemotherapeutic agent believed to form free radicals in vivo, and cancer cell resistance to 17AAG is believed to be a thiol-dependent process. Inhibitors of thiol-dependent hydroperoxide metabolism [L-buthionine-S,R-sulfoximine (BSO) and auranofin] were combined with the glucose metabolism inhibitor 2-deoxy-D-glucose (2DG) to determine if 17AAG-mediated cancer cell killing could be enhanced. When 2DG (20 mM, 24 h), BSO (1 mM, 24 h), and auranofin (500 nM, 3 h) were combined with 17AAG, cell killing was significantly enhanced in three human cancer cell lines (PC-3, SUM159, MDA-MB-231). Furthermore, the toxicity of this drug combination was significantly greater in SUM159 human breast cancer cells, relative to HMEC normal human breast epithelial cells. Increases in toxicity seen with this drug combination also correlated with increased glutathione (GSH) and thioredoxin (Trx) oxidation and depletion. Furthermore, treatment with the thiol antioxidant NAC (15 mM, 24 h) was able to significantly protect from drug-induced toxicity and ameliorate GSH oxidation, Trx oxidation, and Trx depletion. These data strongly support the hypothesis that simultaneous inhibition of GSH- and Trx-dependent metabolism is necessary to sensitize human breast and prostate cancer cells to 2DG + 17AAG-mediated killing via enhancement of thiol-dependent oxidative stress. These results suggest that simultaneous targeting of both GSH and Trx metabolism could represent an effective strategy for chemosensitization in human cancer cells. (C) 2011 Elsevier Inc. All rights reserved. C1 [Scarbrough, Peter M.; Mapuskar, Kranti A.; Spitz, Douglas R.] Univ Iowa, Free Rad & Radiat Biol Program, Dept Radiat Oncol, Holden Comprehens Canc Ctr, Iowa City, IA 52240 USA. [Mapuskar, Kranti A.; Spitz, Douglas R.] Univ Iowa, Human Toxicol Program, Dept Occupat & Environm Hlth, Iowa City, IA 52240 USA. [Mattson, David M.] Roswell Pk Canc Inst, Breast Radiat Oncol Program, Dept Radiat Med, Buffalo, NY 14263 USA. [Gius, David] Vanderbilt Ingram Canc Ctr, Dept Radiat Oncol, Nashville, TN 37232 USA. [Gius, David] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Watson, Walter H.] Univ Louisville, Div Gastroenterol Hepatol & Nutr, Dept Med, Louisville, KY 40292 USA. RP Spitz, DR (reprint author), Univ Iowa, Free Rad & Radiat Biol Program, Dept Radiat Oncol, Holden Comprehens Canc Ctr, Iowa City, IA 52240 USA. EM douglas-spitz@uiowa.edu FU NIH [R01CA133114, R01CA100045, T32CA078586, P30CA086862]; Department of Radiation Oncology, University of Iowa FX The authors thank the Radiation and Free Radical Research Core Laboratory at The University of Iowa and Dr. Michel L. McCormick for his assistance in running glutathione assays. The authors also thank Drs. Melissa A. Fath, Andrean L. Simons, and Yueming Zhu, for their helpful discussions during the design of these experiments. This work was supported in part by NIH Grants R01CA133114, R01CA100045, T32CA078586, and P30CA086862 as well as the Department of Radiation Oncology at The University of Iowa. NR 33 TC 36 Z9 37 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JAN 15 PY 2012 VL 52 IS 2 BP 436 EP 443 DI 10.1016/j.freeradbiomed.2011.10.493 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 878IB UT WOS:000299247600021 PM 22100505 ER PT J AU Mukhopadhyay, P Horvath, B Zsengeller, Z Zielonka, J Tanchian, G Holovac, E Kechrid, M Patel, V Stillman, IE Parikh, SM Joseph, J Kalyanaraman, B Pacher, P AF Mukhopadhyay, Partha Horvath, Bela Zsengeller, Zsuzsanna Zielonka, Jacek Tanchian, Galin Holovac, Eileen Kechrid, Malek Patel, Vivek Stillman, Isaac E. Parikh, Samir M. Joseph, Joy Kalyanaraman, Balaraman Pacher, Pal TI Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Nephropathy; Cisplatin; Oxidative stress; Mitochondria; Mitochondrial antioxidants; Free radicals ID ACUTE-RENAL-FAILURE; ACUTE KIDNEY INJURY; INDUCED NEPHROTOXICITY; RESPIRATORY-CHAIN; NITRIC-OXIDE; CELL-DEATH; ALPHA; PEROXYNITRITE; CHEMOTHERAPY; DYSFUNCTION AB Cisplatin is a widely used antineoplastic agent; however, its major limitation is the development of dose-dependent nephrotoxicity whose precise mechanisms are poorly understood. Here we show not only that mitochondrial dysfunction is a feature of cisplatin nephrotoxicity, but also that targeted delivery of superoxide dismutase mimetics to mitochondria largely prevents the renal effects of cisplatin. Cisplatin induced renal oxidative stress, deterioration of mitochondrial structure and function, an intense inflammatory response, histopathological injury, and renal dysfunction. A single systemic dose of mitochondrially targeted antioxidants, MitoQ or Mito-CP, dose-dependently prevented cisplatin-induced renal dysfunction. Mito-CP also prevented mitochondrial injury and dysfunction, renal inflammation, and tubular injury and apoptosis. Despite being broadly renoprotective against cisplatin, Mito-CP did not diminish cisplatin's antineoplastic effect in a human bladder cancer cell line. Our results highlight the central role of mitochondrially generated oxidants in the pathogenesis of cisplatin nephrotoxicity. Because similar compounds seem to be safe in humans, mitochondrially targeted antioxidants may represent a novel therapeutic approach against cisplatin nephrotoxicity. (C) 2011 Elsevier Inc. All rights reserved. C1 [Mukhopadhyay, Partha; Horvath, Bela; Tanchian, Galin; Holovac, Eileen; Kechrid, Malek; Patel, Vivek; Pacher, Pal] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Zsengeller, Zsuzsanna; Stillman, Isaac E.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Zielonka, Jacek; Joseph, Joy; Kalyanaraman, Balaraman] Med Coll Wisconsin, Dept Biophys, Free Rad Res Ctr, Milwaukee, WI 53226 USA. [Zsengeller, Zsuzsanna; Stillman, Isaac E.; Parikh, Samir M.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Parikh, Samir M.] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02215 USA. [Horvath, Bela] Semmelweis Univ, Inst Human Physiol & Clin Expt Res, Budapest, Hungary. RP Pacher, P (reprint author), NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. EM pacher@mail.nih.gov RI Horvath, Bela/A-7368-2009; Pacher, Pal/B-6378-2008; MUKHOPADHYAY, PARTHA/G-3890-2010; Zielonka, Jacek/N-9546-2014 OI Pacher, Pal/0000-0001-7036-8108; MUKHOPADHYAY, PARTHA/0000-0002-1178-1274; Zielonka, Jacek/0000-0002-2524-0145 FU NIH/NIAAA; National Institutes of Health [RO1CA152810]; Hungarian Scientific Research Fund fellowship (OTKA-NKTH-EU) [MB08 80238] FX This study was supported by the Intramural Research Program of NIH/NIAAA (to P.P.) and by National Institutes of Health Grant RO1CA152810 (B.K.). Dr. Horvath is the recipient of a Hungarian Scientific Research Fund fellowship (OTKA-NKTH-EU MB08 80238). The authors are indebted to Dan Brown and Lena Ellezian for help with electron microscopy sample preparation, Dr. George Kunos (the Scientific Director of the NIAAA) for providing key resources, and the American Society of Nephrology (Carl Gottschalk award to S.M.P.). Dr. Pacher dedicates this study to his beloved mother ken Bolfert, who died from complications of chemotherapy. NR 39 TC 72 Z9 76 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JAN 15 PY 2012 VL 52 IS 2 BP 497 EP 506 DI 10.1016/j.freeradbiomed.2011.11.001 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 878IB UT WOS:000299247600027 PM 22120494 ER PT J AU Hershko, AY Charles, N Olivera, A Alvarez-Errico, D Rivera, J AF Hershko, Alon Y. Charles, Nicolas Olivera, Ana Alvarez-Errico, Damiana Rivera, Juan TI Cutting Edge: Persistence of Increased Mast Cell Numbers in Tissues Links Dermatitis to Enhanced Airway Disease in a Mouse Model of Atopy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ALLERGIC DERMATITIS; ASTHMA; CHILDHOOD; MARCH; EXPOSURE; ECZEMA; MICE AB The development of chronic allergic dermatitis in early life has been associated with increased onset and severity of allergic asthma later in life. However, the mechanisms linking these two diseases are poorly understood. In this study, we report that the development of oxazolone-induced chronic allergic dermatitis, in a mouse model, caused enhanced OVA-induced allergic asthma after the resolution of the former disease. Our findings show that oxazolone-induced dermatitis caused a marked increase in tissue mast cells, which persisted long after the resolution of this disease. Subsequent OVA sensitization and airway challenge of mice that had recovered from dermatitis resulted in increased allergic airway hyperreactivity. The findings demonstrate that the accumulation of mast cells during dermatitis has the detrimental effect of increasing allergic airway hypersensitivity. Importantly, our findings also show that exposure to a given allergen can modify the immune response to an unrelated allergen. The Journal of Immunology, 2012, 188: 531-535. C1 [Hershko, Alon Y.; Charles, Nicolas; Olivera, Ana; Alvarez-Errico, Damiana; Rivera, Juan] NIAMSD, Mol Immunol Sect, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Rivera, J (reprint author), NIAMSD, Mol Immunol Sect, Immunogenet Mol Lab, NIH, Bldg 10,Room 13C103, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov RI Charles, Nicolas/P-5430-2014 OI Charles, Nicolas/0000-0002-5416-5834 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health; American Physician fellowship; Israel Science Foundation FX This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. A.Y.H. also was supported by an American Physician fellowship and the Morasha Program of the Israel Science Foundation. NR 21 TC 10 Z9 12 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2012 VL 188 IS 2 BP 531 EP 535 DI 10.4049/jimmunol.1102703 PG 5 WC Immunology SC Immunology GA 879IU UT WOS:000299323700004 PM 22180615 ER PT J AU Tang, XB Tian, LJ Esteso, G Choi, SC Barrow, AD Colonna, M Borrego, F Coligan, JE AF Tang, Xiaobin Tian, Linjie Esteso, Gloria Choi, Seung-Chul Barrow, Alexander D. Colonna, Marco Borrego, Francisco Coligan, John E. TI Leukocyte-Associated Ig-like Receptor-1-Deficient Mice Have an Altered Immune Cell Phenotype SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; DISCOIDIN DOMAIN RECEPTOR-1; ZONE B-CELLS; T-CELLS; INHIBITORY RECEPTOR; DENDRITIC CELLS; TYROSINE-PHOSPHATASE; COLLAGEN INTERACTION; AUTOIMMUNE-DISEASES; ACTIVATION AB Cross-linking of the collagen binding receptor leukocyte-associated Ig-like receptor-1 (LAIR-1) in vitro delivers an inhibitory signal that is able to downregulate activation-mediated signals. To study the in vivo function of LAIR-1, we generated LAIR-1(-/-) mice. They are healthy and fertile and have normal longevity; however, they show certain phenotypic characteristics distinct from wildtype mice, including increased numbers of splenic B, regulatory T, and dendritic cells. As LAIR-1(-/-) mice age, the splenic T cell population shows a higher frequency of activated and memory T cells. Because LAIR-1(+/+) and LAIR-1(-/-) T cells traffic with equal proficiency to peripheral lymphoid organs, this is not likely due to abnormal T lymphocyte trafficking. LAIR-1(-/-) mice have lower serum levels of IgG1 and, in response to T-dependent immunization with trinitrophenyl-OVA, switch less efficiently to Ag specific IgG2a and IgG2b, whereas switching to IgG1 is not affected. Several mouse disease models, including experimental autoimmune encephalitis and colitis, were used to examine the effect of LAIR-1 deficiency, and no differences in the responses of LAIR-1(-/-) and LAIR-1(+/+) mice were observed. Taken together, these observations indicate that LAIR-1 plays a role in regulating immune cells and suggest that any adverse effects of its absence may be balanced in vivo by other inhibitory receptors. The Journal of Immunology, 2012, 188: 548-558. C1 [Tang, Xiaobin; Tian, Linjie; Esteso, Gloria; Choi, Seung-Chul; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Barrow, Alexander D.; Colonna, Marco] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Borrego, Francisco] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. RP Coligan, JE (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Twinbrook 2,Room 205,12441 Parklawn Dr, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov RI Tian, Linjie/E-6878-2014; OI Colonna, Marco/0000-0001-5222-4987 FU National Institute of Allergy and Infectious Diseases; European Commission FX This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases. A. D. B. is the recipient of a Marie Curie International Outgoing fellowship from the European Commission Framework Programme (FP)7. NR 58 TC 16 Z9 19 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2012 VL 188 IS 2 BP 548 EP 558 DI 10.4049/jimmunol.1102044 PG 11 WC Immunology SC Immunology GA 879IU UT WOS:000299323700007 PM 22156345 ER PT J AU Hubner, MP Shi, YH Torrero, MN Mueller, E Larson, D Soloviova, K Gondorf, F Hoerauf, A Killoran, KE Stocker, JT Davies, SJ Tarbell, KV Mitre, E AF Huebner, Marc P. Shi, Yinghui Torrero, Marina N. Mueller, Ellen Larson, David Soloviova, Kateryna Gondorf, Fabian Hoerauf, Achim Killoran, Kristin E. Stocker, J. Thomas Davies, Stephen J. Tarbell, Kristin V. Mitre, Edward TI Helminth Protection against Autoimmune Diabetes in Nonobese Diabetic Mice Is Independent of a Type 2 Immune Shift and Requires TGF-beta SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; TRICHURIS-SUIS THERAPY; NOD MICE; TH17 CELLS; MULTIPLE-SCLEROSIS; HYGIENE HYPOTHESIS; INTERFERON-GAMMA; IFN-GAMMA; INFECTION; INHIBITION AB Leading hypotheses to explain helminth-mediated protection against autoimmunity postulate that type 2 or regulatory immune responses induced by helminth infections in the host limit pathogenic Th1-driven autoimmune responses. We tested these hypotheses by investigating whether infection with the filarial nematode Litomosoides sigmodontis prevents diabetes onset in IL-4-deficient NOD mice and whether depletion or absence of regulatory T cells, IL-10, or TGF-beta alters helminth-mediated protection. In contrast to IL-4-competent NOD mice, IL-4-deficient NOD mice failed to develop a type 2 shift in either cytokine or Ab production during L. sigmodontis infection. Despite the absence of a type 2 immune shift, infection of IL-4-deficient NOD mice with L. sigmodontis prevented diabetes onset in all mice studied. Infections in immunocompetent and IL-4-deficient NOD mice were accompanied by increases in CD4(+)CD25(+)Foxp3(+) regulatory T cell frequencies and numbers, respectively, and helminth infection increased the proliferation of CD4(+)Foxp3(+) cells. However, depletion of CD25(+) cells in NOD mice or Foxp3(+) T cells from splenocytes transferred into NOD. scid mice did not decrease helminth-mediated protection against diabetes onset. Continuous depletion of the anti-inflammatory cytokine TGF-beta, but not blockade of IL-10 signaling, prevented the beneficial effect of helminth infection on diabetes. Changes in Th17 responses did not seem to play an important role in helminth-mediated protection against autoimmunity, because helminth infection was not associated with a decreased Th17 immune response. This study demonstrates that L. sigmodontis-mediated protection against diabetes in NOD mice is not dependent on the induction of a type 2 immune shift but does require TGF-beta. The Journal of Immunology, 2012, 188: 559-568. C1 [Huebner, Marc P.; Shi, Yinghui; Torrero, Marina N.; Mueller, Ellen; Larson, David; Killoran, Kristin E.; Davies, Stephen J.; Mitre, Edward] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Huebner, Marc P.; Gondorf, Fabian; Hoerauf, Achim] Univ Hosp Bonn, Inst Med Microbiol Immunol & Parasitol, D-53105 Bonn, Germany. [Soloviova, Kateryna; Stocker, J. Thomas] Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. [Tarbell, Kristin V.] NIDDKD, Immune Tolerance Sect, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Mitre, E (reprint author), Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Microbiol & Immunol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM emitre@usuhs.mil FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [1DP2DK083131]; European Union under Research Executive Agency [GA 276704] FX This work was supported by Grant 1DP2DK083131 from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases; part of this project was supported by the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2007-2013 under Research Executive Agency Grant GA 276704. NR 61 TC 49 Z9 50 U1 0 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2012 VL 188 IS 2 BP 559 EP 568 DI 10.4049/jimmunol.1100335 PG 10 WC Immunology SC Immunology GA 879IU UT WOS:000299323700008 PM 22174447 ER PT J AU Roffe, E Rothfuchs, AG Santiago, HC Marino, APMP Ribeiro-Gomes, FL Eckhaus, M Antonelli, LRV Murphy, PM AF Roffe, Ester Rothfuchs, Antonio Gigliotti Santiago, Helton C. Marino, Ana Paula M. P. Ribeiro-Gomes, Flavia L. Eckhaus, Michael Antonelli, Lis R. V. Murphy, Philip M. TI IL-10 Limits Parasite Burden and Protects against Fatal Myocarditis in a Mouse Model of Trypanosoma cruzi Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELLS; CHAGAS-DISEASE; IFN-GAMMA; CARDIAC INFLAMMATION; TISSUE PARASITISM; IMMUNE-RESPONSE; MICE DEFICIENT; ACUTE-PHASE; EXPRESSION; SUSCEPTIBILITY AB Chagas' disease is a zoonosis prevalent in Latin America that is caused by the protozoan Trypanosoma cruzi. The immunopathogenesis of cardiomyopathy, the main clinical problem in Chagas' disease, has been extensively studied but is still poorly understood. In this study, we systematically compared clinical, microbiologic, pathologic, immunologic, and molecular parameters in two mouse models with opposite susceptibility to acute myocarditis caused by the myotropic Colombiana strain of T. cruzi: C3H/HeSnJ (100% mortality, uncontrolled parasitism) and C57BL/6J (<10% mortality, controlled parasitism). T. cruzi induced differential polarization of immunoregulatory cytokine mRNA expression in the hearts of C57BL/6J versus C3H/HeSnJ mice; however, most differences were small. The difference in IL-10 expression was exceptional (C57BL/6J 8.7-fold greater than C3H/HeSnJ). Consistent with this, hearts from infected C57BL/6J mice, but not C3H/HeSnJ mice, had a high frequency of total IL-10-producing CD8(+) T cells and both CD4(+) and CD8(+) subsets of IFN-gamma(+)IL-10(+) double-producing T cells. Furthermore, T. cruzi infection of IL-10(-/-) C57BL/6J mice phenocopied fatal infection in wild-type C3H/HeSnJ mice with complete loss of parasite control. Adoptive transfer experiments indicated that T cells were a source of protective IL-10. Thus, in this system, IL-10 production by T cells promotes T. cruzi control and protection from fatal acute myocarditis. The Journal of Immunology, 2012, 188: 649-660. C1 [Roffe, Ester; Marino, Ana Paula M. P.; Murphy, Philip M.] NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Rothfuchs, Antonio Gigliotti; Antonelli, Lis R. V.] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Rothfuchs, Antonio Gigliotti] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17177 Stockholm, Sweden. [Santiago, Helton C.] NIAID, Helminth Immunol Sect, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. [Ribeiro-Gomes, Flavia L.] NIAID, Intracellular Parasite Biol Sect, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. [Eckhaus, Michael] NIH, Div Vet Resources, Off Res Serv, Off Director, Bethesda, MD 20892 USA. [Antonelli, Lis R. V.] Fundacao Oswaldo Cruz, Rene Rachou Res Ctr, Immunopathol Lab, BR-30190002 Belo Horizonte, MG, Brazil. RP Murphy, PM (reprint author), NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike,MSC 1888,Bldg 10,Room 11N113, Bethesda, MD 20892 USA. EM pmm@nih.gov RI Santiago, Helton/F-8704-2012; Roffe, Ester/H-4688-2012; Rothfuchs, Antonio/F-5981-2013; Vacinas, Inct/J-9431-2013; Antonelli, Lis/G-2907-2012; Ribeiro-Gomes, Flavia/F-7609-2015 OI Santiago, Helton/0000-0002-5695-8256; Rothfuchs, Antonio/0000-0001-6001-7240; FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services. NR 41 TC 28 Z9 28 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2012 VL 188 IS 2 BP 649 EP 660 DI 10.4049/jimmunol.1003845 PG 12 WC Immunology SC Immunology GA 879IU UT WOS:000299323700018 PM 22156594 ER PT J AU Gordon, SN Kines, RC Kutsyna, G Ma, ZM Hryniewicz, A Roberts, JN Fenizia, C Hidajat, R Brocca-Cofano, E Cuburu, N Buck, CB Bernardo, ML Robert-Guroff, M Miller, CJ Graham, BS Lowy, DR Schiller, JT Franchini, G AF Gordon, Shari N. Kines, Rhonda C. Kutsyna, Galyna Ma, Zhong-Min Hryniewicz, Anna Roberts, Jeffery N. Fenizia, Claudio Hidajat, Rachmat Brocca-Cofano, Egidio Cuburu, Nicolas Buck, Christopher B. Bernardo, Marcelino L. Robert-Guroff, Marjorie Miller, Christopher J. Graham, Barney S. Lowy, Douglas R. Schiller, John T. Franchini, Genoveffa TI Targeting the Vaginal Mucosa with Human Papillomavirus Pseudovirion Vaccines Delivering Simian Immunodeficiency Virus DNA SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-LYMPHOCYTE RESPONSES; FEMALE GENITAL-TRACT; RHESUS MACAQUES; SIVMAC251 INFECTION; DENDRITIC CELLS; HIV-1 VACCINE; DOUBLE-BLIND; IMMUNITY; TRANSMISSION; NONOXYNOL-9 AB The majority of HIV infections occur via mucosal transmission. Vaccines that induce memory T and B cells in the female genital tract may prevent the establishment and systemic dissemination of HIV. We tested the immunogenicity of a vaccine that uses human papillomavirus (HPV)-based gene transfer vectors, also called pseudovirions (PsVs), to deliver SIV genes to the vaginal epithelium. Our findings demonstrate that this vaccine platform induces gene expression in the genital tract in both cynomolgus and rhesus macaques. Intravaginal vaccination with HPV16, HPV45, and HPV58 PsVs delivering SIV Gag DNA induced Gag-specific Abs in serum and the vaginal tract, and T cell responses in blood, vaginal mucosa, and draining lymph nodes that rapidly expanded following intravaginal exposure to SIVmac251. HPV PsV-based vehicles are immunogenic, which warrant further testing as vaccine candidates for HIV and may provide a useful model to evaluate the benefits and risks of inducing high levels of SIV-specific immune responses at mucosal sites prior to SIV infection. The Journal of Immunology, 2012, 188: 714-723. C1 [Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Gordon, Shari N.; Kutsyna, Galyna; Hryniewicz, Anna; Fenizia, Claudio; Hidajat, Rachmat; Brocca-Cofano, Egidio; Robert-Guroff, Marjorie; Franchini, Genoveffa] NIH, Immune Biol Retroviral Infect Sect, Vaccine Branch, Bethesda, MD 20892 USA. [Kines, Rhonda C.; Roberts, Jeffery N.; Cuburu, Nicolas; Buck, Christopher B.; Lowy, Douglas R.; Schiller, John T.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ma, Zhong-Min; Miller, Christopher J.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 94118 USA. [Ma, Zhong-Min; Miller, Christopher J.] Univ Calif Davis, Ctr Comparat Med, Davis, CA 94118 USA. [Bernardo, Marcelino L.] Sci Applicat Int Corp, Frederick, MD 21702 USA. [Graham, Barney S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, NIH, Ctr Canc Res, Bldg 41,Room D804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov OI Buck, Christopher/0000-0003-3165-8094 FU National Institutes of Health FX This work was supported by the National Institutes of Health intramural budget of G.F. and J.T.S. NR 37 TC 16 Z9 16 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2012 VL 188 IS 2 BP 714 EP 723 DI 10.4049/jimmunol.1101404 PG 10 WC Immunology SC Immunology GA 879IU UT WOS:000299323700025 PM 22174446 ER PT J AU Sanders, K Degn, LL Mundy, WR Zucker, RM Dreher, K Zhao, BZ Roberts, JE Boyes, WK AF Sanders, Kristen Degn, Laura L. Mundy, William R. Zucker, Robert M. Dreher, Kevin Zhao, Baozhong Roberts, Joan E. Boyes, William K. TI In Vitro Phototoxicity and Hazard Identification of Nano-scale Titanium Dioxide SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Nanoparticles; Titanium dioxide; Phototoxicity; Retinal pigment epithelium ID MEDIATED PHOTOCATALYZED DEGRADATION; LENS EPITHELIAL-CELLS; TIO2 PHOTOCATALYSIS; OXIDANT GENERATION; AQUEOUS SUSPENSION; LIGHT-SCATTERING; TOXICITY; NANOPARTICLES; CYTOTOXICITY; IRRADIATION AB Titanium dioxide nanoparticles (nano-TiO(2)) catalyze reactions under UV radiation and are hypothesized to cause phototoxicity. A human-derived line of retinal pigment epithelial cells (ARPE-19) was treated with six samples of nano-TiO(2) and exposed to UVA radiation. The TiO(2) nanoparticles were independently characterized to have mean primary particle sizes and crystal structures of 22 nm anatase/rutile, 25 nm anatase, 31 nm anatase/rutile, 59 nm anatase/rutile, 142 nm anatase, and 214 nm rutile. Particles were suspended in cell culture media, sonicated, and assessed for stability and aggregation by dynamic light scattering. Cells were treated with 0, 0.3, 1, 3, 10, 30, or 100 mu g/ml nano-TiO(2) in media for 24 hrs and then exposed to UVA (2 hrs, 7.53 J/cm(2)) or kept in the dark. Viability was assessed 24 hrs after the end of UVA exposure by microscopy with a live/dead assay (calcein-AM/propidium iodide). Exposure to higher concentrations of nano-TiO(2) with UVA lowered cell viability. The 25 nm anatase and 31 nm anatase/rutile were the most phototoxic (LC(50) with UVA<5 mu g/ml), while the 142 nm anatase and 214 nm rutile were the least phototoxic. An acellular assay ranked TiO(2) nanoparticles for their UVA photocatalytic reactivities. The particles were found to be capable of generating thiobarbituric acid reactive substances (TBARS) under UVA. Flow cytometry showed that nano-TiO(2) combined with UVA decreased cell viability and increased the generation of reactive oxygen species (ROS, measured by Mitosox). LC(50) values under UVA were correlated with TBARS reactivity, particle size, and surface area. (C) 2011 Elsevier Inc. All rights reserved. C1 [Sanders, Kristen; Degn, Laura L.; Zucker, Robert M.; Boyes, William K.] US EPA, Tox Assessment Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Sanders, Kristen; Dreher, Kevin] US EPA, Environm Publ Hlth Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Mundy, William R.] US EPA, Integrated Syst Toxicol Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Zhao, Baozhong; Roberts, Joan E.] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC USA. [Roberts, Joan E.] Fordham Univ, New York, NY 10023 USA. [Zhao, Baozhong] Natl Ctr Nanosci & Technol, Beijing, Peoples R China. RP Boyes, WK (reprint author), US EPA, Tox Assessment Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, B105-05, Res Triangle Pk, NC 27711 USA. EM boyes.william@epa.gov RI Zhao, Baozhong/B-5865-2011 FU [EP09D000042] FX K. Sanders was supported by a contract to EPA (EP09D000042). Thanks are extended to Theresa Freudenrich for her excellent advice and guidance with cell culture, to Kaitlin Daniel for her evaluation of the flow cytometi-y data and preparation of Figs. 4 and 5, and to Sarah Karafas for her help with the Mitosox experiments. The authors are indebted to Amy Wang, Christy Powers, Steve Diamond, Tom Long, and Carl Blackman for editorial comments on a previous version of the manuscript. This manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S.E.P.A. and approved for publication. Mention of trade names and commercial products does riot constitute endorsement or recommendation for use. NR 56 TC 44 Z9 44 U1 5 U2 47 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JAN 15 PY 2012 VL 258 IS 2 BP 226 EP 236 DI 10.1016/j.taap.2011.10.023 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 882RU UT WOS:000299582400008 PM 22115978 ER PT J AU Corsini, E Sangiovanni, E Avogadro, A Galbiati, V Viviani, B Marinovich, M Galli, CL Dell'Agli, M Germolec, DR AF Corsini, Emanuela Sangiovanni, Enrico Avogadro, Anna Galbiati, Valentina Viviani, Barbara Marinovich, Marina Galli, Corrado L. Dell'Agli, Mario Germolec, Dori R. TI In vitro characterization of the immunotoxic potential of several perfluorinated compounds (PFCs) SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Perfluorinated compounds; Immunosuppression; PPAR-alpha receptor; Cytokine; Whole blood assay ID NF-KAPPA-B; ACTIVATED RECEPTOR-ALPHA; SPRAGUE-DAWLEY RATS; PEROXISOME PROLIFERATOR; PERFLUOROOCTANOIC ACID; HUMORAL IMMUNITY; P65 SUBUNIT; CD RATS; MICE; EXPOSURE AB We have previously shown that PFOA and PFOS directly suppress cytokine secretion in immune cells, with different mechanisms of action. In particular, we have demonstrated a role for PPAR-alpha in PFOA-induced immunotoxicity, and that PFOS has an inhibitory effect on LPS-induced I-kappa B degradation. These studies investigate the immunomodulatory effects of four other PFCs, namely PFBS, PFOSA, PFDA, and fluorotelomer using in vitro assays. The release of the pro-inflammatory cytokines IL-6 and TNF-alpha was evaluated in lipolysaccharide (LPS)-stimulated human peripheral blood leukocytes ( hPBL) and in the human promyelocytic cell line THP-1, while the release of IL-10 and IFN-gamma was evaluated in phytohemagglutinin (PHA)-stimulated hPBL All PFCs suppressed LPS-induced TNF-alpha production in hPBL and THP-1 cells, while IL-6 production was suppressed by PFOSA, PFOS, PFDA and fluorotelomer. PFBS, PFOSA, PFOS, PFDA and fluorotelomer inhibited PHA-induced IL-10 release, while IFN-gamma secretion was affected by PFOSA, PFOS, PFDA and fluorotelomer. Leukocytes obtained from female donors appear to be more sensitive to the in vitro immunotoxic effects of PFCs when their responses are compared to the results obtained using leukocytes from male donors. Mechanistic investigations demonstrated that inhibition of TNF-alpha release in TIP-1 cells occurred at the transcriptional level. All PFCs, including PFOA and PFOS, decreased LPS-induced NF-kappa B activation. With the exception of PFOA, none of the PFCs tested was able to activate PPAR alpha driven transcription in transiently transfected THP-1 cells, excluding a role for PPAR alpha in the immunomodulation observed. PFBS and PFDA prevented LPS-induced I-kappa B degradation. Overall, these studies suggest that PFCs affect NF-kappa B activation, which directly suppresses cytokine secretion by immune cells. Our results indicate that PFOA is the least active of the PFCs examined followed by PFBS, PFDA, PFOS, PFOSA and fluorotelomer. (C) 2011 Elsevier Inc. All rights reserved. C1 [Corsini, Emanuela; Avogadro, Anna; Galbiati, Valentina; Viviani, Barbara; Marinovich, Marina; Galli, Corrado L.] Univ Milan, Dept Pharmacol Sci, Toxicol Lab, I-20133 Milan, Italy. [Sangiovanni, Enrico; Dell'Agli, Mario] Univ Milan, Dept Pharmacol Sci, Lab Pharmacognosy, I-20133 Milan, Italy. [Germolec, Dori R.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, NIH, Res Triangle Pk, NC USA. RP Corsini, E (reprint author), Univ Milan, Dept Pharmacol Sci, Toxicol Lab, Via Balzaretti 9, I-20133 Milan, Italy. EM emanuela.corsini@unimi.it RI Dell'Agli, Mario/E-5253-2011; OI Dell'Agli, Mario/0000-0001-5378-402X; Viviani, Barbara/0000-0002-0935-0459; Galli, Corrado Lodovico/0000-0003-0078-5488; Marinovich, Marina/0000-0003-0625-8101; SANGIOVANNI, ENRICO/0000-0003-2811-8628 FU National Institute of Environmental Health Sciences, National Institutes of Health FX We would like to thank Dr. Chad Blystone and Dr. Jamie DeWitt for their review and helpful suggestions. This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. NR 49 TC 46 Z9 48 U1 3 U2 43 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JAN 15 PY 2012 VL 258 IS 2 BP 248 EP 255 DI 10.1016/j.taap.2011.11.004 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 882RU UT WOS:000299582400010 PM 22119708 ER PT J AU van de Vijver, E Maddalena, A Sanal, O Holland, SM Uzel, G Madkaikar, M de Boer, M van Leeuwen, K Koker, MY Parvaneh, N Fischer, A Law, SKA Klein, N Tezcan, FI Unal, E Patiroglu, T Belohradsky, BH Schwartz, K Somech, R Kuijpers, TW Roos, D AF van de Vijver, Edith Maddalena, Anne Sanal, Ozden Holland, Steven M. Uzel, Gulbu Madkaikar, Manisha de Boer, Martin van Leeuwen, Karin Koker, M. Yavuz Parvaneh, Nima Fischer, Alain Law, S. K. Alex Klein, Nigel Tezcan, F. Ilhan Unal, Ekrem Patiroglu, Turkan Belohradsky, Bernd H. Schwartz, Klaus Somech, Raz Kuijpers, Taco W. Roos, Dirk TI Hematologically important mutations: Leukocyte adhesion deficiency (first update) SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article DE LAD-I; LAD-II; LAD-III; beta Integrins; GDP-fucose transporter; Kindlin-3 ID GDP-FUCOSE TRANSPORTER; CELL-SURFACE EXPRESSION; POINT MUTATION; BETA-2 INTEGRINS; GENETIC-ANALYSIS; CD18; PATIENT; TYPE-1; LAD; KINDLIN-3 AB Leukocyte adhesion deficiency (LAD) is an immunodeficiency caused by defects in the adhesion of leukocytes (especially neutrophils) to the blood vessel wall. As a result, patients with LAD suffer from severe bacterial infections and impaired wound healing, accompanied by neutrophilia. In LAD-I, mutations are found in ITGB2, the gene that encodes the beta subunit of the beta(2) integrins. This syndrome is characterized directly after birth by delayed separation of the umbilical cord. In the rare LAD-II disease, the fucosylation of selectin ligands is disturbed, caused by mutations in SLC35C1, the gene that encodes a GDP-fucose transporter of the Golgi system. LAD-II patients lack the H and Lewis Le(a) and Le(b) blood group antigens. Finally, in LAD-III (also called LAD-I/variant) the conformational activation of the hematopoietically expressed beta integrins is disturbed, leading to leukocyte and platelet dysfunction. This last syndrome is caused by mutations in FERMT3, encoding the kindlin-3 protein in all blood cells that is involved in the regulation of beta integrin conformation. (C) 2011 Elsevier Inc. All rights reserved. C1 [van de Vijver, Edith; de Boer, Martin; van Leeuwen, Karin; Kuijpers, Taco W.; Roos, Dirk] Sanquin Res, NL-1066 CX Amsterdam, Netherlands. [van de Vijver, Edith; de Boer, Martin; van Leeuwen, Karin; Kuijpers, Taco W.; Roos, Dirk] Univ Amsterdam, Acad Med Ctr, Landsteiner Lab, NL-1105 AZ Amsterdam, Netherlands. [van de Vijver, Edith; Kuijpers, Taco W.] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, NL-1105 AZ Amsterdam, Netherlands. [Maddalena, Anne] GeneDx, Gaithersburg, MD USA. [Sanal, Ozden; Tezcan, F. Ilhan] Hacettepe Univ, Div Immunol, Childrens Hosp, Ankara, Turkey. [Holland, Steven M.; Uzel, Gulbu] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Madkaikar, Manisha] King Edward Mem Hosp, ICMR, Natl Inst Immunohaematol, Bombay, Maharashtra, India. [Koker, M. Yavuz] Erciyes Univ, Immunol Lab, Kayseri, Turkey. [Koker, M. Yavuz] Erciyes Univ, Cappadocia BM Transplant Ctr, Kayseri, Turkey. [Parvaneh, Nima] Univ Tehran Med Sci, Infect Dis Res Ctr, Tehran, Iran. [Fischer, Alain] Necker Univ Hosp, Dept Pediat Immunol, Paris, France. [Fischer, Alain] Necker Univ Hosp, Inserm Res Unit 429, Paris, France. [Law, S. K. Alex] Nanyang Technol Univ, Sch Biol Sci, Singapore, Singapore. [Klein, Nigel] UCL, Great Ormond St Childrens Hosp, London, England. [Klein, Nigel] UCL, Inst Child Hlth, London, England. [Unal, Ekrem; Patiroglu, Turkan] Erciyes Univ, Div Pediat Immunol, Childrens Hosp, Kayseri, Turkey. [Belohradsky, Bernd H.] Univ Childrens Hosp, Dr von Haunersches Kinderspital, Munich, Germany. [Schwartz, Klaus] Univ Clin, Ulm, Germany. [Somech, Raz] Edmond & Lily Safra Childrens Hosp, Pediat Immunol Serv, Chaim Sheba Merd Ctr, Tel Hashomer, Israel. RP Roos, D (reprint author), Sanquin Res, Plesmanlaan 125, NL-1066 CX Amsterdam, Netherlands. EM d.roos@sanquin.nl RI koker, Mustafa Yavuz/A-7296-2012 OI koker, Mustafa Yavuz/0000-0001-7061-8525 FU Landsteiner Foundation for Blood Transfusion Research, Amsterdam, The Netherlands [LSBR 0619]; Jeffrey Modell Foundation FX EvdV was supported by the Landsteiner Foundation for Blood Transfusion Research, Amsterdam, The Netherlands (LSBR 0619). The Jeffrey Modell Foundation is acknowledged for their support to Dr Somech. NR 68 TC 43 Z9 43 U1 1 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD JAN 15 PY 2012 VL 48 IS 1 BP 53 EP 61 DI 10.1016/j.bcmd.2011.10.004 PG 9 WC Hematology SC Hematology GA 877MM UT WOS:000299186600012 PM 22134107 ER PT J AU Smrz, D Wilson, TM Metcalfe, DD Gilfillan, AM AF Smrz, Daniel Wilson, Todd M. Metcalfe, Dean D. Gilfillan, Alasdair M. TI Providing the TORC for cell cycle progression in neoplastic mast cells SO CELL CYCLE LA English DT Editorial Material ID MTORC1 C1 [Smrz, Daniel; Wilson, Todd M.; Metcalfe, Dean D.; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Gilfillan, AM (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM agilfillan@niaid.nih.gov RI Smrz, Daniel/D-4853-2014 OI Smrz, Daniel/0000-0003-0143-8744 NR 11 TC 0 Z9 1 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JAN 15 PY 2012 VL 11 IS 2 BP 210 EP 211 DI 10.4161/cc.11.2.18976 PG 2 WC Cell Biology SC Cell Biology GA 877GB UT WOS:000299164200006 PM 22214664 ER PT J AU Lee, JH Giovannetti, E Hwang, JH Petrini, I Wang, QY Voortman, J Wang, YH Steinberg, SM Funel, N Meltzer, PS Wang, YS Giaccone, G AF Lee, Jih-Hsiang Giovannetti, Elisa Hwang, Jin-Hyeok Petrini, Iacopo Wang, Qiuyan Voortman, Johannes Wang, Yonghong Steinberg, Seth M. Funel, Niccola Meltzer, Paul S. Wang, Yisong Giaccone, Giuseppe TI Loss of 18q22.3 Involving the Carboxypeptidase of Glutamate-like Gene Is Associated with Poor Prognosis in Resected Pancreatic Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; NUCLEOTIDE POLYMORPHISM ARRAYS; HOMOZYGOUS DELETIONS; DUCTAL ADENOCARCINOMA; TARGET GENES; CELL-LINES; IDENTIFICATION; REVEALS; CARCINOMA; MARKERS AB Purposes: Pancreatic cancer is the fourth leading cause of cancer-related death, and studies on the clinical relevance of its genomic imbalances are warranted. Experimental Design: Recurrent copy number alterations of cytobands and genes were analyzed by array comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens. Prognostic markers identified by aCGH were validated by PCR gene copy number assay in an independent validation cohort of 61 resected pancreatic cancers. The functions of gene identified were evaluated by proliferation, cell cycle, and migration assays in pancreatic cancer cells. Results: We showed recurrent copy number gains and losses in the first cohort. Loss of 18q22.3 was significantly associated with short-term overall survival in the first cohort (P = 0.019). This cytoband includes the carboxypeptidase of glutamate-like (CPGL) gene. CPGL gene deletion was associated with shorter overall survival in the validation cohort (P = 0.003). CPGL deletion and mutations of TP53 or Kras seem to be independent events. A Cox model analysis of the two cohorts combined showed that loss of 18q22.3/deletion of the CPGL gene was an independent poor prognostic factor for overall survival (HR = 2.72, P = 0.0007). Reconstitution of CPGL or its splicing variant CPGL-B into CPGL-negative pancreatic cancer cells attenuated cell growth, migration, and induced G(1) accumulation. Conclusion: Loss of 18q22.3/deletion of the CPGL gene is a poor prognostic marker in resected pancreatic cancer, and functional studies suggest the CPGL gene as growth suppressor gene in pancreatic cancer. Clin Cancer Res; 18(2); 524-33. (C) 2011 AACR. C1 [Lee, Jih-Hsiang; Hwang, Jin-Hyeok; Petrini, Iacopo; Wang, Qiuyan; Voortman, Johannes; Wang, Yisong; Giaccone, Giuseppe] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wang, Yonghong; Meltzer, Paul S.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. [Giovannetti, Elisa; Voortman, Johannes] Vrije Univ Amsterdam, Dept Med Oncol, Amsterdam, Netherlands. [Hwang, Jin-Hyeok] Seoul Natl Univ, Bundang Hosp, Dept Internal Med, Seoul, South Korea. [Funel, Niccola] Univ Pisa, Dept Oncol, Pisa, Italy. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Hwang, Jin-Hyeok/J-5735-2012; Petrini, Iacopo/K-7316-2016; Giaccone, Giuseppe/E-8297-2017; OI Petrini, Iacopo/0000-0002-7752-6866; Giaccone, Giuseppe/0000-0002-5023-7562; Giovannetti, Elisa/0000-0002-7565-7504; Funel, Niccola/0000-0002-5028-2363 FU National Cancer Institute at the NIH; NOW (Nederlandse Organisatie voor Wetenschappelijk Onderzoek-Netherlands Organization for Scientific Research) [91611046] FX This work was supported by the intramural research program of National Cancer Institute at the NIH and by the VENI grant from NOW (Nederlandse Organisatie voor Wetenschappelijk Onderzoek-Netherlands Organization for Scientific Research) with the project number 91611046. NR 47 TC 10 Z9 11 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2012 VL 18 IS 2 BP 524 EP 533 DI 10.1158/1078-0432.CCR-11-1903 PG 10 WC Oncology SC Oncology GA 879HR UT WOS:000299320800021 PM 22128300 ER PT J AU Shu, S Liu, X Kriebel, PW Daniels, MP Korn, ED AF Shu, Shi Liu, Xiong Kriebel, Paul W. Daniels, Mathew P. Korn, Edward D. TI Actin cross-linking proteins cortexillin I and II are required for cAMP signaling during Dictyostelium chemotaxis and development SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ADENYLYL-CYCLASE; LEADING-EDGE; BUNDLING PROTEINS; CLEAVAGE FURROW; CELL-MIGRATION; ACTIVATION; MYOSIN; CYTOKINESIS; RECEPTOR; LOCALIZATION AB Starvation induces Dictyostelium amoebae to secrete cAMP, toward which other amoebae stream, forming multicellular mounds that differentiate and develop into fruiting bodies containing spores. We find that the double deletion of cortexillin (ctx) I and II alters the actin cytoskeleton and substantially inhibits all molecular responses to extracellular cAMP. Synthesis of cAMP receptor and adenylyl cyclase A (ACA) is inhibited, and activation of ACA, RasC, and RasG, phosphorylation of extracellular signal regulated kinase 2, activation of TORC2, and stimulation of actin polymerization and myosin assembly are greatly reduced. As a consequence, cell streaming and development are completely blocked. Expression of ACA-yellow fluorescent protein in the ctxI/ctxII-null cells significantly rescues the wild-type phenotype, indicating that the primary chemotaxis and development defect is the inhibition of ACA synthesis and cAMP production. These results demonstrate the critical importance of a properly organized actin cytoskeleton for cAMP-signaling pathways, chemotaxis, and development in Dictyostelium. C1 [Shu, Shi; Liu, Xiong; Korn, Edward D.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Kriebel, Paul W.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Daniels, Mathew P.] NHLBI, Electron Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. RP Korn, ED (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM edk@nih.gov RI Korn, Edward/F-9929-2012 FU National, Heart, Lung, and Blood Institute; National Cancer Institute, National Institutes of Health FX We thank the Dictyostelium Stock Center for the ctxA-B-, ctxB-, abpA-, abpC-, and fim- cells and GFP-PI3K plasmids; Parvin Bolourani and Gerald Weeks for performing the Western blots for RasC and RasG; Patricia S. Connelly for scanning electron microscopy; Carole A. Parent for ACA and cAR1 antibodies and GFP-CRAC and ACA-YFP plasmids; Alan R. Kimmel for RBD-Byr bacteria and assistance in preparation of the RBD beads; Douglas N. Robinson for ctxA- cells; Angelica A. Noegel for AGHR2 cells; and Tian Jin for cAR1-YFP plasmids. This work was supported by the Intramural Research Programs of the National, Heart, Lung, and Blood Institute, and the National Cancer Institute, National Institutes of Health. NR 51 TC 10 Z9 10 U1 0 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JAN 15 PY 2012 VL 23 IS 2 BP 390 EP 400 DI 10.1091/mbc.E11-09-0764 PG 11 WC Cell Biology SC Cell Biology GA 876LC UT WOS:000299108000014 PM 22114350 ER PT J AU Dang, MT Yokoi, F Cheetham, CC Lu, J Vo, V Lovinger, DM Li, YQ AF Dang, Mai T. Yokoi, Fumiaki Cheetham, Chad C. Lu, Jun Viet Vo Lovinger, David M. Li, Yuqing TI An anticholinergic reverses motor control and corticostriatal LTD deficits in Dyt1 Delta GAG knock-in mice SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Dopamine receptor; Dystonia; Long-term depression; torsinA; Trihexyphenidyl ID LONG-TERM DEPRESSION; EARLY-ONSET DYSTONIA; TORSION DYSTONIA; SYNAPTIC PLASTICITY; MOUSE MODEL; ASSOCIATIVE PLASTICITY; STRIATAL DOPAMINE; RECEPTOR-BINDING; DORSAL STRIATUM; CA2+ CHANNELS AB DYT1 early-onset generalized torsion dystonia is an inherited movement disorder associated with mutations in DYT1 that codes for torsinA protein. The most common mutation seen in this gene is a trinucleotide deletion of GAG. We previously reported a motor control deficit on a beam-walking task in our Dyt1 Delta GAG knock-in heterozygous mice. In this report we show the reversal of this motor deficit with the anticholinergic trihexyphenidyl (THP), a drug commonly used to treat movement problems in dystonia patients. THP also restored the reduced corticostriatal long-term depression (LTD) observed in these mice. Corticostriatal LTD has long been known to be dependent on D2 receptor activation. In this mouse model, striatal D2 receptors were expressed at lower quantities in comparison to wild-type mice. Furthermore, the mice were also partially resistant to FPL64176, an agonist of L-type calcium channels that have been previously reported to cause severe dystonic-like symptoms in wild-type mice. Our findings collectively suggest that altered communication between cholinergic interneurons and medium spiny neurons is responsible for the LTD deficit and that this synaptic plasticity modification may be involved in the striatal motor control abnormalities in our mouse model of DYT1 dystonia. (C) 2011 Elsevier B.V. All rights reserved. C1 [Dang, Mai T.] Hosp Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Yokoi, Fumiaki; Li, Yuqing] Univ Florida, Coll Med, Dept Neurol, Gainesville, FL 32610 USA. [Cheetham, Chad C.; Lu, Jun] Univ Alabama, Sch Med, Dept Neurol, Ctr Neurodegenerat & Expt Therapeut, Birmingham, AL 35294 USA. [Viet Vo] Univ Illinois, Champaign, IL 61801 USA. [Lovinger, David M.] NIAAA, NIH, Rockville, MD 20852 USA. RP Li, YQ (reprint author), POB 100236, Gainesville, FL 32610 USA. EM yuqing.li@neurology.ufl.edu RI Li, Yuqing/G-1596-2011 OI Li, Yuqing/0000-0003-1211-5529 FU National Institutes of Health [NS37409, NS47466, NS47692, NS54246, NS57098, NS65273, NS72876, NS74423]; Dystonia Medical Research Foundation; Bachmann-Strauss Dystonia and Parkinson Foundation; State of Illinois; Beckman Institute for Advanced Science and Technology; Lucille P. Markey Charitable Trust; UAB and UF Departments of Neurology; Tyler's Hope for a Dystonia Cure, Inc.; Saga Medical School, Saga, Japan; Division of Intramural Clinical and Basic Research of the National Institute on Alcohol Abuse and Alcoholism/NIH FX We thank Mark P. DeAndrade, Dr.Yuanhu Jin, Miki Jinno, for their excellent technical assistance; Dr. David Standaert for helpful discussions; Melissa LaVigne for drawing Fig. 5. Work in the laboratory of Y.L. was supported by National Institutes of Health Grants NS37409, NS47466, NS47692, NS54246, NS57098, NS65273, NS72876, and NS74423, the Dystonia Medical Research Foundation, the Bachmann-Strauss Dystonia and Parkinson Foundation, start-up funds from the State of Illinois, the Beckman Institute for Advanced Science and Technology, the Lucille P. Markey Charitable Trust, UAB and UF Departments of Neurology, and Tyler's Hope for a Dystonia Cure, Inc. F.Y. was partly supported by Saga Medical School, Saga, Japan. D.M.L. was supported by the Division of Intramural Clinical and Basic Research of the National Institute on Alcohol Abuse and Alcoholism/NIH. NR 52 TC 29 Z9 29 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JAN 15 PY 2012 VL 226 IS 2 BP 465 EP 472 DI 10.1016/j.bbr.2011.10.002 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 871YW UT WOS:000298774600015 PM 21995941 ER PT J AU Skinbjerg, M Sibley, DR Javitch, JA Abi-Dargham, A AF Skinbjerg, Mette Sibley, David R. Javitch, Jonathan A. Abi-Dargham, Anissa TI Imaging the high-affinity state of the dopamine D-2 receptor in vivo: Fact or fiction? SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE D-2 receptor; High-affinity state; Agonist binding; PET imaging ID POSITRON-EMISSION-TOMOGRAPHY; PROTEIN-COUPLED RECEPTORS; BETA-ADRENERGIC-RECEPTORS; AMPHETAMINE-SENSITIZED ANIMALS; HETEROTRIMERIC G-PROTEINS; NONHUMAN PRIMATE BRAIN; ENDOGENOUS DOPAMINE; INTACT-CELLS; EX-VIVO; AGONIST RADIOTRACER AB Positron Emission Tomography (PET) has been used for more than three decades to image and quantify dopamine D-2 receptors (D2R) in vivo with antagonist radioligands but in the recent years agonist radioligands have also been employed. In vitro competition studies have demonstrated that agonists bind to both a high and a low-affinity state of the D(2)Rs, of which the high affinity state reflects receptors that are coupled to G-proteins and the low-affinity state reflects receptors uncoupled from G-proteins. In contrast, antagonists bind with uniform affinity to the total pool of receptors. Results of these studies led to the proposal that D(2)Rs exist in high and low-affinity states for agonists in vivo and sparked the development and use of agonist radioligands for PET imaging with the primary purpose of measuring the proportion of receptors in the high-affinity (activating) state. Although several lines of research support the presence of high and low-affinity states of D(2)Rs and their detection by in vivo imaging paradigms, a growing body of controversial data has now called this into question. These include both in vivo and ex vivo studies of anesthesia effects, rodent models with increased proportions of high-affinity state D(2)Rs as well as the molecular evidence for stable receptor-G-protein complexes. In this commentary we review these data and discuss the evidence for the in vivo existence of D(2)Rs configured in high and low-affinity states and whether or not the high-affinity state of the D2R can, in fact, be imaged in vivo with agonist radioligands. (C) 2011 Elsevier Inc.Elsevier Inc. All rights reserved. C1 [Skinbjerg, Mette; Abi-Dargham, Anissa] New York State Psychiat Inst & Hosp, Dept Translat Imaging, New York, NY 10032 USA. [Skinbjerg, Mette; Javitch, Jonathan A.; Abi-Dargham, Anissa] Columbia Univ, Dept Psychiat, New York, NY USA. [Javitch, Jonathan A.] Columbia Univ, Ctr Mol Recognit, New York, NY USA. [Javitch, Jonathan A.] New York State Psychiat Inst & Hosp, Dept Mol Therapeut, New York, NY 10032 USA. [Sibley, David R.] Natl Inst Neurol Disorders & Stroke, Mol Neuropharmacol Sect, Bethesda, MD USA. RP Skinbjerg, M (reprint author), New York State Psychiat Inst & Hosp, Dept Translat Imaging, 1051 Riverside Dr,Unit 31, New York, NY 10032 USA. EM ms4148@columbia.edu FU NIDA NIH HHS [K05 DA022413]; NIMH NIH HHS [R01 MH054137] NR 71 TC 27 Z9 27 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JAN 15 PY 2012 VL 83 IS 2 BP 193 EP 198 DI 10.1016/j.bcp.2011.09.008 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 874FO UT WOS:000298941000002 PM 21945484 ER PT J AU Wu, XF Scelo, G Purdue, MP Rothman, N Johansson, M Ye, YQ Wang, ZM Zelenika, D Moore, LE Wood, CG Prokhortchouk, E Gaborieau, V Jacobs, KB Chow, WH Toro, JR Zaridze, D Lin, J Lubinski, J Trubicka, J Szeszenia-Dabrowska, N Lissowska, J Rudnai, P Fabianova, E Mates, D Jinga, V Bencko, V Slamova, A Holcatova, I Navratilova, M Janout, V Boffetta, P Colt, JS Davis, FG Schwartz, KL Banks, RE Selby, PJ Harnden, P Berg, CD Hsing, AW Grubb, RL Boeing, H Vineis, P Clavel-Chapelon, F Palli, D Tumino, R Krogh, V Panico, S Duell, EJ Quiros, JR Sanchez, MJ Navarro, C Ardanaz, E Dorronsoro, M Khaw, KT Allen, NE Bueno-de-Mesquita, HB Peeters, PHM Trichopoulos, D Linseisen, J Ljungberg, B Overvad, K Tjonneland, A Romieu, I Riboli, E Stevens, VL Thun, MJ Diver, WR Gapstur, SM Pharoah, PD Easton, DF Albanes, D Virtamo, J Vatten, L Hveem, K Fletcher, T Koppova, K Cussenot, O Cancel-Tassin, G Benhamou, S Hildebrandt, MA Pu, X Foglio, M Lechner, D Hutchinson, A Yeager, M Fraumeni, JF Lathrop, M Skryabin, KG McKay, JD Gu, J Brennan, P Chanock, SJ AF Wu, Xifeng Scelo, Ghislaine Purdue, Mark P. Rothman, Nathaniel Johansson, Mattias Ye, Yuanqing Wang, Zhaoming Zelenika, Diana Moore, Lee E. Wood, Christopher G. Prokhortchouk, Egor Gaborieau, Valerie Jacobs, Kevin B. Chow, Wong-Ho Toro, Jorge R. Zaridze, David Lin, Jie Lubinski, Jan Trubicka, Joanna Szeszenia-Dabrowska, Neonilia Lissowska, Jolanta Rudnai, Peter Fabianova, Eleonora Mates, Dana Jinga, Viorel Bencko, Vladimir Slamova, Alena Holcatova, Ivana Navratilova, Marie Janout, Vladimir Boffetta, Paolo Colt, Joanne S. Davis, Faith G. Schwartz, Kendra L. Banks, Rosamonde E. Selby, Peter J. Harnden, Patricia Berg, Christine D. Hsing, Ann W. Grubb, Robert L., III Boeing, Heiner Vineis, Paolo Clavel-Chapelon, Francoise Palli, Domenico Tumino, Rosario Krogh, Vittorio Panico, Salvatore Duell, Eric J. Ramon Quiros, Jose Sanchez, Maria-Jose Navarro, Carmen Ardanaz, Eva Dorronsoro, Miren Khaw, Kay-Tee Allen, Naomi E. Bueno-de-Mesquita, H. Bas Peeters, Petra H. M. Trichopoulos, Dimitrios Linseisen, Jakob Ljungberg, Borje Overvad, Kim Tjonneland, Anne Romieu, Isabelle Riboli, Elio Stevens, Victoria L. Thun, Michael J. Diver, W. Ryan Gapstur, Susan M. Pharoah, Paul D. Easton, Douglas F. Albanes, Demetrius Virtamo, Jarmo Vatten, Lars Hveem, Kristian Fletcher, Tony Koppova, Kvetoslava Cussenot, Olivier Cancel-Tassin, Geraldine Benhamou, Simone Hildebrandt, Michelle A. Pu, Xia Foglio, Mario Lechner, Doris Hutchinson, Amy Yeager, Meredith Fraumeni, Joseph F., Jr. Lathrop, Mark Skryabin, Konstantin G. McKay, James D. Gu, Jian Brennan, Paul Chanock, Stephen J. TI A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23 SO HUMAN MOLECULAR GENETICS LA English DT Article ID POSTMENOPAUSAL WOMEN; KIDNEY CANCER; RISK-FACTORS; BODY-SIZE; EPIDEMIOLOGY; METAANALYSIS; TYPE-2 AB Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome- wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 x 10(-10) and P = 6.07 x 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR. C1 [Wood, Christopher G.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Scelo, Ghislaine; Johansson, Mattias; Gaborieau, Valerie; Romieu, Isabelle; McKay, James D.; Brennan, Paul] IARC, F-69008 Lyon, France. [Purdue, Mark P.; Rothman, Nathaniel; Wang, Zhaoming; Moore, Lee E.; Jacobs, Kevin B.; Chow, Wong-Ho; Toro, Jorge R.; Colt, Joanne S.; Hsing, Ann W.; Albanes, Demetrius; Hutchinson, Amy; Yeager, Meredith; Fraumeni, Joseph F., Jr.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Berg, Christine D.] NCI, Dept Hlth & Human Serv, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Wang, Zhaoming; Jacobs, Kevin B.; Hutchinson, Amy; Yeager, Meredith] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Zelenika, Diana; Foglio, Mario; Lechner, Doris; Lathrop, Mark] Ctr Natl Genotypage, Commissariat Energie Atom, Inst Genom, F-91000 Evry, France. [Prokhortchouk, Egor] Russian Acad Sci, Ctr Bioengn, Moscow 117312, Russia. [Zaridze, David] Russian NN Blokhin Canc Res Ctr, Moscow 115478, Russia. [Lubinski, Jan; Trubicka, Joanna] Pomeranian Med Univ, Dept Genet & Pathomorphol, Int Hereditary Canc Ctr, Szczecin, Poland. [Szeszenia-Dabrowska, Neonilia] Inst Occupat Med, Dept Epidemiol, PL-90950 Lodz, Poland. [Lissowska, Jolanta] Inst Oncol, PL-02781 Warsaw, Poland. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, PL-02781 Warsaw, Poland. [Rudnai, Peter] Natl Inst Environm Hlth, Dept Environm Epidemiol, H-1097 Budapest, Hungary. [Wu, Xifeng; Ye, Yuanqing; Lin, Jie; Hildebrandt, Michelle A.; Pu, Xia; Gu, Jian] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. [Fabianova, Eleonora; Koppova, Kvetoslava] Reg Author Publ Hlth Banska Bystrica, Banska 97556, Bystrica, Slovakia. [Mates, Dana] Natl Inst Publ Hlth, Bucharest 050463, Romania. [Jinga, Viorel] T Burghele Clin Urol, Bucharest, Romania. [Bencko, Vladimir; Slamova, Alena; Holcatova, Ivana] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague 12800 2, Czech Republic. [Navratilova, Marie] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno 65653, Czech Republic. [Janout, Vladimir] Palacky Univ, Olomouc 77515, Czech Republic. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo] Int Prevent Res Inst, F-69006 Lyon, France. [Davis, Faith G.] Univ Illinois, Sch Publ Hlth, Div Epidemiol Biostat, Chicago, IL 60612 USA. [Schwartz, Kendra L.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA. [Schwartz, Kendra L.] Wayne State Univ, Dept Family Med, Detroit, MI 48201 USA. [Banks, Rosamonde E.; Selby, Peter J.] St James Univ Hosp, Canc Res UK Ctr, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England. [Harnden, Patricia] St James Univ Hosp, Dept Pathol, Leeds LS9 7TF, W Yorkshire, England. [Grubb, Robert L., III; Vineis, Paolo] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Boeing, Heiner] German Inst Human Nutr, Dept Epidemiol, D-14558 Potsdam, Nuthetal, Germany. [Peeters, Petra H. M.; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London SW7 2AZ, England. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, MRC HPA Ctr Environm & Hlth, London SW7 2AZ, England. [Vineis, Paolo] HuGeF Fdn, I-10100 Turin, Italy. [Clavel-Chapelon, Francoise] Inst Gustave Roussy, INSERM, Ctr Res Epidemiol & Populat Hlth, U1018, F-94805 Villejuif, France. [Clavel-Chapelon, Francoise] Paris S Univ, UMRS 1018, F-94805 Villejuif, France. [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. [Krogh, Vittorio] Fdn IRCCS Ist Nazl Tumori, Nutr Epidemiol Unit, I-20133 Milan, Italy. [Panico, Salvatore] Univ Naples Federico 2, Dept Clin & Expt Med, I-80131 Naples, Italy. [Duell, Eric J.] Catalan Inst Oncol ICO IDIBELL, Unit Nutr Environm & Canc, Canc Epidemiol Res Program, Barcelona 08907, Spain. [Ramon Quiros, Jose] Publ Hlth & Hlth Planning Directorate, Asturias, Spain. [Sanchez, Maria-Jose] Andalusian Sch Publ Hlth, Granada 18011, Spain. [Sanchez, Maria-Jose; Navarro, Carmen; Ardanaz, Eva; Dorronsoro, Miren] CIBERESP, CIBER, Madrid 28029, Spain. [Navarro, Carmen] Reg Council Hlth & Consumer Affairs, Dept Epidemiol, Murcia 30008, Spain. [Ardanaz, Eva] Publ Hlth Inst Navarra, Pamplona, Spain. [Dorronsoro, Miren] Basque Reg Hlth Dept, Publ Hlth Div Gipuzkoa, San Sebastian 20113, Spain. [Khaw, Kay-Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Dept Gerontol, Cambridge CB2 0XY, England. [Allen, Naomi E.] Univ Oxford, Canc Epidemiol Unit, Nuffield Dept Clin Med, Oxford OX3 7LF, England. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Peeters, Petra H. M.] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, NL-3508 GA Utrecht, Netherlands. [Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Linseisen, Jakob] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Linseisen, Jakob] Helmholtz Ctr Munich, Inst Epidemiol 1, D-85764 Neuherberg, Germany. [Ljungberg, Borje] Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, S-90185 Umea, Sweden. [Overvad, Kim; Easton, Douglas F.] Aarhus Univ, Dept Epidemiol, Sch Publ Hlth, DK-8000 Aarhus, Denmark. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, DK-2100 Copenhagen, Denmark. [Stevens, Victoria L.; Thun, Michael J.; Diver, W. Ryan; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Pharoah, Paul D.] Univ Cambridge, Dept Oncol, Cambridge CB1 8RN, England. [Pharoah, Paul D.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FIN-00300 Helsinki, Finland. [Vatten, Lars; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7489 Trondheim, Norway. [Fletcher, Tony] Univ London, London Sch Hyg & Trop Med, London WC1H 9SH, England. [Cussenot, Olivier; Cancel-Tassin, Geraldine] Univ Paris 06, Tenon Hosp, APHP, CeRePP,ER2, F-75020 Paris, France. [Benhamou, Simone] INSERM, U946, F-75010 Paris, France. [Benhamou, Simone] Inst Gustave Roussy, CNRS, UMR8200, F-94805 Villejuif, France. [Skryabin, Konstantin G.] Kurchatov Sci Ctr, Moscow, Russia. RP Wu, XF (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. EM xwu@mdanderson.org; chanocks@mail.nih.gov RI Pu, Xia/H-2670-2012; Zaridze, David/K-5605-2013; Linseisen, Jakob/B-5353-2014; Krogh, Vittorio/K-2628-2016; Clavel-Chapelon, Francoise/G-6733-2014; Berg , Christine/K-1047-2014; Janout, Vladimir/M-5133-2014; SANCHEZ-PEREZ, MARIA JOSE/D-1087-2011; Albanes, Demetrius/B-9749-2015; Szeszenia-Dabrowska, Neonila/F-7190-2010; Purdue, Mark/C-9228-2016; Prokhortchouk, Egor/I-9108-2014; Benhamou, Simone/K-6554-2015; Panico, Salvatore/K-6506-2016; OI Linseisen, Jakob/0000-0002-9386-382X; Krogh, Vittorio/0000-0003-0122-8624; SANCHEZ-PEREZ, MARIA JOSE/0000-0003-4817-0757; Purdue, Mark/0000-0003-1177-3108; Duell, Eric J/0000-0001-5256-0163; Panico, Salvatore/0000-0002-5498-8312; mates, dana/0000-0002-6219-9807; Lissowska, Jolanta/0000-0003-2695-5799; Banks, Rosamonde/0000-0002-0042-8715; PALLI, Domenico/0000-0002-5558-2437; Cancel-Tassin, Geraldine/0000-0002-9583-6382 FU US National Institutes of Health (NIH) [R01CA 98897]; MD Anderson Research Trust; French Institut National du Cancer (INCa); National Cancer Institute (NCI), NIH FX The study was partially supported by the US National Institutes of Health (NIH) grant R01CA 98897 (X.W.), MD Anderson Research Trust (X.W.), French Institut National du Cancer (INCa) for those studies coordinated by IARC/CNG and the intramural research program of the National Cancer Institute (NCI), NIH for those studies coordinated by the NCI. NR 19 TC 35 Z9 39 U1 1 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JAN 15 PY 2012 VL 21 IS 2 BP 456 EP 462 DI 10.1093/hmg/ddr479 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 870GW UT WOS:000298658300019 PM 22010048 ER PT J AU Sithanandam, G Fornwald, LW Fields, JR Morris, NL Anderson, LM AF Sithanandam, Gunamani Fornwald, Laura W. Fields, Janet R. Morris, Nicole L. Anderson, Lucy M. TI Anti-tumor efficacy of naked siRNAs for ERBB3 or AKT2 against lung adenocarcinoma cell xenografts SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE lung cancer treatment; siRNA; ERBB3; AKT2; in vivo xenograft ID GROWTH-FACTOR RECEPTOR; INTERFERING RNAS; KINASE DOMAIN; CANCER; ACTIVATION; DELIVERY; TUMORIGENESIS; THERAPEUTICS; EXPRESSION; SURVIVAL AB The use of siRNAs against specific molecular targets has potential for cancer therapy but has been thought to be limited by the need for formulation to improve cellular uptake. Lung adenocarcinoma cells are markedly suppressed in culture by siRNAs to the receptor ERBB3 or its downstream signaling partner AKT2. We now demonstrate that naked, unformulated siRNAs to ERBB3 or AKT2, administered i.v. as saline solutions, 2 mu g/g five times per week for 3 weeks (total dose 30 mu g/g), were effective suppressors of growth of A549 human lung adenocarcinoma cell xenografts in athymic mice, 12 mice per group, in four different experiments. ERBB3 and AKT2 siRNAs each inhibited growth by 7090% on average, compared to saline-treated or untreated controls; a nonsilencing siRNA was without significant effect. Lesser but significant effects were noted with a total dose of 12 mu g/g. With the higher dose, effects persisted for several weeks after the end of treatment. Expected reductions of ERBB3 and AKT2 mRNAs and proteins occurred and correlated with decrease in tumor volume. There were no significant changes in serum cytokines. These results show that naked siRNAs to ERBB3 or AKT2 may have potential for lung cancer therapy. C1 [Fields, Janet R.; Anderson, Lucy M.] NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. [Sithanandam, Gunamani; Fornwald, Laura W.] SAIC Frederick Inc, Basic Sci Program, Frederick, MD USA. [Morris, Nicole L.] SAIC Frederick Inc, Lab Anim Sci Program, Frederick, MD USA. RP Anderson, LM (reprint author), NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, POB B,Bldg 538, Frederick, MD 21702 USA. EM LMAndersonPhD@gmail.com FU National Institutes of Health [HHSN261200800001E] FX Grant sponsor: National Institutes of Health (Intramural Research Program, Federal funds); Grant number: HHSN261200800001E NR 33 TC 7 Z9 7 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2012 VL 130 IS 2 BP 251 EP 258 DI 10.1002/ijc.26041 PG 8 WC Oncology SC Oncology GA 864QI UT WOS:000298254400002 PM 21387307 ER PT J AU Kadowaki, M Yoshioka, H Kamitani, H Watanabe, T Wade, PA Eling, TE AF Kadowaki, Mitsutoshi Yoshioka, Hiroki Kamitani, Hideki Watanabe, Takashi Wade, Paul A. Eling, Thomas E. TI DNA methylation-mediated silencing of nonsteroidal anti-inflammatory drug-activated gene (NAG-1/GDF15) in glioma cell lines SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE NAG-1; GDF15; glioblastoma; DNA methylation ID TGF-BETA SUPERFAMILY; GROWTH-FACTOR-BETA; FACTOR-15/MACROPHAGE INHIBITORY CYTOKINE-1; HUMAN GLIOBLASTOMA; TUMOR-SUPPRESSOR; P53 MUTATIONS; EXPRESSION; CANCER; NAG-1; PROGRESSION AB Nonsteroidal anti-inflammatory drug-activated gene, NAG-1, a transforming growth factor-beta member, is involved in tumor progression and development. The association between NAG-1 expression and development and progression of glioma has not been well defined. Glioblastoma cell lines have lower basal expression of NAG-1 than other gliomas and normal astrocytes. Most primary human gliomas have very low levels of NAG-1 expression. NAG-1 basal expression appeared to inversely correlate with tumor grade in glioma. Aberrant promoter hypermethylation is a common mechanism for silencing of tumor suppressor genes in cancer cells. In glioblastoma cell lines, NAG-1 expression was increased by the demethylating agent, 5-aza-2'-deoxycytidine. To investigate whether the NAG-1 gene was silenced by hypermethylation in glioblastoma, we examined DNA methylation status using genomic bisulfite sequencing. The NAG-1 promoter was densely methylated in several glioblastoma cell lines as well as in primary oligodendroglioma tumor samples, which have low basal expression of NAG-1. DNA methylation at two specific sites (-53 and +55 CpG sites) in the NAG-1 promoter was strongly associated with low NAG-1 expression. The methylation of the NAG-1 promoter at the -53 site blocks Egr-1 binding and thereby suppresses Nag-1 induction. Treatment of cells with low basal NAG-1 expression with NAG-1 inducer also did not increase NAG-1. Incubation with a demethylation chemical increased Nag-1 basal expression and subsequent incubation with a NAG-1 inducer increased NAG-1 expression. We concluded from these data that methylation of specific promoter sequences causes transcriptional silencing of the NAG-1 locus in glioma and may ultimately contribute to tumor progression. C1 [Kadowaki, Mitsutoshi; Wade, Paul A.; Eling, Thomas E.] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Kadowaki, Mitsutoshi; Yoshioka, Hiroki; Kamitani, Hideki; Watanabe, Takashi] Tottori Univ, Fac Med, Inst Neurol Sci, Div Neurosurg, Yonago, Tottori 683, Japan. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eling@niehs.nih.gov FU NIH, NIEHS FX Grant sponsor: NIH, NIEHS Intramural Research Program NR 40 TC 12 Z9 13 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2012 VL 130 IS 2 BP 267 EP 277 DI 10.1002/ijc.26082 PG 11 WC Oncology SC Oncology GA 864QI UT WOS:000298254400004 PM 21437897 ER PT J AU Castro, FA Ivansson, EL Schmitt, M Juko-Pecirep, I Kjellberg, L Hildesheim, A Gyllensten, UB Pawlita, M AF Castro, Felipe A. Ivansson, Emma L. Schmitt, Markus Juko-Pecirep, Ivana Kjellberg, Lennart Hildesheim, Allan Gyllensten, Ulf B. Pawlita, Michael TI Contribution of TMC6 and TMC8 (EVER1 and EVER2) variants to cervical cancer susceptibility SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cervical cancer; EVER1; EVER2; polymorphism; TMC6; TMC8 ID EPIDERMODYSPLASIA-VERRUCIFORMIS; HUMAN-PAPILLOMAVIRUS; GENETIC ASSOCIATION; LOCI; PATHOGENESIS; INFECTION; PROTEINS; GENOME; RISK; MAPS AB Cervical cancer (CxCa) is caused by persistent human papillomavirus (HPV) infection; genetic predisposition is also suspected to play a role. Our study is a targeted candidate gene follow-up based on: (i) strong clinical evidence demonstrating that mutations in the TMC6 and TMC8 (EVER1 and EVER2) genes associate with the HPV-associated disease epidermodysplasia verruciformis (EV) and (ii) recent epidemiological data suggesting a genetic susceptibility conferred by polymorphisms in such genes for skin and CxCa. Clarifying the association of the TMC6/8 genes with risk of CxCa will help in understanding why some HPV-infected women develop persistent infection, cervical lesions and eventually cancer while others do not. Twenty-two single nucleotide polymorphisms (SNPs) harboring the TMC6/8 genes were genotyped in 2,989 cases with cervical intraepithelial neoplasia grade III or invasive CxCa and 2,281 controls from the Swedish population. Association was evaluated in logistic regression models. Two SNPs displayed association with cervical disease: rs2290907 [odds ratio (OR)GGvsAA = 0.6, 95% confidence interval (95% CI): 0.30.9, p = 0.02)] and rs16970849 (ORAGvsGG = 0.8, 95% CI: 0.660.98, p = 0.03). The present data support the involvement of the TMC6/8 region in CxCa susceptibility but further analyses are needed to replicate our findings, fully characterize the region and understand the function of the genetic variants involved. C1 [Castro, Felipe A.; Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Rockville, MD USA. [Castro, Felipe A.; Schmitt, Markus; Pawlita, Michael] German Canc Res Ctr, Div Genome Modificat & Carcinogenesis, Heidelberg, Germany. [Ivansson, Emma L.; Juko-Pecirep, Ivana; Gyllensten, Ulf B.] Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Kjellberg, Lennart] Umea Univ, Dept Clin Sci Obstet & Gynaecol, Umea, Sweden. [Kjellberg, Lennart] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. RP Castro, FA (reprint author), NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Rockville, MD USA. EM felipe.castro@nih.gov RI Schmitt, Markus/B-6410-2008; Pawlita, Labor/C-9720-2011; Castro, Felipe/N-4241-2013; Hildesheim, Allan/B-9760-2015; Waterboer, Tim/G-1252-2010; OI Schmitt, Markus/0000-0002-7827-6694; Hildesheim, Allan/0000-0003-0257-2363; Pawlita, Michael/0000-0002-4720-8306 FU Swedish Cancer Foundation FX Grant sponsor: Swedish Cancer Foundation NR 26 TC 15 Z9 15 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2012 VL 130 IS 2 BP 349 EP 355 DI 10.1002/ijc.26016 PG 7 WC Oncology SC Oncology GA 864QI UT WOS:000298254400012 PM 21387292 ER PT J AU Humphrey, GW Mekhedov, E Blank, PS de Morree, A Pekkurnaz, G Nagaraju, K Zimmerberg, J AF Humphrey, Glen W. Mekhedov, Elena Blank, Paul S. de Morree, Antoine Pekkurnaz, Gulcin Nagaraju, Kanneboyina Zimmerberg, Joshua TI GREG cells, a dysferlin-deficient myogenic mouse cell line SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Dysferlin; Myoblast; Myotube; Resealing ID PLASMA-MEMBRANE REPAIR; NULL SKELETAL-MUSCLE; MUSCULAR-DYSTROPHY; REQUIREMENT; MYOFERLIN; RECOVERY; FUSION; MODEL; 2B AB The dysferlinopathies (e.g. LGMD2b, Myoshi myopathy) are progressive, adult-onset muscle wasting syndromes caused by mutations in the gene coding for dysferlin. Dysferlin is a large (similar to 200 kDa) membrane-anchored protein, required for maintenance of plasmalemmal integrity in muscle fibers. To facilitate analysis of dysferlin function in muscle cells, we have established a dysferlin-deficient myogenic cell line (GREG cells) from the A/J mouse, a genetic model for dysferlinopathy. GREG cells have no detectable dysferlin expression, but proliferate normally in growth medium and fuse into functional myotubes in differentiation medium. GREG myotubes exhibit deficiencies in plasma membrane repair, as measured by laser wounding in the presence of FM1-43 dye. Under the wounding conditions used, the majority (similar to 66%) of GREG myotubes lack membrane repair capacity, while no membrane repair deficiency was observed in dysferlin-normal C2C12 myotubes, assayed under the same conditions. We discuss the possibility that the observed heterogeneity in membrane resealing represents genetic compensation for dysferlin deficiency. Published by Elsevier Inc. C1 [Humphrey, Glen W.; Mekhedov, Elena; Blank, Paul S.; Pekkurnaz, Gulcin; Zimmerberg, Joshua] Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [de Morree, Antoine] Leiden Univ, Med Ctr, Ctr Human Genet, Leiden, Netherlands. [Nagaraju, Kanneboyina] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. RP Zimmerberg, J (reprint author), Eunice Kennedy Schriver Natl Inst Child Hlth & Hu, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM zimmerbj@mail.nih.gov OI de Morree, Antoine/0000-0002-8316-4531 FU NICHD, NIH; Jain Foundation FX This work was supported by the intramural program of the NICHD, NIH; and the Jain Foundation. NR 26 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD JAN 15 PY 2012 VL 318 IS 2 BP 127 EP 135 DI 10.1016/j.yexcr.2011.10.004 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 859VB UT WOS:000297902800004 PM 22020321 ER PT J AU Guez-Barber, D Fanous, S Harvey, BK Zhang, YQ Lehrmann, E Becker, KG Picciotto, MR Hope, BT AF Guez-Barber, Danielle Fanous, Sanya Harvey, Brandon K. Zhang, Yongqing Lehrmann, Elin Becker, Kevin G. Picciotto, Marina R. Hope, Bruce T. TI FACS purification of immunolabeled cell types from adult rat brain SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Glia; Genes; Microarray; qPCR ID TRANSLATIONAL PROFILING APPROACH; FLOW CYTOMETRIC ANALYSIS; HIPPOCAMPAL-NEURONS; NERVE-TERMINALS; STRIATUM; RECEPTOR; LOCALIZATION; EXPRESSION; SYSTEM; PDE10A AB Molecular analysis of brain tissue is greatly complicated by having many different classes of neurons and glia interspersed throughout the brain. Fluorescence-activated cell sorting (FACS) has been used to purify selected cell types from brain tissue. However, its use has been limited to brain tissue from embryos or transgenic mice with promoter-driven reporter genes. To overcome these limitations, we developed a FACS procedure for dissociating intact cell bodies from adult wild-type rat brains and sorting them using commercially available antibodies against intracellular and extracellular proteins. As an example, we isolated neurons using a NeuN antibody and confirmed their identity using microarray and real time PCR of mRNA from the sorted cells. Our FACS procedure allows rapid, high-throughput, quantitative assays of molecular alterations in identified cell types with widespread applications in neuroscience. Published by Elsevier B.V. C1 [Guez-Barber, Danielle; Fanous, Sanya; Harvey, Brandon K.; Hope, Bruce T.] NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, Baltimore, MD 21224 USA. [Zhang, Yongqing; Lehrmann, Elin; Becker, Kevin G.] NIA, Res Resources Branch, IRP, NIH,DHHS, Baltimore, MD 21224 USA. [Guez-Barber, Danielle; Picciotto, Marina R.] Yale Univ, Dept Psychiat, New Haven, CT 06508 USA. RP Hope, BT (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM danielle.guez@yale.edu; fanoussa@mail.nih.gov; brandon.harvey@nih.gov; yongqing.zhang@nih.gov; kevin.becker@nih.gov; marina.picciotto@yale.edu; bhope@intra.nida.nih.gov RI Picciotto, Marina/F-8747-2012; Hope, Bruce/A-9223-2010; OI Picciotto, Marina/0000-0002-4404-1280; Hope, Bruce/0000-0001-5804-7061; Lehrmann, Elin/0000-0002-9869-9475; Becker, Kevin/0000-0002-6794-6656 FU NIH; NIDA [F30DA024931]; NIA; NIH MSTP TG [T32GM07205]; Charles B.G. Murphy Chair in Psychiatry; State of Connecticut, Department of Mental Health and Addiction Services; [DA00436]; [DA14241] FX This research was supported by the Intramural Research Programs of the NIH, NIDA and NIA. DGB was supported by NIH MSTP TG T32GM07205, Award Number F30DA024931 from NIDA, and the Charles B.G. Murphy Chair in Psychiatry. MRP was supported by DA00436, DA14241 and the State of Connecticut, Department of Mental Health and Addiction Services. We thank Joe Chrest and Lee Blosser for technical assistance with FACS, as well as Sam Golden for assistance with rats. We thank Mary Kay Lobo and Eric Nestler for sharing open communication that helped improve this technique. NR 31 TC 47 Z9 47 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD JAN 15 PY 2012 VL 203 IS 1 BP 10 EP 18 DI 10.1016/j.jneumeth.2011.08.045 PG 9 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 859SM UT WOS:000297896100002 PM 21911005 ER PT J AU Huang, JH Fecher, P Ilgen, G Hu, KN Yang, J AF Huang, J. -H. Fecher, P. Ilgen, G. Hu, K. -N. Yang, J. TI Speciation of arsenite and arsenate in rice grain - Verification of nitric acid based extraction method and mass sample survey SO FOOD CHEMISTRY LA English DT Article DE Arsenite; Arsenate; Arsenic speciation; Rice grain; Nitric acid extraction ID HUMAN HEALTH; ION CHROMATOGRAPHY; RISK-ASSESSMENT; ICP-MS; SPECTROMETRY; METABOLITES; PRODUCTS; EXPOSURE; FLOUR AB Arsenite and arsenate speciation was performed in 121 commercially purchased samples of 12 rice types to understand their relative relevance in rice grain. General effectiveness of a recently developed extraction protocol based on 0.28 M nitric acid at 95 degrees C was verified by checking the recovery of total grain arsenic and by comparing arsenic speciation in NIST-CRM-1568a, NMIJ-CRM-7503a and IMEP-107 with certificated and literature values. The arsenic speciation highlights the predominance of arsenite in 115 and dimethylarsinic acid in six samples and common minor components including arsenate. monomethylarsonic acid and two unknown arsenical species. Our data also indicate potential influences of other trace elements on As speciation in rice grain. Averagely, arsenite accounts for 90% of inorganic grain arsenic regardless of geographic origin, rice type, grain size, cultural practice and polish treatment. The high arsenite predominance indicates an elevated toxic effect of arsenic in rice than is perceived to date. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Huang, J. -H.] Swiss Fed Inst Technol Zurich ETH Zurich, Inst Biogeochem & Pollutant Dynam, CH-8092 Zurich, Switzerland. [Fecher, P.] Bavarian Hlth & Food Safety Author LGL, D-91058 Erlangen, Germany. [Ilgen, G.] Univ Bayreuth, Bayreuth Ctr Ecol & Environm Res BayCEER, D-95440 Bayreuth, Germany. [Hu, K. -N.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Yang, J.] Sichuan Univ, Coll Architecture & Environm, Chengdu 610065, Peoples R China. RP Huang, JH (reprint author), Swiss Fed Inst Technol Zurich ETH Zurich, Inst Biogeochem & Pollutant Dynam, CH-8092 Zurich, Switzerland. EM jenhow.huang@env.ethz.ch FU Swiss National Science Foundation [PZ00P2_122212]; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX We are grateful to Momotaro Chio (Japan) and Cindy Wuz (Taiwan) for the help with collecting rice samples. We appreciate Eric Decker (OH, USA) for language editing. Financial support of J.H.H. comes from Swiss National Science Foundation Ambizione fellowship (PZ00P2_122212). K.N.H. is supported by a fellowship from the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 31 TC 37 Z9 39 U1 6 U2 47 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0308-8146 J9 FOOD CHEM JI Food Chem. PD JAN 15 PY 2012 VL 130 IS 2 BP 453 EP 459 DI 10.1016/j.foodchem.2011.07.059 PG 7 WC Chemistry, Applied; Food Science & Technology; Nutrition & Dietetics SC Chemistry; Food Science & Technology; Nutrition & Dietetics GA 838DQ UT WOS:000296267400033 ER PT J AU Clay, R CdeBaca, L De Cock, KM Goosby, E Guttmacher, A Jacobs, S Pablos-Mendez, A Polaski, S Sheldon, G Steinberg, D AF Clay, Robert CdeBaca, Luis De Cock, Kevin M. Goosby, Eric Guttmacher, Alan Jacobs, Susan Pablos-Mendez, Ariel Polaski, Sandra Sheldon, George Steinberg, Donald TI A call for coordinated and evidence-based action to protect children outside of family care SO LANCET LA English DT Editorial Material C1 [Clay, Robert; Pablos-Mendez, Ariel; Steinberg, Donald] US Agcy Int Dev, Washington, DC 20005 USA. [CdeBaca, Luis; Goosby, Eric; Jacobs, Susan; Sheldon, George] US Dept State, Washington, DC 20520 USA. [De Cock, Kevin M.] Ctr Dis Control & Prevent, Ctr Global Hlth, Atlanta, GA USA. [Guttmacher, Alan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Polaski, Sandra] US Dept Labor, Washington, DC 20210 USA. RP Clay, R (reprint author), US Agcy Int Dev, Washington, DC 20005 USA. EM rclay@usaid.gov NR 14 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JAN 14 PY 2012 VL 379 IS 9811 BP E6 EP E8 DI 10.1016/S0140-6736(11)61821-7 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 879GM UT WOS:000299317700002 PM 22166902 ER PT J AU Rasmussen, RA Siddappa, NB Lakhashe, SK Watkins, J Villinger, F Ibegbu, C Florese, RH Robert-Guroff, M Montefiori, DC Forthal, DN O'Connor, D Ruprecht, RM AF Rasmussen, Robert A. Siddappa, Nagadenahalli B. Lakhashe, Samir K. Watkins, Jennifer Villinger, Francois Ibegbu, Chris Florese, Ruth H. Robert-Guroff, Marjorie Montefiori, David C. Forthal, Donald N. O'Connor, David Ruprecht, Ruth M. CA Clade C Program Project Grp TI High-level, lasting antiviral immunity induced by a bimodal AIDS vaccine and boosted by live-virus exposure: prevention of viremia SO AIDS LA English DT Article DE AIDS; clade C; long-term immunity; prevention of viremia; simian/human immunodeficiency virus; vaccine ID SIMIAN-IMMUNODEFICIENCY-VIRUS; CLADE-C ENV; RHESUS MACAQUES; ANTIRETROVIRAL THERAPY; HIV VACCINES; HLA-B; REPLICATION; ANTIBODIES; INFECTION; LYMPHOCYTES AB Objective: To characterize the correlates of protection from systemic infection in a vaccinated rhesus macaque, RAt-9, which had been challenged sequentially with two related clade C simian/human immunodeficiency viruses (SHIV-Cs) yet remained aviremic for more than 5 years despite indirect evidence of cryptic infection. Design: To measure long-term anti-SHIV-C immunity, host genetics and gene-expression patterns for protective correlates. Methods: Long-term immune reactivity was evaluated and identification of virus in RAt-9 was attempted by RT-PCR analysis of concentrated plasma and blood transfer to CD8(+) cell-depleted infant macaques. Full MHC genotyping of RAt-9, TRIM5 alpha and KIR3DL allelic expression analysis of PBMC, and microarray gene expression analysis were performed. Results: All attempts to detect/isolate virus, including blood transfer to CD8(+) cell-depleted infant rhesus macaques, were negative, and the animal maintained normal levels of memory CD4(+) T cells in both peripheral blood and gut tissues. However, RAt-9 maintained high levels of anti-SHIV-C humoral and cellular immunity, including reactivity to nonvaccine neoantigens (Nef and Rev), up to 63 months postinitial challenge, suggesting chronic sub-threshold infection. RAt-9 expressed the Mamu A*001 allele negative for B*008 and B*017, had a B13 serotype, and had increased expression of killer-cell immunoglobulin-like receptors (KIRs) previously linked to favorable outcomes of lentiviral infection. Elements of the gene expression profiling coincided with genotyping results. RAt-9 also displayed CD8(+) cell noncytotoxic antiviral response (CNAR) activity. Conclusion: Monkey RAt-9 is the first example of a virus-exposed, persistently aviremic animal that has maintained long-term, high-level cellular and humoral antiviral immunity in the absence of an identifiable cryptic reservoir. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Rasmussen, Robert A.; Siddappa, Nagadenahalli B.; Lakhashe, Samir K.; Watkins, Jennifer; Ruprecht, Ruth M.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Rasmussen, Robert A.; Siddappa, Nagadenahalli B.; Lakhashe, Samir K.; Watkins, Jennifer; Ruprecht, Ruth M.] Harvard Univ, Sch Med, Boston, MA USA. [Villinger, Francois] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Villinger, Francois; Ibegbu, Chris] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Florese, Ruth H.; Robert-Guroff, Marjorie] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Durham, NC USA. [Forthal, Donald N.] Univ Calif Irvine, Div Infect Dis, Dept Med, Sch Med, Irvine, CA 92717 USA. [O'Connor, David] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. RP Ruprecht, RM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,JFB 809, Boston, MA 02215 USA. EM ruth_ruprecht@dfci.harvard.edu RI Lakhashe, Samir/F-1150-2014; OI Byrareddy, Siddappa /0000-0002-7423-1763; o'connor, david/0000-0003-2139-470X FU NIH [PO1 AI48240, RR-00165, RR00168]; Center for AIDS Research Immunology [P30 AI060354, P30 A01050409] FX Support is acknowledged by NIH grants PO1 AI48240 to R.A.R., S.L.H, J.G.E. and R.M.R., RR-00165 to the YNPRC, RR00168 to the NEPRC, and by Center for AIDS Research Immunology Core grants, P30 AI060354 and P30 A01050409. NR 39 TC 2 Z9 2 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 14 PY 2012 VL 26 IS 2 BP 149 EP 155 DI 10.1097/QAD.0b013e32834d3c4f PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 866KF UT WOS:000298378800004 PM 21941166 ER PT J AU Hazra, R Cohen, RA Gonin, R Monteiro, JP Hofer, CB Negra, MD Ruz, NP AF Hazra, Rohan Cohen, Rachel A. Gonin, Rene Monteiro, Jacqueline P. Hofer, Cristina B. Negra, Marinella D. Ruz, Noris P. CA NISDI Pediat Study Grp 2011 TI Lipid levels in the second year of life among HIV-infected and HIV-exposed uninfected Latin American children SO AIDS LA English DT Article DE antiretroviral; cholesterol; lipids; pediatrics; triglycerides ID ANTIRETROVIRAL THERAPY; CHILDHOOD; COHORT AB Background: Dyslipidemia is observed among older children and adults with HIV. We examined nonfasting cholesterol and triglycerides in two groups of 12-23-month-old Latin American children - HIV-infected vs. HIV-exposed but uninfected (HEU). Methods: HIV-infected and HEU children in Latin America and Jamaica were enrolled in an observational cohort. Eligibility for this analysis required having cholesterol and triglyceride results available during the second year of life. Results: HIV-infected (n = 83) children were slightly older at the time of lipid testing than the HEU (n 681). Forty percent of the HIV-infected children were on protease inhibitor-based antiretroviral therapy (ART); 41% were not on ART. There was no statistically significant difference in mean cholesterol concentrations (mg/dl) by HIV status; however, the HIV-infected children had higher mean triglyceride concentrations. The prevalence of high cholesterol (>200 mg/dl) and high triglycerides (>110 mg/dl) was higher among the HIV-infected vs. HEU. Among the HIV-infected children, mean cholesterol and triglyceride concentrations varied by ART. Children receiving no ART had a significantly lower mean cholesterol concentration. Those receiving protease inhibitor-containing ART had a significantly higher mean triglyceride concentration compared to the other two antiretroviral regimen groups. Conclusion: A greater proportion of HIV-infected children at 12-23 months have hyperlipidemia when compared to HEU children, with the highest triglyceride concentrations observed among those receiving protease inhibitor-containing ART, and the lowest cholesterol levels among those not receiving ART. Implications of these findings will require continued follow-up of HIV-infected children who initiate therapy early in life. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Hazra, Rohan] CRMC NICHD NIH, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. [Cohen, Rachel A.; Gonin, Rene] Westat Corp, Rockville, MD USA. [Monteiro, Jacqueline P.] Univ Sao Paulo, Dept Puericultura & Pediat, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto, Brazil. [Hofer, Cristina B.] Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil. [Negra, Marinella D.] Inst Infectol Emilio Ribas, Sao Paulo, Brazil. [Ruz, Noris P.] Hosp Infantil Mexico Dr Federico Gomez, Mexico City, DF, Mexico. RP Hazra, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, NIH, 6100 Execut Blvd,Room 4B11, Bethesda, MD 20892 USA. EM hazrar@mail.nih.gov RI Mussi-Pinhata, Marisa/G-6568-2012; Monteiro, Jacqueline/F-6987-2012 FU NICHD [N01-HD-3-3345, HHSN267200800001C, N01-HD-8-0001] FX Supported by NICHD Contract N01-HD-3-3345 (2002-2007) and by NICHD Contract HHSN267200800001C (NICHD Control N01-HD-8-0001) (2007-2012). NR 12 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 14 PY 2012 VL 26 IS 2 BP 235 EP 240 DI 10.1097/QAD.0b013e32834dc5fc PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 866KF UT WOS:000298378800013 PM 22008654 ER PT J AU Enoch, MA Zhou, ZF Kimura, M Mash, DC Yuan, QP Goldman, D AF Enoch, Mary-Anne Zhou, Zhifeng Kimura, Mitsuru Mash, Deborah C. Yuan, Qiaoping Goldman, David TI GABAergic Gene Expression in Postmortem Hippocampus from Alcoholics and Cocaine Addicts; Corresponding Findings in Alcohol-Naive P and NP Rats SO PLOS ONE LA English DT Article ID LONG-TERM POTENTIATION; GABA(A) RECEPTORS; ALLOSTERIC MODULATOR; DRINKING BEHAVIOR; PREFERRING RATS; ETHANOL; BRAIN; VULNERABILITY; NEUROGENESIS; DEPENDENCE AB Background: By performing identical studies in humans and rats, we attempted to distinguish vulnerability factors for addiction from neurobiological effects of chronic drug exposure. We focused on the GABAergic system within the hippocampus, a brain region that is a constituent of the memory/conditioning neuronal circuitry of addiction that is considered to be important in drug reinforcement behaviors in animals and craving and relapse in humans. Methodology: Using RNA-Seq we quantified mRNA transcripts in postmortem total hippocampus from alcoholics, cocaine addicts and controls and also from alcohol-naive, alcohol preferring (P) and non-preferring (NP) rats selectively bred for extremes of alcohol-seeking behavior that also show a general addictive tendency. A pathway-targeted analysis of 25 GABAergic genes encoding proteins implicated in GABA synthesis, metabolism, synaptic transmission and re-uptake was undertaken. Principal Findings: Directionally consistent and biologically plausible overlapping and specific changes were detected: 14/25 of the human genes and 12/25 of the rat genes showed nominally significant differences in gene expression (global p values: 9X10(-14), 7X10(-11) respectively). Principal FDR-corrected findings were that GABBR1 was down-regulated in alcoholics, cocaine addicts and P rats with congruent findings in NSF, implicated in GABAB signaling efficacy, potentially resulting in increased synaptic GABA. GABRG2, encoding the gamma2 subunit required for postsynaptic clustering of GABAA receptors together with GPHN, encoding the associated scaffolding protein gephryin, were both down-regulated in alcoholics and cocaine addicts but were both up-regulated in P rats. There were also expression changes specific to cocaine addicts (GAD1, GAD2), alcoholics (GABRA2) and P rats (ABAT, GABRG3). Conclusions/Significance: Our study confirms the involvement of the GABAergic system in alcoholism but also reveals a hippocampal GABA input in cocaine addiction. Congruent findings in human addicts and P rats provide clues to predisposing factors for alcohol and drug addiction. Finally, the results of this study have therapeutic implications. C1 [Enoch, Mary-Anne; Zhou, Zhifeng; Kimura, Mitsuru; Yuan, Qiaoping; Goldman, David] NIAAA, NIH, Bethesda, MD USA. [Mash, Deborah C.] Univ Miami, Sch Med, Miami, FL USA. RP Enoch, MA (reprint author), NIAAA, NIH, Bethesda, MD USA. EM maenoch@niaaa.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health; U.S. Public Health Service from National Institute on Drug Abuse [DA06227]; University of Miami Brain Bank FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, and by U.S. Public Health Service Grant from National Institute on Drug Abuse DA06227 for the human postmortem specimens from the University of Miami Brain Bank. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 35 Z9 35 U1 0 U2 24 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 JAN 13 PY 2012 VL 7 IS 1 AR e29369 DI 10.1371/journal.pone.0029369 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 906QI UT WOS:000301361500008 PM 22253714 ER PT J AU Le Nouen, C Toquin, D Muller, H Raue, R Kean, KM Langlois, P Cherbonnel, M Eterradossi, N AF Le Nouen, Cyril Toquin, Didier Mueller, Hermann Raue, Ruediger Kean, Katherine M. Langlois, Patrick Cherbonnel, Martine Eterradossi, Nicolas TI Different Domains of the RNA Polymerase of Infectious Bursal Disease Virus Contribute to Virulence SO PLOS ONE LA English DT Article ID CAPSID PROTEIN VP3; PANCREATIC NECROSIS VIRUS; GENOME SEGMENT-B; DOUBLE-STRANDED-RNA; BIRNAVIRUS VP1; ACTIVE-SITE; IN-VITRO; NONSTRUCTURAL PROTEIN; GENETIC-RELATIONSHIPS; PATHOGENIC PHENOTYPE AB Background: Infectious bursal disease virus (IBDV) is a pathogen of worldwide significance to the poultry industry. IBDV has a bi-segmented double-stranded RNA genome. Segments A and B encode the capsid, ribonucleoprotein and non-structural proteins, or the virus polymerase (RdRp), respectively. Since the late eighties, very virulent (vv) IBDV strains have emerged in Europe inducing up to 60% mortality. Although some progress has been made in understanding the molecular biology of IBDV, the molecular basis for the pathogenicity of vvIBDV is still not fully understood. Methodology, Principal Findings: Strain 88180 belongs to a lineage of pathogenic IBDV phylogenetically related to vvIBDV. By reverse genetics, we rescued a molecular clone (mc88180), as pathogenic as its parent strain. To study the molecular basis for 88180 pathogenicity, we constructed and characterized in vivo reassortant or mosaic recombinant viruses derived from the 88180 and the attenuated Cu-1 IBDV strains. The reassortant virus rescued from segments A of 88180 (A88) and B of Cu-1 (BCU1) was milder than mc88180 showing that segment B is involved in 88180 pathogenicity. Next, the exchange of different regions of BCU1 with their counterparts in B88 in association with A88 did not fully restore a virulence equivalent to mc88180. This demonstrated that several regions if not the whole B88 are essential for the in vivo pathogenicity of 88180. Conclusion, Significance: The present results show that different domains of the RdRp, are essential for the in vivo pathogenicity of IBDV, independently of the replication efficiency of the mosaic viruses. C1 [Le Nouen, Cyril; Toquin, Didier; Cherbonnel, Martine; Eterradossi, Nicolas] French Agcy Food Environm & Occupat Hlth Safety A, OIE Reference Lab Infect Bursal Dis, Immunol & Parasitol Unit, Ploufragan, France. [Mueller, Hermann; Raue, Ruediger] Univ Leipzig, Fac Vet Med, Inst Virol, Leipzig, Germany. [Kean, Katherine M.] Inst Pasteur, CNRS URA 3015, Paris, France. [Langlois, Patrick] French Agcy Food Environm & Occupat Hlth Safety A, Virus Genet & Biosecur Unit, Ploufragan, France. RP Le Nouen, C (reprint author), NIAID, LID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM nicolas.eterradossi@anses.fr FU AFSSA [PR-2002/7]; European Union; Conseil Regional de Bretagne FX This work was supported by AFSSA grant PR-2002/7, by European Union Concerted Action Cost 839, and by Conseil Regional de Bretagne. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 78 TC 13 Z9 13 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 13 PY 2012 VL 7 IS 1 AR e28064 DI 10.1371/journal.pone.0028064 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 906QI UT WOS:000301361500001 ER PT J AU Yang, HP Zuna, RE Schiffman, M Walker, JL Sherman, ME Landrum, LM Moxley, K Gold, MA Dunn, ST Allen, RA Zhang, R Long, R Wang, SS Wentzensen, N AF Yang, Hannah P. Zuna, Rosemary E. Schiffman, Mark Walker, Joan L. Sherman, Mark E. Landrum, Lisa M. Moxley, Katherine Gold, Michael A. Dunn, S. Terence Allen, Richard A. Zhang, Roy Long, Rodney Wang, Sophia S. Wentzensen, Nicolas TI Clinical and Pathological Heterogeneity of Cervical Intraepithelial Neoplasia Grade 3 SO PLOS ONE LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPES; EARLY END-POINTS; NATURAL-HISTORY; LOOP EXCISION; CANCER; LESIONS; WOMEN; DETERMINANTS; METAANALYSIS; PROGRESSION AB Objective: Cervical intraepithelial neoplasia grade 3 (CIN3), the immediate cervical cancer precursor, is a target of cervical cancer prevention. However, less than half of CIN3s will progress to cancer. Routine treatment of all CIN3s and the majority of CIN2s may lead to overtreatment of many lesions that would not progress. To improve our understanding of CIN3 natural history, we performed a detailed characterization of CIN3 heterogeneity in a large referral population in the US. Methods: We examined 309 CIN3 cases in the SUCCEED, a large population-based study of women with abnormal cervical cancer screening results. Histology information for 12 individual loop electrosurgical excision procedure (LEEP) segments was evaluated for each woman. We performed case-case comparisons of CIN3s to analyze determinants of heterogeneity and screening test performance. Results: CIN3 cases varied substantially by size (1-10 LEEP segments) and by presentation with concomitant CIN2 and CIN1. All grades of CINs were equally distributed over the cervical surface. In half of the women, CIN3 lesions were found as multiple distinct lesions on the cervix. Women with large and solitary CIN3 lesions were more likely to be older, have longer sexual activity span, and have fewer multiple high risk HPV infections. Screening frequency, but not HPV16 positivity, was an important predictor of CIN3 size. Large CIN3 lesions were also characterized by high-grade clinical test results. Conclusions: We demonstrate substantial heterogeneity in clinical and pathological presentation of CIN3 in a US population. Time since sexual debut and participation in screening were predictors of CIN3 size. We did not observe a preferential site of CIN3 on the cervical surface that could serve as a target for cervical biopsy. Cervical cancer screening procedures were more likely to detect larger CIN3s, suggesting that CIN3s detected by multiple independent diagnostic tests may represent cases with increased risk of invasion. C1 [Yang, Hannah P.; Schiffman, Mark; Sherman, Mark E.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Zuna, Rosemary E.; Dunn, S. Terence; Allen, Richard A.; Zhang, Roy] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Walker, Joan L.; Landrum, Lisa M.; Moxley, Katherine] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA. [Gold, Michael A.] Vanderbilt Univ, Dept Obstet & Gynecol, Nashville, TN USA. [Long, Rodney] Natl Lib Med, Bethesda, MD USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Div Canc Etiol, Duarte, CA USA. RP Yang, HP (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. EM yanghan@mail.nih.gov FU US National Cancer Institute, Division of Cancer Epidemiology and Genetics in the Hormonal and Reproductive Epidemiology Branch FX This work was supported by the intramural research program at the US National Cancer Institute, Division of Cancer Epidemiology and Genetics in the Hormonal and Reproductive Epidemiology Branch. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 7 Z9 10 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 13 PY 2012 VL 7 IS 1 AR e29051 DI 10.1371/journal.pone.0029051 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 906QI UT WOS:000301361500005 PM 22253702 ER PT J AU Thangudu, RR Bryant, SH Panchenko, AR Madej, T AF Thangudu, Ratna Rajesh Bryant, Stephen H. Panchenko, Anna R. Madej, Thomas TI Modulating Protein-Protein Interactions with Small Molecules: The Importance of Binding Hotspots SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein structures; molecular interactions; protein-protein interactions; drug development hotspots ID STRUCTURE-BASED DESIGN; INTERACTION INHIBITORS; CRYSTAL-STRUCTURE; DRUG DISCOVERY; GENE-ONTOLOGY; DATABASE; COMPLEX; DOMAIN; INTERFACES; SITES AB The modulation of protein-protein interactions (PPIs) by small drug-like molecules is a relatively new area of research and has opened up new opportunities in drug discovery. However, the progress made in this area is limited to a handful of known cases of small molecules that target specific diseases. With the increasing availability of protein structure complexes, it is highly important to devise strategies exploiting homologous structure space on a large scale for discovering putative PPIs that could be attractive drug targets. Here, we propose a scheme that allows performing large-scale screening of all protein complexes and finding putative small-molecule and/or peptide binding sites overlapping with protein-protein binding sites (so-called "multibinding sites"). We find more than 600 nonredundant proteins from 60 protein families with multibinding sites. Moreover, we show that the multibinding sites are mostly observed in transient complexes, largely overlap with the binding hotspots and are more evolutionarily conserved than other interface sites. We investigate possible mechanisms of how small molecules may modulate protein-protein binding and discuss examples of new candidates for drug design. Published by Elsevier Ltd. C1 [Thangudu, Ratna Rajesh; Bryant, Stephen H.; Panchenko, Anna R.; Madej, Thomas] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, 8600 Rockville Pike,Bldg 38A, Bethesda, MD 20894 USA. EM panch@ncbi.nlm.nih.gov; madej@ncbi.nlm.nih.gov FU National Institutes of Health/Department of Health and Human Services (National Library of Medicine) FX This work was supported by National Institutes of Health/Department of Health and Human Services (Intramural Research Program of the National Library of Medicine). NR 58 TC 28 Z9 28 U1 6 U2 27 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 13 PY 2012 VL 415 IS 2 BP 443 EP 453 DI 10.1016/j.jmb.2011.12.026 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 888VK UT WOS:000300032500017 PM 22198293 ER PT J AU Huppke, P Brende, C Kalscheuer, V Korenke, GC Marquardt, I Freisinger, P Christodoulou, J Hillebrand, M Pitelet, G Wilson, C Gruber-Sedlmayr, U Ullmann, R Haas, S Elpeleg, O Nurnberg, G Nurnberg, P Dad, S Moller, LB Kaler, SG Gartner, J AF Huppke, Peter Brende, Cornelia Kalscheuer, Vera Korenke, Georg Christoph Marquardt, Iris Freisinger, Peter Christodoulou, John Hillebrand, Merle Pitelet, Gaele Wilson, Callum Gruber-Sedlmayr, Ursula Ullmann, Reinhard Haas, Stefan Elpeleg, Orly Nuernberg, Gudrun Nuernberg, Peter Dad, Shzeena Moller, Lisbeth Birk Kaler, Stephen G. Gaertner, Jutta TI Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ACETYL-COA TRANSPORTER; DOMINANT SPASTIC PARAPLEGIA; MENKES DISEASE; CANDIDATE GENE; PROTEIN; ENCODES; METABOLISM; FEATURES; DEFECTS; ATROPHY AB Low copper and ceruloplasmin in serum are the diagnostic hallmarks for Menkes disease, Wilson disease, and aceruloplasminemia. We report on five patients from four unrelated families with these biochemical findings who presented with a lethal autosomal-recessive syndrome of congenital cataracts, hearing loss, and severe developmental delay. Cerebral MRI showed pronounced cerebellar hypoplasia and hypomyelination. Homozygosity mapping was performed and displayed a region of commonality among three families at chromosome 3q25. Deep sequencing and conventional sequencing disclosed homozygous or compound heterozygous mutations for all affected subjects in SLC33A1 encoding a highly conserved acetylCoA transporter (AT-1) required for acetylation of multiple gangliosides and glycoproteins. The mutations were found to cause reduced or absent AT-1 expression and abnormal intracellular localization of the protein. We also showed that AT-1 knockdown in HepG2 cells leads to reduced ceruloplasmin secretion, indicating that the low copper in serum is due to reduced ceruloplasmin levels and is not a sign of copper deficiency. The severity of the phenotype implies an essential role of AT-1 in proper posttranslational modification of numerous proteins, without which normal lens and brain development is interrupted. Furthermore, AT-1 defects are a new and important differential diagnosis in patients with low copper and ceruloplasmin in serum. C1 [Huppke, Peter; Brende, Cornelia; Hillebrand, Merle; Gaertner, Jutta] Univ Gottingen, Dept Pediat & Pediat Neurol, D-37075 Gottingen, Germany. [Kalscheuer, Vera; Ullmann, Reinhard] Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany. [Korenke, Georg Christoph; Marquardt, Iris] Childrens Hosp, Dept Neuropediat, D-26133 Oldenburg, Germany. [Freisinger, Peter] Klinikum Steinenberg, Dept Pediat, D-72764 Reutlingen, Germany. [Christodoulou, John] Univ Sydney, Childrens Hosp Westmead, Western Sydney Genet Program, Westmead, NSW 2145, Australia. [Christodoulou, John] Univ Sydney, Sydney Med Sch, Discipline Genet Med, Westmead, NSW 2145, Australia. [Christodoulou, John] Univ Sydney, Sydney Med Sch, Discipline Paediat & Child Hlth, Westmead, NSW 2145, Australia. [Pitelet, Gaele] CHU Nice, Serv Neuropediat, F-6200 Nice, France. [Wilson, Callum] Starship Childrens Hosp, Natl Metab Serv, Auckland 1142, New Zealand. [Gruber-Sedlmayr, Ursula] Med Univ Graz, Dept Pediat, A-8010 Graz, Austria. [Haas, Stefan] Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany. [Elpeleg, Orly] Hebrew Univ Jerusalem, Med Ctr, Dept Genet & Metab Dis, Monique & Jacques Roboh Dept Genet Res, IL-91050 Jerusalem, Israel. [Nuernberg, Gudrun; Nuernberg, Peter] Univ Cologne, Cologne Ctr Genom, CMMC, D-50931 Cologne, Germany. [Nuernberg, Gudrun; Nuernberg, Peter] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany. [Dad, Shzeena; Moller, Lisbeth Birk] Kennedy Ctr, Dept Appl Human Mol Genet, DK-2600 Glostrup, Denmark. [Kaler, Stephen G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Human Copper Metab, Mol Med Program, NIH, Bethesda, MD 20814 USA. RP Huppke, P (reprint author), Univ Gottingen, Dept Pediat & Pediat Neurol, D-37075 Gottingen, Germany. EM phuppke@med.uni-goettingen.de RI Christodoulou, John/E-5866-2015; OI Christodoulou, John/0000-0002-8431-0641; Kalscheuer, Vera/0000-0001-6898-3259 FU European Union [241995]; GENCODYS; National Institutes of Health, Bethesda, MD [HD008768-08]; German Research Foundation [GA 354/9-1] FX We thank Ines Muller and Melanie Bienek for excellent technical assistance. Part of this work was financed by the European Union's Seventh Framework Program under grant agreement number 241995, project GENCODYS, the Intramural Research Program of the National Institutes of Health, Bethesda, MD (Project #HD008768-08), and the German Research Foundation (GA 354/9-1). NR 22 TC 25 Z9 28 U1 2 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JAN 13 PY 2012 VL 90 IS 1 BP 61 EP 68 DI 10.1016/j.ajhg.2011.11.030 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 880LR UT WOS:000299409100005 PM 22243965 ER PT J AU Pullen, NA Barnstein, BO Falanga, YT Wang, ZQ Suzuki, R Tamang, TDL Khurana, MC Harry, EA Draber, P Bunting, KD Mizuno, K Wilson, BS Ryan, JJ AF Pullen, Nicholas A. Barnstein, Brian O. Falanga, Yves T. Wang, Zhengqi Suzuki, Ryo Tamang, Tenchee D. Lama Khurana, Michele C. Harry, Emily A. Draber, Petr Bunting, Kevin D. Mizuno, Kazuya Wilson, Bridget S. Ryan, John J. TI Novel Mechanism for Fc epsilon RI-mediated Signal Transducer and Activator of Transcription 5 (STAT5) Tyrosine Phosphorylation and the Selective Influence of STAT5B over Mast Cell Cytokine Production SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALLERGIC RESPONSES; PROLIFERATION; EXPRESSION; SURVIVAL; DOMAINS; PATHWAY; ASTHMA; KINASE; GAB2; DEGRANULATION AB Previous studies indicate that STAT5 expression is required for mast cell development, survival, and IgE-mediated function. STAT5 tyrosine phosphorylation is swiftly and transiently induced by activation of the high affinity IgE receptor, Fc epsilon RI. However, the mechanism for this mode of activation remains unknown. In this study we observed that STAT5 co-localizes with Fc epsilon RI in antigen-stimulated mast cells. This localization was supported by cholesterol depletion of membranes, which ablated STAT5 tyrosine phosphorylation. Through the use of various pharmacological inhibitors and murine knock-out models, we found that IgE-mediated STAT5 activation is dependent upon Fyn kinase, independent of Syk, PI3K, Akt, Bruton's tyrosine kinase, and JAK2, and enhanced in the context of Lyn kinase deficiency. STAT5 immunoprecipitation revealed that unphosphorylated protein preassociates with Fyn and that this association diminishes significantly during mast cell activation. SHP-1 tyrosine phosphatase deficiency modestly enhanced STAT5 phosphorylation. This effect was more apparent in the absence of Gab2, a scaffolding protein that docks with multiple negative regulators, including SHP-1, SHP-2, and Lyn. Targeting of STAT5A or B with specific siRNA pools revealed that IgE-mediated mast cell cytokine production is selectively dependent upon the STAT5B isoform. Altogether, these data implicate Fyn as the major positive mediator of STAT5 after Fc epsilon RI engagement and demonstrate importantly distinct roles for STAT5A and STAT5B in mast cell function. C1 [Pullen, Nicholas A.; Barnstein, Brian O.; Falanga, Yves T.; Tamang, Tenchee D. Lama; Khurana, Michele C.; Harry, Emily A.; Ryan, John J.] Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. [Pullen, Nicholas A.; Barnstein, Brian O.; Falanga, Yves T.; Tamang, Tenchee D. Lama; Khurana, Michele C.; Harry, Emily A.; Ryan, John J.] Virginia Commonwealth Univ, Asthma & Allerg Dis Cooperat Res Ctr, Richmond, VA 23284 USA. [Wang, Zhengqi; Bunting, Kevin D.] Emory Univ, Aflac Canc Ctr Childrens Healthcare Atlanta, Atlanta, GA 30345 USA. [Wang, Zhengqi; Bunting, Kevin D.] Emory Univ, Dept Pediat, Atlanta, GA 30345 USA. [Suzuki, Ryo] NIAMS, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. [Draber, Petr] Acad Sci Czech Republic, Dept Signal Transduct, Inst Mol Genet, Prague 4, Czech Republic. [Mizuno, Kazuya] Tokyo Metropolitan Org Med Res, Tokyo Metropolitan Inst Neurosci, Tokyo 1838526, Japan. [Wilson, Bridget S.] Univ New Mexico, Dept Pathol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. RP Ryan, JJ (reprint author), Virginia Commonwealth Univ, Dept Biol, 1000 W Cary St, Richmond, VA 23284 USA. EM jjryan@vcu.edu RI Draber, Petr/G-3412-2014 OI Draber, Petr/0000-0002-3986-2025 FU National Institutes of Health [1R01 AI59638, R01DK059380, AI051575, GM065794]; Virginia Commonwealth University [U19A1077435]; Ministry of Education, Youth and Sports of the Czech Republic [1M0506]; Grant Agency of the Czech Republic [P302/10/1759, 301/09/1826] FX This work was supported, in whole or in part, by National Institutes of Health Grants 1R01 AI59638 (to J. R.), R01DK059380 (to K. D. B.), and AI051575 and GM065794 (to B. S. W.). This work was also supported by Virginia Commonwealth University Allergy Core Grant U19A1077435, Ministry of Education, Youth and Sports of the Czech Republic Project 1M0506 (to P. D.), and Grant Agency of the Czech Republic Grants P302/10/1759 and 301/09/1826 (to P. D.). NR 43 TC 11 Z9 12 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 13 PY 2012 VL 287 IS 3 BP 2045 EP 2054 DI 10.1074/jbc.M111.311142 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 879HT UT WOS:000299321000045 PM 22130676 ER PT J AU Lonsdorf, AS Kramer, BF Fahrleitner, M Schonberger, T Gnerlich, S Ring, S Gehring, S Schneider, SW Kruhlak, MJ Meuth, SG Nieswandt, B Gawaz, M Enk, AH Langer, HF AF Lonsdorf, Anke S. Kraemer, Bjoern F. Fahrleitner, Manuela Schoenberger, Tanja Gnerlich, Stephan Ring, Sabine Gehring, Sarah Schneider, Stefan W. Kruhlak, Michael J. Meuth, Sven G. Nieswandt, Bernhard Gawaz, Meinrad Enk, Alexander H. Langer, Harald F. TI Engagement of alpha IIb beta 3 (GPIIb/IIIa) with alpha nu beta 3 Integrin Mediates Interaction of Melanoma Cells with Platelets A CONNECTION TO HEMATOGENOUS METASTASIS SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CONFORMATION-SPECIFIC BLOCKADE; ENDOTHELIAL PROGENITOR CELLS; SINGLE-CHAIN ANTIBODIES; GLYCOPROTEIN IB-ALPHA; IN-VITRO; ADHERENT PLATELETS; COUNTER-RECEPTOR; LUNG METASTASIS; VESSEL WALL; V INTEGRINS AB A mutual relationship exists between metastasizing tumor cells and components of the coagulation cascade. The exact mechanisms as to how platelets influence blood-borne metastasis, however, remain poorly understood. Here, we used murine B16 melanoma cells to observe functional aspects of how platelets contribute to the process of hematogenous metastasis. We found that platelets interfere with a distinct step of the metastasis cascade, as they promote adhesion of melanoma cells to the endothelium in vitro under shear conditions. Constitutively active platelet receptor GPIIb/IIIa (integrin alpha IIb beta 3) expressed on Chinese hamster ovary cells promoted melanoma cell adhesion in the presence of fibrinogen, whereas blocking antibodies to a nu beta 3 integrin on melanoma cells or to GPIIb/IIIa significantly reduced melanoma cell adhesion to platelets. Furthermore, using intravital microscopy, we observed functional platelet-melanoma cell interactions, as platelet depletion resulted in significantly reduced melanoma cell adhesion to the injured vascular wall in vivo. Using a mouse model of hematogenous metastasis to the lung, we observed decreased metastasis of B16 melanoma cells to the lung by treatment with a mAb blocking the a nu subunit of a nu beta 3 integrin. This effect was significantly reduced when platelets were depleted in vivo. Thus, the engagement of GPIIb/IIIa with a nu beta 3 integrin interaction mediates tumor cell-platelet interactions and highlights how this interaction is involved in hematogenous tumor metastasis. C1 [Lonsdorf, Anke S.; Ring, Sabine; Enk, Alexander H.] Univ Heidelberg, Dept Dermatol, Univ Hosp, D-69115 Heidelberg, Germany. [Kraemer, Bjoern F.; Fahrleitner, Manuela; Schoenberger, Tanja; Gnerlich, Stephan; Gehring, Sarah; Gawaz, Meinrad; Langer, Harald F.] Univ Tubingen, Dept Cardiovasc Med, Univ Hosp, D-72076 Tubingen, Germany. [Schneider, Stefan W.] Univ Heidelberg, Dept Dermatol, D-68167 Mannheim, Germany. [Schneider, Stefan W.] Med Fac Mannheim, D-68167 Mannheim, Germany. [Kruhlak, Michael J.] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Meuth, Sven G.] Univ Munster, Inst Physiol, Neurol Clinic Inflammatory Disorders Nervous Syst, D-48149 Munster, Germany. [Nieswandt, Bernhard] Univ Wurzburg, Dept Vasc Med, Deutsch Forsch Gemeinschaft Res Ctr Expt Biomed, D-97080 Wurzburg, Germany. [Nieswandt, Bernhard] Univ Wurzburg, Rudolf Virchow Ctr, Deutsch Forsch Gemeinschaft Res Ctr Expt Biomed, D-97080 Wurzburg, Germany. RP Lonsdorf, AS (reprint author), Univ Heidelberg, Dept Dermatol, Univ Hosp, Vossstr 11, D-69115 Heidelberg, Germany. EM anke.lonsdorf@med.uni-heidelberg.de; harald.langer@med.uni-tuebingen.de FU National Institutes of Health; University of Tubingen (Center for Interdisciplinary Clinical Research); Volkswagen Foundation; Wilhelm Sander Foundation; Deutsche Forschungsgemeinschaft; Ruprecht-Karls-University of Heidelberg; Clinical Research Unit of German Research Council [KFO 274]; Deutsche Forschungsgemeinschaft [SFB/TR23] FX This work was supported, in whole or in part, by National Institutes of Health research career transition award (to A. S. L.). This work was also supported by the University of Tubingen (Center for Interdisciplinary Clinical Research, junior group program), the Volkswagen Foundation (Lichtenberg program), and Wilhelm Sander Foundation (to H. F. L.).; Supported in part by Deutsche Forschungsgemeinschaft and the Olympia-Morata-Programme of the Ruprecht-Karls-University of Heidelberg.; Members of the Tuebingen Platelet Investigative Consortium funded by the Clinical Research Unit KFO 274 of the German Research Council.; Supported by Deutsche Forschungsgemeinschaft Grant SFB/TR23. NR 63 TC 33 Z9 37 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 13 PY 2012 VL 287 IS 3 BP 2168 EP 2178 DI 10.1074/jbc.M111.269811 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 879HT UT WOS:000299321000056 PM 22102277 ER PT J AU Lazzaro, F Novarina, D Amara, F Watt, DL Stone, JE Costanzo, V Burgers, PM Kunkel, TA Plevani, P Muzi-Falconil, M AF Lazzaro, Federico Novarina, Daniele Amara, Flavio Watt, Danielle L. Stone, Jana E. Costanzo, Vincenzo Burgers, Peter M. Kunkel, Thomas A. Plevani, Paolo Muzi-Falconil, Marco TI RNase H and Postreplication Repair Protect Cells from Ribonucleotides Incorporated in DNA SO MOLECULAR CELL LA English DT Article ID AICARDI-GOUTIERES-SYNDROME; YEAST REPLICATIVE POLYMERASES; SACCHAROMYCES-CEREVISIAE; CRYSTAL-STRUCTURE; TRANSLESION SYNTHESIS; TOPOISOMERASE-I; DAMAGE; ZETA; SPECIFICITY; INSTABILITY AB The chemical identity and integrity of the genome is challenged by the incorporation of ribonucleoside triphosphates (rNTPs) in place of deoxyribonucleoside triphosphates (dNTPs) during replication. Misincorporation is limited by the selectivity of DNA replicases. We show that accumulation of ribonucleoside monophosphates (rNMPs) in the genome causes replication stress and has toxic consequences, particularly in the absence of RNase H1 and RNase H2, which remove rNMPs. We demonstrate that postreplication repair (PAR) pathways MMS2-dependent template switch and Pol zeta-dependent bypass are crucial for tolerating the presence of rNMPs in the chromosomes; indeed, we show that Pol efficiently replicates over 1-4 rNMPs. Moreover, cells lacking RNase H accumulate mono- and polyu-biquitylated PCNA and have a constitutively activated PRR. Our findings describe a crucial function for RNase H1, RNase H2, template switch, and translesion DNA synthesis in overcoming rNTPs misincorporated during DNA replication, and may be relevant for the pathogenesis of Aicardi-Goutieres syndrome. C1 [Lazzaro, Federico; Novarina, Daniele; Amara, Flavio; Plevani, Paolo; Muzi-Falconil, Marco] Univ Milan, Dipartimento Sci Biomol & Biotecnol, I-20133 Milan, Italy. [Watt, Danielle L.; Stone, Jana E.; Kunkel, Thomas A.] Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Watt, Danielle L.; Stone, Jana E.; Kunkel, Thomas A.] Natl Inst Environm Hlth Sci, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Costanzo, Vincenzo] Canc Res UK, Genome Stabil Unit, Clare Hall Labs, London Res Inst, S Mimms EN6 3LD, Herts, England. [Burgers, Peter M.] Washington Univ, Dept Biochem & Mol Biophys, Sch Med, St Louis, MO 63110 USA. RP Plevani, P (reprint author), Univ Milan, Dipartimento Sci Biomol & Biotecnol, I-20133 Milan, Italy. EM paolo.plevani@unimi.it; marco.muzifalconi@unimi.it RI Lazzaro, Federico/J-3585-2013; Muzi-Falconi, Marco/A-6035-2012; OI Lazzaro, Federico/0000-0001-6415-2925; Muzi-Falconi, Marco/0000-0001-7046-6090; PLEVANI, PAOLO/0000-0003-1869-2626 FU AIRC; MIUR [FIRB RBFR10S3UQ]; Fondazione Cariplo; Telethon-Italy [GGP11003]; Fondazione Buzzati-Traverso; Division of Intramural Research of the NIH [Z01ES065070]; ERC [206281]; EMBO; [NIHGM32431] FX We thank H. Ulrich, A. Aguilera, and C. Santocanale for strains and reagents; J. Williams and A. Clark for comments on the manuscript; S. Sabbioneda, S. Carnevali, F. Spadaro, and the members of our laboratories for discussions. This work was supported by grants from AIRC, MIUR, and Fondazione Cariplo to P.P. and M.M.-F. and MIUR (FIRB RBFR10S3UQ) to F.L. The financial support of Telethon-Italy (grant number GGP11003) is gratefully acknowledged. F.L. was partially supported by a fellowship from Fondazione Buzzati-Traverso. Part of this work was supported by Project Z01ES065070 to T.A.K. from the Division of Intramural Research of the NIH and grant NIHGM32431 to P.M.B. Cancer Research UK, an ERC start-up grant (206281), the Lister Institute of Preventive Medicine, and the EMBO Young Investigator Program supported V.C. NR 50 TC 75 Z9 75 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 13 PY 2012 VL 45 IS 1 BP 99 EP 110 DI 10.1016/j.molcel.2011.12.019 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 879AE UT WOS:000299301300013 PM 22244334 ER PT J AU Wu, WM Thomas, JA Cheng, NQ Black, LW Steven, AC AF Wu, Weimin Thomas, Julie A. Cheng, Naiqian Black, Lindsay W. Steven, Alasdair C. TI Bubblegrams Reveal the Inner Body of Bacteriophage phi KZ SO SCIENCE LA English DT Article ID RADIATION-DAMAGE; T7 C1 [Wu, Weimin; Cheng, Naiqian; Steven, Alasdair C.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Thomas, Julie A.; Black, Lindsay W.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. RP Steven, AC (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov RI Wu, Weimin/B-4063-2012 FU Intramural NIH HHS [Z01 AR027015-13]; NIAID NIH HHS [AI11676, R01 AI011676, R21 AI011676] NR 8 TC 20 Z9 20 U1 0 U2 10 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 13 PY 2012 VL 335 IS 6065 BP 182 EP 182 DI 10.1126/science.1214120 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 875LZ UT WOS:000299033100043 PM 22246767 ER PT J AU Aldworth, ZN Bender, JA Miller, JP AF Aldworth, Zane N. Bender, John A. Miller, John P. TI Information Transmission in Cercal Giant Interneurons Is Unaffected by Axonal Conduction Noise SO PLOS ONE LA English DT Article ID SPIKE-TIMING PRECISION; CONFIDENCE-INTERVALS; SYNAPTIC PLASTICITY; NEURAL CODE; CRICKET; PROPAGATION; NERVE; MORPHOLOGY; STIMULUS; FIBERS AB What are the fundamental constraints on the precision and accuracy with which nervous systems can process information? One constraint must reflect the intrinsic "noisiness" of the mechanisms that transmit information between nerve cells. Most neurons transmit information through the probabilistic generation and propagation of spikes along axons, and recent modeling studies suggest that noise from spike propagation might pose a significant constraint on the rate at which information could be transmitted between neurons. However, the magnitude and functional significance of this noise source in actual cells remains poorly understood. We measured variability in conduction time along the axons of identified neurons in the cercal sensory system of the cricket Acheta domesticus, and used information theory to calculate the effects of this variability on sensory coding. We found that the variability in spike propagation speed is not large enough to constrain the accuracy of neural encoding in this system. C1 [Aldworth, Zane N.; Bender, John A.; Miller, John P.] Montana State Univ, Ctr Computat Biol, Bozeman, MT 59717 USA. RP Aldworth, ZN (reprint author), NICHHD, Lab Cellular & Synapt Physiol, NIH, Bethesda, MD 20892 USA. EM zaldworth@gmail.com FU National Institute of Mental Health (NIMH) [2R01 MH-064416]; US National Science Foundation [EF-0425878, IGERT DGE-9972824]; Kopriva fellowship; NIH FX This work was supported by grants from the National Institute of Mental Health to J.P.M. (NIMH 2R01 MH-064416), the US National Science Foundation to J.P.M. (EF-0425878) and to Z.N.A. (IGERT DGE-9972824), and by a Kopriva fellowship to Z.N.A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank M. Stopfer and Clara Bodelon for helpful comments on the manuscript. Information theoretic analyses in this study were conducted with the Spike Train Analysis Toolkit, a neuroinformatics resource funded by the NIH's Human Brain Project. NR 53 TC 2 Z9 2 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 12 PY 2012 VL 7 IS 1 AR e30115 DI 10.1371/journal.pone.0030115 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 906OY UT WOS:000301357100040 PM 22253900 ER PT J AU Damera, G Druey, KM Cooper, PR Krymskaya, VP Soberman, RJ Amrani, Y Hoshi, T Brightling, CE Panettieri, RA AF Damera, Gautam Druey, Kirk M. Cooper, Philip R. Krymskaya, Vera P. Soberman, Roy J. Amrani, Yassine Hoshi, Toshinori Brightling, Christopher E. Panettieri, Reynold A., Jr. TI An RGS4-Mediated Phenotypic Switch of Bronchial Smooth Muscle Cells Promotes Fixed Airway Obstruction in Asthma SO PLOS ONE LA English DT Article ID RGS PROTEINS; PHOSPHATIDYLINOSITOL 3-KINASE; EXPRESSION; GROWTH; REGULATORS; PROLIFERATION; THERMOPLASTY; MECHANISMS; KINASE; ADULTS AB In severe asthma, bronchodilator-and steroid-insensitive airflow obstruction develops through unknown mechanisms characterized by increased lung airway smooth muscle (ASM) mass and stiffness. We explored the role of a Regulator of G-protein Signaling protein (RGS4) in the ASM hyperplasia and reduced contractile capacity characteristic of advanced asthma. Using immunocytochemical staining, ASM expression of RGS4 was determined in endobronchial biopsies from healthy subjects and those from subjects with mild, moderate and severe asthma. Cell proliferation assays, agonist-induced calcium mobilization and bronchoconstriction were determined in cultured human ASM cells and in human precision cut lung slices. Using gain-and loss-of-function approaches, the precise role of RGS proteins was determined in stimulating human ASM proliferation and inhibiting bronchoconstriction. RGS4 expression was restricted to a subpopulation of ASM and was specifically upregulated by mitogens, which induced a hyperproliferative and hypocontractile ASM phenotype similar to that observed in recalcitrant asthma. RGS4 expression was markedly increased in bronchial smooth muscle of patients with severe asthma, and expression correlated significantly with reduced pulmonary function. Whereas RGS4 inhibited G protein-coupled receptor (GPCR)-mediated bronchoconstriction, unexpectedly RGS4 was required for PDGF-induced proliferation and sustained activation of PI3K, a mitogenic signaling molecule that regulates ASM proliferation. These studies indicate that increased RGS4 expression promotes a phenotypic switch of ASM, evoking irreversible airway obstruction in subjects with severe asthma. C1 [Damera, Gautam; Cooper, Philip R.; Krymskaya, Vera P.; Panettieri, Reynold A., Jr.] Univ Penn, Airways Biol Initiat, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. [Druey, Kirk M.] NIAID, NIH, Bethesda, MD 20892 USA. [Soberman, Roy J.] Harvard Univ, Sch Med, Boston, MA USA. [Amrani, Yassine; Brightling, Christopher E.] Univ Leicester, Leicester, Leics, England. [Hoshi, Toshinori] Univ Penn, Dept Physiol, Philadelphia, PA 19104 USA. RP Damera, G (reprint author), Univ Penn, Airways Biol Initiat, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. EM rap@mail.med.upenn.edu RI Amrani, Yassine/A-1826-2013 FU National Institutes of Health [RO1-HL097796, R01-AI068871, RO1-GM057654, RO1-GM078579] FX The National Institutes of Health RO1-HL097796 to RAP, R01-AI068871 to RJS and RO1-GM057654 and RO1-GM078579 to TH. CEB is a Welcome Trust Senior Fellow. All funding sources supported the design, execution and interpretation of the results. None of the sources played a role in the performance, decision to publish or preparation of the manuscript. National Disease Research Interchange (NDRI) provided the human tissue for the studies. NR 41 TC 12 Z9 12 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 12 PY 2012 VL 7 IS 1 AR e28504 DI 10.1371/journal.pone.0028504 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 906OY UT WOS:000301357100002 PM 22253691 ER PT J AU Coate, TM Raft, S Zhao, XM Ryan, AK Crenshaw, EB Kelley, MW AF Coate, Thomas M. Raft, Steven Zhao, Xiumei Ryan, Aimee K. Crenshaw, E. Bryan, III Kelley, Matthew W. TI Otic Mesenchyme Cells Regulate Spiral Ganglion Axon Fasciculation through a Pou3f4/EphA4 Signaling Pathway SO NEURON LA English DT Article ID INNER-EAR; MAMMALIAN COCHLEA; AUDITORY NEURONS; EPH RECEPTORS; MOUSE; GUIDANCE; MOTOR; BRAIN; DROSOPHILA; MIGRATION AB Peripheral axons from auditory spiral ganglion neurons (SGNs) form an elaborate series of radially and spirally oriented projections that interpret complex aspects of the auditory environment. However, the developmental processes that shape these axon tracts are largely unknown. Radial bundles are comprised of dense SGN fascicles that project through otic mesenchyme to form synapses within the cochlea. Here, we show that radial bundle fasciculation and synapse formation are disrupted when Pou3f4 (DFNX2) is deleted from otic mesenchyme. Further, we demonstrate that Pou3f4 binds to and directly regulates expression of Epha4, Epha4(-/-) mice present similar SGN defects, and exogenous EphA4 promotes SGN fasciculation in the absence of Pou3f4. Finally, Efnb2 deletion in SGNs leads to similar fasciculation defects, suggesting that ephrin-B2/EphA4 interactions are critical during this process. These results indicate a model whereby Pou3f4 in the otic mesenchyme establishes an Eph/ephrin-mediated fasciculation signal that promotes inner radial bundle formation. C1 [Coate, Thomas M.; Kelley, Matthew W.] Natl Inst Deafness & Other Commun Disorders, Lab Cochlear Dev, NIH, Bethesda, MD 20892 USA. [Raft, Steven] Natl Inst Deafness & Other Commun Disorders, Sensory Cell Regenerat & Dev Sect, NIH, Bethesda, MD 20892 USA. [Zhao, Xiumei] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Ryan, Aimee K.] McGill Univ, Res Inst, Ctr Hlth, Dept Pediat, Montreal, PQ H3A 2T5, Canada. [Crenshaw, E. Bryan, III] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Coate, TM (reprint author), Natl Inst Deafness & Other Commun Disorders, Lab Cochlear Dev, NIH, Bethesda, MD 20892 USA. EM coatet@nidcd.nih.gov FU National Deafness and Other Communication Disorders Intramural Research Program FX We thank the members of the Kelley laboratory for their valuable discussions and technical assistance during this work. We thank Dr. Lisa Cunningham (NIH/National Institute on Deafness and other Communication Disorders [NIDCD]), Dr. Doris Wu (NIH/NIDCD), and Dr. Maria J. Donoghue (Georgetown University) for the critical reading of this manuscript. Epha4 null tissue was a kind gift from Dr. Maria J. Donoghue. Mr. Jonathan Stuckey was very helpful with the illustration in Figure 8. The National Deafness and Other Communication Disorders Intramural Research Program funded this work. NR 60 TC 31 Z9 31 U1 3 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JAN 12 PY 2012 VL 73 IS 1 BP 49 EP 63 DI 10.1016/j.neuron.2011.10.029 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 880YP UT WOS:000299446800007 PM 22243746 ER PT J AU Scheinberg, P Nunez, O Weinstein, B Scheinberg, P Wu, CO Young, NS AF Scheinberg, Phillip Nunez, Olga Weinstein, Barbara Scheinberg, Priscila Wu, Colin O. Young, Neal S. TI Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia SO BLOOD LA English DT Article ID ANTI-THYMOCYTE GLOBULIN; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; RABBIT ANTITHYMOCYTE GLOBULIN; HIGH-DOSE CYCLOPHOSPHAMIDE; COLONY-STIMULATING FACTOR; PLUS CYCLOSPORINE; IMMUNOSUPPRESSIVE TREATMENT; ANTILYMPHOCYTE GLOBULIN; TRANSPLANT RECIPIENTS; RENAL-TRANSPLANTATION AB Antithymocyte globulin (ATG) + cyclosporine is effective in restoring hematopoiesis in severe aplastic anemia (SAA). We hypothesized that the humanized anti-CD52 mAb alemtuzumab might be active in SAA because of its lymphocytotoxic properties. We investigated alemtuzumab monotherapy from 2003-2010 in treatment-naive, relapsed, and refractory SAA in 3 separate research protocols at the National Institutes of Health. Primary outcome was hematologic response at 6 months. For refractory disease, patients were randomized between rabbit ATG + cyclosporine (n = 27) and alemtuzumab (n = 27); the response rate for alemtuzumab was 37% (95% confidence interval [CI], 18%-57%) and for rabbit ATG 33% (95% CI, 14%-52%; P = .78). The 3-year survival was 83% (95% CI, 68%-99%) for alemtuzumab and 60% (95% CI, 43%-85%) for rabbit ATG (P = .16). For relapsed disease (n = 25), alemtuzumab was administered in a single-arm study; the response rate was 56% (95% CI, 35%-77%) and the 3-year survival was 86% (95% CI, 72%-100%). In treatment-naive patients (n = 16), alemtuzumab was compared with horse and rabbit ATG in a 3-arm randomized study; the response rate was 19% (95% CI 0%-40%), and the alemtuzumab arm was discontinued early. We conclude that alemtuzumab is effective in SAA, but best results are obtained in the relapsed and refractory settings. The present trials were registered at www.clinicaltrials.gov as NCT00195624, NCT00260689, and NCT00065260. (Blood. 2012;119(2):345-354) C1 [Scheinberg, Phillip; Nunez, Olga; Weinstein, Barbara; Scheinberg, Priscila; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wu, Colin O.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Scheinberg, P (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10 CRC,Rm 3-5140,MSC 1202, Bethesda, MD 20892 USA. EM scheinbp@mail.nih.gov; scheinbp@mail.nih.gov OI Scheinberg, Phillip/0000-0002-9047-4538 FU National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD FX This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD. NR 48 TC 31 Z9 41 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 12 PY 2012 VL 119 IS 2 BP 345 EP 354 DI 10.1182/blood-2011-05-352328 PG 10 WC Hematology SC Hematology GA 878PL UT WOS:000299268900011 PM 22067384 ER PT J AU Nagai, K Ochi, T Fujiwara, H An, J Shirakata, T Mineno, J Kuzushima, K Shiku, H Melenhorst, JJ Gostick, E Price, DA Ishii, E Yasukawa, M AF Nagai, Kozo Ochi, Toshiki Fujiwara, Hiroshi An, Jun Shirakata, Toshiaki Mineno, Junichi Kuzushima, Kiyotaka Shiku, Hiroshi Melenhorst, J. Joseph Gostick, Emma Price, David A. Ishii, Eiichi Yasukawa, Masaki TI Aurora kinase A-specific T-cell receptor gene transfer redirects T lymphocytes to display effective antileukemia reactivity SO BLOOD LA English DT Article ID CANCER REGRESSION; ANTIGEN RECEPTOR; LEUKEMIA-CELLS; STEM-CELLS; TARGET; IMMUNOTHERAPY; LYMPHOMA; THERAPY; MOUSE; TCR AB Aurora kinase A (AURKA) is overexpressed in leukemias. Previously, we demonstrated that AURKA-specific CD8(+) T cells specifically and selectively lysed leukemia cells, indicating that AURKA is an excellent target for immunotherapy. In this study, we examined the feasibility of adoptive therapy using redirected T cells expressing an HLA-A*0201-restricted AURKA(207-215)-specific T-cell receptor (TCR). Retrovirally transduced T cells recognized relevant peptide-pulsed but not control target cells. Furthermore, TCR-redirected CD8(+) T cells lysed AURKA-overexpressing human leukemic cells in an HLA-A*0201-restricted manner, but did not kill HLA-A*0201(+) normal cells, including hematopoietic progenitors. In addition, AURKA(207-215)-specific TCR-transduced CD4(+) T cells displayed target-responsive Th1 cytokine production. Finally, AURKA(207-215)-specific TCR-transduced CD8(+) T cells displayed antileukemia efficacy in a xenograft mouse model. Collectively, these data demonstrate the feasibility of redirected T cell-based AURKA-specific immunotherapy for the treatment of human leukemia. (Blood. 2012;119(2):368-376) C1 [Nagai, Kozo; Ochi, Toshiki; Fujiwara, Hiroshi; An, Jun; Shirakata, Toshiaki; Yasukawa, Masaki] Ehime Univ, Dept Bioregulatory Med, Grad Sch Med, Toon, Ehime 7910295, Japan. [Fujiwara, Hiroshi; Yasukawa, Masaki] Ehime Univ, Dept Cell Growth & Canc Regulat, Proteomed Res Ctr, Toon, Ehime 7910295, Japan. [Mineno, Junichi] Takara Bio Inc, Ctr Cell & Gene Therapy, Shiga, Japan. [Kuzushima, Kiyotaka] Aichi Canc Ctr, Div Immunol, Aichi, Japan. [Shiku, Hiroshi] Mie Univ, Dept Canc Vaccine & Immunogene Therapy, Grad Sch Med, Tsu, Mie, Japan. [Melenhorst, J. Joseph] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Gostick, Emma; Price, David A.] Cardiff Univ, Dept Infect Immun & Biochem, Sch Med, Cardiff, S Glam, Wales. [Ishii, Eiichi] Ehime Univ, Dept Pediat, Grad Sch Med, Toon, Ehime 7910295, Japan. RP Fujiwara, H (reprint author), Ehime Univ, Dept Bioregulatory Med, Grad Sch Med, Toon, Ehime 7910295, Japan. EM yunarief@m.ehime-u.ac.jp; yasukawa@m.ehime-u.ac.jp RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Health, Labor and Welfare; Third Term Comprehensive Control Research for Cancer FX This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan to T.O., H.F., and M.Y., a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare to M.Y., and a grant from the Third Term Comprehensive Control Research for Cancer to K.K. D.A.P. is a Medical Research Council (United Kingdom) Senior Clinical Fellow. NR 49 TC 12 Z9 14 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 12 PY 2012 VL 119 IS 2 BP 368 EP 376 DI 10.1182/blood-2011-06-360354 PG 9 WC Hematology SC Hematology GA 878PL UT WOS:000299268900014 PM 22025529 ER PT J AU Liu, Y Belkina, NV Park, C Nambiar, R Loughhead, SM Patino-Lopez, G Ben-Aissa, K Hao, JJ Kruhlak, MJ Qi, H von Andrian, UH Kehrl, JH Tyska, MJ Shaw, S AF Liu, Yin Belkina, Natalya V. Park, Chung Nambiar, Raj Loughhead, Scott M. Patino-Lopez, Genaro Ben-Aissa, Khadija Hao, Jian-Jiang Kruhlak, Michael J. Qi, Hai von Andrian, Ulrich H. Kehrl, John H. Tyska, Matthew J. Shaw, Stephen TI Constitutively active ezrin increases membrane tension, slows migration, and impedes endothelial transmigration of lymphocytes in vivo in mice SO BLOOD LA English DT Article ID ERM PROTEINS; PLASMA-MEMBRANE; MYOSIN-I; CELL POLARIZATION; T-LYMPHOCYTES; THREONINE 558; PHOSPHORYLATION; MOESIN; ADHESION; ACTIVATION AB ERM (ezrin, radixin moesin) proteins in lymphocytes link cortical actin to plasma membrane, which is regulated in part by ERM protein phosphorylation. To assess whether phosphorylation of ERM proteins regulates lymphocyte migration and membrane tension, we generated transgenic mice whose T-lymphocytes express low levels of ezrin phosphomimetic protein (T567E). In these mice, T-cell number in lymph nodes was reduced by 27%. Lymphocyte migration rate in vitro and in vivo in lymph nodes decreased by 18% to 47%. Lymphocyte membrane tension increased by 71%. Investigations of other possible underlying mechanisms revealed impaired chemokine-induced shape change/lamellipod extension and increased integrin-mediated adhesion. Notably, lymphocyte homing to lymph nodes was decreased by 30%. Unlike most described homing defects, there was not impaired rolling or sticking to lymph node vascular endothelium but rather decreased migration across that endothelium. Moreover, decreased numbers of transgenic T cells in efferent lymph suggested defective egress. These studies confirm the critical role of ERM dephosphorylation in regulating lymphocyte migration and transmigration. Of particular note, they identify phospho-ERM as the first described regulator of lymphocyte membrane tension, whose increase probably contributes to the multiple defects observed in the ezrin T567E transgenic mice. (Blood. 2012;119(2):445-453) C1 [Liu, Yin; Belkina, Natalya V.; Patino-Lopez, Genaro; Ben-Aissa, Khadija; Hao, Jian-Jiang; Kruhlak, Michael J.; Shaw, Stephen] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Park, Chung; Kehrl, John H.] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. [Nambiar, Raj; Tyska, Matthew J.] Vanderbilt Univ, Med Ctr, Dept Cell & Dev Biol, Nashville, TN USA. [Loughhead, Scott M.; von Andrian, Ulrich H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Qi, Hai] NIAID, Immunol Lab, Bethesda, MD 20892 USA. RP Shaw, S (reprint author), NIH, 10 Ctr Dr,MSC 1360,Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. EM shaws@mail.nih.gov RI von Andrian, Ulrich/A-5775-2008; OI Patino-Lopez, Genaro/0000-0002-8716-722X; Kehrl, John/0000-0002-6526-159X FU National Human Genome Research Institute; National Cancer Institute; National Institutes of Health [R01-DK075555]; American Heart Association [09GRNT2310188, 0825358E] FX This work was supported by the intramural programs of National Human Genome Research Institute and National Cancer Institute. M.J.T. and R.N. were supported by the National Institutes of Health (R01-DK075555) and the American Heart Association (grant-in-aid 09GRNT2310188 and postdoctoral fellowship 0825358E). NR 50 TC 33 Z9 34 U1 1 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 12 PY 2012 VL 119 IS 2 BP 445 EP 453 DI 10.1182/blood-2011-07-368860 PG 9 WC Hematology SC Hematology GA 878PL UT WOS:000299268900021 PM 22106344 ER PT J AU Wang, HS Beaty, N Chen, S Qi, CF Masiuk, M Shin, DM Morse, HC AF Wang, Hongsheng Beaty, Natalie Chen, Sophia Qi, Chen-Feng Masiuk, Marek Shin, Dong-Mi Morse, Herbert C., III TI The CXCR7 chemokine receptor promotes B-cell retention in the splenic marginal zone and serves as a sink for CXCL12 SO BLOOD LA English DT Article ID EXPRESSION; LIGANDS; MIGRATION; RDC1 AB The splenic marginal zone (MZ) is comprised of specialized populations of B cells, dendritic cells, and macrophages that are uniquely arrayed outside the white pulp follicles to screen the blood for bacterial and other particulate Ags. Mechanisms responsible for MZ B-cell formation, localization, retention, and function are understood to include antigenic specificity, transcription factors, integrins, and surface receptors for soluble ligands such as S1P. Here, we add to this repertoire by demonstrating that the receptor for CXCL12, CXCR7, is expressed on MZ but not on follicular B cells. Treatment of mice with CXCR7 inhibitors led to disruption of MZ architecture, reduced numbers of MZ B cells, and altered granulocyte homeostasis associated with increasing serum levels of CXCL12. CXCR7 thus appears to function as a scavenger receptor for CXCL12 on MZ B cells. (Blood. 2012;119(2):465-468) C1 [Wang, Hongsheng; Beaty, Natalie; Chen, Sophia; Qi, Chen-Feng; Shin, Dong-Mi; Morse, Herbert C., III] NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. [Masiuk, Marek] Pomeranian Med Univ, Dept Pathol, Szczecin, Poland. RP Morse, HC (reprint author), NIAID, Immunogenet Lab, Virol & Cellular Immunol Sect, 5640 Fishers Ln,Twinbrook 1, Rockville, MD 20852 USA. EM wanghongs@niaid.nih.gov; hmorse@niaid.nih.gov RI Masiuk, Marek/M-8485-2014; OI Morse, Herbert/0000-0002-9331-3705 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 23 TC 23 Z9 23 U1 1 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 12 PY 2012 VL 119 IS 2 BP 465 EP 468 DI 10.1182/blood-2011-03-343608 PG 4 WC Hematology SC Hematology GA 878PL UT WOS:000299268900023 PM 22110250 ER PT J AU Hou, X Majik, MS Kim, K Pyee, Y Lee, Y Alexander, V Chung, HJ Lee, HW Chandra, G Lee, JH Park, SG Choi, WJ Kim, HO Phan, K Gao, ZG Jacobson, KA Choi, S Lee, SK Jeong, LS AF Hou, Xiyan Majik, Mahesh S. Kim, Kyunglim Pyee, Yuna Lee, Yoonji Alexander, Varughese Chung, Hwa-Jin Lee, Hyuk Woo Chandra, Girish Lee, Jin Hee Park, Seul-gi Choi, Won Jun Kim, Hea Ok Phan, Khai Gao, Zhan-Guo Jacobson, Kenneth A. Choi, Sun Lee, Sang Kook Jeong, Lak Shin TI Structure-Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A(2A) and A(3) Adenosine Receptor Ligands SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ADENINE-DERIVATIVES; SELECTIVE AGONISTS; HIGHLY POTENT; ANTAGONISTS; RAT; NUCLEOSIDES; APOPTOSIS; BINDING; D-4'-THIOADENOSINE; DISCOVERY AB Truncated N-6-substituted-4'-oxo- and 4'-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A(2A) and A(3) adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA(2A)AR, but hydrophobic C8 substitution abolished binding at the hA(2A)AR. However, most of synthesized compounds displayed medium to high binding affinity at the hA(3)AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA(2A)AR agonists. C2 substitution probed geometrically through hA(2A)ARdocking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA(2A)AR agonist and hA(3)AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases. C1 [Hou, Xiyan; Majik, Mahesh S.; Kim, Kyunglim; Lee, Yoonji; Alexander, Varughese; Lee, Hyuk Woo; Chandra, Girish; Lee, Jin Hee; Park, Seul-gi; Choi, Won Jun; Kim, Hea Ok; Choi, Sun; Jeong, Lak Shin] Ewha Womans Univ, Coll Pharm, Lab Med Chem, Seoul 120750, South Korea. [Hou, Xiyan; Majik, Mahesh S.; Kim, Kyunglim; Lee, Yoonji; Alexander, Varughese; Lee, Hyuk Woo; Chandra, Girish; Lee, Jin Hee; Park, Seul-gi; Choi, Won Jun; Kim, Hea Ok; Choi, Sun; Jeong, Lak Shin] Ewha Womans Univ, Dept Bioinspired Sci, Seoul 120750, South Korea. [Pyee, Yuna; Chung, Hwa-Jin; Lee, Sang Kook] Seoul Natl Univ, Coll Pharm, Seoul 151742, South Korea. [Choi, Won Jun] Dongguk Univ, Coll Pharm, Kyonggi Do 410774, South Korea. [Phan, Khai; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jeong, LS (reprint author), Ewha Womans Univ, Coll Pharm, Lab Med Chem, Seoul 120750, South Korea. EM lakjeong@ewha.ac.kr RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Basic Science Research [2008-314-E00304]; National Core Research Center [2011-0006244]; World Class University [R31-2008-000-10010-0]; National Leading Research Lab [2011-0028885]; Brain Research Center of the 21st Century Frontier Research from National Research Foundation (NRF), Korea [2011K000289]; NIDDK, NIH, Bethesda, MD, U.S. FX This work was supported by the grants from Basic Science Research (Grant 2008-314-E00304), the National Core Research Center (Grant 2011-0006244), the World Class University (Grant R31-2008-000-10010-0), National Leading Research Lab Program (Grant 2011-0028885), and Brain Research Center of the 21st Century Frontier Research (Grant 2011K000289) from National Research Foundation (NRF), Korea, and the Intramural Research Program of NIDDK, NIH, Bethesda, MD, U.S. NR 42 TC 18 Z9 18 U1 0 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JAN 12 PY 2012 VL 55 IS 1 BP 342 EP 356 DI 10.1021/jm201229j PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 874SQ UT WOS:000298978800026 PM 22142423 ER PT J AU Romagnoli, R Baraldi, PG Salvador, MK Preti, D Tabrizi, MA Brancale, A Fu, XH Li, J Zhang, SZ Hamel, E Bortolozzi, R Basso, G Viola, G AF Romagnoli, Romeo Baraldi, Pier Giovanni Salvador, Maria Kimatrai Preti, Delia Tabrizi, Mojgan Aghazadeh Brancale, Andrea Fu, Xian-Hua Li, Jun Zhang, Su-Zhan Hamel, Ernest Bortolozzi, Roberta Basso, Giuseppe Viola, Giampietro TI Synthesis and Evaluation of 1,5-Disubstituted Tetrazoles as Rigid Analogues of Combretastatin A-4 with Potent Antiproliferative and Antitumor Activity SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTIMITOTIC AGENTS; CELL-DEATH; MICROTUBULE DYNAMICS; MEDICINAL CHEMISTRY; NATURAL-PRODUCTS; TUBULIN; APOPTOSIS; CANCER; COLCHICINE; UPDATE AB Tubulin, the major structural component of microtubules, is a target for the development of anticancer agents. Two series of 1,5-diaryl substituted 1,2,3,4-tetrazoles were concisely synthesized, using a palladium-catalyzed cross-coupling reaction, and identified as potent antiproliferative agents and novel tubulin polymerization inhibitors that act at the colchicine site. SAR analysis indicated that compounds with a 4-ethoxyphenyl group at the N-1 or C-5 position of the 1,2,3,4-tetrazole ring exhibited maximal activity. Several of these compounds also had potent activity in inhibiting the growth of multidrug resistant cells overexpressing P-glycoprotein. Active compounds induced apoptosis through the mitochondrial pathway with activation of caspase-9 and caspase-3. Furthermore, compound 41 significantly reduced in vivo the growth of the HT-29 xenograft in a nude mouse model, suggesting that 41 is a promising new antimitotic agent with clinical potential. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Preti, Delia; Tabrizi, Mojgan Aghazadeh] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Brancale, Andrea; Bortolozzi, Roberta] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales. [Fu, Xian-Hua; Li, Jun; Zhang, Su-Zhan] Zhejiang Univ, Sch Med, Affiliated Hosp 2,Canc Inst, China Natl Minist Educ,Key Lab Canc Prevent & Int, Hangzhou 310009, Zhejiang, Peoples R China. [Basso, Giuseppe; Viola, Giampietro] Univ Padua, Dipartimento Pediat, Lab Oncoematol, I-35131 Padua, Italy. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. EM rmr@unife.it; pgb@unife.it; giampietro.viola1@unipd.it RI Viola, Giampietro/I-4095-2012; Aghazadeh Tabrizi, Mojgan/I-9169-2014; Brancale, Andrea/N-9445-2014; Bortolozzi, Roberta/D-4950-2015; Baraldi, Pier Giovanni/B-7933-2017; preti, delia/G-9916-2015; Romagnoli, Romeo/G-9887-2015 OI Viola, Giampietro/0000-0001-9329-165X; Brancale, Andrea/0000-0002-9728-3419; Bortolozzi, Roberta/0000-0002-3357-4815; BASSO, GIUSEPPE/0000-0002-2634-9302; preti, delia/0000-0002-1075-3781; FU Intramural NIH HHS [Z99 CA999999] NR 60 TC 37 Z9 38 U1 1 U2 40 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JAN 12 PY 2012 VL 55 IS 1 BP 475 EP 488 DI 10.1021/jm2013979 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 874SQ UT WOS:000298978800037 PM 22136312 ER PT J AU Deflorian, F Kumar, TS Phan, K Gao, ZG Xu, F Wu, HX Katritch, V Stevens, RC Jacobson, KA AF Deflorian, Francesca Kumar, T. Santhosh Phan, Khai Gao, Zhan-Guo Xu, Fei Wu, Huixian Katritch, Vsevolod Stevens, Raymond C. Jacobson, Kenneth A. TI Evaluation of Molecular Modeling of Agonist Binding in Light of the Crystallographic Structure of an Agonist-Bound A(2A) Adenosine Receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; SITE-DIRECTED MUTAGENESIS; CRYSTAL-STRUCTURE; LIGAND RECOGNITION; DRUG DISCOVERY; DERIVATIVES; ANTAGONIST; RESIDUES; GPCR; IDENTIFICATION AB Molecular modeling of agonist binding to the human A(2A) adenosine receptor (AR) was assessed and extended in light of crystallographic structures. Heterocyclic adenine nitrogens of cocrystallized agonist overlaid corresponding positions of the heterocyclic base of a bound triazolotriazine antagonist, and ribose moiety was coordinated in a hydrophilic region, as previously predicted based on modeling using the inactive receptor. Automatic agonist docking of 20 known potent nucleoside agonists to agonist-bound A(2A)AR crystallographic structures predicted new stabilizing protein interactions to provide a structural basis for previous empirical structure activity relationships consistent with previous mutagenesis results. We predicted binding of novel C2 terminal amino acid conjugates of A(2A)AR agonist CGS21680 and used these models to interpret effects on binding affinity of newly synthesized agonists. D-Amino acid conjugates were generally more potent than L-stereoisomers and free terminal carboxylates more potent than corresponding methyl esters. Amino acid moieties were coordinated close to extracellular loops 2 and 3. Thus, molecular modeling is useful in probing ligand recognition and rational design of GPCR-targeting compounds with specific pharmacological profiles. C1 [Deflorian, Francesca; Kumar, T. Santhosh; Phan, Khai; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Xu, Fei; Wu, Huixian; Katritch, Vsevolod; Stevens, Raymond C.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; Wu, Huixian/N-6353-2014; Katritch, Vsevolod/Q-8357-2016 OI Jacobson, Kenneth/0000-0001-8104-1493; Katritch, Vsevolod/0000-0003-3883-4505; Wu, Huixian/0000-0003-1357-9747; FU NIH; National Institute of Diabetes and Digestive and Kidney Diseases; PSI; National Institute of General Medical Sciences [U54 GM094618] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases and the PSI:Biology program, National Institute of General Medical Sciences U54 GM094618. We thank Dr. Stefano Costanzi (NIDDK) and Dr. Soo-Kyung Kim (California Institute of Technology) for helpful discussion. NR 57 TC 23 Z9 23 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JAN 12 PY 2012 VL 55 IS 1 BP 538 EP 552 DI 10.1021/jm201461q PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 874SQ UT WOS:000298978800042 PM 22104008 ER PT J AU Huang, HS Allen, JA Mabb, AM King, IF Miriyala, J Taylor-Blake, B Sciaky, N Dutton, JW Lee, HM Chen, X Jin, J Bridges, AS Zylka, MJ Roth, BL Philpot, BD AF Huang, Hsien-Sung Allen, John A. Mabb, Angela M. King, Ian F. Miriyala, Jayalakshmi Taylor-Blake, Bonnie Sciaky, Noah Dutton, J. Walter, Jr. Lee, Hyeong-Min Chen, Xin Jin, Jian Bridges, Arlene S. Zylka, Mark J. Roth, Bryan L. Philpot, Benjamin D. TI Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons SO NATURE LA English DT Article ID ANGELMAN SYNDROME GENE; PRADER-WILLI-SYNDROME; ANTISENSE TRANSCRIPT; I INHIBITORS; UBIQUITIN LIGASE; MURINE UBE3A; EXPRESSION; SNRPN; MOUSE; CAMPTOTHECIN AB Angelman syndrome is a severe neurodevelopmental disorder caused bydeletion ormutation of the maternal allele of the ubiquitin protein ligase E3A (UBE3A)(1-3). In neurons, the paternal allele of UBE3A is intact but epigenetically silenced(4-6), raising the possibility that Angelman syndrome could be treated by activating this silenced allele to restore functional UBE3A protein(7,8). Using an unbiased, high-content screen in primary cortical neurons from mice, we identify twelve topoisomerase I inhibitors and four topoisomerase II inhibitors that unsilence the paternal Ube3a allele. These drugs included topotecan, irinotecan, etoposide and dexrazoxane (ICRF-187). At nanomolar concentrations, topotecan upregulated catalytically active UBE3A in neurons from maternal Ube3a-null mice. Topotecan concomitantly downregulated expression of the Ube3a antisense transcript that overlaps the paternal copy of Ube3a(9-11). These results indicate that topotecan unsilences Ube3a in cis by reducing transcription of an imprinted antisense RNA. When administered in vivo, topotecan unsilenced the paternal Ube3a allele in several regions of the nervous system, including neurons in the hippocampus, neocortex, striatum, cerebellum and spinal cord. Paternal expression of Ube3a remained elevated in a subset of spinal cord neurons for at least 12 weeks after cessation of topotecan treatment, indicating that transient topoisomerase inhibition can have enduring effects on gene expression. Although potential off-target effects remain to be investigated, our findings suggest a therapeutic strategy for reactivating the functional but dormant allele of Ube3a in patients with Angelman syndrome. C1 [Huang, Hsien-Sung; Mabb, Angela M.; King, Ian F.; Miriyala, Jayalakshmi; Taylor-Blake, Bonnie; Dutton, J. Walter, Jr.; Zylka, Mark J.; Philpot, Benjamin D.] Univ N Carolina, Sch Med, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA. [Allen, John A.; Sciaky, Noah; Lee, Hyeong-Min; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Chen, Xin; Jin, Jian] Univ N Carolina, Eshelman Sch Pharm, Ctr Integrat Chem Biol & Drug Discovery, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Bridges, Arlene S.] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Zylka, Mark J.; Roth, Bryan L.; Philpot, Benjamin D.] Univ N Carolina, Carolina Inst Dev Disabil, Chapel Hill, NC 27599 USA. [Zylka, Mark J.; Roth, Bryan L.; Philpot, Benjamin D.] Univ N Carolina, Ctr Neurosci, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Div Chem Biol & Med Chem, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, NIMH, Psychoact Drug Screening Program, Dept Pharmacol,Sch Med, Chapel Hill, NC 27599 USA. RP Zylka, MJ (reprint author), Univ N Carolina, Sch Med, Dept Cell & Mol Physiol, Chapel Hill, NC 27599 USA. EM zylka@med.unc.edu; bryan_roth@med.unc.edu; bphilpot@med.unc.edu RI Lee, HM/D-2777-2011; Allen, John/D-6141-2011; OI Mabb, Angela/0000-0002-3000-8690; Huang, Hsien-Sung/0000-0003-2657-3635 FU Simons Foundation Autism Research Initiative (SFARI); Angelman Syndrome Foundation; National Institute of Mental Health (NIMH) [R01MH093372]; National Eye Institute [R01EY018323]; NC TraCS [50KR41016, 10KR20910]; National Institute of Neurological Disorders and Stroke (NINDS) [R01NS060725, R01NS067688, 5F32NS067712, 5P30NS045892]; National Institutes of Health (NIH) [HHSN-271-2008-00025-C, T32HD040127-07]; Michael Hooker Distinguished Chair of Pharmacology; National Institute on Drug Abuse (NIDA); Brain and Behavior Research Foundation; University of North Carolina-Carolina Institute for Developmental Disabilities; US Department of Defense [AR093464]; National Institute of Child Health and Human Development (NICHD) [P30HD03110] FX We thank A. Beaudet and Y.-h. Jiang for providing Ube3a-YFP and Ube3am-/rho+ mice; T. Riday and J. E. Han for assistance in i.c.v. mini-osmotic pump infusion; A. Burns for assistance in maintaining mouse colonies; V. Gukassyan for help with the Surveyor and confocal imaging systems; K. McNaughton for help with tissue sectioning; W. Zamboni for providing belotecan, rubitecan and silatecan; and W. Janzen and the Center of Integrative Chemical Biology and Drug Discovery for providing the epigenetic library. B. D. P., M.J.Z. and B. L. R. were supported by the Simons Foundation Autism Research Initiative (SFARI) and by the Angelman Syndrome Foundation. B. D. P. and M.J.Z. were supported by the National Institute of Mental Health (NIMH) (R01MH093372). B. D. P. was supported by the National Eye Institute (R01EY018323) and NC TraCS (50KR41016). M.J.Z. was supported by the National Institute of Neurological Disorders and Stroke (NINDS) (R01NS060725, R01NS067688). B. L. R. was supported by national Institutes of Health (NIH) HHSN-271-2008-00025-C, the NIMH Psychoactive Drug Screening Program, the Michael Hooker Distinguished Chair of Pharmacology, and grants from NIMH and the National Institute on Drug Abuse (NIDA). H.-S. H. was supported by a NARSAD grant from the Brain and Behavior Research Foundation Young Investigator Award and NC TraCS (10KR20910). J. A. A. was supported by NIH T32HD040127-07, the University of North Carolina-Carolina Institute for Developmental Disabilities, and an Autism Concept Award AR093464 from the US Department of Defense. A. M. M. was supported by a National Research Service Award from NINDS (5F32NS067712). I. F. K. was supported by a Joseph E. Wagstaff Postdoctoral Research Fellowship from the Angelman Syndrome Foundation. Assay development costs were partially supported by NINDS (5P30NS045892). Confocal and montage imaging was performed at the University of North Carolina at Chapel Hill Confocal and Multiphoton Imaging Facility, which is co-funded by grants from NINDS (5P30NS045892) and the National Institute of Child Health and Human Development (NICHD) (P30HD03110). NR 38 TC 109 Z9 114 U1 9 U2 46 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 12 PY 2012 VL 481 IS 7380 BP 185 EP + DI 10.1038/nature10726 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 874TO UT WOS:000298981200036 ER PT J AU Fritz, JH Rojas, OL Simard, N McCarthy, DD Hapfelmeier, S Rubino, S Robertson, SJ Larijani, M Gosselin, J Ivanov, II Martin, A Casellas, R Philpott, DJ Girardin, SE McCoy, KD Macpherson, AJ Paige, CJ Gommerman, JL AF Fritz, Joerg H. Rojas, Olga Lucia Simard, Nathalie McCarthy, Douglas D. Hapfelmeier, Siegfried Rubino, Stephen Robertson, Susan J. Larijani, Mani Gosselin, Jean Ivanov, Ivaylo I. Martin, Alberto Casellas, Rafael Philpott, Dana J. Girardin, Stephen E. McCoy, Kathy D. Macpherson, Andrew J. Paige, Christopher J. Gommerman, Jennifer L. TI Acquisition of a multifunctional IgA(+) plasma cell phenotype in the gut SO NATURE LA English DT Article ID B-CELLS; DENDRITIC CELLS; BACTERIAL-INFECTION; AID EXPRESSION; STROMAL CELLS; BONE-MARROW; HOMEOSTASIS; MICROBIOTA; PROGENITORS; MATURATION AB The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells(2). However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS), and expressmany molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA(+) plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-a and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells. C1 [Fritz, Joerg H.; Rojas, Olga Lucia; Simard, Nathalie; McCarthy, Douglas D.; Robertson, Susan J.; Larijani, Mani; Martin, Alberto; Philpott, Dana J.; Paige, Christopher J.; Gommerman, Jennifer L.] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada. [Simard, Nathalie; Paige, Christopher J.] Princess Margaret Hosp, Univ Hlth Network, Ontario Canc Inst, Toronto, ON M5G 2M9, Canada. [Hapfelmeier, Siegfried; McCoy, Kathy D.; Macpherson, Andrew J.] Univ Bern, Dept Klin Forsch Gastroenterol, CH-3010 Bern, Switzerland. [Rubino, Stephen; Girardin, Stephen E.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada. [Gosselin, Jean] Univ Laval, Dept Mol Med, Quebec City, PQ G1V 4G2, Canada. [Ivanov, Ivaylo I.] Columbia Univ, Coll Phys & Surg, Dept Microbiol & Immunol, Med Ctr, New York, NY 10032 USA. [Casellas, Rafael] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Gommerman, JL (reprint author), Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada. EM jen.gommerman@utoronto.ca RI Hapfelmeier, Siegfried/B-6005-2011 OI Hapfelmeier, Siegfried/0000-0002-6913-7932 FU CIHR [9862, 89783, 114972, 67157]; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health; NIH [R00 DK085329-02]; CCFA [2388] FX We thank D. White in the Faculty of Medicine Flow Cytometry core facility and H. Singh for critical reading of the manuscript. We thank E. Verdu for providing additional germ-free mice at short notice, and we also thank C. Guidos for numerous Rag22/ 2 mice for mixed bone marrow chimeras. C. J. P. is supported by a CIHR operating grant MOP number 9862. R. C. is supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. I. I. I. is supported by NIH (R00 DK085329-02) and CCFA (CDA # 2388). A. M. is supported by a CIHR operating grant MOP number 89783. J. H. F. acknowledges support by an APART-fellowship of the Austrian Academy of Sciences, McGill start-up funds and a CIHR operating grant MOP number 114972. N. S. acknowledges the support of a CIHR Doctoral Award. J. L. G. is funded by the Canadian Institutes of Health Research (CIHR) and acknowledges the support of CIHR operating grant MOP number 67157 as well as infrastructure support from the Ontario Research Fund and that Canadian Foundation for Innovation. All authors have reviewed and agree with the content of the manuscript. NR 29 TC 83 Z9 88 U1 1 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 12 PY 2012 VL 481 IS 7380 BP 199 EP + DI 10.1038/nature10698 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 874TO UT WOS:000298981200039 PM 22158124 ER PT J AU Pilotto, A Rengo, F Marchionni, N Sancarlo, D Fontana, A Panza, F Ferrucci, L AF Pilotto, Alberto Rengo, Franco Marchionni, Niccolo Sancarlo, Daniele Fontana, Andrea Panza, Francesco Ferrucci, Luigi CA FIRI-SIGG Study Grp TI Comparing the Prognostic Accuracy for All-Cause Mortality of Frailty Instruments: A Multicentre 1-Year Follow-Up in Hospitalized Older Patients SO PLOS ONE LA English DT Article ID COMPREHENSIVE GERIATRIC ASSESSMENT; LONG-TERM MORTALITY; ELDERLY-PATIENTS; INDEX; VALIDATION; DISABILITY; PREDICTION; PEOPLE; HEALTH; POPULATION AB Background: Frailty is a dynamic age-related condition of increased vulnerability characterized by declines across multiple physiologic systems and associated with an increased risk of death. We compared the predictive accuracy for one-month and one-year all-cause mortality of four frailty instruments in a large population of hospitalized older patients in a prospective multicentre cohort study. Methods and Findings: On 2033 hospitalized patients aged >= 65 years from twenty Italian geriatric units, we calculated the frailty indexes derived from the Study of Osteoporotic Fractures (FI-SOF), based on the cumulative deficits model (FI-CD), based on a comprehensive geriatric assessment (FI-CGA), and the Multidimensional Prognostic Index (MPI). The overall mortality rates were 8.6% after one-month and 24.9% after one-year follow-up. All frailty instruments were significantly associated with one-month and one-year all-cause mortality. The areas under the receiver operating characteristic (ROC) curves estimated from age-and sex-adjusted logistic regression models, accounting for clustering due to centre effect, showed that the MPI had a significant higher discriminatory accuracy than FI-SOF, FI-CD, and FI-CGA after one month (areas under the ROC curves: FI-SOF = 0.685 vs. FI-CD = 0.738 vs. FI-CGA = 0.724 vs. MPI = 0.765, p<0.0001) and one year of follow-up (areas under the ROC curves: FI-SOF = 0.694 vs. FI-CD = 0.729 vs. FI-CGA = 0.727 vs. MPI = 0.750, p<0.0001). The MPI showed a significant higher discriminatory power for predicting one-year mortality also in hospitalized older patients without functional limitations, without cognitive impairment, malnourished, with increased comorbidity, and with a high number of drugs. Conclusions: All frailty instruments were significantly associated with short-and long-term all-cause mortality, but MPI demonstrated a significant higher predictive power than other frailty instruments in hospitalized older patients. C1 [Pilotto, Alberto] S Antonio Hosp, Azienda ULSS Padova 16, Geriatr Unit, Padua, Italy. [Pilotto, Alberto; Sancarlo, Daniele; Panza, Francesco] Inst Care & Sci Res Casa Sollievo Sofferenza, Gerontol Geriatr Res Lab, Foggia, Italy. [Rengo, Franco] Univ Naples Federico 2, Chair Geriatr, Naples, Italy. [Rengo, Franco] Inst Care & Sci Res, Salvatore Maugeri Fdn, Benevento, Italy. [Marchionni, Niccolo] Univ Florence, Dept Geriatr, Florence, Italy. [Fontana, Andrea] Inst Care & Sci Res Casa Sollievo Sofferenza, Unit Biostat, Foggia, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Harbor Hosp Ctr, Baltimore, MD 21224 USA. RP Pilotto, A (reprint author), S Antonio Hosp, Azienda ULSS Padova 16, Geriatr Unit, Padua, Italy. EM alberto.pilotto@operapadrepio.it RI Corsonello, Andrea/A-5637-2013; Fontana, Andrea/J-8584-2016; Sancarlo, Daniele/C-1056-2017; OI Corsonello, Andrea/0000-0002-7276-3256; Fontana, Andrea/0000-0002-6660-5315; Sancarlo, Daniele/0000-0001-9541-6364; Panza, Francesco/0000-0002-7220-0656 FU Ministero della Salute, Italy, IRCCS; National Institute of Aging, Baltimore, USA FX This work was supported by the Ministero della Salute, Italy, IRCCS Research Program 2009-2011, Line 2: "Malattie complesse'' and by the Intramural Research Program of the National Institute of Aging, Baltimore, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 59 Z9 59 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 11 PY 2012 VL 7 IS 1 AR e29090 DI 10.1371/journal.pone.0029090 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 906ON UT WOS:000301355700015 PM 22247767 ER PT J AU Lavine, JS Bjornstad, ON de Blasio, BF Storsaeter, J AF Lavine, Jennie S. Bjornstad, Ottar N. de Blasio, Birgitte Freiesleben Storsaeter, Jann TI Short-lived immunity against pertussis, age-specific routes of transmission, and the utility of a teenage booster vaccine SO VACCINE LA English DT Article ID SENEGAL AB Background: Pertussis incidence has been increasing for the past two decades in Norway, as in much of the highly vaccinated world. The greatest increase is in teenagers, although the most severe cases occur in infants. A teenage booster is recommended globally, largely with the aim of reducing infant incidence. However few countries have implemented the booster, and almost no data have been published on its utility in preventing infant cases. We aim to assess the duration of vaccine-induced immunity, and the possibility for a teenage-booster vaccine to protect infants in Norway. Methods and findings: We used a unique data set that merged case reports with a national vaccine registry from Norway, 1996-2010, to assess age- and cohort-specific hazards of infection. We also developed and implemented a likelihood-based method for estimating the duration of immunity, taking into account age-contact data relevant for pertussis transmission. The risk of infection in thirteen-year olds increased nearly four-fold, however the hazard in infants did not significantly change. The seasonality of cases in pre-school-aged children differed from that of school-aged children. The introduction of a childhood booster vaccine provided indirect protection for unvaccinated members of the cohort, but little protection to neighboring cohorts. Additionally, we found evidence for increasingly rapid infection after three doses of vaccine, potentially caused by significant and heterogeneous loss of immunity. An estimated 15% of vaccinated individuals lost their immunity within five years after vaccination. Conclusions: Immunity induced by the acellular pertussis vaccine prevents both disease and transmission, but is short-lived and heterogeneous. The age-mixing patterns lead to little contact between teenagers and infants. Therefore, while a teenage booster vaccine campaign would likely provide strong protection for cohorts of teenagers, it would provide little protection for infants. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Lavine, Jennie S.] Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Lavine, Jennie S.; Bjornstad, Ottar N.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Lavine, Jennie S.; Bjornstad, Ottar N.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [de Blasio, Birgitte Freiesleben] Univ Oslo, Inst Basic Med Sci, Dept Biostat, N-0317 Oslo, Norway. [de Blasio, Birgitte Freiesleben] Norwegian Inst Publ Hlth, Div Infect Dis Control, Dept Infect Dis Epidemiol, N-0403 Oslo, Norway. [Storsaeter, Jann] Norwegian Inst Publ Hlth, Div Infect Dis Control, Dept Vaccines, N-0403 Oslo, Norway. RP Lavine, JS (reprint author), Dept Ecol & Evolutionary Biol, 2019 Kraus Nat Sci Bldg,830 N Univ, Ann Arbor, MI 48109 USA. EM jennie.lavine@gmail.com; onb1@psu.edu; b.f.d.blasio@medisin.uio.no; Jann.Storsaeter@fhi.no RI Bjornstad, Ottar/I-4518-2012 FU Norwegian Research Council [166056/V50]; RAPIDD of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Bill and Melinda Gates Foundation FX We thank Inger Cappelen, Venelina Kostova, Synne Sandbu, and Audun Aase at the Folkehelseinstituttet in Oslo for supplying the data and providing comments on the manuscript. This work was supported by funding from the Norwegian Research Council (BFB: Projects 166056/V50) the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (ONB) and a grant from the Bill and Melinda Gates Foundation (ONB). NR 25 TC 38 Z9 39 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 11 PY 2012 VL 30 IS 3 BP 544 EP 551 DI 10.1016/j.vaccine.2011.11.065 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 912PO UT WOS:000301812300008 PM 22119924 ER PT J AU Atkins, KE Shim, E Pitzer, VE Galvani, AP AF Atkins, Katherine E. Shim, Eunha Pitzer, Virginia E. Galvani, Alison P. TI Impact of rotavirus vaccination on epidemiological dynamics in England and Wales SO VACCINE LA English DT Article DE Rotavirus gastroenteritis; Mathematical model; Dynamic epidemiological model; Vaccine intervention; Herd protection ID COST-EFFECTIVENESS; UNITED-STATES; POTENTIAL IMPACT; CHILDREN; INFECTIONS; EFFICACY; MODEL; GASTROENTERITIS; TRANSMISSION; PROTECTION AB Rotavirus infection causes severe gastroenteritis (RVGE) in children worldwide. Its disease burden has been reduced in countries where mass vaccination programs have been introduced. However, England and Wales have not yet implemented such a mass vaccination program. This paper uses a dynamic model to predict the effect of a mass vaccination program in England and Wales beginning in the fall of 2011. The dynamic model is parameterized with country-specific data for the introduction of a rotavirus vaccine. We report the impact of vaccination, in both the short- and long-term, on disease incidence reduction, timing of seasonal epidemics and the level of herd protection. Our results predict that vaccination can reduce the burden of severe RVGE by 70% and delay the rotavirus epidemic peak by two and a half months with a coverage of 95%. Our calculations further show that herd protection accounts for about a quarter of the reduction in RVGE incidence. If vaccine-induced protection does not wane over three years, severe RVGE in children under five years of age could be eliminated within two years after the introduction of vaccination. This work lays the foundation for policy-makers to determine the impact of a mass vaccination program against rotavirus in England and Wales. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Atkins, Katherine E.; Galvani, Alison P.] Yale Univ, Sch Publ Hlth, New Haven, CT 06510 USA. [Shim, Eunha] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Pitzer, Virginia E.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Pitzer, Virginia E.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Atkins, KE (reprint author), Yale Univ, Sch Publ Hlth, 135 Coll St, New Haven, CT 06510 USA. EM katherine.atkins@yale.edu; eshim@pitt.edu; vepitzer@princeton.edu; alison.galvani@yale.edu OI Pitzer, Virginia/0000-0003-1015-2289 FU RAPIDD of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We thank J. Edmunds and J. Harris for data provision, S. Carroll and S. Quilici from Sanofi Pasteur MSD and R. Pitman from Oxford Outcomes for comments and advice. KEA, ES and APG thank their sponsors Sanofi Pasteur MSD. VEP was supported by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 41 TC 28 Z9 29 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 11 PY 2012 VL 30 IS 3 BP 552 EP 564 DI 10.1016/j.vaccine.2011.11.064 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 912PO UT WOS:000301812300009 PM 22133508 ER PT J AU Roger, JE Ranganath, K Zhao, L Cojocaru, RI Brooks, M Gotoh, N Veleri, S Hiriyanna, A Rachel, RA Campos, MM Fariss, RN Wong, WT Swaroop, A AF Roger, Jerome E. Ranganath, Keerthi Zhao, Lian Cojocaru, Radu I. Brooks, Matthew Gotoh, Norimoto Veleri, Shobi Hiriyanna, Avinash Rachel, Rivka A. Campos, Maria Mercedes Fariss, Robert N. Wong, Wai T. Swaroop, Anand TI Preservation of Cone Photoreceptors after a Rapid yet Transient Degeneration and Remodeling in Cone-Only Nrl(-/-) Mouse Retina SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LEBER CONGENITAL AMAUROSIS; ALPHA-A-CRYSTALLIN; MORPHOMETRIC-ANALYSIS; MACULAR DEGENERATION; MAMMALIAN RETINA; CELL-DEATH; PIGMENT EPITHELIUM; PROGENITOR CELLS; DEFICIENT MICE; BLOOD-VESSELS AB Cone photoreceptors are the primary initiator of visual transduction in the human retina. Dysfunction or death of rod photoreceptors precedes cone loss inmanyretinal and macular degenerative diseases, suggesting a rod-dependent trophic support for cone survival. Rod differentiation and homeostasis are dependent on the basic motif leucine zipper transcription factor neural retina leucine zipper (NRL). The loss of Nrl (Nrl(-/-)) in mice results in a retina with predominantly S-opsin-containing cones that exhibit molecular and functional characteristics of wild-type cones. Here, we report that Nrl(-/-) retina undergoes a rapid but transient period of degeneration in early adulthood, with cone apoptosis, retinal detachment, alterations in retinal vessel structure, and activation and translocation of retinal microglia. However, cone degeneration stabilizes by 4 months of age, resulting in a thinner but intact outer nuclear layer with residual cones expressing S-and M-opsins and a preserved photopic electroretinogram. At this stage, microglia translocate back to the inner retina and reacquire a quiescent morphology. Gene profiling analysis during the period of transient degeneration reveals misregulation of genes related to stress response and inflammation, implying their involvement in cone death. The Nrl(-/-) mouse illustrates the long-term viability of cones in the absence of rods and retinal pigment epithelium defects in a rodless retina. We propose that Nrl(-/-) retina may serve as a model for elucidating mechanisms of cone homeostasis and degeneration that would be relevant to understanding diseases of the cone-dominant human macula. C1 [Roger, Jerome E.; Ranganath, Keerthi; Cojocaru, Radu I.; Brooks, Matthew; Gotoh, Norimoto; Veleri, Shobi; Hiriyanna, Avinash; Rachel, Rivka A.; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Zhao, Lian; Wong, Wai T.] NEI, Unit Neuron Glia Interact, NIH, Bethesda, MD 20892 USA. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, 6 Ctr Dr, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov RI Wong, Wai/B-6118-2017; OI Wong, Wai/0000-0003-0681-4016; Roger, Jerome/0000-0002-5061-230X FU National Eye Institute FX This work was supported by the intramural program of the National Eye Institute. We thank Harsha Rajasimha for help with RNAseq data and Chun Y. Gao for technical assistance. NR 82 TC 22 Z9 22 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 11 PY 2012 VL 32 IS 2 BP 528 EP 541 DI 10.1523/JNEUROSCI.3591-11.2012 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 876QE UT WOS:000299121800014 PM 22238088 ER PT J AU Ghazizadeh, A Ambroggi, F Odean, N Fields, HL AF Ghazizadeh, Ali Ambroggi, Frederic Odean, Naomi Fields, Howard L. TI Prefrontal Cortex Mediates Extinction of Responding by Two Distinct Neural Mechanisms in Accumbens Shell SO JOURNAL OF NEUROSCIENCE LA English DT Article ID REWARD-SEEKING BEHAVIOR; REACTION-TIME-TASK; NUCLEUS-ACCUMBENS; TOPOGRAPHICAL ORGANIZATION; NEURONAL RESPONSES; DIRECTED BEHAVIOR; INCENTIVE CUES; RAT; IMPULSIVITY; PERFORMANCE AB Suppression of ill-timed or competing actions optimizes goal-directed behaviors. Diminished inhibitory control over such actions is a central feature of such disorders as impulsivity, obesity, and drug addiction. The ventromedial prefrontal cortex (vmPFC) is involved in suppression of unreinforced actions. Using reversible inactivation in rats, we demonstrate that vmPFC activity is also required for inhibition of unreinforced actions extinguished during learning of a cued appetitive task and that behavioral disinhibition following vmPFC inactivation depends on dopamine signaling in nucleus accumbens shell (NAcS). Combining electrophysiological recording in NAcS with vmPFC inactivation in rats reveals two neural mechanisms by which vmPFC inhibits unreinforced actions. The first is by suppressing phasic excitations that promote behavioral cue responding. The second is by increasing the basal firing of NAcS neurons that tonically inhibit reward seeking. These results identify the vmPFC and the NAcS as critical elements of the circuits relevant to suppression of inappropriate actions. C1 [Ghazizadeh, Ali; Ambroggi, Frederic; Odean, Naomi; Fields, Howard L.] Univ Calif San Francisco, Wheeler Ctr Neurobiol Addict, Ernest Gallo Clin & Res Ctr, Emeryville, CA 94608 USA. [Ghazizadeh, Ali; Ambroggi, Frederic; Odean, Naomi; Fields, Howard L.] Univ Calif San Francisco, Dept Neurol, Emeryville, CA 94608 USA. [Ghazizadeh, Ali; Fields, Howard L.] Univ Calif San Francisco, Joint Grad Grp Bioengn, Emeryville, CA 94608 USA. [Ghazizadeh, Ali; Fields, Howard L.] Univ Calif Berkeley, Berkeley, CA 94720 USA. RP Ghazizadeh, A (reprint author), NEI, Sensorimotor Res Lab, NIH, 49 Convent Dr,Bldg 49,Room 2C28, Bethesda, MD 20892 USA. EM ali.ghazizadehehsaei@nih.gov FU state of California for medical research on alcohol and substance abuse; Wheeler Center for the Neurobiology of Addiction at the University of California, San Francisco FX This work was supported by funds provided by the state of California for medical research on alcohol and substance abuse and the Wheeler Center for the Neurobiology of Addiction at the University of California, San Francisco. NR 26 TC 34 Z9 34 U1 0 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 11 PY 2012 VL 32 IS 2 BP 726 EP 737 DI 10.1523/JNEUROSCI.3891-11.2012 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 876QE UT WOS:000299121800034 PM 22238108 ER PT J AU Cellitti, SE Shaffer, J Jones, DH Mukherjee, T Gurumurthy, M Bursulaya, B Boshoff, HI Choi, I Nayyar, A Lee, YS Cherian, J Niyomrattanakit, P Dick, T Manjunatha, UH Barry, CE Spraggon, G Geierstanger, BH AF Cellitti, Susan E. Shaffer, Jennifer Jones, David H. Mukherjee, Tathagata Gurumurthy, Meera Bursulaya, Badry Boshoff, Helena I. Choi, Inhee Nayyar, Amit Lee, Yong Sok Cherian, Joseph Niyomrattanakit, Pornwaratt Dick, Thomas Manjunatha, Ujjini H. Barry, Clifton E., III Spraggon, Glen Geierstanger, Bernhard H. TI Structure of Ddn, the Deazaflavin-Dependent Nitroreductase from Mycobacterium tuberculosis Involved in Bioreductive Activation of PA-824 SO STRUCTURE LA English DT Article ID BACTERIAL LUCIFERASE FAMILY; SECONDARY-STRUCTURE; COENZYME F-420; F-420-DEPENDENT GLUCOSE-6-PHOSPHATE-DEHYDROGENASE; NITROIMIDAZOPYRAN PA-824; ALCOHOL-DEHYDROGENASE; CIRCULAR-DICHROISM; DRUG CANDIDATE; NITRIC-OXIDE; PROTEIN AB Tuberculosis continues to be a global health threat, making bicyclic nitroimidazoles an important new class of therapeutics. A deazaflavin-dependent nitroreductase (Ddn) from Mycobacterium tuberculosis catalyzes the reduction of nitroimidazoles such as PA-824, resulting in intracellular release of lethal reactive nitrogen species. The N-terminal 30 residues of Ddn are functionally important but are flexible or access multiple conformations, preventing structural characterization of the full-length, enzymatically active enzyme. Several structures were determined of a truncated, inactive Ddn protein core with and without bound F-420 deazaflavin coenzyme as well as of a catalytically competent homolog from Nocardia farcinica. Mutagenesis studies based on these structures identified residues important for binding of F420 and PA-824. The proposed orientation of the tail of PA-824 toward the N terminus of Ddn is consistent with current structure-activity relationship data. C1 [Cellitti, Susan E.; Shaffer, Jennifer; Jones, David H.; Bursulaya, Badry; Spraggon, Glen; Geierstanger, Bernhard H.] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. [Mukherjee, Tathagata; Boshoff, Helena I.; Choi, Inhee; Nayyar, Amit; Barry, Clifton E., III] NIAID, TB Res Stn, NIH, Bethesda, MD 20892 USA. [Gurumurthy, Meera; Cherian, Joseph; Niyomrattanakit, Pornwaratt; Dick, Thomas; Manjunatha, Ujjini H.] Novartis Inst Trop Dis, Singapore 138670, Singapore. [Lee, Yong Sok] NIH, Ctr Mol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Spraggon, G (reprint author), Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA. EM gspraggon@gnf.org; bgeierst@gnf.org RI Barry, III, Clifton/H-3839-2012; Cherian, Joseph/Q-2522-2016 FU Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]; The Bill and Melinda Gates Foundation; Wellcome Trust through the Grand Challenges in Global Health Initiative to the Novartis Institute for Tropical Diseases (NITD); NIAID; Center for Information Technology FX The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under contract no. DE-AC02-05CH11231. This work was funded, in part, by a grant from The Bill and Melinda Gates Foundation and the Wellcome Trust through the Grand Challenges in Global Health Initiative to the Novartis Institute for Tropical Diseases (NITD) and NIAID; by the NIH intramural research program of NIAID to C.E.B. and of the Center for Information Technology to Y.S.L.; and by NITD. We would like to thank Dr. P. McPhie, Laboratory of Biochemistry and Genetics, NIDDK, NIH for allowing us to run the CD experiments and helping us with the analysis; P. Abdubek, C. Chen, J. Feuerhelm, J. Grant, H. Klock, A. Kreusch, A. Nopakun, L. Okach, C. Puckett, and T. Wooten at the Genomics Institute of the Novartis Research Foundation (GNF) for technical assistance; and S. Lesley (GNF) and C. Noble (NITD) for their valuable comments. S.E.C., U.H.M., C.E.B., G.S., and B.H.G. designed experiments and prepared the manuscript. C.E.B., U.H.M., and T.D. initiated the study and wrote the grants that provided funding. The following data were generated and analyzed by the indicated contributors: molecular biology and protein production and purification by S.E.C., J.S., T.M., and H.I.M.B.; crystallization and structure calculations by S.E.C. and G.S.; NMR by D.H.J.; activity assays by T.M. and P.N.; CD by T.M.; Trp fluorescence by M.G.; computational modeling by B.B., IC., and Y.S.L.; and chemical synthesis by A.N. and J.C. U.H.M., C.E.B., G.S., and B.H.G. were the subteam leaders at the respective sites and supervised the respective experiments. NR 62 TC 24 Z9 25 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD JAN 11 PY 2012 VL 20 IS 1 BP 101 EP 112 DI 10.1016/j.str.2011.11.001 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 877PY UT WOS:000299195600011 PM 22244759 ER PT J AU Goldin, LR Kristinsson, SY Liang, XS Derolf, AR Landgren, O Bjorkholm, M AF Goldin, Lynn R. Kristinsson, Sigurdur Y. Liang, Xueying Sharon Derolf, Asa R. Landgren, Ola Bjorkholm, Magnus TI Familial Aggregation of Acute Myeloid Leukemia and Myelodysplastic Syndromes SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MYELOPROLIFERATIVE NEOPLASMS; 1ST-DEGREE RELATIVES; PLATELET DISORDER; HODGKIN LYMPHOMA; RISK; MUTATIONS; ETIOLOGY; SWEDEN; MALIGNANCIES; CANCER AB Purpose Apart from rare pedigrees with multiple cases of acute myeloid leukemia (AML), there is limited data on familial aggregation of AML and myelodysplastic syndromes (MDSs) in the population. Patients and Methods Swedish population-based registry data were used to evaluate risk of AML, MDS, and other malignancies among 24,573 first-degree relatives of 6,962 patients with AML and 1,388 patients with MDS compared with 106,224 first-degree relatives of matched controls. We used a marginal survival model to calculate familial aggregation. Results AML and/or MDS did not aggregate significantly in relatives of patients with AML. There was a modest risk ratio (RR, 1.3; 95% CI, 0.9 to 1.8) in myeloproliferative/myeloid malignancies combined. The risks for any hematologic or any solid tumor were modestly but significantly increased. Relatives of patients with MDS did not show an increased risk for any hematologic tumors. In contrast, we found a significantly increased risk (RR, 6.5; 95% CI, 1.1 to 38.0) of AML/MDS and of all myeloid malignancies combined (RR, 3.1; 95% CI, 1.0 to 9.8) among relatives of patients diagnosed at younger than age 21 years. Conclusion We did not find evidence for familial aggregation of the severe end of the spectrum of myeloid malignancies (AML and MDS). The risks of myeloproliferative neoplasms were modestly increased with trends toward significance, suggesting a possible role of inheritance. In contrast, although limited in sample size, relatives of young patients with AML were at increased risk of AML/MDS, suggesting that germline genes may play a stronger role in these patients. The increased risk of all hematologic malignancies and of solid tumors among relatives of patients with AML suggests that genes for malignancy in general and/or other environmental factors may be shared. J Clin Oncol 30:179-183. (C) 2011 by American Society of Clinical Oncology C1 [Goldin, Lynn R.] NCI, Genet Epidemiol Branch, DCEG, Bethesda, MD 20892 USA. [Landgren, Ola] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kristinsson, Sigurdur Y.; Derolf, Asa R.; Bjorkholm, Magnus] Karolinska Univ Hosp Solna, Stockholm, Sweden. [Kristinsson, Sigurdur Y.; Derolf, Asa R.; Bjorkholm, Magnus] Karolinska Inst, Stockholm, Sweden. RP Goldin, LR (reprint author), NCI, Genet Epidemiol Branch, DCEG, 6120 Execut Blvd,Room 7124,MSC 7236, Bethesda, MD 20892 USA. EM goldinl@mail.nih.gov RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU National Cancer Institute, National Institutes of Health; Adolf H. Lundin Charitable Foundation, Swedish Cancer Society; Stockholm County Council; Karolinska Institutet FX Supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, and by grants from the Adolf H. Lundin Charitable Foundation, Swedish Cancer Society, and the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet. NR 28 TC 12 Z9 15 U1 0 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2012 VL 30 IS 2 BP 179 EP 183 DI 10.1200/JCO.2011.37.1203 PG 5 WC Oncology SC Oncology GA 923KU UT WOS:000302619000019 PM 22162584 ER PT J AU Kubler-Kielb, J Whitfield, C Katzenellenbogen, E Vinogradov, E AF Kubler-Kielb, Joanna Whitfield, Chris Katzenellenbogen, Ewa Vinogradov, Evgeny TI Identification of the methyl phosphate substituent at the non-reducing terminal mannose residue of the O-specific polysaccharides of Klebsiella pneumoniae O3, Hafnia alvei PCM 1223 and Escherichia coli 09/09a LPS SO CARBOHYDRATE RESEARCH LA English DT Article DE Hafnia; Klebsiella; LPS; Methyl phosphate; O-specific polysaccharide ID COLI; ANTIGEN; CHAIN; LIPOPOLYSACCHARIDES; EXPORT AB O-specific polysaccharides of Gram-negative bacteria are synthesized by two different mechanisms: polymerization of the pre-formed O-repeating unit or sequential addition of the monosaccharides to the growing polysaccharide chain. In the second case, growth of the polymer can be further subdivided into two groups depending on the presence or absence of a special monosaccharide or non-sugar substituent that terminates the glycan. A family of polymannose O-polysaccharides provides prototypes for the chain terminating process. Polysaccharides of Klebsiella pneumoniae 03, Hafnia alvei PCM 1223, and Escherichia coli 09 have the same penta-mannose repeating unit. E. coli 09a has tetra-mannose repeat and this structure can be produced by mutants of E. coli 09. The mechanism of biosynthesis of H. alvei 1223 O-polysaccharide has not been reported. Here we show that all above polysaccharides contain the same modification at the non-reducing end; presence of a methyl phosphate group at 0-3 of alpha-mannopyranose, that serves as the signal for termination of the chain elongation. Crown Copyright (C) 2011 Published by Elsevier Ltd. All rights reserved. C1 [Vinogradov, Evgeny] CNR, Inst Biol Sci, Ottawa, ON K1A 0R6, Canada. [Kubler-Kielb, Joanna] NICHHD, NIH, Bethesda, MD 20892 USA. [Whitfield, Chris] Univ Guelph, Dept Mol & Cellular Biol, Guelph, ON N1G 2W1, Canada. [Katzenellenbogen, Ewa] Polish Acad Sci, Inst Immunol & Expt Therapy, PL-53114 Wroclaw, Poland. RP Vinogradov, E (reprint author), CNR, Inst Biol Sci, 100 Sussex Dr, Ottawa, ON K1A 0R6, Canada. EM evguenii.vinogradov@nrc.ca FU NIH, NICHD FX This research was supported in part by the Intramural Research Program of the NIH, NICHD. NR 16 TC 11 Z9 11 U1 2 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 EI 1873-426X J9 CARBOHYD RES JI Carbohydr. Res. PD JAN 10 PY 2012 VL 347 IS 1 BP 186 EP 188 DI 10.1016/j.carres.2011.11.019 PG 3 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 890FL UT WOS:000300130400029 PM 22169179 ER PT J AU Sheehan, FT AF Sheehan, Frances T. TI The 3D in vivo Achilles' tendon moment arm, quantified during active muscle control and compared across sexes SO JOURNAL OF BIOMECHANICS LA English DT Article DE Ankle; MRI; Dynamic; Moment arm; Lever arm; Soleus; Gastrocnemius ID SHOE DESIGN; SUBTALAR; RUPTURE; LENGTH; MODEL; WALKING; JOINTS; ANKLE; SHAPE; FOOT AB The Achilles' tendon moment arm (ATma) is a critical quantity in that it defines the triceps surae's ability to generate a moment on the calcaneus, which is then transferred to the foot. This measure has been primarily acquired two-dimensionally in small male populations. Thus, the primary purpose of this study was to establish the first in vivo three-dimensional measures of the ATma, measured noninvasively during dynamic activity in a large normative population, inclusive of both males and female subjects (n=20). Subjects were each placed supine in a 1.51 MRI and asked to repeat a simulated toeraise while a full sagittal-cine-phase contrast (dynamic) MRI dataset was acquired. From these data, the 3D and 2D Alma was calculated. The Alma was scaled by the distal tibial width, based on a correlation analysis. The 2D Alma overestimated its 3D counterpart by 3.1 mm, on average. The scaled Alma was no different between the male and female cohorts, but the scaled Achilles' tendon area was smaller in the male cohort. The magnitudes of the Alma were most similar to previously reported values when variations in ankle angle were taken into account. The results of this study have important implications for the applicability of Alma data to both clinical questions and modeling. Any future studies should adapt the Alma based on subject size and/or sex, ensure compatibility between the manner in which the ankle angle is defined and the data being used, and account for the influence that muscle force has on the 3D Alma. Published by Elsevier Ltd. C1 NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Sheehan, FT (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Bldg 10 CRC RM 1-1469,10 Ctr Dr MSC 1604, Bethesda, MD 20892 USA. EM fsheehan@cc.nih.gov RI sheehan, frances/B-6962-2009 FU Department at the National Institutes of Health; NIH Clinical Center FX I wish to thank Andrea R. Seisler and Tracy Rausch for the assistance in device design & fabrication along with data collection. I would also like to thank Bonnie Damaska, Jamie Fraunhaffer, Jere McLucas, and the Diagnostic Radiology Department at the National Institutes of Health for their support and research time. This research was supported in part by the NIH Clinical Center Intramural Research Program. NR 26 TC 9 Z9 9 U1 1 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD JAN 10 PY 2012 VL 45 IS 2 BP 225 EP 230 DI 10.1016/j.jbiomech.2011.11.001 PG 6 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 885BX UT WOS:000299754600003 PM 22138193 ER PT J AU Calvo, E Barasoain, I Matesanz, R Pera, B Camafeita, E Pineda, O Hamel, E Vanderwal, CD Andreu, JM Lopez, JA Diaz, JF AF Calvo, Enrique Barasoain, Isabel Matesanz, Ruth Pera, Benet Camafeita, Emilio Pineda, Oriol Hamel, Ernest Vanderwal, Christopher D. Manuel Andreu, Jose Lopez, Juan A. Fernando Diaz, Jose TI Cyclostreptin Derivatives Specifically Target Cellular Tubulin and Further Map the Paclitaxel Site SO BIOCHEMISTRY LA English DT Article ID MICROTUBULE-STABILIZING AGENTS; STATHMIN-LIKE DOMAIN; ALPHA-BETA-TUBULIN; MASS-SPECTROMETRY; BINDING-SITE; TAXOID SITE; HIGH-AFFINITY; ANTIMITOTIC SUBSTANCE; DRUG BIOACTIVATION; ANTITUMOR AGENT AB Cyclostreptin is the first microtubule-stabilizing agent whose mechanism of action was discovered to involve formation of a covalent bond with tubulin. Treatment of cells with cyclostreptin irreversibly stabilizes their microtubules because cyclostreptin forms a covalent bond to beta-tubulin at either the T220 or the N228 residue, located at the microtubule pore or luminal taxoid binding site, respectively. Because of its unique mechanism of action, cyclostreptin overcomes P-glycoprotein-mediated multidrug resistance in tumor cells. We used a series of reactive cyclostreptin analogues, 6-chloroacetyl-cyclostreptin, 8-chloroacetyl-cyclostreptin, and [C-14-acetyl]-8-acetyl-cyclostreptin, to characterize the cellular target of the compound and to map the binding site. The three analogues were cytotoxic and stabilized microtubules in both sensitive and multidrug resistant tumor cells. In both types of cells, we identified beta-tubulin as the only or the predominantly labeled cellular protein, indicating that covalent binding to microtubules is sufficient to prevent drug efflux mediated by P-glycoprotein. 6-Chloroacetyl-cydostreptin, 8-diloroacetyl-cyclostreptin, and 8-acetyl-cyclostreptin labeled both microtubules and unassembled tubulin at a single residue of the same tryptic peptide of beta-tubulin as was labeled by cyclostreptin (219-LTTPTYGDLNHLVSATMSGVTTCLR-243), but labeling with the analogues occurred at different positions of the peptide. 8-Acetyl-cyclostreptin reacted with either T220 or N228, as did the natural product, while 8-chloroacetyl-cyclostreptin formed a cross-link to C241. Finally, 6-chloroacetyl-cyclostreptin reacted with any of the three residues, thus labeling the pathway for cyclostreptin-like compounds, leading from the pore where these compounds enter the microtubule to the luminal binding pocket. C1 [Barasoain, Isabel; Matesanz, Ruth; Pera, Benet; Manuel Andreu, Jose; Fernando Diaz, Jose] CSIC, Ctr Invest Biol, CIB, Madrid 28040, Spain. [Calvo, Enrique; Camafeita, Emilio; Lopez, Juan A.] Ctr Nacl Invest Cardiovasc, Unidad Prote, Madrid, Spain. [Pineda, Oriol] Univ Barcelona, Fac Quim, E-08028 Barcelona, Spain. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Vanderwal, Christopher D.] Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA. RP Barasoain, I (reprint author), CSIC, Ctr Invest Biol, CIB, C Ramiro de Maeztu 9, Madrid 28040, Spain. EM i.barasoain@cib.csic.es; fer@cib.csic.es RI Lopez, Juan Antonio/G-7750-2015; OI Lopez, Juan Antonio/0000-0002-9097-6060; Andreu, Jose M/0000-0001-8064-6933; Diaz, J. Fernando/0000-0003-2743-3319 FU Ministerio de Ciencia e Innovacion [BIO2010-16351]; Comunidad Autonoma de Madrid [BIPPED2]; Fundacion Pro CNIC FX This work was supported in part by Grant BIO2010-16351 from Ministerio de Ciencia e Innovacion (to J.F.D.) and grant BIPPED2 from Comunidad Autonoma de Madrid. The CNIC is supported by the Ministerio de Ciencia e Innovacion and the Fundacion Pro CNIC. NR 54 TC 11 Z9 11 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 10 PY 2012 VL 51 IS 1 BP 329 EP 341 DI 10.1021/bi201380p PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 873UB UT WOS:000298907400036 PM 22148836 ER PT J AU Xie, Q Bradley, R Kang, L Koeman, J Ascierto, ML Worschech, A De Giorgi, V Wang, E Kefene, L Su, YL Essenburg, C Kaufman, DW DeKoning, T Enter, MA O'Rourke, TJ Marincola, FM Vande Woude, GF AF Xie, Qian Bradley, Robert Kang, Liang Koeman, Julie Ascierto, Maria Libera Worschech, Andrea De Giorgi, Valeria Wang, Ena Kefene, Lisa Su, Yanli Essenburg, Curt Kaufman, Dafna W. DeKoning, Tom Enter, Mark A. O'Rourke, Timothy J. Marincola, Francesco M. Vande Woude, George F. TI Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hepatocyte growth factor-autocrine loop; molecular marker; oncogene addiction; targeted therapy ID FACTOR/SCATTER FACTOR; STEM-CELLS; GLIOMA; AMPLIFICATION; METASTASIS; XENOGRAFTS; TUMORS; EGFR; MICE; GELDANAMYCINS AB Because oncogene MET and EGF receptor (EGFR) inhibitors are in clinical development against several types of cancer, including glioblastoma, it is important to identify predictive markers that indicate patient subgroups suitable for such therapies. We investigated in vivo glioblastoma models characterized by hepatocyte growth factor (HGF) autocrine or paracrine activation, or by MET or EGFR amplification, for their susceptibility to MET inhibitors. HGF autocrine expression correlated with high phospho-MET levels in HGF autocrine cell lines, and these lines showed high sensitivity to MET inhibition in vivo. An HGF paracrine environment may enhance glioblastoma growth in vivo but did not indicate sensitivity to MET inhibition. EGFRvIII amplification predicted sensitivity to EGFR inhibition, but in the same tumor, increased copies of MET from gains of chromosome 7 did not result in increased MET activity and did not predict sensitivity to MET inhibitors. Thus, HGF autocrine glioblastoma bears an activated MET signaling pathway that may predict sensitivity to MET inhibitors. Moreover, serum HGF levels may serve as a biomarker for the presence of autocrine tumors and their responsiveness to MET therapeutics. C1 [Xie, Qian; Bradley, Robert; Kang, Liang; Koeman, Julie; Kefene, Lisa; Su, Yanli; Essenburg, Curt; Kaufman, Dafna W.; DeKoning, Tom; Vande Woude, George F.] Van Andel Res Inst, Grand Rapids, MI 49503 USA. [Ascierto, Maria Libera; Worschech, Andrea; De Giorgi, Valeria; Wang, Ena; Marincola, Francesco M.] NIH, Trans Natl Inst Hlth Ctr Human Immunol, Bethesda, MD 20892 USA. [Ascierto, Maria Libera; Worschech, Andrea; De Giorgi, Valeria; Wang, Ena; Marincola, Francesco M.] NIH, Dept Transfus Med, Infect Dis & Immunogenet Sect, Ctr Clin, Bethesda, MD 20892 USA. [Enter, Mark A.; O'Rourke, Timothy J.] Spectrum Hlth, Grand Rapids, MI 49503 USA. RP Xie, Q (reprint author), Van Andel Res Inst, Grand Rapids, MI 49503 USA. EM qian.xie@vai.org; george.vandewoude@vai.org RI Ascierto, Maria Libera/A-9239-2012; Worschech, Andrea/I-3919-2012; De Giorgi, Valeria/D-4582-2017 OI Worschech, Andrea/0000-0002-4303-8653; NR 36 TC 48 Z9 49 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 10 PY 2012 VL 109 IS 2 BP 570 EP 575 DI 10.1073/pnas.1119059109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 874IS UT WOS:000298950200048 PM 22203985 ER PT J AU Goloudina, AR Tanoue, K Hammann, A Fourmaux, E Le Guezennec, X Bulavin, DV Mazur, SJ Appella, E Garrido, C Demidov, ON AF Goloudina, Anastasia R. Tanoue, Kan Hammann, Arlette Fourmaux, Eric Le Guezennec, Xavier Bulavin, Dmitry V. Mazur, Sharlyn J. Appella, Ettore Garrido, Carmen Demidov, Oleg N. TI Wip1 promotes RUNX2-dependent apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE caspases; Bcl-2 family; dephosphorylation; intestine ID CHEMICAL INHIBITOR; P53 MUTATIONS; DNA-DAMAGE; IN-VIVO; PHOSPHATASE; CELLS; RUNX2; PPM1D; GENE; SUPPRESSOR AB The inactivation of the p53 tumor suppressor pathway in many cancers often increases their resistance to anticancer therapy. Here we show that a previously proposed strategy directed to Wip1 inhibition could be ineffective in tumors lacking p53. On the contrary, Wip1 overexpression sensitized these tumors to chemotherapeutic agents. This effect was mediated through interaction between Wip1 and RUNX2 that resulted, in response to anticancer treatment, in RUNX2-dependent transcriptional induction of the proapoptotic Bax protein. The potentiating effects of Wip1 overexpression on chemotherapeutic agents were directed only to tumor cells lacking p53. The overexpression of Wip1 in normal tissues provided protection from cisplatin-induced apoptosis through decreased strength of upstream signaling to p53. Thus, Wip1 phosphatase promotes apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents. C1 [Goloudina, Anastasia R.; Hammann, Arlette; Fourmaux, Eric; Garrido, Carmen; Demidov, Oleg N.] Univ Burgundy, INSERM, Unite Mixte Rech 866, F-21078 Dijon, France. [Tanoue, Kan; Mazur, Sharlyn J.; Appella, Ettore] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Le Guezennec, Xavier; Bulavin, Dmitry V.] Inst Mol & Cell Biol, Cell Cycle Control & Tumorigenesis Grp, Singapore 138673, Singapore. [Garrido, Carmen; Demidov, Oleg N.] Univ Burgundy, Fac Med & Pharm, F-21078 Dijon, France. [Garrido, Carmen] Univ Dijon, Ctr Hosp, F-21000 Dijon, France. RP Demidov, ON (reprint author), Univ Burgundy, INSERM, Unite Mixte Rech 866, F-21078 Dijon, France. EM oleg.demidov@u-bourgogne.fr RI ASTAR, IMCB/E-2320-2012; LE GUEZENNEC, Xavier/G-9635-2012; OI LE GUEZENNEC, Xavier/0000-0002-1590-1325; Demidov, Oleg/0000-0003-4323-7174 FU Ligue Contre le Cancer La Conference de Coordination Interregionale du Grand Est and Conseil Regional de Bourgogne; National Cancer Institute, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN 261 2008 00001E] FX We are thankful to Dr. Alexei Arnaoutov, Dr. Vladimir Kuznetsov, and Dr. Laurent Lagrost for productive discussions and methodological help; to Dr. Roman Eliseev and Dr. Hicham Drissi for Runx2 and Bax-promoter vectors. C. Garrido group has the label "La Ligue Contre le Cancer." This work was supported by the Ligue Contre le Cancer La Conference de Coordination Interregionale du Grand Est and Conseil Regional de Bourgogne, and in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, and federal funds from the National Cancer Institute, National Institutes of Health, under HHSN 261 2008 00001E. NR 57 TC 15 Z9 15 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 10 PY 2012 VL 109 IS 2 BP E68 EP E75 DI 10.1073/pnas.1107017108 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 874IS UT WOS:000298950200007 PM 22065775 ER PT J AU Hutchins, BI Li, L Kalil, K AF Hutchins, B. Ian Li, Li Kalil, Katherine TI Wnt-Induced Calcium Signaling Mediates Axon Growth and Guidance in the Developing Corpus Callosum SO SCIENCE SIGNALING LA English DT Article ID IN-VIVO; FOREBRAIN; OUTGROWTH; NETRIN-1 AB Wnt5a gradients guide callosal axons by repulsion through Ryk receptors in vivo. We recently found that Wnt5a repels cortical axons and promotes axon outgrowth through calcium signaling in vitro. Here, using cortical slices, we show that Wnt5a signals through Ryk to guide and promote outgrowth of callosal axons after they cross the midline. Calcium transient frequencies in callosal growth cones positively correlate with axon outgrowth rates in vitro. In cortical slices, calcium release through inositol 1,4,5-trisphosphate (IP3) receptors and calcium entry through transient receptor potential channels modulate axon growth and guidance. Knocking down Ryk inhibits calcium signaling in cortical axons, reduces rates of axon outgrowth subsequent to midline crossing, and causes axon guidance defects. Calcium- and calmodulin-dependent protein kinase II (CaMKII) is required downstream of Wnt-induced calcium signaling for postcrossing callosal axon growth and guidance. Taken together, these results suggest that growth and guidance of postcrossing callosal axons by Wnt-Ryk-calcium signaling involves axon repulsion through CaMKII. C1 [Hutchins, B. Ian; Li, Li; Kalil, Katherine] Univ Wisconsin, Neurosci Training Program, Madison, WI 53706 USA. [Kalil, Katherine] Univ Wisconsin, Dept Neurosci, Madison, WI 53706 USA. RP Hutchins, BI (reprint author), NINDS, Cellular & Dev Neurobiol Sect, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM bruce.hutchins@nih.gov RI Hutchins, Ian/A-5713-2009 OI Hutchins, Ian/0000-0001-7657-552X FU NIH [NS14428, GM801642]; Herman I. Shapiro fellowship; University of Wisconsin Graduate School FX This work was supported by NIH grants NS14428 to K.K. and GM801642 to B.I.H. and a Herman I. Shapiro fellowship and a grant from the University of Wisconsin Graduate School to L.L. We thank J. Nakai and Addgene.org for providing the GCaMP2 plasmid. This work was later published in Developmental Neurobiology (16) and Frontiers in Neuroanatomy (17). NR 17 TC 7 Z9 7 U1 1 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JAN 10 PY 2012 VL 5 IS 206 AR pt1 DI 10.1126/scisignal.2002523 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 875DU UT WOS:000299011400003 PM 22234611 ER PT J AU Wells, SA Robinson, BG Gagel, RF Dralle, H Fagin, JA Santoro, M Baudin, E Elisei, R Jarzab, B Vasselli, JR Read, J Langmuir, P Ryan, AJ Schlumberger, MJ AF Wells, Samuel A., Jr. Robinson, Bruce G. Gagel, Robert F. Dralle, Henning Fagin, James A. Santoro, Massimo Baudin, Eric Elisei, Rossella Jarzab, Barbara Vasselli, James R. Read, Jessica Langmuir, Peter Ryan, Anderson J. Schlumberger, Martin J. TI Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the European-Society-for-Medical-Oncology (ESMO) CY OCT 08-12, 2010 CL Milan, ITALY SP European Soc Med Oncol (ESMO) ID ENDOCRINE NEOPLASIA SYNDROMES; RET PROTOONCOGENE; CARCINOMA; MUTATIONS; ZD6474; GUIDELINES; SURVIVAL; EFFICACY; THERAPY; KINASES AB Purpose There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC. Patients and Methods Patients with advanced MTC were randomly assigned in a 2: 1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments. Results Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P < .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%). Conclusion Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761). J Clin Oncol 30:134-141. (C) 2011 by American Society of Clinical Oncology C1 [Wells, Samuel A., Jr.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Robinson, Bruce G.] Univ Sydney, Kolling Inst Med Res, Sydney, NSW 2006, Australia. [Gagel, Robert F.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Dralle, Henning] Univ Halle Wittenberg, Halle, Germany. [Fagin, James A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Santoro, Massimo] Univ Naples Federico II, Naples, Italy. [Baudin, Eric; Schlumberger, Martin J.] Inst Gustave Roussy, Villejuif, France. [Elisei, Rossella] Univ Pisa, Pisa, Italy. [Jarzab, Barbara] Maria Sklodowska Curie Mem Canc Ctr, Gliwice, Poland. [Langmuir, Peter] AstraZeneca, Wilmington, DE USA. [Read, Jessica] AstraZeneca, Macclesfield, Cheshire, England. [Ryan, Anderson J.] Univ Oxford, Oxford, England. RP Wells, SA (reprint author), NCI, Med Oncol Branch, NIH, Bldg 10,Room 13N-240E MSC 1206,9000 Rockville Pi, Bethesda, MD 20892 USA. EM wellss@mail.nih.gov RI Ryan, Anderson/O-7701-2015 OI Ryan, Anderson/0000-0001-6241-7969 NR 29 TC 381 Z9 386 U1 4 U2 46 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 10 PY 2012 VL 30 IS 2 BP 134 EP 141 DI 10.1200/JCO.2011.35.5040 PG 8 WC Oncology SC Oncology GA 923KU UT WOS:000302619000013 PM 22025146 ER PT J AU Chiang, CY Karuri, SW Kshatriya, PP Schwartz, J Schwarzbauer, JE Karuri, NW AF Chiang, Chunyi Karuri, Stella W. Kshatriya, Pradnya P. Schwartz, Jeffrey Schwarzbauer, Jean E. Karuri, Nancy W. TI Surface Derivatization Strategy for Combinatorial Analysis of Cell Response to Mixtures of Protein Domains SO LANGMUIR LA English DT Article ID INTEGRIN SPECIFICITY; EXTRACELLULAR-MATRIX; FIBRONECTIN; ADHESION; BIOMATERIALS; FIBRILLOGENESIS; MONOLAYERS; BINDING; SITES AB We report a robust strategy for conjugating mixtures of two or more protein domains to nonfouling polyurethane surfaces. In our strategy, the carbamate groups of polyurethane are reacted with zirconium alkoxide from the vapor phase to give a surface-bound oxide that serves as a chemical layer that can be used to bond organics to the polymer substrate. A hydroxyallcylphosphonate monolayer was synthesized on this layer, which was then used to covalently bind primary amine groups in protein domains using chloroformate-derived cross-linking. The effectiveness of this synthesis strategy was gauged by using an ELISA to measure competitive, covalent bonding of cell-binding (III9-10) and fibronectin-binding (III1-2) domains of the cell adhesion protein fibronectin. Cell adhesion, spreading, and fibronectin matrix assembly were examined on surfaces conjugated with single domains, a 1:1 surface mixture of III1-2 and III9-10, and a recombinant protein "duplex" containing both domains in one fusion protein. The mixture performed as well as or better than the other surfaces in these assays. Our surface activation strategy is amenable to a wide range of polymer substrates and free amino group-containing protein fragments. As such, this technique may be used to create biologically specific materials through the immobilization of specific protein groups or mixtures thereof on a substrate surface. C1 [Kshatriya, Pradnya P.; Karuri, Nancy W.] IIT, Dept Chem & Biol Engn, Chicago, IL 60616 USA. [Chiang, Chunyi] IIT, Dept Biol Chem & Phys Sci, Chicago, IL 60616 USA. [Karuri, Stella W.] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. [Schwartz, Jeffrey] Princeton Univ, Dept Chem, Princeton, NJ 08544 USA. [Schwarzbauer, Jean E.] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. RP Karuri, NW (reprint author), IIT, Dept Chem & Biol Engn, Chicago, IL 60616 USA. EM nkaruri1@iit.edu FU National Institutes of Health [CA044627, GM059383]; New Jersey Center for Biomaterials through NIBIB from the National Institutes of Health [T32EB-005583] FX This study was supported by funding from National Institutes of Health to JES (CA044627 and GM059383). This project was initiated while NWK was supported by the New Jersey Center for Biomaterials through NIBIB Training Program Grant T32EB-005583 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of Biomedical Imaging and Bioengineering or the National Institutes of Health. NWK is grateful to Casey Jones and Kung-Ching Liao for help with surface chemistry and to Ji Young Shim for technical help. NR 24 TC 4 Z9 4 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD JAN 10 PY 2012 VL 28 IS 1 BP 548 EP 556 DI 10.1021/la202053k PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 873TC UT WOS:000298904900071 PM 22103809 ER PT J AU Tong, YR Giaime, E Yamaguchi, H Ichimura, T Liu, YM Si, HQ Cai, HB Bonventre, JV Shen, J AF Tong, Youren Giaime, Emilie Yamaguchi, Hiroo Ichimura, Takaharu Liu, Yumin Si, Huiqing Cai, Huaibin Bonventre, Joseph V. Shen, Jie TI Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway SO MOLECULAR NEURODEGENERATION LA English DT Article DE LRRK2; Parkinson's disease; knockout; LC3; p62; lysosomal proteins; cathepsins; lipofuscin ID PROTEIN-DEGRADATION PATHWAYS; SPORADIC PARKINSONS-DISEASE; HUMAN ALPHA-SYNUCLEIN; NEURODEGENERATIVE DISEASE; URINARY BIOMARKER; TRANSGENIC MICE; DEFICIENT MICE; KIDNEY INJURY; LEWY BODIES; LRRK2 GENE AB Background: Dominantly inherited missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, but its normal physiological function remains unclear. We previously reported that loss of LRRK2 causes impairment of protein degradation pathways as well as increases of apoptotic cell death and inflammatory responses in the kidney of aged mice. Results: Our analysis of LRRK2-/- kidneys at multiple ages, such as 1, 4, 7, and 20 months, revealed unique age-dependent development of a variety of molecular, cellular, and ultrastructural changes. Gross morphological abnormalities of the kidney, including altered size, weight, texture, and color, are evident in LRRK2-/- mice at 3-4 months of age, along with increased accumulation of autofluorescent granules in proximal renal tubules. The ratio of kidney/body weight in LRRK2-/- mice is increased at 1, 4, and 7 months of age (similar to 10% at 1 month, and similar to 20% at 4 and 7 months), whereas the ratio is drastically decreased at 20 months of age (similar to 50%). While kidney filtration function evaluated by levels of blood urea nitrogen and serum creatinine is not significantly affected in LRRK2-/- mice at 12-14 months of age, expression of kidney injury molecule-1, a sensitive and specific biomarker for epithelial cell injury of proximal renal tubules, is up-regulated (similar to 10-fold). Surprisingly, loss of LRRK2 causes age-dependent bi-phasic alterations of the autophagic activity in LRRK2-/- kidneys, which is unchanged at 1 month of age, enhanced at 7 months but reduced at 20 months, as evidenced by corresponding changes in the levels of LC3-I/II, a reliable autophagy marker, and p62, an autophagy substrate. Levels of alpha-synuclein and protein carbonyls, a general oxidative damage marker, are also decreased in LRRK2-/- kidneys at 7 months of age but increased at 20 months. Interestingly, the age-dependent bi-phasic alterations in autophagic activity in LRRK2-/- kidneys is accompanied by increased levels of lysosomal proteins and proteases at 1, 7, and 20 months of age as well as progressive accumulation of autolysosomes and lipofuscin granules at 4, 7-10, and 20 months of age. Conclusions: LRRK2 is important for the dynamic regulation of autophagy function in vivo. C1 [Tong, Youren; Giaime, Emilie; Yamaguchi, Hiroo; Si, Huiqing; Shen, Jie] Harvard Univ, Sch Med, Brigham & Womens Hosp, Program Neurosci,Ctr Neurol Dis,Dept Neurol, Boston, MA 02115 USA. [Ichimura, Takaharu; Liu, Yumin; Bonventre, Joseph V.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Renal Div, Boston, MA 02115 USA. [Cai, Huaibin] NIA, Unit Transgenesis, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Tong, YR (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Program Neurosci,Ctr Neurol Dis,Dept Neurol, Boston, MA 02115 USA. EM ytong@rics.bwh.harvard.edu; jshen@rics.bwh.harvard.edu RI Cai, Huaibin/H-3359-2013 OI Cai, Huaibin/0000-0002-8596-6108 FU National Institute of Neurological Disorders and Stroke [R01 NS071251, R01 NS041779, R01 NS052745]; Michael J. Fox Foundation; National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK039773, R01 DK072381]; National Institute on Aging FX We thank Huailong Zhao for technical assistance. This work was supported by grants from the National Institute of Neurological Disorders and Stroke (R01 NS071251, R01 NS041779, and R01 NS052745) and the Michael J. Fox Foundation (to J.S.) and grants from the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK039773 and R01 DK072381 to J.V.B.) and by the Intramural Research Program of National Institute on Aging (to H.C.). NR 54 TC 73 Z9 75 U1 4 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD JAN 9 PY 2012 VL 7 AR 2 DI 10.1186/1750-1326-7-2 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 909QM UT WOS:000301579300001 PM 22230652 ER PT J AU Melara, RD Tong, YX Rao, A AF Melara, Robert D. Tong, Yunxia Rao, Aparna TI Control of working memory: Effects of attention training on target recognition and distractor salience in an auditory selection task SO BRAIN RESEARCH LA English DT Article DE Event related potential; Working memory; Attention training; Inhibitory control; Auditory selective attention ID SERIAL VISUAL PRESENTATION; INFERIOR FRONTAL JUNCTION; EVENT-RELATED FMRI; COGNITIVE CONTROL; TIME-COURSE; STROOP TASK; INTENSITY PERCEPTION; ANTERIOR CINGULATE; BRAIN; BLINK AB Behavioral and electrophysiological measures of target and distractor processing were examined in an auditory selective attention task before and after three weeks of distractor suppression training. Behaviorally, training improved target recognition and led to less conservative and more rapid responding. Training also effectively shortened the temporal distance between distractors and targets needed to achieve a fixed level of target sensitivity. The effects of training on event-related potentials were restricted to the distracting stimulus: earlier N1 latency, enhanced P2 amplitude, and weakened P3 amplitude. Nevertheless, as distractor P2 amplitude increased, so too did target P3 amplitude, connecting experience-dependent changes in distractor processing with greater distinctiveness of targets in working memory. We consider the effects of attention training on the processing priorities, representational noise, and inhibitory processes operating in working memory. (C) 2011 Elsevier B.V. All rights reserved. C1 [Melara, Robert D.] CUNY, City Coll, Dept Psychol, New York, NY 10031 USA. [Tong, Yunxia] NIMH, Gene Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Rao, Aparna] Univ Minnesota, Dept Speech Language Hearing Sci, Minneapolis, MN 55455 USA. RP Melara, RD (reprint author), CUNY, City Coll, Dept Psychol, 138th St & Convent Ave,NAC 7-120, New York, NY 10031 USA. EM rmelara@ccny.cuny.edu; yunxia@mail.nih.gov; raoxx098@umn.edu NR 85 TC 6 Z9 7 U1 4 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 9 PY 2012 VL 1430 BP 68 EP 77 DI 10.1016/j.brainres.2011.10.036 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 895ZA UT WOS:000300534000009 PM 22099165 ER PT J AU Fu, YS Qin, WB Cao, H Xu, R Tan, Y Lu, T Wang, HR Tong, WX Rong, X Li, G Yuan, MQ Li, CH Abe, KJ Lu, L Chen, GH AF Fu, Yongshui Qin, Weibing Cao, Hong Xu, Ru Tan, Yi Lu, Teng Wang, Hongren Tong, Wangxia Rong, Xia Li, Gang Yuan, Manqiong Li, Chunhua Abe, Kenji Lu, Ling Chen, Guihua TI HCV 6a Prevalence in Guangdong Province Had the Origin from Vietnam and Recent Dissemination to Other Regions of China: Phylogeographic Analyses SO PLOS ONE LA English DT Article ID HEPATITIS-C-VIRUS; INJECTION-DRUG USERS; MAXIMUM-LIKELIHOOD-ESTIMATION; MOLECULAR EPIDEMIOLOGY; SOUTHERN CHINA; GENOTYPE DISTRIBUTION; HEROIN USERS; BLOOD-DONORS; INFECTION; SEQUENCES AB Background: Recently in China, HCV 6a infection has shown a fast increase among patients and blood donors, possibly due to IDU linked transmission. Methodology/Findings: We recruited 210 drug users in Shanwei city, Guangdong province. Among them, HCV RNA was detected in 150 (71.4%), both E1 and NS5B genes were sequenced in 136, and 6a genotyped in 70. Of the 6a sequences, most were grouped into three clusters while 23% represent emerging strains. For coalescent analysis, additional 6a sequences were determined among 21 blood donors from Vietnam, 22 donors from 12 provinces of China, and 36 IDUs from Liuzhou City in Guangxi Province. Phylogeographic analyses indicated that Vietnam could be the origin of 6a in China. The Guangxi Province, which borders Vietnam, could be the first region to accept 6a for circulation. Migration from Yunnan, which also borders Vietnam, might be equally important, but it was only detected among IDUs in limited regions. From Guangxi, 6a could have further spread to Guangdong, Yunnan, Hainan, and Hubei provinces. However, evidence showed that only in Guangdong has 6a become a local epidemic, making Guangdong the second source region to disseminate 6a to the other 12 provinces. With a rate of 2.737 x 10(-3) (95% CI: 1.792 x 10(-3) to 3.745 x 10(-3)), a Bayesian Skyline Plot was portrayed. It revealed an exponential 6a growth during 1994-1998, while before and after 1994-1998 slow 6a growths were maintained. Concurrently, 1994-1998 corresponded to a period when contaminated blood transfusion was common, which caused many people being infected with HIV and HCV, until the Chinese government outlawed the use of paid blood donations in 1998. Conclusions/Significance: With an origin from Vietnam, 6a has become a local epidemic in Guangdong Province, where an increasing prevalence has subsequently led to 6a spread to many other regions of China. C1 [Fu, Yongshui] Sun Yat Sen Univ, Coll Med, Dept Biochem, Guangzhou, Guangdong, Peoples R China. [Fu, Yongshui; Xu, Ru; Rong, Xia] Guangzhou Blood Ctr, Guangzhou, Guangdong, Peoples R China. [Qin, Weibing] Family Planning Res Inst Guangdong Prov, Guangzhou, Guangdong, Peoples R China. [Qin, Weibing; Wang, Hongren; Li, Gang] Sun Yat Sen Univ, Affiliated Hosp 3, Vaccine Inst, Guangzhou, Guangdong, Peoples R China. [Cao, Hong; Tong, Wangxia] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Infect Dis, Guangzhou, Guangdong, Peoples R China. [Tan, Yi] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lu, Teng] Univ So Calif, Los Angeles, CA USA. [Yuan, Manqiong; Li, Chunhua; Lu, Ling] Univ Kansas, Med Ctr, Viral Oncol Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Abe, Kenji] Natl Inst Infect Dis, Dept Pathol, Shinjuku Ku, Tokyo 1628640, Japan. [Lu, Ling; Chen, Guihua] Sun Yat Sen Univ, Affiliated Hosp 3, Lab Hepatol, Guangzhou, Guangdong, Peoples R China. RP Lu, L (reprint author), Univ Kansas, Med Ctr, Viral Oncol Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. EM llu@kumc.edu FU National Institute of Allergy and Infectious Diseases [1R01AI080734-01A]; Bureau of Health, Guangzhou City, China [2008-ZDi-10, 2009-ZDa-05]; National Natural Science Foundation of China [30872162] FX The project described was supported by a grant from the National Institute of Allergy and Infectious Diseases (1R01AI080734-01A, Dr. Ling Lu); two grants from the Bureau of Health, Guangzhou City, China (No. 2008-ZDi-10, 2009-ZDa-05, Dr. Yongshui Fu) (http://www.gzmed.gov.cn); and a grant from the National Natural Science Foundation of China (No. 30872162, Dr. Yongshui Fu) (http://www.nsfc.gov.cn). The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 37 Z9 45 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 9 PY 2012 VL 7 IS 1 AR e28006 DI 10.1371/journal.pone.0028006 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 102TA UT WOS:000315865800001 PM 22253686 ER PT J AU Pulliam, JRC Epstein, JH Dushoff, J Rahman, SA Bunning, M Jamaluddin, AA Hyatt, AD Field, HE Dobson, AP Daszak, P AF Pulliam, Juliet R. C. Epstein, Jonathan H. Dushoff, Jonathan Rahman, Sohayati A. Bunning, Michel Jamaluddin, Aziz A. Hyatt, Alex D. Field, Hume E. Dobson, Andrew P. Daszak, Peter CA HERG TI Agricultural intensification, priming for persistence and the emergence of Nipah virus: a lethal bat-borne zoonosis SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE Nipah virus; epidemic enhancement; infectious disease dynamics; emerging pathogens; zoonosis; flying fox ID PENINSULAR MALAYSIA; PTEROPUS-VAMPYRUS; HENIPAVIRUS INFECTION; PUBLIC-HEALTH; FRUIT BATS; DISEASES; PARAMYXOVIRUS; TRANSMISSION; ENCEPHALITIS; BANGLADESH AB Emerging zoonoses threaten global health, yet the processes by which they emerge are complex and poorly understood. Nipah virus (NiV) is an important threat owing to its broad host and geographical range, high case fatality, potential for human-to-human transmission and lack of effective prevention or therapies. Here, we investigate the origin of the first identified outbreak of NiV encephalitis in Malaysia and Singapore. We analyse data on livestock production from the index site (a commercial pig farm in Malaysia) prior to and during the outbreak, on Malaysian agricultural production, and from surveys of NiV's wildlife reservoir (flying foxes). Our analyses suggest that repeated introduction of NiV from wildlife changed infection dynamics in pigs. Initial viral introduction produced an explosive epizootic that drove itself to extinction but primed the population for enzootic persistence upon reintroduction of the virus. The resultant within-farm persistence permitted regional spread and increased the number of human infections. This study refutes an earlier hypothesis that anomalous El Nino Southern Oscillation-related climatic conditions drove emergence and suggests that priming for persistence drove the emergence of a novel zoonotic pathogen. Thus, we provide empirical evidence for a causative mechanism previously proposed as a precursor to widespread infection with H5N1 avian influenza and other emerging pathogens. C1 [Epstein, Jonathan H.; Daszak, Peter; HERG] EcoHlth Alliance, New York, NY 10001 USA. [Pulliam, Juliet R. C.; Dushoff, Jonathan; Dobson, Andrew P.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Pulliam, Juliet R. C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Rahman, Sohayati A.] Vet Res Inst, Dept Vet Serv, Ipoh, Perak, Malaysia. [Rahman, Sohayati A.] Univ Putra Malaysia, Serdang, Selangor, Malaysia. [Bunning, Michel] USAF, Lackland AFB, San Antonio, TX 78201 USA. [Jamaluddin, Aziz A.] Minist Agr, Dept Vet Serv, Putrajaya, Malaysia. [Hyatt, Alex D.] CSIRO, Australian Anim Hlth Lab, Geelong, Vic, Australia. [Field, Hume E.] Dept Employment Econ Dev & Innovat, Biosecur Sci Lab, Brisbane, Qld, Australia. RP Daszak, P (reprint author), EcoHlth Alliance, 460 W 34th St,17th Floor, New York, NY 10001 USA. EM daszak@ecohealthalliance.org RI Pulliam, Juliet/A-6516-2008 OI Pulliam, Juliet/0000-0003-3314-8223 FU NIH/NSF [R01-TW05869]; Pew Charitable Trusts [2000-002558]; Princeton University Center for Health and Wellbeing; Science and Technology Directorate, Department of Homeland Security and Fogarty International Center, National Institutes of Health FX P.D. conceived and directed the study; P. D. and J.R.C.P. co-wrote the paper with assistance from J.H.E.; J.R.C.P. designed and conducted the modelling and statistical analyses with J.D. and A. P. D., and conducted all fieldwork related to livestock; J.H.E. and S. A. R. led the bat survey work, and S. A. R. conducted some of the sample testing. M. B. collected field data on pig production during the NiV outbreak investigation. A.A.J. facilitated data acquisition and all field activities in Malaysia. A. D. H. directed sample testing. H. E. F. assisted in study design, helped direct field activities and provided veterinary input. All authors were involved in the design of the study and the interpretation of the results and commented on the manuscript. All other HERG authors discussed study design and interpretation of data. We thank T. Hughes, J. Westrom, Abdul Karim bin Abdul Hamid, Abdul Nordin bin Harul, Zaini bin Che Mamat, Ong B. L., Lim Y. S., S. P. Loganathan, Chang K. W., R. Mehendran, C. Smith, Lim B. L., A. A. Chmura, S. S. Hassan, E. McKenzie, C. Pearson, T. Kunz, T. Ksiazek, A. Zubaid, S. A. Levin, K. Hampson, P. R. Hosseini and A. M. Kilpatrick. We also thank the owners and managers of the index farm for their cooperation. Data for this project were provided by the Director General, Department of Veterinary Services, Ministry of Agriculture and Agro-based Industry, Malaysia. Agricultural land-use data have been provided by the Director General, Soil Resource Management and Conservation Division, Department of Agriculture, Ministry of Agriculture and Agro-based Industry, Malaysia. Special permits for trapping and sampling wild bats were provided by the Department of Wildlife and National Parks, Malaysia (Perhilitan). This work was supported primarily by an NIH/NSF Ecology of Infectious Diseases award (Fogarty International Center R01-TW05869), with additional support from the Australian Biosecurity Cooperative Research Centre for Emerging Infectious Diseases (AB-CRC), the Pew Charitable Trusts (grant 2000-002558), a Princeton University Center for Health and Wellbeing graduate research grant to J. P., a National Science Foundation Graduate Research Fellowship to J. P. and the Research and Policy for Infectious Disease Dynamics (RAPIDD) programme of the Science and Technology Directorate, Department of Homeland Security and Fogarty International Center, National Institutes of Health. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (http://biowulf.nih.gov). NR 45 TC 80 Z9 81 U1 1 U2 77 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 EI 1742-5662 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD JAN 7 PY 2012 VL 9 IS 66 BP 89 EP 101 DI 10.1098/rsif.2011.0223 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 852CE UT WOS:000297322800008 PM 21632614 ER PT J AU Altmann, SE Brandt, CR Jahrling, PB Blaney, JE AF Altmann, Sharon E. Brandt, Curtis R. Jahrling, Peter B. Blaney, Joseph E. TI Antiviral activity of the EB peptide against zoonotic poxviruses SO VIROLOGY JOURNAL LA English DT Article DE EB peptide; vaccinia; cowpox; monkeypox; poxvirus entry; poxvirus attachment ID VIRION MEMBRANE-PROTEIN; VACCINIA-VIRUS ENTRY; CELL-CELL FUSION; ESSENTIAL COMPONENT; HOST-CELLS; L1 PROTEIN; INHIBITION; COMPLEX; GENE; INFECTION AB Background: The EB peptide is a 20-mer that was previously shown to have broad spectrum in vitro activity against several unrelated viruses, including highly pathogenic avian influenza, herpes simplex virus type I, and vaccinia, the prototypic orthopoxvirus. To expand on this work, we evaluated EB for in vitro activity against the zoonotic orthopoxviruses cowpox and monkeypox and for in vivo activity in mice against vaccinia and cowpox. Findings: In yield reduction assays, EB had an EC50 of 26.7 mu M against cowpox and 4.4 mu M against monkeypox. The EC50 for plaque reduction was 26.3 mu M against cowpox and 48.6 mu M against monkeypox. A scrambled peptide had no inhibitory activity against either virus. EB inhibited cowpox in vitro by disrupting virus entry, as evidenced by a reduction of the release of virus cores into the cytoplasm. Monkeypox was also inhibited in vitro by EB, but at the attachment stage of infection. EB showed protective activity in mice infected intranasally with vaccinia when co-administered with the virus, but had no effect when administered prophylactically one day prior to infection or therapeutically one day post-infection. EB had no in vivo activity against cowpox in mice. Conclusions: While EB did demonstrate some in vivo efficacy against vaccinia in mice, the limited conditions under which it was effective against vaccinia and lack of activity against cowpox suggest EB may be more useful for studying orthopoxvirus entry and attachment in vitro than as a therapeutic against orthopoxviruses in vivo. C1 [Altmann, Sharon E.; Jahrling, Peter B.; Blaney, Joseph E.] NIAID, Emerging Viral Pathogens Sect, NIH, Bethesda, MD 20892 USA. [Brandt, Curtis R.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI 53706 USA. [Brandt, Curtis R.] Univ Wisconsin, Dept Med Microbiol & Immunol, Madison, WI 53706 USA. [Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD 21702 USA. RP Altmann, SE (reprint author), NIAID, Emerging Viral Pathogens Sect, NIH, Bethesda, MD 20892 USA. EM altmannse@niaid.nih.gov FU NIAID Division of Intramural Research; [AI52049]; [EYP30-016665] FX The authors thank Grant McFadden (University of Florida) for the gift of the cowpox-GFP virus and Roselyn Eisenberg and Gary Cohen for the R236 anti-core antibody. The authors thank Russ Byrum, Isis Alexander and Bernardo Rosa for technical assistance. This work was supported in part by the NIAID Division of Intramural Research and by grants AI52049 and EYP30-016665 to Curtis R. Brandt. All animal work was performed under a NIAID-approved protocol and in compliance with NIAID's Institutional Animal Care and Use Committee. NR 25 TC 5 Z9 5 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD JAN 6 PY 2012 VL 9 AR 6 DI 10.1186/1743-422X-9-6 PG 6 WC Virology SC Virology GA 950LV UT WOS:000304651700003 PM 22225618 ER PT J AU Dolinska, MB Wingfield, PT Sergeev, YV AF Dolinska, Monika B. Wingfield, Paul T. Sergeev, Yuri V. TI beta B1-Crystallin: Thermodynamic Profiles of Molecular Interactions SO PLOS ONE LA English DT Article ID BETA-CRYSTALLINS; HUMAN LENS; ASSOCIATION; PROTEINS; HETEROOLIGOMERS; DEAMIDATION; STABILITY; SEQUENCE; COMPLEX; ALTERS AB Backgroud: beta-Crystallins are structural proteins maintaining eye lens transparency and opacification. Previous work demonstrated that dimerization of both beta A3 and beta B2 crystallins (beta A3 and beta B2) involves endothermic enthalpy of association (similar to 8 kcal/mol) mediated by hydrophobic interactions. Methodology/Principal Findings: Thermodynamic profiles of the associations of dimeric beta A3 and beta B1 and tetrameric beta B1/beta A3 were measured using sedimentation equilibrium. The homo-and heteromolecular associations of beta B1 crystallin are dominated by exothermic enthalpy (-13.3 and -24.5 kcal/mol, respectively). Conclusions/Significance: Global thermodynamics of beta B1 interactions suggest a role in the formation of stable protein complexes in the lens via specific van der Waals contacts, hydrogen bonds and salt bridges whereas those b-crystallins which associate by predominately hydrophobic forces participate in a weaker protein associations. C1 [Dolinska, Monika B.; Sergeev, Yuri V.] NEI, NIH, Bethesda, MD 20892 USA. [Wingfield, Paul T.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Dolinska, MB (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM sergeevy@nei.nih.gov FU National Institutes of Health [Z01-EY000476-01] FX This work was supported by National Institutes of Health (Z01-EY000476-01 to Y.V.S.). No additional external funding received for this study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 1 Z9 1 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 6 PY 2012 VL 7 IS 1 AR e29227 DI 10.1371/journal.pone.0029227 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 904IR UT WOS:000301188800007 PM 22238594 ER PT J AU McGraw, LA Davis, JK Thomas, PJ Young, LJ Thomas, JW AF McGraw, Lisa A. Davis, Jamie K. Thomas, Pamela J. Young, Larry J. Thomas, James W. CA NISC Comparative Sequencing TI BAC-Based Sequencing of Behaviorally-Relevant Genes in the Prairie Vole SO PLOS ONE LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; NUCLEOTIDE DIVERSITY; MICROTUS-OCHROGASTER; NUCLEAR GENES; VASOPRESSIN; EXPRESSION; GENOME; SUBSTITUTIONS; CONSTRUCTION; POPULATIONS AB The prairie vole (Microtus ochrogaster) is an important model organism for the study of social behavior, yet our ability to correlate genes and behavior in this species has been limited due to a lack of genetic and genomic resources. Here we report the BAC-based targeted sequencing of behaviorally-relevant genes and flanking regions in the prairie vole. A total of 6.4 Mb of non-redundant or haplotype-specific sequence assemblies were generated that span the partial or complete sequence of 21 behaviorally-relevant genes as well as an additional 55 flanking genes. Estimates of nucleotide diversity from 13 loci based on alignments of 1.7 Mb of haplotype-specific assemblies revealed an average pair-wise heterozygosity (8.4x10(-3)). Comparative analyses of the prairie vole proteins encoded by the behaviorally-relevant genes identified > 100 substitutions specific to the prairie vole lineage. Finally, our sequencing data indicate that a duplication of the prairie vole AVPR1A locus likely originated from a recent segmental duplication spanning a minimum of 105 kb. In summary, the results of our study provide the genomic resources necessary for the molecular and genetic characterization of a high-priority set of candidate genes for regulating social behavior in the prairie vole. C1 [McGraw, Lisa A.; Young, Larry J.] Emory Univ, Ctr Translat Social Neurosci, Atlanta, GA 30322 USA. [McGraw, Lisa A.; Young, Larry J.] N Carolina State Univ, Yerkes Natl Primate Res Ctr, Raleigh, NC 27695 USA. [Davis, Jamie K.; Thomas, James W.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Thomas, Pamela J.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Thomas, Pamela J.; NISC Comparative Sequencing] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Young, Larry J.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. RP McGraw, LA (reprint author), N Carolina State Univ, Dept Biol, Raleigh, NC 27695 USA. EM lamcgraw@ncsu.edu OI McGraw, Lisa/0000-0001-9627-9082 FU National Human Genome Research Institute of the National Institutes of Health; National Institutes of Health [1R21MH082225]; NIH [MH064692]; [1F32MH079661]; [RR00165] FX The NIH Intramural Sequencing Center was supported by the Intramural Research Program of the National Human Genome Research Institute (www.genome.gov/) of the National Institutes of Health (www.nih.gov). JWT, JKD, and LJY were supported by National Institutes of Health grant 1R21MH082225 and LAM by grant 1F32MH079661. LJY was further supported by NIH MH064692, Autism Speaks (www.autismspeaks.org) and RR00165 to YNPRC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 5 Z9 5 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 6 PY 2012 VL 7 IS 1 AR e29345 DI 10.1371/journal.pone.0029345 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 904IR UT WOS:000301188800013 PM 22238603 ER PT J AU Mukherjee, J Tremblay, JM Leysath, CE Ofori, K Baldwin, K Feng, XC Bedenice, D Webb, RP Wright, PM Smith, LA Tzipori, S Shoemaker, CB AF Mukherjee, Jean Tremblay, Jacqueline M. Leysath, Clinton E. Ofori, Kwasi Baldwin, Karen Feng, Xiaochuan Bedenice, Daniela Webb, Robert P. Wright, Patrick M. Smith, Leonard A. Tzipori, Saul Shoemaker, Charles B. TI A Novel Strategy for Development of Recombinant Antitoxin Therapeutics Tested in a Mouse Botulism Model SO PLOS ONE LA English DT Article ID HEAVY-CHAIN ANTIBODIES; G IMMUNE-COMPLEXES; MONOCLONAL-ANTIBODIES; BINDING-AGENTS; HIGH-AFFINITY; LIGHT-CHAIN; NEUROTOXIN; FRAGMENTS; DOMAIN; NEUTRALIZATION AB Antitoxins are needed that can be produced economically with improved safety and shelf life compared to conventional antisera-based therapeutics. Here we report a practical strategy for development of simple antitoxin therapeutics with substantial advantages over currently available treatments. The therapeutic strategy employs a single recombinant 'targeting agent' that binds a toxin at two unique sites and a 'clearing Ab' that binds two epitopes present on each targeting agent. Co-administration of the targeting agent and the clearing Ab results in decoration of the toxin with up to four Abs to promote accelerated clearance. The therapeutic strategy was applied to two Botulinum neurotoxin (BoNT) serotypes and protected mice from lethality in two different intoxication models with an efficacy equivalent to conventional antitoxin serum. Targeting agents were a single recombinant protein consisting of a heterodimer of two camelid anti-BoNT heavy-chain-only Ab VH (VHH) binding domains and two E-tag epitopes. The clearing mAb was an anti-E-tag mAb. By comparing the in vivo efficacy of treatments that employed neutralizing vs. non-neutralizing agents or the presence vs. absence of clearing Ab permitted unprecedented insight into the roles of toxin neutralization and clearance in antitoxin efficacy. Surprisingly, when a post-intoxication treatment model was used, a toxin-neutralizing heterodimer agent fully protected mice from intoxication even in the absence of clearing Ab. Thus a single, easy-to-produce recombinant protein was as efficacious as polyclonal antiserum in a clinically-relevant mouse model of botulism. This strategy should have widespread application in antitoxin development and other therapies in which neutralization and/or accelerated clearance of a serum biomolecule can offer therapeutic benefit. C1 [Mukherjee, Jean; Tremblay, Jacqueline M.; Ofori, Kwasi; Baldwin, Karen; Feng, Xiaochuan; Bedenice, Daniela; Tzipori, Saul; Shoemaker, Charles B.] Tufts Cummings Sch Vet Med, Dept Biomed Sci, North Grafton, MA USA. [Leysath, Clinton E.] NIAID, NIH, Bethesda, MD 20892 USA. [Webb, Robert P.; Wright, Patrick M.; Smith, Leonard A.] USA, Med Res Inst Infect Dis, Frederick, MD USA. RP Mukherjee, J (reprint author), Tufts Cummings Sch Vet Med, Dept Biomed Sci, North Grafton, MA USA. EM charles.shoemaker@tufts.edu FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); Department of Health and Human Services [N01-AI-30050, U54 AI057159]; NIAID, Bethesda, MD, USA FX This project was funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and the Department of Health and Human Services, under Contract No. N01-AI-30050 and Award Number U54 AI057159. Some work was also supported by the Intramural Research Program of the NIAID, Bethesda, MD, USA. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIAID or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 34 Z9 34 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 6 PY 2012 VL 7 IS 1 AR e29941 DI 10.1371/journal.pone.0029941 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 904IR UT WOS:000301188800050 PM 22238680 ER PT J AU Abd-Elmoniem, KZ Tomas, MS Sasano, T Soleimanifard, S Vonken, EJP Youssef, A Agarwal, H Dimaano, VL Calkins, H Stuber, M Prince, JL Abraham, TP Abraham, MR AF Abd-Elmoniem, Khaled Z. Tomas, Miguel Santaularia Sasano, Tetsuo Soleimanifard, Sahar Vonken, Evert-Jan P. Youssef, Amr Agarwal, Harsh Dimaano, Veronica L. Calkins, Hugh Stuber, Matthias Prince, Jerry L. Abraham, Theodore P. Abraham, M. Roselle TI Assessment of distribution and evolution of Mechanical dyssynchrony in a porcine model of myocardial infarction by cardiovascular magnetic resonance SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article ID CARDIAC RESYNCHRONIZATION THERAPY; LEFT-VENTRICULAR DYSSYNCHRONY; HEART-FAILURE; STRAIN; TACHYCARDIA; TISSUE; CARDIOMYOPATHY; VALIDATION; ACTIVATION; CONDUCTION AB Background: We sought to investigate the relationship between infarct and dyssynchrony post-myocardial infarct (MI), in a porcine model. Mechanical dyssynchrony post-MI is associated with left ventricular (LV) remodeling and increased mortality. Methods: Cine, gadolinium-contrast, and tagged cardiovascular magnetic resonance (CMR) were performed pre-MI, 9 +/- 2 days (early post-MI), and 33 +/- 10 days (late post-MI) post-MI in 6 pigs to characterize cardiac morphology, location and extent of MI, and regional mechanics. LV mechanics were assessed by circumferential strain (eC). Electro-anatomic mapping (EAM) was performed within 24 hrs of CMR and prior to sacrifice. Results: Mean infarct size was 21 +/- 4% of LV volume with evidence of post-MI remodeling. Global eC significantly decreased post MI (-27 +/- 1.6% vs. -18 +/- 2.5% (early) and -17 +/- 2.7% (late), p < 0.0001) with no significant change in peri-MI and MI segments between early and late time-points. Time to peak strain (TTP) was significantly longer in MI, compared to normal and peri-MI segments, both early (440 +/- 40 ms vs. 329 +/- 40 ms and 332 +/- 36 ms, respectively; p = 0.0002) and late post-MI (442 +/- 63 ms vs. 321 +/- 40 ms and 355 +/- 61 ms, respectively; p = 0.012). The standard deviation of TTP in 16 segments (SD16) significantly increased post-MI: 28 +/- 7 ms to 50 +/- 10 ms (early, p = 0.012) to 54 +/- 19 ms (late, p = 0.004), with no change between early and late post-MI time-points (p = 0.56). TTP was not related to reduction of segmental contractility. EAM revealed late electrical activation and greatly diminished conduction velocity in the infarct (5.7 +/- 2.4 cm/s), when compared to peri-infarct (18.7 +/- 10.3 cm/s) and remote myocardium (39 +/- 20.5 cm/s). Conclusions: Mechanical dyssynchrony occurs early after MI and is the result of delayed electrical and mechanical activation in the infarct. C1 [Tomas, Miguel Santaularia; Sasano, Tetsuo; Vonken, Evert-Jan P.; Youssef, Amr; Dimaano, Veronica L.; Calkins, Hugh; Abraham, Theodore P.; Abraham, M. Roselle] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD 21218 USA. [Abd-Elmoniem, Khaled Z.] NIDDK, Biomed & Metab Imaging Branch, NIH, Bethesda, MD USA. [Tomas, Miguel Santaularia] Hosp Espanol Mexico, Div Cardiol, Dept Med, Mexico City, DF, Mexico. [Soleimanifard, Sahar; Agarwal, Harsh; Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Stuber, Matthias] Johns Hopkins Univ, Div Magnet Resonance Res, Dept Radiol, Baltimore, MD 21218 USA. RP Abraham, MR (reprint author), Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD 21218 USA. EM mabraha3@jhmi.edu RI Prince, Jerry/A-3281-2010; Centre d'imagerie Biomedicale, CIBM/B-5740-2012; Abd-Elmoniem, Khaled/B-9289-2008; OI Prince, Jerry/0000-0002-6553-0876; Abd-Elmoniem, Khaled/0000-0002-1001-1702; Stuber, Matthias/0000-0001-9843-2028 FU Donald W. Reynolds Foundation; Medtronic; St Jude Medical FX We thank John Terrovitis, MD for help with designing the imaging protocol, Michael Schar, PhD for kindly providing the technical expertise for critical portions of the CMR imaging, Kevin Mills, BS and Mohammed Zauher, BS for help with animal studies. This work was supported by the Donald W. Reynolds Foundation. We would also like to thank Ronnie Abbo and Biosense Webster for providing us the catheters and the CARTO XP system used in this study. We are grateful to Dr. Henry Halperin for use of his research EP laboratory.; Dr. Calkins receives research support from Medtronic, St Jude Medical, and Boston Scientific and serves as a consultant for Medtronic. All other authors have reported that they have no relationships to disclose. NR 38 TC 7 Z9 7 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JAN 6 PY 2012 VL 14 AR 1 DI 10.1186/1532-429X-14-1 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 892XJ UT WOS:000300318600001 PM 22226320 ER PT J AU Lubelski, D Ponzio, TA Gainer, H AF Lubelski, Daniel Ponzio, Todd A. Gainer, Harold TI Effects of A-CREB, a dominant negative inhibitor of CREB, on the expression of c-fos and other immediate early genes in the rat SON during hyperosmotic stimulation in vivo SO BRAIN RESEARCH LA English DT Article DE C-FOS; CREB; A-CREB; AAV; SON; Vasopressin ID CAMP-RESPONSIVE ELEMENT; COMPLEX FACTOR ELK-1; SUPRAOPTIC NUCLEUS; PROTEIN-KINASE; NERVOUS-SYSTEM; OSMOTIC-STRESS; CELL-DEATH; TRANSCRIPTION; PHOSPHORYLATION; ACTIVATION AB Intraperitoneal administration of hypertonic saline to the rat supraoptic nucleus (SON) increases the expression of several immediate early genes (IEG) and the vasopressin gene. These increases have usually been attributed to action of the cyclic-AMP Response Element Binding Protein (CREB). In this paper, we study the role of CREB in these events in vivo by delivering a potent dominant-negative form of CREB, known as A-CREB, to the rat SON through the use of an adeno-associated viral (AAV) vector. Preliminary experiments on HEK 293 cells in vitro showed that the A-CREB vector that we used completely eliminated CREB-induced c-fos expression. We stereotaxically injected this AAV-A-CREB into one SON and a control AAV into the contralateral SON of the same rat. Two weeks following these injections we injected hypertonic saline intraperitoneally into the rat. Using this paradigm, we could measure the relative effects of inhibiting CREB on the induced expression of c-fos, ngfi-a, ngfi-b, and vasopressin genes in the A-CREB AAV injected SON versus the control AAV injected SON in the same rat. We found only a small (20%) decrease of c-fos expression and a 30% decrease of ngfi-b expression in the presence of the A-CREB. There were no significant changes in expression found in the other IEGs nor in vasopressin that were produced by the A-CREB. This suggests that CREB may play only a minor role in the expression of IEGs and vasopressin in the osmotically activated SON in vivo. Published by Elsevier B.V. C1 [Lubelski, Daniel; Ponzio, Todd A.; Gainer, Harold] NINDS, Neurochem Lab, Mol Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), NINDS, Neurochem Lab, Mol Neurosci Sect, NIH, 9000 Rockville Pike,Bld 49,Rm 5A78,MSC 4479, Bethesda, MD 20892 USA. EM DLubelski@gmail.com; ponziot@mail.nih.gov; GainerH@ninds.nih.gov OI Lubelski, Daniel/0000-0002-9403-9509 FU NINDS, NIH FX This research was supported by the Intramural Research Program of the NINDS, NIH. We would like to thank Dr. Kory Johnson (NINDS, NIH) for his advice about statistical tests, and Dr. C. Vinson (NCI, NIH) for his gift of the A-CREB plasmid. NR 54 TC 12 Z9 12 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 6 PY 2012 VL 1429 BP 18 EP 28 DI 10.1016/j.brainres.2011.10.033 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 892DZ UT WOS:000300268200003 PM 22079318 ER PT J AU Kitanaka, N Kitanaka, J Hall, FS Uhl, GR Watabe, K Kubo, H Takahashi, H Tatsuta, T Morita, Y Takemura, M AF Kitanaka, Nobue Kitanaka, Junichi Hall, F. Scott Uhl, George R. Watabe, Kaname Kubo, Hitoshi Takahashi, Hitoshi Tatsuta, Tomohiro Morita, Yoshio Takemura, Motohiko TI A single administration of methamphetamine to mice early in the light period decreases running wheel activity observed during the dark period SO BRAIN RESEARCH LA English DT Article DE Methamphetamine; Running wheel activity; Motivated behavior; Attention deficit hyperactivity disorder ID BEHAVIORAL SENSITIZATION; AMPHETAMINE WITHDRAWAL; SEXUAL-BEHAVIOR; ANIMAL-MODELS; RATS; BRAIN; PSYCHOMOTOR; CONSEQUENCES; EXPRESSION; DEPRESSION AB Repeated intermittent administration of amphetamines acutely increases appetitive and consummatory aspects of motivated behaviors as well as general activity and exploratory behavior, including voluntary running wheel activity. Subsequently, if the drug is withdrawn, the frequency of these behaviors decreases, which is thought to be indicative of dysphoric symptoms associated with amphetamine withdrawal. Such decreases may be observed after chronic treatment or even after single drug administrations. In the present study, the effect of acute methamphetamine (METH) on running wheel activity, horizontal locomotion, appetitive behavior (food access), and consummatory behavior (food and water intake) was investigated in mice. A multi-configuration behavior apparatus designed to monitor the five behaviors was developed, where combined measures were recorded simultaneously. In the first experiment, naive male ICR mice showed gradually increasing running wheel activity over three consecutive days after exposure to a running wheel, while mice without a running wheel showed gradually decreasing horizontal locomotion, consistent with running wheel activity being a positively motivated form of natural motor activity. In experiment 2, increased horizontal locomotion and food access, and decreased food intake, were observed for the initial 3 h after acute METH challenge. Subsequently, during the dark phase period decreased running wheel activity and horizontal locomotion were observed. The reductions in running wheel activity and horizontal locomotion may be indicative of reduced dopaminergic function, although it remains to be seen if these changes may be more pronounced after more prolonged METH treatments. (C) 2011 Elsevier B.V. All rights reserved. C1 [Kitanaka, Nobue; Kitanaka, Junichi; Takemura, Motohiko] Hyogo Coll Med, Dept Pharmacol, Nishinomiya, Hyogo 6638501, Japan. [Hall, F. Scott; Uhl, George R.] NIDA, Mol Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Watabe, Kaname; Kubo, Hitoshi; Takahashi, Hitoshi] Muromachi Kikai Co Ltd, Tokyo 1030022, Japan. [Tatsuta, Tomohiro] Ibogawa Hosp Furuhashikai Med Corp, Kobe, Hyogo 6711688, Japan. [Morita, Yoshio] Baika Womens Univ, Fac Nursing, Osaka 5678578, Japan. RP Kitanaka, J (reprint author), Hyogo Coll Med, Dept Pharmacol, 1-1 Mukogawa Cho, Nishinomiya, Hyogo 6638501, Japan. RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Ministry of Education, Culture, Sports, Science and Technology of Japan [21790254]; Hyogo College of Medicine; National Institute on Drug Abuse, USA FX The authors are grateful to Professor Y. Ishikawa of Department of Civil Engineering Meijo University, for advice and comments on an earlier version of the description of a multi-configuration behavior apparatus and to Ms. A. Yoshioka of the Department of Pharmacology, Hyogo College of Medicine, for preparing the animal study proposal. This research was supported, in part, by a Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 21790254 to NK), a Grant-in-Aid for Researchers, Hyogo College of Medicine (2011 to NK), and intramural funding from the National Institute on Drug Abuse, USA (GRU and FSH). NR 35 TC 1 Z9 1 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JAN 6 PY 2012 VL 1429 BP 155 EP 163 DI 10.1016/j.brainres.2011.10.037 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 892DZ UT WOS:000300268200017 PM 22079320 ER PT J AU Makiya, M Dolan, M Agulto, L Purcell, R Chen, ZC AF Makiya, Michelle Dolan, Michael Agulto, Liane Purcell, Robert Chen, Zhaochun TI Structural basis of anthrax edema factor neutralization by a neutralizing antibody SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Epitope mapping; Yeast surface display; Neutralization mechanism; Antibody modeling; Protein-protein docking ID YEAST SURFACE DISPLAY; HUMANIZED MONOCLONAL-ANTIBODY; CALMODULIN; TOXIN; CYCLASE; ACTIVATION; INHIBITORS; DISCOVERY; BINDING; VIRUS AB Fine epitope mapping of EF13D, a highly potent neutralizing monoclonal antibody specific for the anthrax edema factor (EF), was accomplished through random mutagenesis and yeast surface display. A yeast-displayed library of single point mutants of an EF domain III (Dill), comprising amino acids 624-800, was constructed by random mutagenesis and screened for reduced binding to EF13D. With this method, residues Leu 667, Set 668, Arg 671, and Arg 672 were identified as key residues important for EF13D binding. They form a contiguous patch on a solvent-exposed surface at one end of the four-helix bundle of DIII. Computational protein-protein docking experiments between anEF13D model and a crystal structure of EF indicate that the EF13D heavy chain complementarity-determining region 3 (HCDR3) is deeply buried within a hydrophobic cleft between two helices of DIII and interacts directly with residues Leu 667, Set 668, Arg 671 and Arg 672, providing an explanation for the high binding affinity. In addition, they show that the HCDR3 binding site overlaps with the binding site of the N-terminal lobe of calmodulin (CaM), an EF enzymatic activator, consistent with a previous finding showing direct competition with CaM that results in neutralization of EF. Identifying the neutralization epitope of EF13D on EF improves our understanding of the neutralization mechanism and has implications for vaccine development. Published by Elsevier Inc. C1 [Makiya, Michelle; Agulto, Liane; Purcell, Robert; Chen, Zhaochun] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Dolan, Michael] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. RP Chen, ZC (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM zc20a@nih.gov FU NIH, NIAID FX This research was supported by the Intramural Research Program of the NIH, NIAID. We thank Dr. Stephen Leppla for providing the recombinant EF and plasmid containing EF-coding gene and Dr. Dane Wittrup for providing yeast strain EBY100 and yeast display vector pCTCON2. NR 23 TC 5 Z9 5 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 6 PY 2012 VL 417 IS 1 BP 324 EP 329 DI 10.1016/j.bbrc.2011.11.108 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 881MU UT WOS:000299491600055 PM 22155239 ER PT J AU Fujimoto, M Hayashi, T Su, TP AF Fujimoto, Michiko Hayashi, Teruo Su, Tsung-Ping TI The role of cholesterol in the association of endoplasmic reticulum membranes with mitochondria SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE MAM; Mitochondria-associated membrane; Phospholipid transport; Cholesterol; Sigma-1 receptor; Lipid raft ID LIPID RAFTS; CA2+; ER; APOPTOSIS; MICRODOMAINS; TRANSPORT; CONTACT; CELL AB The unique endoplasmic reticulum (ER) subdomain termed the mitochondria-associated ER membrane (MAM) engages the physical connection between the ER and the mitochondrial outer membrane and plays a role in regulating IP3 receptor-mediated Ca2+ influx and the phospholipid transport between the two organelles. The MAM contains certain signaling and membrane-tethering proteins but also lipids including cholesterol. The biophysical role of lipids at the MAM, specifically in the physical interaction between the MAM of the ER and mitochondria, remains not totally clarified. Here we employed the in vitro membrane association assay to investigate the role of cholesterol in the association between MAMs and mitochondria. The purified MAMs and mitochondria were mixed in vitro in a test tube and then the physical association of the two subcellular organelles was quantified indirectly by measuring the presence of the MAM-specific protein sigma-1 receptors in the mitochondria fraction. Purified MAMs contained free cholesterol approximately 7 times higher than that in microsomes. We found that depletion of cholesterol in MAMs with methyl-beta-cyclodextrin (M beta C) significantly increases the association between MAMs and mitochondria, whereas M beta C saturated with cholesterol does not change the association. C-14-Serine pulse-labeling demonstrated that the treatment of living cells with M beta C decreases the level of de novo synthesized C-14-phosphatidylserine (PtSer) and concomitantly increases greatly the synthesis of C-14-phosphatidylethanolamine (PtEt). Apparently, cholesterol depletion increased the PtSer transport from MAMs to mitochondria. Our findings suggest that cholesterol is an important substrate in regulating the association between MAMs of the ER and mitochondria. Published by Elsevier Inc. C1 [Fujimoto, Michiko; Hayashi, Teruo] NIDA, Cellular Stress Signaling Unit, Integrat Neurosci Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, Integrat Neurosci Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Hayashi, T (reprint author), NIDA, Cellular Stress Signaling Unit, Integrat Neurosci Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, 333 Cassell Dr, Baltimore, MD 21224 USA. EM thayashi@mail.nih.gov; tsu@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services; Japan Society for the Promotion of Sciences (JSPS) at NIH FX This study was supported by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. All authors declare no conflict of interest. M. Fujimoto is also supported by Japan Society for the Promotion of Sciences (JSPS) Fellowship for Japanese Biochemical and Behavioral Researchers at NIH. We thank Dr. Mary Pfeiffer for carefully editing the manuscript. NR 27 TC 30 Z9 31 U1 2 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 6 PY 2012 VL 417 IS 1 BP 635 EP 639 DI 10.1016/j.bbrc.2011.12.022 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 881MU UT WOS:000299491600108 PM 22185692 ER PT J AU Barnard, TJ Gumbart, J Peterson, JH Noinaj, N Easley, NC Dautin, N Kuszak, AJ Tajkhorshid, E Bernstein, HD Buchanan, SK AF Barnard, Travis J. Gumbart, James Peterson, Janine H. Noinaj, Nicholas Easley, Nicole C. Dautin, Nathalie Kuszak, Adam J. Tajkhorshid, Emad Bernstein, Harris D. Buchanan, Susan K. TI Molecular Basis for the Activation of a Catalytic Asparagine Residue in a Self-Cleaving Bacterial Autotransporter SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE EspP; autocleavage; outer membrane protein; crystal structure; asparagine cyclization ID GRAM-NEGATIVE BACTERIA; ACTIN-BASED MOTILITY; OUTER-MEMBRANE; ESCHERICHIA-COLI; PASSENGER DOMAIN; TRANSLOCATOR DOMAIN; SHIGELLA-FLEXNERI; PROTEIN; SECRETION; DYNAMICS AB Autotransporters are secreted proteins produced by pathogenic Gram-negative bacteria. They consist of a membrane-embedded beta-domain and an extracellular passenger domain that is sometimes cleaved and released from the cell surface. We solved the structures of three noncleavable mutants of the autotransporter EspP to examine how it promotes asparagine cyclization to cleave its passenger. We found that cyclization is facilitated by multiple factors. The active-site asparagine is sterically constrained to conformations favorable for cyclization, while electrostatic interactions correctly orient the carboxamide group for nucleophilic attack. During molecular dynamics simulations, water molecules were observed to enter the active site and to form hydrogen bonds favorable for increasing the nucleophilicity of the active-site asparagine. When the activated asparagine attacks its main-chain carbonyl carbon, the resulting oxyanion is stabilized by a protonated glutamate. Upon cleavage, this proton could be transferred to the leaving amine group, helping overcome a significant energy barrier. Together, these findings provide insight into factors important for asparagine cyclization, a mechanism broadly used for protein cleavage. Published by Elsevier Ltd. C1 [Barnard, Travis J.; Noinaj, Nicholas; Easley, Nicole C.; Kuszak, Adam J.; Buchanan, Susan K.] NIDDK, Mol Biol Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Gumbart, James] Argonne Natl Lab, Biosci Div, Argonne, IL 60439 USA. [Peterson, Janine H.; Dautin, Nathalie; Bernstein, Harris D.] NIDDK, Genet & Biochem Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Tajkhorshid, Emad] Univ Illinois, Ctr Biophys & Computat Biol, Beckman Inst Adv Sci & Technol, Dept Biochem,Coll Med, Urbana, IL 61801 USA. RP Buchanan, SK (reprint author), Room 4503,Bldg 50,50 South Dr, Bethesda, MD 20892 USA. EM skbuchan@helix.nih.gov OI Tajkhorshid, Emad/0000-0001-8434-1010 FU Argonne National Laboratory; National Institutes of Health [R01-GM086749, R01-GM067887, P41-RR05969, U54-GM087519]; TeraGrid [MCA06N060] FX We would like to thank Jim Fairman, Lothar Esser, and Dan Appella for helpful discussions on the refinement of EspP structures and the reaction mechanism. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Supporting institutions of the Southeast Regional Collaborative Access Team may be found at http://www.ser-cat.org/members.html. J.G. was supported by a Director's Postdoctoral Fellowship from Argonne National Laboratory. E.T. acknowledges support from National Institutes of Health grants R01-GM086749, R01-GM067887, P41-RR05969, and U54-GM087519. Molecular dynamics simulations were performed using supercomputing resources provided through TeraGrid grant MCA06N060. NR 41 TC 18 Z9 19 U1 0 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 6 PY 2012 VL 415 IS 1 BP 128 EP 142 DI 10.1016/j.jmb.2011.10.049 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 886PJ UT WOS:000299866000012 PM 22094314 ER PT J AU Wu, YL Sommers, JA Khan, I de Winter, JP Brosh, RM AF Wu, Yuliang Sommers, Joshua A. Khan, Irfan de Winter, Johan P. Brosh, Robert M., Jr. TI Biochemical Characterization of Warsaw Breakage Syndrome Helicase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SISTER-CHROMATID COHESION; DNA SUBSTRATE-SPECIFICITY; GENOMIC STABILITY; FANCONI-ANEMIA; G-QUADRUPLEX; HOLLIDAY JUNCTIONS; PAPILLOMAVIRUS E2; REPLICATION FORKS; ESCHERICHIA-COLI; BREAST-CANCER AB Mutations in the human ChlR1 gene are associated with a unique genetic disorder known as Warsaw breakage syndrome characterized by cellular defects in sister chromatid cohesion and hypersensitivity to agents that induce replication stress. A role of ChlR1 helicase in sister chromatid cohesion was first evidenced by studies of the yeast homolog Chl1p; however, its cellular functions in DNA metabolism are not well understood. We carefully examined the DNA substrate specificity of purified recombinant human ChlR1 protein and the biochemical effect of a patient-derived mutation, a deletion of a single lysine (K897del) in the extreme C terminus of ChlR1. The K897del clinical mutation abrogated ChlR1 helicase activity on forked duplex or D-loop DNA substrates by perturbing its DNA binding and DNA-dependent ATPase activity. Wild-type ChlR1 required a minimal 5' single-stranded DNA tail of 15 nucleotides to efficiently unwind a simple duplex DNA substrate. The additional presence of a 3' single-stranded DNA tail as short as five nucleotides dramatically increased ChlR1 helicase activity, demonstrating the preference of the enzyme for forked duplex structures. ChlR1 unwound G-quadruplex (G4) DNA with a strong preference for a two-stranded antiparallel G4 (G2') substrate and was only marginally active on a four-stranded parallel G4 structure. The marked difference in ChlR1 helicase activity on the G4 substrates, reflected by increased binding to the G2' substrate, distinguishes ChlR1 from the sequence-related FANCJ helicase mutated in Fanconi anemia. The biochemical results are discussed in light of the known cellular defects associated with ChlR1 deficiency. C1 [Wu, Yuliang; Sommers, Joshua A.; Khan, Irfan; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [de Winter, Johan P.] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, NL-1081 BT Amsterdam, Netherlands. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU National Institutes of Health of the NIA; Fanconi Anemia Research Fund FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the NIA (to R. M. B.). This work was also supported by the Fanconi Anemia Research Fund (to R. M. B.). NR 44 TC 35 Z9 35 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 6 PY 2012 VL 287 IS 2 BP 1007 EP 1021 DI 10.1074/jbc.M111.276022 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 877IE UT WOS:000299170300018 PM 22102414 ER PT J AU Cash, JN Angerman, EB Kattamuri, C Nolan, K Zhao, HY Sidis, Y Keutmann, HT Thompson, TB AF Cash, Jennifer N. Angerman, Elizabeth B. Kattamuri, Chandramohan Nolan, Kristof Zhao, Huaying Sidis, Yisrael Keutmann, Henry T. Thompson, Thomas B. TI Structure of Myostatin.Follistatin-like 3 N-TERMINAL DOMAINS OF FOLLISTATIN-TYPE MOLECULES EXHIBIT ALTERNATE MODES OF BINDING SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MASS-TRANSPORT LIMITATION; SKELETAL-MUSCLE MASS; TGF-BETA; ACTIVIN-BINDING; SURFACE BINDING; MACROMOLECULAR STRUCTURES; BIOLOGICAL-ACTIVITY; THERAPEUTIC TARGET; CRYSTAL-STRUCTURE; GDF-8 PROPEPTIDE AB TGF-beta family ligands are involved in a variety of critical physiological processes. For instance, the TGF-beta ligand myostatin is a staunch negative regulator of muscle growth and a therapeutic target for muscle-wasting disorders. Therefore, it is important to understand the molecular mechanisms of TGF-beta family regulation. One form of regulation is through inhibition by extracellular antagonists such as the follistatin (Fst)-type proteins. Myostatin is tightly controlled by Fst-like 3 (Fstl3), which is the only Fst-type molecule that has been identified in the serum bound to myostatin. Here, we present the crystal structure of myostatin in complex with Fstl3. The structure reveals that the N-terminal domain (ND) of Fstl3 interacts uniquely with myostatin as compared with activin A, because it utilizes different surfaces on the ligand. This results in conformational differences in the ND of Fstl3 that alter its position in the type I receptor-binding site of the ligand. We also show that single point mutations in the ND of Fstl3 are detrimental to ligand binding, whereas corresponding mutations in Fst have little effect. Overall, we have shown that the NDs of Fst-type molecules exhibit distinctive modes of ligand binding, which may affect overall affinity of ligand.Fst-type protein complexes. C1 [Cash, Jennifer N.; Angerman, Elizabeth B.; Kattamuri, Chandramohan; Nolan, Kristof; Thompson, Thomas B.] Univ Cincinnati, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA. [Zhao, Huaying] NIBIB, Lab Cellular Imaging & Mol Biophys, NIH, Bethesda, MD 20892 USA. [Sidis, Yisrael] CHU Vaudois, Dept Endocrinol Diabet & Metab, CH-1011 Lausanne, Switzerland. [Keutmann, Henry T.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. RP Thompson, TB (reprint author), Univ Cincinnati, Dept Mol Genet Biochem & Microbiol, Med Sci Bldg,231 Albert Sabin Way, Cincinnati, OH 45267 USA. EM thompstb@ucmail.uc.edu RI Zhao, Huaying/F-5716-2012 FU National Institutes of Health [GM084186]; Muscular Dystrophy Association [93887]; NIBIB, National Institutes of Health; American Heart Association FX This work was supported, in whole or in part, by National Institutes of Health Grant GM084186 (to T. B. T.). This work was also supported by Muscular Dystrophy Association Grant 93887 (to T. B. T.) and the Intramural Research Program of the NIBIB, National Institutes of Health.; Supported by an American Heart Association predoctoral fellowship. NR 56 TC 28 Z9 30 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 6 PY 2012 VL 287 IS 2 BP 1043 EP 1053 DI 10.1074/jbc.M111.270801 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 877IE UT WOS:000299170300021 PM 22052913 ER PT J AU Nelson, CG Burke, TR AF Nelson, Christopher G. Burke, Terrence R., Jr. TI Samarium Iodide-Mediated Reformatsky Reactions for the Stereoselective Preparation of beta-Hydroxy-gamma-amino Acids: Synthesis of Isostatine and Dolaisoleucine SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID STEREOSPECIFIC SYNTHESIS; ORGANIC-SYNTHESIS; DOLASTATINS; DOLAPROINE; AGENTS AB The synthesis of beta-hydroxy-gamma-amino acids via SmI2-mediated Reformatsky reactions of alpha-chloroacetyloxazolidinones with aminoaldehydes is reported. Diastereoselective coupling is demonstrated to depend on the absolute configuration of the Evans chiral auxiliary employed in the reaction, allowing egthro or threo products to be obtained selectively. The potential utility of the methodology is exemplified by the facile synthesis of biologically relevant N-Boc-isostatine (2b) and N-Boc-dolaisoleucine (3c). C1 [Nelson, Christopher G.; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 FU NIH, Center for Cancer Research, NCI-Frederick; National Cancer Institute, National Institute of Health FX We thank Dr. James Kelley and Christopher Lai (Chemical Biology Laboratory, NCI) for HRMS data and Dr. Joseph Barchi (Chemical Biology Laboratory, NCI) for NMR assistance. This work was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick, and the National Cancer Institute, National Institute of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 20 TC 10 Z9 10 U1 0 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD JAN 6 PY 2012 VL 77 IS 1 BP 733 EP 738 DI 10.1021/jo202091r PG 6 WC Chemistry, Organic SC Chemistry GA 872RS UT WOS:000298827600078 PM 22136325 ER PT J AU Gupta, A AF Gupta, Ashutosh TI NextGen Speaks SO SCIENCE LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Gupta, A (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM guptaas@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 6 PY 2012 VL 335 IS 6064 BP 38 EP 38 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 872YA UT WOS:000298846200033 ER PT J AU Zofall, M Yamanaka, S Reyes-Turcu, FE Zhang, K Rubin, C Grewal, SIS AF Zofall, Martin Yamanaka, Soichiro Reyes-Turcu, Francisca E. Zhang, Ke Rubin, Chanan Grewal, Shiv I. S. TI RNA Elimination Machinery Targeting Meiotic mRNAs Promotes Facultative Heterochromatin Formation SO SCIENCE LA English DT Article ID FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; SELECTIVE ELIMINATION; QUALITY-CONTROL; S. POMBE; CHROMATIN; MEIOSIS; PROTEIN; TRANSCRIPTION; TERMINATION AB Facultative heterochromatin that changes during cellular differentiation coordinates regulated gene expression, but its assembly is poorly understood. Here, we describe facultative heterochromatin islands in fission yeast and show that their formation at meiotic genes requires factors that eliminate meiotic messenger RNAs (mRNAs) during vegetative growth. Blocking production of meiotic mRNA or loss of RNA elimination factors, including Mmi1 and Red1 proteins, abolishes heterochromatin islands. RNA elimination machinery is enriched at meiotic loci and interacts with Clr4/SUV39h, a methyltransferase involved in heterochromatin assembly. Heterochromatin islands disassemble in response to nutritional signals that induce sexual differentiation. This process involves the antisilencing factor Epe1, the loss of which causes dramatic increase in heterochromatic loci. Our analyses uncover unexpected regulatory roles for mRNA-processing factors that assemble dynamic heterochromatin to modulate gene expression. C1 [Zofall, Martin; Yamanaka, Soichiro; Reyes-Turcu, Francisca E.; Zhang, Ke; Rubin, Chanan; Grewal, Shiv I. S.] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Grewal, SIS (reprint author), NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov FU NIH; National Cancer Institute FX We thank T. Sugiyama for constructions of red1 Delta and tagged alleles during his time in the Grewal lab and M. Yamamoto and T. Sugiyama for their gift of strains. Microarray data are avaiable at the National Center for Biotechnology Information Gene Expression Omnibus repository under accession no. GSE33404. This work is supported by the Intramural Research Program of the NIH and National Cancer Institute. NR 24 TC 62 Z9 62 U1 3 U2 11 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 6 PY 2012 VL 335 IS 6064 BP 96 EP 100 DI 10.1126/science.1211651 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 872YA UT WOS:000298846200059 PM 22144463 ER PT J AU Zhu, DM Huang, SH McClellan, H Dai, WL Syed, NR Gebregeorgis, E Mullen, GED Long, C Martin, LB Narum, D Duffy, P Miller, LH Saul, A AF Zhu, Daming Huang, Shuhui McClellan, Holly Dai, Weili Syed, Najam R. Gebregeorgis, Elizabeth Mullen, Gregory E. D. Long, Carole Martin, Laura B. Narum, David Duffy, Patrick Miller, Louis H. Saul, Allan TI Efficient extraction of vaccines formulated in aluminum hydroxide gel by including surfactants in the extraction buffer SO VACCINE LA English DT Article DE Alhydrogel; AMA1; Extraction; SDS; Cetylpyridinium chloride ID APICAL MEMBRANE ANTIGEN-1; CONTAINING ADJUVANTS; INTERSTITIAL FLUID; POSTADSORPTIVE TRANSITIONS; MODEL ANTIGENS; IN-VITRO; ADSORPTION; PROTEINS; ELUTABILITY; FIBRINOGEN AB Efficient antigen extraction from vaccines formulated on aluminum hydroxide gels is a critical step for the evaluation of the quality of vaccines following formulation. It has been shown in our laboratory that the efficiency of antigen extraction from vaccines formulated on Alhydrogel decreased significantly with increased storage time. To increase antigen extraction efficiency, the present study determined the effect of surfactants on antigen recovery from vaccine formulations. The Plasmodium falciparum apical membrane antigen 1 (AMA1) formulated on Alhydrogel and stored at 2-8 degrees C for 3 years was used as a model in this study. The AMA1 on Alhydrogel was extracted in the presence or absence of 30 mM sodium dodecyl sulfate (SDS) or 20 mM cetylpyridinium chloride in the extraction buffer (0.60 M citrate, 0.55 M phosphate, pH 8.5) using our standard antigen extraction protocols. Extracted AMA1 antigen was analyzed by 4-20% Tris-glycine SDS-PAGE followed by silver staining or western blotting. The results showed that inclusion of SDS or cetylpyridinium chloride in extraction buffer increased the antigen recovery dramatically and can be used for efficient characterization of Alhydrogel vaccines. Published by Elsevier Ltd. C1 [Zhu, Daming; Huang, Shuhui; McClellan, Holly; Dai, Weili; Syed, Najam R.; Gebregeorgis, Elizabeth; Mullen, Gregory E. D.; Long, Carole; Martin, Laura B.; Narum, David; Duffy, Patrick; Miller, Louis H.; Saul, Allan] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. RP Zhu, DM (reprint author), NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD 20852 USA. EM dzhu@niaid.nih.gov RI Saul, Allan/I-6968-2013; Martin, Laura/N-1789-2013 OI Saul, Allan/0000-0003-0665-4091; Martin, Laura/0000-0002-4431-4381 FU NIAID, NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. NR 33 TC 6 Z9 6 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 5 PY 2012 VL 30 IS 2 BP 189 EP 194 DI 10.1016/j.vaccine.2011.11.025 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 887YU UT WOS:000299971800014 PM 22107848 ER PT J AU Belshe, RB Leone, PA Bernstein, DI Wald, A Levin, MJ Stapleton, JT Gorfinkel, I Morrow, RLA Ewell, MG Stokes-Riner, A Dubin, G Heineman, TC Schulte, JM Deal, CD AF Belshe, Robert B. Leone, Peter A. Bernstein, David I. Wald, Anna Levin, Myron J. Stapleton, Jack T. Gorfinkel, Iris Morrow, Rhoda L. Ashley Ewell, Marian G. Stokes-Riner, Abbie Dubin, Gary Heineman, Thomas C. Schulte, Joann M. Deal, Carolyn D. CA Herpevac Trial Women TI Efficacy Results of a Trial of a Herpes Simplex Vaccine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VIRUS TYPE-1; GENITAL HERPES; UNITED-STATES; INFECTION; SEROPREVALENCE; EPIDEMIOLOGY; SAFETY AB BACKGROUND Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women. METHODS We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 mu g of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20. RESULTS The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], -29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (-8%; 95% CI, 59 to 26). CONCLUSIONS In a study population that was representative of the general population of HSV-1 and HSV-2 seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; ClinicalTrials.gov number, NCT00057330.) C1 [Belshe, Robert B.] St Louis Univ, Sch Med, Div Infect Dis Allergy & Immunol, St Louis, MO 63104 USA. [Leone, Peter A.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Bernstein, David I.] Cincinnati Childrens Hosp Med Ctr, Div Infect Dis, Cincinnati, OH USA. [Wald, Anna] Univ Washington, Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Dept Med Epidemiol & Lab Med, Seattle, WA 98195 USA. [Morrow, Rhoda L. Ashley] Univ Washington, Childrens Hosp Virol, Dept Lab Med, Seattle, WA 98195 USA. [Levin, Myron J.] Univ Colorado, Sect Pediat Infect Dis, Denver, CO 80202 USA. [Stapleton, Jack T.] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Stapleton, Jack T.] Vet Affairs Med Ctr, Iowa City, IA 52242 USA. [Gorfinkel, Iris] PrimeHlth Clin Res Org, Toronto, ON, Canada. [Ewell, Marian G.; Stokes-Riner, Abbie] EMMES Corp, Rockville, MD USA. [Schulte, Joann M.; Deal, Carolyn D.] NIAID, Bethesda, MD 20892 USA. [Dubin, Gary; Heineman, Thomas C.] GlaxoSmithKline Inc, King Of Prussia, PA USA. RP Belshe, RB (reprint author), St Louis Univ, Sch Med, Div Infect Dis Allergy & Immunol, 1100 S Grand Blvd,DRC-8, St Louis, MO 63104 USA. EM belsherb@slu.edu RI Wald, Anna/B-6272-2012 OI Wald, Anna/0000-0003-3486-6438 FU National Institute of Allergy and Infectious Diseases [N01-AI-45250]; GlaxoSmithKline; MedImmune; Merck; Novartis; Abbott Diagnostics; Genocea; Roche; AiCuris; Washington Vaccine Alliance FX Supported by a contract with the National Institute of Allergy and Infectious Diseases (N01-AI-45250) and by GlaxoSmithKline.; Dr. Belshe reports serving as a board member of Vivaldi Bio-sciences, receiving consulting fees from GlaxoSmithKline, receiving consulting fees and lecture fees from MedImmune, and receiving lecture fees from Merck. Dr. Bernstein reports receiving lecture fees and royalties from GlaxoSmithKline. Dr. Dubin reports being an employee of and receiving stock and travel, accommodation, and meeting expenses from GlaxoSmithKline and receiving royalties from Pfizer. Dr. Gorfinkel reports receiving grants, consulting fees, travel expenses to meetings, fees for participating in review activities, equipment and technical assistance, lecture fees, and payment for developing educational presentations from GlaxoSmithKline, having stock equity in and serving as an investigator for GlaxoSmithKline, and serving as an investigator for AstraZeneca, Bristol-Myers Squibb, Janssen-Ortho, Bayer, PharmaNet, Wyeth, Berlex, Lundbeck, and CombinatoR.x. Dr. Heineman reports being an employee of GlaxoSmithKline and receiving stock equity in GlaxoSmithKline as part of his compensation. Dr. Leone reports receiving consulting fees and speaker fees from GlaxoSmithKline, lecture fees from Novartis and Abbott Diagnostics, and grant support from Genocea. Dr. Levin reports receiving consulting fees and grants from GlaxoSmithKline. Dr. Morrow reports receiving consulting fees from Roche. Dr. Schulte reports owning stock in Pfizer. Dr. Stapleton reports receiving grant support from GlaxoSmithKline. Dr. Wald reports receiving consulting fees from AiCuris and grant support from the Washington Vaccine Alliance. No other potential conflict of interest relevant to this article was reported. NR 21 TC 174 Z9 178 U1 0 U2 15 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 5 PY 2012 VL 366 IS 1 BP 34 EP 43 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 887XY UT WOS:000299968800005 PM 22216840 ER PT J AU Dores, GM Devesa, SS Curtis, RE Linet, MS Morton, LM AF Dores, Graca M. Devesa, Susan S. Curtis, Rochelle E. Linet, Martha S. Morton, Lindsay M. TI Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007 SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; ACUTE PROMYELOCYTIC LEUKEMIA; NON-HISPANIC WHITES; ALPHA FUSION GENE; EARLY DEATH RATE; PROGNOSTIC-SIGNIFICANCE; INCIDENCE RATES; CHILDHOOD; SUBTYPE AB Since 2001, the World Health Organization classification for hematopoietic and lymphoid neoplasms has provided a framework for defining acute leukemia (AL) subtypes, although few population-based studies have assessed incidence patterns and patient survival accordingly. We assessed AL incidence rates (IRs), IR ratios (IRRs), and relative survival in the United States (2001-2007) in one of the first population-based, comprehensive assessments. Most subtypes of acute myeloid leukemia (AML) and acute lympho-blastic leukemia/lymphoma (ALL/L) predominated among males, from twice higher incidence of T-cell ALL/L among males than among females (IRR = 2.20) to nearly equal IRs of acute promyelocytic leukemia (APL; IRR = 1.08). Compared with non-Hispanic whites, Hispanics had significantly higher incidence of B-cell ALL/L (IRR = 1.64) and APL (IRR = 1.28); blacks had lower IRs of nearly all AL subtypes. All ALL/L but only some AML subtypes were associated with a bimodal age pattern. Among AML sub-types, survival was highest for APL and AML with inv(16). B-cell ALL/L had more favorable survival than T-cell ALL/L among the young; the converse occurred at older ages. Limitations of cancer registry data must be acknowledged, but the distinct AL incidence and survival patterns based on the World Health Organization classification support biologic diversity that should facilitate etiologic discovery, prognostication, and treatment advances. (Blood. 2012; 119(1): 34-43) C1 [Dores, Graca M.] Dept Vet Affairs Med Ctr, Oklahoma City, OK 73104 USA. [Dores, Graca M.; Devesa, Susan S.; Curtis, Rochelle E.; Linet, Martha S.; Morton, Lindsay M.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Dores, GM (reprint author), Dept Vet Affairs Med Ctr, 921 NE 13th St, Oklahoma City, OK 73104 USA. EM doresg@mail.nih.gov RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 FU Department of Veterans Affairs Medical Center in Oklahoma City; Department of Health and Human Services, National Cancer Institute, National Institutes of Health FX This work was supported by the Department of Veterans Affairs Medical Center in Oklahoma City; and the Intramural Research Program, Department of Health and Human Services, National Cancer Institute, National Institutes of Health. NR 50 TC 132 Z9 137 U1 1 U2 14 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 5 PY 2012 VL 119 IS 1 BP 34 EP 43 DI 10.1182/blood-2011-04-347872 PG 10 WC Hematology SC Hematology GA 875EE UT WOS:000299012400008 PM 22086414 ER PT J AU Karp, JE Vener, TI Raponi, M Ritchie, EK Smith, BD Gore, SD Morris, LE Feldman, EJ Greer, JM Malek, S Carraway, HE Ironside, V Galkin, S Levis, MJ McDevitt, MA Roboz, GR Gocke, CD Derecho, C Palma, J Wang, YX Kaufmann, SH Wright, JJ Garret-Mayer, E AF Karp, Judith E. Vener, Tatiana I. Raponi, Mitch Ritchie, Ellen K. Smith, B. Douglas Gore, Steven D. Morris, Lawrence E. Feldman, Eric J. Greer, Jacqueline M. Malek, Sami Carraway, Hetty E. Ironside, Valerie Galkin, Steven Levis, Mark J. McDevitt, Michael A. Roboz, Gail R. Gocke, Christopher D. Derecho, Carlo Palma, John Wang, Yixin Kaufmann, Scott H. Wright, John J. Garret-Mayer, Elizabeth TI Multi-institutional phase 2 clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; FARNESYLTRANSFERASE INHIBITOR TIPIFARNIB; RISK MYELODYSPLASTIC SYNDROME; OLDER PATIENTS; INTENSIVE CHEMOTHERAPY; R115777; AGE; THERAPY; AML; CLASSIFICATION AB Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. ArmA(T 600 mg twice a day x 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day x 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771. (Blood. 2012; 119(1): 55-63) C1 [Karp, Judith E.; Smith, B. Douglas; Gore, Steven D.; Greer, Jacqueline M.; Carraway, Hetty E.; Ironside, Valerie; Galkin, Steven; Levis, Mark J.; McDevitt, Michael A.; Gocke, Christopher D.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Div Hematol Malignancies, Baltimore, MD 21231 USA. [Vener, Tatiana I.; Derecho, Carlo; Palma, John; Wang, Yixin] Orthoclin Diagnost, Raritan, NJ USA. [Raponi, Mitch] Centocor OrthoBiotech Oncol R&D, Radnor, PA USA. [Ritchie, Ellen K.; Feldman, Eric J.; Roboz, Gail R.] New York Presbyterian Hosp, Cornell Med Ctr, New York, NY USA. [Morris, Lawrence E.] Bone Marrow Transplant Grp Georgia, Atlanta, GA USA. [Malek, Sami] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Kaufmann, Scott H.] Mayo Clin, Dept Oncol, Rochester, MN USA. [Wright, John J.] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Garret-Mayer, Elizabeth] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. RP Karp, JE (reprint author), Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Div Hematol Malignancies, 1650 Orleans St,CRB 1,Rm 2M44, Baltimore, MD 21231 USA. EM jkarp2@jhmi.edu FU National Cancer Institute [U01 CA70095]; National Cancer Institute Cancer Center [2P30 CA06973-46]; National Center for Research Resources [UL1 RR025005]; Leukemia Lymphoma Society (White Plains, NY) [6047-08]; Dr Robert E. Fischell in memory of his late wife Marian FX This work was supported in part by the National Cancer Institute (cooperative agreement U01 CA70095, J.E.K.), National Cancer Institute Cancer Center (support grant 2P30 CA06973-46), National Center for Research Resources (grant UL1 RR025005), Leukemia Lymphoma Society Translational Research Program (White Plains, NY; grant 6047-08, S.H.K. and J.E.K.), and philanthropic funds from Dr Robert E. Fischell in memory of his late wife Marian (J.E.K.). NR 40 TC 14 Z9 15 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 5 PY 2012 VL 119 IS 1 BP 55 EP 63 DI 10.1182/blood-2011-08-370825 PG 9 WC Hematology SC Hematology GA 875EE UT WOS:000299012400011 PM 22001391 ER PT J AU Chen, J Petrus, M Bamford, R Shih, JH Morris, JC Janik, JE Waldmann, TA AF Chen, Jing Petrus, Mike Bamford, Richard Shih, Joanna H. Morris, John C. Janik, John E. Waldmann, Thomas A. TI Increased serum soluble IL-15R alpha levels in T-cell large granular lymphocyte leukemia SO BLOOD LA English DT Article ID LYMPHOPROLIFERATIVE DISEASE; MULTIPLE-SCLEROSIS; DENDRITIC CELLS; CELIAC-DISEASE; KILLER-CELLS; ALPHA-CHAIN; FAS LIGAND; BETA-CHAIN; IN-VIVO; IL-15 AB Large granular lymphocyte (LGL) leukemia is a clonal lymphoproliferative disease of mature T and natural killer cells. The etiology of LGL leukemia is unknown. IL-15 is an inflammatory cytokine that stimulates T and natural killer cells and is critical for their survival and proliferation. IL-15 signals through a heterotrimeric receptor that is composed of a private receptor, IL-15R alpha and IL-2/IL-15R beta and gamma(c) shared with IL-2. Using a newly developed assay, we demonstrated increased levels of soluble IL-15R alpha in the serum of patients with T-LGL leukemia. Furthermore, IL-15R alpha mRNA levels were also up-regulated in the PBMCs of these patients. FACS analysis indicated that IL-15R alpha was expressed both on monocytes as well as on some CD8(+) leukemic cells of the patients. Interestingly, the mRNA levels of IFN-gamma, a known inducer of IL-15R alpha, were also up-regulated in patients' PBMCs. Moreover, PBMCs of some T-LGL patients proliferated at higher levels in response to exogenously added IL-15 compared with those of normal donors. In summary, our study demonstrated increased expression of IL-15R alpha in T-LGL leukemia. It is conceivable that higher IL-15R alpha expression may lower IL-15 response threshold in vivo and, therefore, may contribute to the pathogenesis of the disease. (Blood. 2012; 119(1): 137-143) C1 [Chen, Jing; Petrus, Mike; Morris, John C.; Janik, John E.; Waldmann, Thomas A.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Bamford, Richard] Transponics, Jacobus, PA USA. [Shih, Joanna H.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NIH, 10 Ctr Dr,Bldg 10,Rm 4N115, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 40 TC 17 Z9 18 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 5 PY 2012 VL 119 IS 1 BP 137 EP 143 DI 10.1182/blood-2011-04-346759 PG 7 WC Hematology SC Hematology GA 875EE UT WOS:000299012400019 PM 22049515 ER PT J AU Zhang, YF Conti, MA Malide, D Dong, F Wang, AB Shmist, YA Liu, CY Zerfas, P Daniels, MP Chan, CC Kozin, E Kachar, B Kelley, MJ Kopp, JB Adelstein, RS AF Zhang, Yingfan Conti, Mary Anne Malide, Daniela Dong, Fan Wang, Aibing Shmist, Yelena A. Liu, Chengyu Zerfas, Patricia Daniels, Mathew P. Chan, Chi-Chao Kozin, Elliot Kachar, Bechara Kelley, Michael J. Kopp, Jeffrey B. Adelstein, Robert S. TI Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A SO BLOOD LA English DT Article ID RESTRICTED MYH9 INACTIVATION; HEAVY-CHAIN; CELL-ADHESION; PROPLATELET FORMATION; FECHTNER-SYNDROME; MICE; DISORDERS; EPSTEIN; EXPRESSION; SPECTRUM AB We have generated 3 mouse lines, each with a different mutation in the nonmuscle myosin II-A gene, Myh9 (R702C, D1424N, and E1841K). Each line develops MYH9- related disease similar to that found in human patients. R702C mutant human cDNA fused with green fluorescent protein was introduced into the first coding exon of Myh9, and D1424N and E1841K mutations were introduced directly into the corresponding exons. Homozygous R702C mice die at embryonic day 10.5-11.5, whereas homozygous D1424N and E1841K mice are viable. All heterozygous and homozygous mutant mice show macrothrombocytopenia with prolonged bleeding times, a defect in clot retraction, and increased extramedullary megakaryocytes. Studies of cultured megakaryocytes and live-cell imaging of megakaryocytes in the BM show that heterozygous R702C megakaryocytes form fewer and shorter proplatelets with less branching and larger buds. The results indicate that disrupted proplatelet formation contributes to the macrothrombocytopenia in mice and most probably in humans. We also observed premature cataract formation, kidney abnormalities, including albuminuria, focal segmental glomerulosclerosis and progressive kidney disease, and mild hearing loss. Our results show that heterozygous mice with mutations in the myosin motor or filament-forming domain manifest similar hematologic, eye, and kidney phenotypes to humans with MYH9-related disease. (Blood. 2012; 119(1): 238-250) C1 [Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Dong, Fan; Kelley, Michael J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Zerfas, Patricia] Div Vet Resources, Off Res Serv, Bethesda, MD USA. [Chan, Chi-Chao] NEI, Bethesda, MD 20892 USA. [Kozin, Elliot; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Kelley, Michael J.] Durham Vet Affairs Med Ctr, Med Serv, Durham, NC USA. [Kopp, Jeffrey B.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Adelstein, RS (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. EM adelster@mail.nih.gov RI Kozin, Elliott/J-1225-2014; OI Kozin, Elliott/0000-0002-0305-0682; Kelley, Michael/0000-0001-9523-6080; Adelstein, Robert/0000-0002-8683-2144; Kopp, Jeffrey/0000-0001-9052-186X FU Division of Intramural Research, NHLBI; National Institute of Diabetes and Digestive and Kidney Diseases, (NIH) [R01HL66192]; Deafness Research Foundation; Department of Veterans Affairs FX This work is supported by Division of Intramural Research, NHLBI, and the National Institute of Diabetes and Digestive and Kidney Diseases, (NIH grant R01HL66192, M.J.K.), and Deafness Research Foundation (M.J.K.). M.J.K. is the recipient of a Merit Review Award from the Department of Veterans Affairs. NR 35 TC 45 Z9 48 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 5 PY 2012 VL 119 IS 1 BP 238 EP 250 DI 10.1182/blood-2011-06-358853 PG 13 WC Hematology SC Hematology GA 875EE UT WOS:000299012400031 PM 21908426 ER PT J AU Jagasia, M Arora, M Flowers, MED Chao, NJ McCarthy, PL Cutler, CS Urbano-Ispizua, A Pavletic, SZ Haagenson, MD Zhang, MJ Antin, JH Bolwell, BJ Bredeson, C Cahn, JY Cairo, M Gale, RP Gupta, V Lee, SJ Litzow, M Weisdorf, DJ Horowitz, MM Hahn, T AF Jagasia, Madan Arora, Mukta Flowers, Mary E. D. Chao, Nelson J. McCarthy, Philip L. Cutler, Corey S. Urbano-Ispizua, Alvaro Pavletic, Steven Z. Haagenson, Michael D. Zhang, Mei-Jie Antin, Joseph H. Bolwell, Brian J. Bredeson, Christopher Cahn, Jean-Yves Cairo, Mitchell Gale, Robert Peter Gupta, Vikas Lee, Stephanie J. Litzow, Mark Weisdorf, Daniel J. Horowitz, Mary M. Hahn, Theresa TI Risk factors for acute GVHD and survival after hematopoietic cell transplantation SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; UNRELATED DONORS; ALLOGENEIC TRANSPLANTATION; CYCLOSPORINE CONCENTRATION; COMPARING METHOTREXATE; IDENTICAL SIBLINGS; SOCIETE-FRANCAISE; RANDOMIZED-TRIAL; APLASTIC-ANEMIA AB Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (19992005) from HLA-identical sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen on AGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PBSCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval [CI], 37%-41%) in the SD cohort and 59% (95% CI, 57%-61%) in the URD cohort. Patients receiving SD transplants with MA + nonTBI + BM and RIC + PBSCs had significantly lower risks of grades B-D AGVHD than patients in other treatment categories. Those receiving URD transplants with MA + TBI + BM, MA + nonTBI + BM, RIC + BM, orRIC + PBSCs had lower risks of grades B-D AGVHD than those in other treatment categories. The 5-year probabilities of survival were 46% (95% CI, 44%-49%) with SD transplants and 33% (95% CI, 31%-35%) with URD transplants. Conditioning intensity, TBI and graft source have a combined effect on risk of AGVHD that must be considered in deciding on a treatment strategy for individual patients. (Blood. 2012; 119(1): 296-307) C1 [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Hematol & Stem Cell Transplantat Sect, Vanderbilt Clin 3973, Nashville, TN 37232 USA. [Arora, Mukta; Weisdorf, Daniel J.] Univ Minnesota, Minneapolis, MN USA. [Flowers, Mary E. D.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Flowers, Mary E. D.; Lee, Stephanie J.] Univ Washington, Seattle, WA 98195 USA. [Chao, Nelson J.] Duke Univ, Med Ctr, Durham, NC USA. [McCarthy, Philip L.; Hahn, Theresa] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Cutler, Corey S.; Antin, Joseph H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Urbano-Ispizua, Alvaro] Hosp Clin Barcelona, Barcelona, Spain. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Haagenson, Michael D.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Zhang, Mei-Jie; Horowitz, Mary M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Bolwell, Brian J.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Bredeson, Christopher] Univ Ottawa, Ottawa Hosp, Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Cahn, Jean-Yves] Ctr Hosp Grenoble, Hosp A Michallon, Grenoble, France. [Cairo, Mitchell] Columbia Univ, New York Med Coll, Med Ctr, New York, NY USA. [Gale, Robert Peter] Ctr Adv Studies Leukemia, Los Angeles, CA USA. [Gupta, Vikas] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Litzow, Mark] Mayo Clin, Rochester, MN USA. RP Jagasia, M (reprint author), Vanderbilt Univ, Med Ctr, Hematol & Stem Cell Transplantat Sect, Vanderbilt Clin 3973, Nashville, TN 37232 USA. EM madan.jagasia@vanderbilt.edu RI Cahn, Jean-Yves/M-6493-2014 FU National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung, and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID); NHLBI [5U01HL069294]; NCI; Health Resources and Services Administration [HHSH234200637015C]; Office of Naval Research [N00014-061-0704, N00014-08-1-0058]; Allos Inc; Amgen Inc; Angioblast; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children's Leukemia Research Association; Fresenius-Biotech North America Inc; Gamida Cell Teva Joint Venture Ltd; Genentech Inc; Genzyme Corporation; GlaxoSmithKline; Kiadis Pharma; Leukemia & Lymphoma Society; Medical College of Wisconsin; Millennium Pharmaceuticals Inc; Milliman USA Inc; Miltenyi Biotec Inc; National Marrow Donor Program; Optum Healthcare Solutions Inc; Otsuka America Pharmaceutical Inc; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix Inc; Swedish Orphan Biovitrum; THERAKOS Inc; Wellpoint Inc FX The CIBMTR is supported by Public Health Service grant/cooperative agreement U24-CA76518 from the National Cancer Institute (NCI); the National Heart, Lung, and Blood Institute (NHLBI); and the National Institute of Allergy and Infectious Diseases (NIAID); grant/cooperative agreement 5U01HL069294 from NHLBI and NCI; contract HHSH234200637015C with Health Resources and Services Administration; grants N00014-061-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from Allos Inc; Amgen Inc; Angioblast; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children's Leukemia Research Association; Fresenius-Biotech North America Inc; Gamida Cell Teva Joint Venture Ltd; Genentech Inc; Genzyme Corporation; GlaxoSmithKline; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Millennium Pharmaceuticals Inc; Milliman USA Inc; Miltenyi Biotec Inc; National Marrow Donor Program; Optum Healthcare Solutions Inc; Otsuka America Pharmaceutical Inc; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix Inc; Swedish Orphan Biovitrum; THERAKOS Inc; and Wellpoint Inc. NR 44 TC 132 Z9 137 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 5 PY 2012 VL 119 IS 1 BP 296 EP 307 DI 10.1182/blood-2011-06-364265 PG 12 WC Hematology SC Hematology GA 875EE UT WOS:000299012400036 PM 22010102 ER PT J AU Kalams, SA Parker, S Jin, X Elizaga, M Metch, B Wang, M Hural, J Lubeck, M Eldridge, J Cardinali, M Blattner, WA Sobieszczyk, M Suriyanon, V Kalichman, A Weiner, DB Baden, LR AF Kalams, Spyros A. Parker, Scott Jin, Xia Elizaga, Marnie Metch, Barbara Wang, Maggie Hural, John Lubeck, Michael Eldridge, John Cardinali, Massimo Blattner, William A. Sobieszczyk, Magda Suriyanon, Vinai Kalichman, Artur Weiner, David B. Baden, Lindsey R. CA NIAID HIV Vaccine Trials Network TI Safety and Immunogenicity of an HIV-1 Gag DNA Vaccine with or without IL-12 and/or IL-15 Plasmid Cytokine Adjuvant in Healthy, HIV-1 Uninfected Adults SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; REPLICATION-DEFECTIVE ADENOVIRUS; CELL GROWTH-FACTOR; IMMUNE-RESPONSES; RHESUS MACAQUES; T-CELLS; COMPARATIVE ABILITY; CANDIDATE VACCINE; ADAPTIVE IMMUNITY; INTERFERON-GAMMA AB Background: DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques. Methodology/Principal Findings: We performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response. Conclusions/Significance: This combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity. C1 [Kalams, Spyros A.] Vanderbilt Univ, Med Ctr, Div Infect Dis, Dept Med,Dept Microbiol & Immunol, Nashville, TN 37235 USA. [Parker, Scott] Univ Alabama Birmingham, Med Ctr, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Jin, Xia] Univ Rochester, Med Ctr, Dept Med, Rochester, NY 14642 USA. [Elizaga, Marnie; Metch, Barbara; Wang, Maggie; Hural, John] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Cardinali, Massimo] NIAID, Bethesda, MD 20892 USA. [Lubeck, Michael] Pfizer Inc, Pearl River, NY USA. [Hural, John] Profectus BioSci Inc, Tarrytown, NY USA. [Blattner, William A.] Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. [Sobieszczyk, Magda] Columbia Univ, Sch Med, New York, NY USA. [Suriyanon, Vinai] Chiang Mai Ram Hosp, Chiang Mai, Thailand. [Kalichman, Artur] Ctr Referencia & Treinamento DST AIDS, Sao Paulo, Brazil. [Weiner, David B.] Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. [Baden, Lindsey R.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. RP Kalams, SA (reprint author), Vanderbilt Univ, Med Ctr, Div Infect Dis, Dept Med,Dept Microbiol & Immunol, Nashville, TN 37235 USA. EM s.kalams@vanderbilt.edu RI Weiner, David/H-8579-2014 FU National Institute of Allergy and Infectious Diseases HIV Vaccine Trials Network; Pfizer; PB; Natinal Institutes of Health [HHSN 80062C] FX These studies were sponsored by the National Institute of Allergy and Infectious Diseases HIV Vaccine Trials Network. The funders, Pfizer and PB had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; ML was an employee of Wyeth (now Pfizer, Inc.) during the course of the trial. JE was formerly employed by Wyeth (now Pfizer), is currently employed by Profectus BioSciences (PB), and holds stock or options in both companies. PB has licensed a portfolio of issued and pending patents from Pfizer in the area of DNA vaccines, is actively developing DNA IL-12 as a product, and support for that development has been provided by the Natinal Institutes of Health under contract HHSN 80062C awarded to JE. The remaining authors have declared that no competing interests exist. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. NR 48 TC 55 Z9 57 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 5 PY 2012 VL 7 IS 1 AR e29231 DI 10.1371/journal.pone.0029231 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 058VE UT WOS:000312662100016 PM 22242162 ER PT J AU Tian, WH Dong, XY Liu, XR Wang, G Dong, ZY Shen, W Zheng, G Lu, JX Chen, JZ Wang, Y Wu, ZJ Wu, XB AF Tian, Wenhong Dong, Xiaoyan Liu, Xuerong Wang, Gang Dong, Zheyue Shen, Wei Zheng, Gang Lu, Jianxin Chen, Jinzhong Wang, Yue Wu, Zhijian Wu, Xiaobing TI High-Throughput Functional MicroRNAs Profiling by Recombinant AAV-Based MicroRNA Sensor Arrays SO PLOS ONE LA English DT Article ID ADENOASSOCIATED VIRUS; IN-VIVO; TRANSLATIONAL REPRESSION; HEPATOCELLULAR-CARCINOMA; CANCER CELLS; DIFFERENTIATION; EXPRESSION; TARGET; IDENTIFICATION; BIOGENESIS AB Background: microRNAs (miRNAs) are small and non-coding RNAs which play critical roles in physiological and pathological processes. A number of methods have been established to detect and quantify miRNA expression. However, method for high-throughput miRNA function detection is still lacking. Principal Findings: We describe an adeno-associated virus (AAV) vector-based microRNA (miRNA) sensor (Asensor) array for high-throughput functional miRNA profiling. Each Asensor contains a Gaussia luciferase (Gluc) and a firefly luciferase (Fluc) expression cassette to sense functional miRNA and to serve as an internal control respectively. Using this array, we acquired functional profiles of 115 miRNAs for 12 cell lines and found "functional miRNA signatures'' for several specific cell lines. The activities of specific miRNAs including the let-7 family, miR-17-92 cluster, miR-221, and miR-222 in HEK 293 cells were compared with their expression levels determined by quantitative reverse transcriptase polymerase chain reaction (QRT-PCR). We also demonstrate two other practical applications of the array, including a comparison of the miRNA activity between HEK293 and HEK293T cells and the ability to monitor miRNA activity changes in K562 cells treated with 12-O-tetradecanoylphorbol-13-acetate (TPA). Conclusions/Significance: Our approach has potential applications in the identification of cell types, the characterization of biological and pathological processes, and the evaluation of responses to interventions. C1 [Wu, Zhijian] NEI, Unit Ocular Gene Therapy, NIH, Bethesda, MD 20892 USA. [Dong, Xiaoyan; Chen, Jinzhong] Fudan Univ, Inst Genet, State Key Lab Genet Engn, Sch Life Sci, Shanghai 200433, Peoples R China. [Tian, Wenhong] Jilin Univ, Coll Life Sci, Changchun 130023, Jilin, Peoples R China. [Dong, Xiaoyan; Dong, Zheyue; Shen, Wei; Zheng, Gang] Beijing FivePlus Mol Med Inst, Beijing, Peoples R China. [Tian, Wenhong; Liu, Xuerong; Wang, Gang; Wang, Yue; Wu, Xiaobing] Chinese Ctr Dis Control & Prevent, Natl Inst Viral Dis Control & Prevent, State Key Lab Mol Virol & Genet Engn, Beijing, Peoples R China. [Liu, Xuerong; Lu, Jianxin] Wenzhou Med Coll, Wenzhou, Zhejiang, Peoples R China. RP Wu, ZJ (reprint author), NEI, Unit Ocular Gene Therapy, NIH, Bethesda, MD 20892 USA. EM wuzh@mail.nih.gov; wuxb0168@vip.sina.com FU China Special Key Program on Infectious Diseases [2008ZX10002-023, 2008ZX10001-012]; State Key Laboratory of Molecular Virology and Genetic Engineering [2008-S-0003] FX This work was supported by grants from the China Special Key Program on Infectious Diseases (2008ZX10002-023 and 2008ZX10001-012) and Research Program from the State Key Laboratory of Molecular Virology and Genetic Engineering (2008-S-0003). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 18 Z9 22 U1 1 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 5 PY 2012 VL 7 IS 1 AR e29551 DI 10.1371/journal.pone.0029551 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 058VE UT WOS:000312662100028 PM 22242174 ER PT J AU Waisberg, M Vickers, BK Yager, SB Lin, CK Pierce, SK AF Waisberg, Michael Vickers, Brandi K. Yager, Stephanie B. Lin, Christina K. Pierce, Susan K. TI Testing in Mice the Hypothesis That Melanin Is Protective in Malaria Infections SO PLOS ONE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; MELANOCYTES IN-VITRO; VITAMIN-D; CEREBRAL MALARIA; PLASMODIUM-CHABAUDI; MULTIPLE-SCLEROSIS; IMMUNE-RESPONSES; HUMAN-SKIN; CELLS; GROWTH AB Malaria has had the largest impact of any infectious disease on shaping the human genome, exerting enormous selective pressure on genes that improve survival in severe malaria infections. Modern humans originated in Africa and lost skin melanization as they migrated to temperate regions of the globe. Although it is well documented that loss of melanization improved cutaneous Vitamin D synthesis, melanin plays an evolutionary ancient role in insect immunity to malaria and in some instances melanin has been implicated to play an immunoregulatory role in vertebrates. Thus, we tested the hypothesis that melanization may be protective in malaria infections using mouse models. Congenic C57BL/6 mice that differed only in the gene encoding tyrosinase, a key enzyme in the synthesis of melanin, showed no difference in the clinical course of infection by Plasmodium yoelii 17XL, that causes severe anemia, Plasmodium berghei ANKA, that causes severe cerebral malaria or Plasmodium chabaudi AS that causes uncomplicated chronic disease. Moreover, neither genetic deficiencies in vitamin D synthesis nor vitamin D supplementation had an effect on survival in cerebral malaria. Taken together, these results indicate that neither melanin nor vitamin D production improve survival in severe malaria. C1 [Waisberg, Michael; Vickers, Brandi K.; Yager, Stephanie B.; Lin, Christina K.; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Waisberg, M (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM waisbergm@niaid.nih.gov; spierce@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 6 Z9 6 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 5 PY 2012 VL 7 IS 1 AR e29493 DI 10.1371/journal.pone.0029493 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 058VE UT WOS:000312662100025 PM 22242171 ER PT J AU Yu, CR Lee, YS Mahdi, RM Surendran, N Egwuagu, CE AF Yu, Cheng-Rong Lee, Yun Sang Mahdi, Rashid M. Surendran, Narayanan Egwuagu, Charles E. TI Therapeutic Targeting of STAT3 (Signal Transducers and Activators of Transcription 3) Pathway Inhibits Experimental Autoimmune Uveitis SO PLOS ONE LA English DT Article ID BLOOD-BRAIN-BARRIER; T(H)17 CELL-DIFFERENTIATION; CENTRAL-NERVOUS-SYSTEM; T-CELLS; MULTIPLE-SCLEROSIS; IN-VIVO; ENCEPHALOMYELITIS; ADHESION; DISEASE; UVEORETINITIS AB Mice with targeted deletion of STAT3 in CD4(+) T-cells do not develop experimental autoimmune uveitis (EAU) or experimental autoimmune encephalomyelitis (EAE), in part, because they cannot generate pathogenic Th17 cells. In this study, we have used ORLL-NIH001, a small synthetic compound that inhibits transcriptional activity of STAT3, to ameliorate EAU, an animal model of human posterior uveitis. We show that by attenuating inflammatory properties of uveitogenic lymphocytes, ORLL-NIH001 inhibited the recruitment of inflammatory cells into the retina during EAU and prevented the massive destruction of the neuroretina caused by pro-inflammatory cytokines produced by the autoreactive lymphocytes. Decrease in disease severity observed in ORLL-NIH001-treated mice, correlated with the down-regulation of alpha 4 beta 1 and alpha 4 beta 7 integrin activation and marked reduction of CCR6 and CXCR3 expression, providing a mechanism by which ORLL-NIH001 mitigated EAU. Furthermore, we show that ORLL-NIH001 inhibited the expansion of human Th17 cells, underscoring its potential as a drug for the treatment of human uveitis. Two synthetic molecules that target the Th17 lineage transcription factors, ROR gamma t and ROR alpha, have recently been suggested as potential drugs for inhibiting Th17 development and treating CNS inflammatory diseases. However, inhibiting STAT3 pathways completely blocks Th17 development, as well as, prevents trafficking of inflammatory cells into CNS tissues, making STAT3 a more attractive therapeutic target. Thus, use of ORLL-NIH001 to target the STAT3 transcription factor, thereby antagonizing Th17 expansion and expression of proteins that mediate T cell chemotaxis, provides an attractive new therapeutic approach for treatment of posterior uveitis and other CNS autoimmune diseases mediated by Th17 cells. C1 [Yu, Cheng-Rong; Lee, Yun Sang; Mahdi, Rashid M.; Egwuagu, Charles E.] NEI, Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. [Surendran, Narayanan] Orchid Res Labs Ltd, Madras, Tamil Nadu, India. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov FU National Eye Institute; National Institutes of Health; [EY000350-11 DIR] FX The National Eye Institute and National Institutes of Health Intramural Research Programs funded this research. Funding was for the study entitled "Development of Immunologic therapies against uveitis'' (Project # EY000350-11 DIR). This study was conducted as part of our service and duty as US government employees. The study design, data collection and analysis, decision to publish, or preparation of the manuscript were by individuals listed in this manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 21 Z9 21 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 5 PY 2012 VL 7 IS 1 AR e29742 DI 10.1371/journal.pone.0029742 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 058VE UT WOS:000312662100033 PM 22238646 ER PT J AU Lou, S Xu, BY Huang, QF Zhi, N Cheng, F Wong, S Brown, K Delwart, E Liu, ZW Qiu, JM AF Lou, Sai Xu, Baoyan Huang, Qinfeng Zhi, Ning Cheng, Fang Wong, Susan Brown, Kevin Delwart, Eric Liu, Zhengwen Qiu, Jianming TI Molecular characterization of the newly identified human parvovirus 4 in the family Parvoviridae SO VIROLOGY LA English DT Article DE Parvovirus; Gene expression ID ERYTHROID PROGENITOR CELLS; MINOR CAPSID PROTEIN; VP1 N-TERMINUS; MINUTE VIRUS; HUMAN BOCAVIRUS; TRANSCRIPTION PROFILE; NONSTRUCTURAL PROTEIN; UNIQUE REGION; B19 PARVOVIRUS; CYCLE ARREST AB Human parvovirus 4 (PARV4) is an emerging human virus, and little is known about the molecular aspects of PARV4 apart from its incomplete genome sequence, which lacks information of the termini. We analyzed the gene expression profile of PARV4 using a nearly full-length HPV4 genome in a replication competent system in 293 cells. We found that PARV4 utilizes two promoters to transcribe non-structural protein- and structural protein-encoding mRNAs, respectively, which were polyadenylated at the right end of the genome. Three major proteins, including the large non-structural protein NS1a, whose mRNA is spliced, and capsid proteins VP1 and VP2, were detected. Additional functional analysis of the NS1a revealed its capability to induce cell cycle arrest at G2/M phase in ex vivo-generated human hematopoietic stem cells. Taken together, our characterization of the molecular features of PARV4 suggests that PARV4 represents a new genus in the family Parvoviridae. (C) 2011 Elsevier Inc. All rights reserved. C1 [Lou, Sai; Liu, Zhengwen] Xi An Jiao Tong Univ, Dept Infect Dis, Affiliated Hosp 1, Sch Med, Xian 710061, Shaanxi Provinc, Peoples R China. [Xu, Baoyan; Zhi, Ning; Wong, Susan; Brown, Kevin] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Huang, Qinfeng; Cheng, Fang; Qiu, Jianming] Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS 66103 USA. [Delwart, Eric] Blood Syst Res Inst, San Francisco, CA USA. RP Liu, ZW (reprint author), Xi An Jiao Tong Univ, Dept Infect Dis, Affiliated Hosp 1, Sch Med, Xian 710061, Shaanxi Provinc, Peoples R China. EM liuzhengwen2011@gmail.com OI Delwart, Eric/0000-0002-6296-4484 FU NIAID [R01 AI070723] FX This work was supported by PHS grant R01 AI070723 from NIAID to JQ. We thank the members of Qiu lab for their valuable discussions. NR 55 TC 9 Z9 12 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 5 PY 2012 VL 422 IS 1 BP 59 EP 69 DI 10.1016/j.virol.2011.09.033 PG 11 WC Virology SC Virology GA 859UW UT WOS:000297902300007 PM 22044541 ER PT J AU Hummon, AB Pitt, JJ Camps, J Emons, G Skube, SB Huppi, K Jones, TL Beissbarth, T Kramer, F Grade, M Difilippantonio, MJ Ried, T Caplen, NJ AF Hummon, Amanda B. Pitt, Jason J. Camps, Jordi Emons, Georg Skube, Susan B. Huppi, Konrad Jones, Tamara L. Beissbarth, Tim Kramer, Frank Grade, Marian Difilippantonio, Michael J. Ried, Thomas Caplen, Natasha J. TI Systems-wide RNAi analysis of CASP8AP2/FLASH shows transcriptional deregulation of the replication-dependent histone genes and extensive effects on the transcriptome of colorectal cancer cells SO MOLECULAR CANCER LA English DT Article DE CASP8AP2; FLASH; RNAi screening; RNAi analysis; siRNA; replication-dependent histone transcripts ID NF-KAPPA-B; SIGNALING PATHWAY; MESSENGER-RNAS; CAJAL BODIES; IN-VIVO; S-PHASE; C-MYB; FLASH; APOPTOSIS; ACTIVATION AB Background: Colorectal carcinomas (CRC) carry massive genetic and transcriptional alterations that influence multiple cellular pathways. The study of proteins whose loss-of-function (LOF) alters the growth of CRC cells can be used to further understand the cellular processes cancer cells depend upon for survival. Results: A small-scale RNAi screen of similar to 400 genes conducted in SW480 CRC cells identified several candidate genes as required for the viability of CRC cells, most prominently CASP8AP2/FLASH. To understand the function of this gene in maintaining the viability of CRC cells in an unbiased manner, we generated gene specific expression profiles following RNAi. Silencing of CASP8AP2/FLASH resulted in altered expression of over 2500 genes enriched for genes associated with cellular growth and proliferation. Loss of CASP8AP2/FLASH function was significantly associated with altered transcription of the genes encoding the replication-dependent histone proteins as a result of the expression of the non-canonical polyA variants of these transcripts. Silencing of CASP8AP2/FLASH also mediated enrichment of changes in the expression of targets of the NF kappa B and MYC transcription factors. These findings were confirmed by whole transcriptome analysis of CASP8AP2/FLASH silenced cells at multiple time points. Finally, we identified and validated that CASP8AP2/FLASH LOF increases the expression of neurofilament heavy polypeptide (NEFH), a protein recently linked to regulation of the AKT1/beta-catenin pathway. Conclusions: We have used unbiased RNAi based approaches to identify and characterize the function of CASP8AP2/FLASH, a protein not previously reported as required for cell survival. This study further defines the role CASP8AP2/FLASH plays in the regulating expression of the replication-dependent histones and shows that its LOF results in broad and reproducible effects on the transcriptome of colorectal cancer cells including the induction of expression of the recently described tumor suppressor gene NEFH. C1 [Pitt, Jason J.; Huppi, Konrad; Jones, Tamara L.; Caplen, Natasha J.] NCI, Gene Silencing Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Hummon, Amanda B.; Camps, Jordi; Emons, Georg; Grade, Marian; Difilippantonio, Michael J.; Ried, Thomas] NCI, Canc Genom Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Hummon, Amanda B.; Skube, Susan B.] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. [Beissbarth, Tim; Kramer, Frank] Univ Med Ctr Gottingen, Dept Med Stat, Gottingen, Germany. [Emons, Georg; Grade, Marian] Univ Med Ctr Gottingen, Dept Gen & Visceral Surg, Gottingen, Germany. [Difilippantonio, Michael J.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Caplen, NJ (reprint author), NCI, Gene Silencing Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM ncaplen@mail.nih.gov RI Beissbarth, Tim/B-3129-2013; Caplen, Natasha/H-2768-2016 OI Beissbarth, Tim/0000-0001-6509-2143; Caplen, Natasha/0000-0002-0001-9460 FU NIH, National Cancer Institute, Center for Cancer Research; NCI FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. ABH was supported in part by a Sallie Rosen Kaplen Fellowship from the NCI. We thank Danny Wangsa, Hesed Padilla-Nash, Chanelle Case and Sudhir Varma for technical assistance. NR 46 TC 8 Z9 9 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD JAN 4 PY 2012 VL 11 AR 1 DI 10.1186/1476-4598-11-1 PG 22 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 909YK UT WOS:000301603300001 PM 22216762 ER PT J AU Baljinnyam, B Klauzinska, M Saffo, S Callahan, R Rubin, JS AF Baljinnyam, Bolormaa Klauzinska, Malgorzata Saffo, Saad Callahan, Robert Rubin, Jeffrey S. TI Recombinant R-spondin2 and Wnt3a Up- and Down-Regulate Novel Target Genes in C57MG Mouse Mammary Epithelial Cells SO PLOS ONE LA English DT Article ID ARYL-HYDROCARBON RECEPTOR; APICAL ECTODERMAL RIDGE; BETA-CATENIN PATHWAY; E3 UBIQUITIN LIGASE; WNT/BETA-CATENIN; R-SPONDIN; SYNERGISTIC INDUCTION; SIGNALING PATHWAY; RETINOIC ACID; CANCER CELLS AB R-spondins (Rspos) comprise a family of four secreted proteins that have important roles in cell proliferation, cell fate determination and organogenesis. Rspos typically exert their effects by potentiating the Wnt/beta-catenin signaling pathway. To systematically investigate the impact of Rspo/Wnt on gene expression, we performed a microarray analysis using C57MG mouse mammary epithelial cells treated with recombinant Rspo2 and/or Wnt3a. We observed the up- and down-regulation of several previously unidentified target genes, including ones that encode proteins involved in immune responses, effectors of other growth factor signaling pathways and transcription factors. Dozens of these changes were validated by quantitative real time RT-PCR. Time course experiments showed that Rspo2 typically had little or no effect on Wnt-dependent gene expression at 3 or 6 h, but enhanced expression at 24 h, consistent with biochemical data indicating that Rspo2 acts primarily to sustain rather than acutely increase Wnt pathway activation. Up-regulation of gene expression was inhibited by pre-treatment with Dickkopf1, a Wnt/beta-catenin pathway antagonist, and by siRNA knockdown of beta-catenin expression. While Dickkopf1 blocked Rspo2/Wnt3a-dependent down-regulation, a number of down-regulated genes were not affected by beta-catenin knockdown, suggesting that in these instances down-regulation was mediated by a beta-catenin-independent mechanism. C1 [Baljinnyam, Bolormaa; Saffo, Saad; Rubin, Jeffrey S.] NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. [Klauzinska, Malgorzata; Callahan, Robert] NCI, Oncogenet Sect, Mammary Biol & Tumorigenesis Lab, Bethesda, MD 20892 USA. RP Baljinnyam, B (reprint author), NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. EM rubinj@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 9 Z9 10 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 4 PY 2012 VL 7 IS 1 AR e29455 DI 10.1371/journal.pone.0029455 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 902VE UT WOS:000301070200029 PM 22238613 ER PT J AU Mellata, M Maddux, JT Nam, T Thomson, N Hauser, H Stevens, MP Mukhopadhyay, S Sarker, S Crabbe, A Nickerson, CA Santander, J Curtiss, R AF Mellata, Melha Maddux, Jacob T. Nam, Timothy Thomson, Nicholas Hauser, Heidi Stevens, Mark P. Mukhopadhyay, Suman Sarker, Shameema Crabbe, Aurelie Nickerson, Cheryl A. Santander, Javier Curtiss, Roy, III TI New Insights into the Bacterial Fitness-Associated Mechanisms Revealed by the Characterization of Large Plasmids of an Avian Pathogenic E. coli SO PLOS ONE LA English DT Article ID COMPLETE DNA-SEQUENCE; ESCHERICHIA-COLI; VIRULENCE FACTORS; BIOFILM FORMATION; SALMONELLA-MINNESOTA; COMPARATIVE GENOMICS; TSH AUTOTRANSPORTER; NEONATAL MENINGITIS; CHI-7122 O78K80H9; CARBON NUTRITION AB Extra-intestinal pathogenic E. coli (ExPEC), including avian pathogenic E. coli (APEC), pose a considerable threat to both human and animal health, with illness causing substantial economic loss. APEC strain chi 7122 (O78:K80:H9), containing three large plasmids [pChi7122-1 (IncFIB/FIIA-FIC), pChi7122-2 (IncFII), and pChi7122-3 (IncI(2))]; and a small plasmid pChi7122-4 (ColE2-like), has been used for many years as a model strain to study the molecular mechanisms of ExPEC pathogenicity and zoonotic potential. We previously sequenced and characterized the plasmid pChi7122-1 and determined its importance in systemic APEC infection; however the roles of the other pChi7122 plasmids were still ambiguous. Herein we present the sequence of the remaining pChi7122 plasmids, confirming that pChi7122-2 and pChi7122-3 encode an ABC iron transport system (eitABCD) and a putative type IV fimbriae respectively, whereas pChi7122-4 is a cryptic plasmid. New features were also identified, including a gene cluster on pChi7122-2 that is not present in other E. coli strains but is found in Salmonella serovars and is predicted to encode the sugars catabolic pathways. In vitro evaluation of the APEC chi 7122 derivative strains with the three large plasmids, either individually or in combinations, provided new insights into the role of plasmids in biofilm formation, bile and acid tolerance, and the interaction of E. coli strains with 3-D cultures of intestinal epithelial cells. In this study, we show that the nature and combinations of plasmids, as well as the background of the host strains, have an effect on these phenomena. Our data reveal new insights into the role of extra-chromosomal sequences in fitness and diversity of ExPEC in their phenotypes. C1 [Mellata, Melha; Maddux, Jacob T.; Nam, Timothy; Sarker, Shameema; Crabbe, Aurelie; Nickerson, Cheryl A.; Santander, Javier; Curtiss, Roy, III] Arizona State Univ, Biodesign Inst, Tempe, AZ 85281 USA. [Nickerson, Cheryl A.; Santander, Javier; Curtiss, Roy, III] Arizona State Univ, Sch Life Sci, Tempe, AZ USA. [Thomson, Nicholas; Hauser, Heidi] Wellcome Trust Sanger Inst, Cambridge, England. [Stevens, Mark P.] Univ Edinburgh, Roslin Inst, Roslin, Midlothian, Scotland. [Stevens, Mark P.] Univ Edinburgh, Royal Dick Sch Vet Studies, Roslin, Midlothian, Scotland. [Mukhopadhyay, Suman] NIAID, Zoonot Dis Bacteriol & Mycol Branch, Div Microbiol & Infect Dis, NIH,HHS, Bethesda, MD 20892 USA. RP Mellata, M (reprint author), Arizona State Univ, Biodesign Inst, Tempe, AZ 85281 USA. EM melha.mellata@asu.edu OI Ravel, Jacques/0000-0002-0851-2233 FU U.S. Department of Agriculture National Research Initiative (USDA NRI) CSREES [2007-35201-18519]; National Institutes of Health [R21 AI090416] FX Funding for research was provided by the U.S. Department of Agriculture National Research Initiative (USDA NRI) CSREES grant 2007-35201-18519 to Dr. Curtiss III, and National Institutes of Health grant R21 AI090416 to Dr. Mellata. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 90 TC 11 Z9 11 U1 5 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 4 PY 2012 VL 7 IS 1 AR e29481 DI 10.1371/journal.pone.0029481 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 902VE UT WOS:000301070200030 PM 22238616 ER PT J AU Menashe, I Figueroa, JD Garcia-Closas, M Chatterjee, N Malats, N Picornell, A Maeder, D Yang, Q Prokunina-Olsson, L Wang, ZM Real, FX Jacobs, KB Baris, D Thun, M Albanes, D Purdue, MP Kogevinas, M Hutchinson, A Fu, YP Tang, W Burdette, L Tardon, A Serra, C Carrato, A Garcia-Closas, R Lloreta, J Johnson, A Schwenn, M Schned, A Andriole, G Black, A Jacobs, EJ Diver, RW Gapstur, SM Weinstein, SJ Virtamo, J Caporaso, NE Landi, MT Fraumeni, JF Chanock, SJ Silverman, DT Rothman, N AF Menashe, Idan Figueroa, Jonine D. Garcia-Closas, Montserrat Chatterjee, Nilanjan Malats, Nuria Picornell, Antoni Maeder, Dennis Yang, Qi Prokunina-Olsson, Ludmila Wang, Zhaoming Real, Francisco X. Jacobs, Kevin B. Baris, Dalsu Thun, Michael Albanes, Demetrius Purdue, Mark P. Kogevinas, Manolis Hutchinson, Amy Fu, Yi-Ping Tang, Wei Burdette, Laurie Tardon, Adonina Serra, Consol Carrato, Alfredo Garcia-Closas, Reina Lloreta, Josep Johnson, Alison Schwenn, Molly Schned, Alan Andriole, Gerald, Jr. Black, Amanda Jacobs, Eric J. Diver, Ryan W. Gapstur, Susan M. Weinstein, Stephanie J. Virtamo, Jarmo Caporaso, Neil E. Landi, Maria Teresa Fraumeni, Joseph F., Jr. Chanock, Stephen J. Silverman, Debra T. Rothman, Nathaniel TI Large-Scale Pathway-Based Analysis of Bladder Cancer Genome-Wide Association Data from Five Studies of European Background SO PLOS ONE LA English DT Article ID NAT2 SLOW ACETYLATION; AROMATIC-AMINES; CONFERS SUSCEPTIBILITY; GENETIC-VARIATION; MISSING HERITABILITY; SEQUENCE VARIANT; COMPLEX DISEASE; REPAIR PATHWAY; GSTM1 NULL; RISK AB Pathway analysis of genome-wide association studies (GWAS) offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n = 5 studies). Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome), and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and similar to 90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway-based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP]) were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P <= 0.01. To minimize false positives, we used the I-2 statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways ('Aromatic amine metabolism' [P-GSEA = 0.0100, P-ARTP = 0.0020], 'NAD biosynthesis' [P-GSEA = 0.0018, P-ARTP = 0.0086], 'NAD salvage' [P-ARTP = 0.0068], 'Clathrin derived vesicle budding' [P-ARTP = 0.0018], 'Lysosome vesicle biogenesis' [P-GSEA = 0.0023, P-ARTP < 0.00012], 'Retrograde neurotrophin signaling' [P-GSEA = 0.00840], and 'Mitotic metaphase/anaphase transition' [P-GSEA = 0.0040]) remained. These pathways seem to belong to three fundamental cellular processes (metabolic detoxification, mitosis, and clathrin-mediated vesicles). Identification of the aromatic amine metabolism pathway provides support for the ability of this approach to identify pathways with established relevance to bladder carcinogenesis. C1 [Menashe, Idan; Figueroa, Jonine D.; Chatterjee, Nilanjan; Maeder, Dennis; Yang, Qi; Prokunina-Olsson, Ludmila; Baris, Dalsu; Albanes, Demetrius; Purdue, Mark P.; Fu, Yi-Ping; Tang, Wei; Black, Amanda; Weinstein, Stephanie J.; Caporaso, Neil E.; Landi, Maria Teresa; Fraumeni, Joseph F., Jr.; Chanock, Stephen J.; Silverman, Debra T.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Garcia-Closas, Montserrat] Inst Canc Res, Surrey, England. [Malats, Nuria; Picornell, Antoni; Real, Francisco X.] Spanish Natl Canc Res Ctr, Madrid, Spain. [Wang, Zhaoming; Jacobs, Kevin B.; Hutchinson, Amy; Burdette, Laurie] SAIC Frederick Inc, Core Genotype Facil, Natl Canc Inst Frederick, Frederick, MD USA. [Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Thun, Michael; Jacobs, Eric J.; Diver, Ryan W.; Gapstur, Susan M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Kogevinas, Manolis] Municipal Inst Med Res, Barcelona, Spain. [Kogevinas, Manolis; Tardon, Adonina; Serra, Consol] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. [Carrato, Alfredo] Ramon y Cajal Univ Hosp, Madrid, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna, Spain. [Lloreta, Josep] Univ Pompeu Fabra, Hosp Mar, IMIM, Barcelona, Spain. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. [Schned, Alan] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Hanover, NH 03756 USA. [Andriole, Gerald, Jr.] Washington Univ, Sch Med, Dept Urol, St Louis, MO USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Helsinki, Finland. RP Menashe, I (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM menashei@mail.nih.gov RI Tang, Wei/H-7103-2013; Serra, C/E-6879-2014; Lloreta, J/I-2112-2014; Albanes, Demetrius/B-9749-2015; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Real Arribas, Francisco/H-5275-2015; Purdue, Mark/C-9228-2016; Kogevinas, Manolis/C-3918-2017; OI Tang, Wei/0000-0002-7089-4391; Serra, C/0000-0001-8337-8356; Lloreta, J/0000-0003-1644-9470; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Real Arribas, Francisco/0000-0001-9501-498X; Purdue, Mark/0000-0003-1177-3108; Prokunina-Olsson, Ludmila/0000-0002-9622-2091 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics [NCI N02-CP-11015, NCI N02-CP-01037]; FIS/Spain [98/1274, 00/0745, PI061614, G03/174]; Fundacio Marato TV3; Red Tematica Investigacion Cooperativa en Cancer (RTICC); Consolider ONCOBIO; The National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) [HG-06-033-NCI-01, RO1HL091172-01]; Johns Hopkins University Center for Inherited Disease Research [U01HG004438, NIH HHSN268200782096C]; NIH Genes, Environment and Health Initiative [GEI] [HG-06-033-NCI-01, RO1HL091172-01]; GENEVA Coordination Center [U01 HG004446]; National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics; Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health; NIH; National Cancer Institute; U.S. Public Health Service from the National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004]; [EU-FP7-201663]; [RO1- CA089715]; [CA34627] FX This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Support for individual studies that participated in the effort is as follows: SBCS (Dr. Silverman) - Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural contract number NCI N02-CP-11015. FIS/Spain 98/1274, FIS/Spain 00/0745, PI061614, and G03/174, Fundacio Marato TV3, Red Tematica Investigacion Cooperativa en Cancer (RTICC), Consolider ONCOBIO, EU-FP7-201663; and RO1- CA089715 and CA34627. NEBCS (Dr. Silverman) - Intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics and intramural contract number NCI N02-CP-01037 PLCO (Dr. Purdue) - The National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C), and study coordination at the GENEVA (Dr. Caporaso)-The NIH Genes, Environment and Health Initiative [GEI] partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C) and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. Genotyping for the remaining part of PLCO and all ATBC and CPS-II samples were supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. ATBC (Dr. Albanes) - This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, and N01-RC-37004 from the National Cancer Institute, Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 20 Z9 21 U1 2 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 4 PY 2012 VL 7 IS 1 AR e29396 DI 10.1371/journal.pone.0029396 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 902VE UT WOS:000301070200026 PM 22238607 ER PT J AU Mothe, B Llano, A Ibarrondo, J Zamarreno, J Schiaulini, M Miranda, C Ruiz-Riol, M Berger, CT Herrero, MJ Palou, E Plana, M Rolland, M Khatri, A Heckerman, D Pereyra, F Walker, BD Weiner, D Paredes, R Clotet, B Felber, BK Pavlakis, GN Mullins, JI Brander, C AF Mothe, Beatriz Llano, Anuska Ibarrondo, Javier Zamarreno, Jennifer Schiaulini, Mattia Miranda, Cristina Ruiz-Riol, Marta Berger, Christoph T. Jose Herrero, M. Palou, Eduard Plana, Montse Rolland, Morgane Khatri, Ashok Heckerman, David Pereyra, Florencia Walker, Bruce D. Weiner, David Paredes, Roger Clotet, Bonaventura Felber, Barbara K. Pavlakis, George N. Mullins, James I. Brander, Christian TI CTL Responses of High Functional Avidity and Broad Variant Cross-Reactivity Are Associated with HIV Control SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD8(+) T-CELLS; VIRAL LOAD; INFECTION; EPITOPE; GAG; LYMPHOCYTES; IMMUNE; POLYFUNCTIONALITY; IMMUNODOMINANCE AB Cytotoxic T lymphocyte (CTL) responses targeting specific HIV proteins, in particular Gag, have been associated with relative control of viral replication in vivo. However, Gag-specific CTL can also be detected in individuals who do not control the virus and it remains thus unclear how Gag-specific CTL may mediate the beneficial effects in some individuals but not in others. Here, we used a 10mer peptide set spanning HIV Gag-p24 to determine immunogen-specific T-cell responses and to assess functional properties including functional avidity and cross-reactivity in 25 HIV-1 controllers and 25 non-controllers without protective HLA class I alleles. Our data challenge the common belief that Gag-specific T cell responses dominate the virus-specific immunity exclusively in HIV-1 controllers as both groups mounted responses of comparable breadths and magnitudes against the p24 sequence. However, responses in controllers reacted to lower antigen concentrations and recognized more epitope variants than responses in non-controllers. These cross-sectional data, largely independent of particular HLA genetics and generated using direct ex-vivo samples thus identify T cell responses of high functional avidity and with broad variant reactivity as potential functional immune correlates of relative HIV control. C1 [Mothe, Beatriz; Llano, Anuska; Ibarrondo, Javier; Zamarreno, Jennifer; Schiaulini, Mattia; Ruiz-Riol, Marta; Paredes, Roger; Clotet, Bonaventura; Brander, Christian] Hosp Badalona Germans Trias & Pujol, IrsiCaixa AIDS Res Inst HIVACAT, Barcelona, Spain. [Mothe, Beatriz; Miranda, Cristina; Paredes, Roger; Clotet, Bonaventura] Hosp Badalona Germans Trias & Pujol, Lluita Sida Fdn, Barcelona, Spain. [Mothe, Beatriz; Schiaulini, Mattia] Univ Autonoma Barcelona, E-08193 Barcelona, Spain. [Berger, Christoph T.; Pereyra, Florencia; Walker, Bruce D.] MIT & Harvard, Ragon Inst MGH, Boston, MA USA. [Jose Herrero, M.; Palou, Eduard] Hosp Badalona Germans Trias & Pujol, Dept Immunol, LIRAD Banc Sang & Teixits, Barcelona, Spain. [Plana, Montse] Univ Barcelona, HIVACAT, Hosp Clin, AIDS Res Grp IDIBAPS, Barcelona, Spain. [Rolland, Morgane; Mullins, James I.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Khatri, Ashok] Massachusetts Gen Hosp, Peptide Prot Core Facil, Boston, MA 02114 USA. [Heckerman, David] Microsoft Res, Redmond, WA USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Weiner, David] Univ Penn, Philadelphia, PA 19104 USA. [Felber, Barbara K.; Pavlakis, George N.] NCI Frederick, Frederick, MD USA. [Brander, Christian] ICREA, Barcelona, Spain. RP Mothe, B (reprint author), Hosp Badalona Germans Trias & Pujol, IrsiCaixa AIDS Res Inst HIVACAT, Barcelona, Spain. EM cbrander@irsicaixa.es OI Brander, Christian/0000-0002-0548-5778 FU Bill and Melinda Gates Foundation; Red de Investigacion de Sida (RIS) [RD06/04]; Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Spanish FIPSE [36-0737-09] FX This work was funded by Bill and Melinda Gates Foundation and was supported in part by the Red de Investigacion de Sida (RIS) (RD06/04), Instituto de Salud Carlos III (ISCIII), Madrid, Spain and the Spanish FIPSE 36-0737-09. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 64 Z9 64 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 4 PY 2012 VL 7 IS 1 AR e29717 DI 10.1371/journal.pone.0029717 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 902VE UT WOS:000301070200043 PM 22238642 ER PT J AU Hirata, T Amano, T Nakatake, Y Amano, M Piao, Y Hoang, HG Ko, MSH AF Hirata, Tetsuya Amano, Tomokazu Nakatake, Yuhki Amano, Misa Piao, Yulan Hoang, Hien G. Ko, Minoru S. H. TI Zscan4 transiently reactivates early embryonic genes during the generation of induced pluripotent stem cells SO SCIENTIFIC REPORTS LA English DT Article ID COPY NUMBER; REPROGRAMMING FACTORS; SOMATIC-CELLS; MOUSE; EXPRESSION; MICROARRAY; INDUCTION; FETAL; MICE; TRANSPOSITION AB The generation of induced pluripotent stem cells (iPSCs) by the forced expression of defined transcription factors in somatic cells holds great promise for the future of regenerative medicine. However, the initial reprogramming mechanism is still poorly understood. Here we show that Zscan4, expressed transiently in 2-cell embryos and embryonic stem cells (ESCs), efficiently produces iPSCs from mouse embryo fibroblasts when coexpressed with Klf4, Oct4, and Sox2. Interestingly, the forced expression of Zscan4 is required only for the first few days of iPSC formation. Microarray analysis revealed transient and early induction of preimplantation-specific genes in a Zscan4-dependent manner. Our work indicates that Zscan4 is a previously unidentified potent natural factor that facilitates the reprogramming process and reactivates early embryonic genes. C1 [Hirata, Tetsuya; Amano, Tomokazu; Nakatake, Yuhki; Amano, Misa; Piao, Yulan; Hoang, Hien G.; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Ko, MSH (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. EM kom@mail.nih.gov RI Ko, Minoru/B-7969-2009; Amano, Tomokazu/F-9720-2013; Nakatake, Yuhki/K-5405-2013 OI Ko, Minoru/0000-0002-3530-3015; FU NIH, National Institute on Aging FX We thank Hong Yu, Carole Stagg, Yong Qian, and Dawood Dudekula for technical assistance. This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 46 TC 33 Z9 33 U1 3 U2 9 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 JAN 4 PY 2012 VL 2 AR 208 DI 10.1038/srep00208 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 896LU UT WOS:000300568700001 PM 22355722 ER PT J AU Fenster, C Vullhorst, D Buonanno, A AF Fenster, Catherine Vullhorst, Detlef Buonanno, Andres TI Acute neuregulin-1 signaling influences AMPA receptor mediated responses in cultured cerebellar granule neurons SO BRAIN RESEARCH BULLETIN LA English DT Article DE Cerebellar granule neurons; Neuregulin-1; ErbB; Chemical LTP; Synaptic plasticity ID LONG-TERM POTENTIATION; NMDA RECEPTORS; HIPPOCAMPAL-NEURONS; SILENT SYNAPSES; ERBB4; EXPRESSION; RAT; SUBUNIT; INTERNEURONS; ACTIVATION AB Neuregulin-1 (NRG1) is a trophic and differentiation factor that signals through ErbB receptor tyrosine kinases to regulate nervous system development. Previous studies have demonstrated that NRG1 affects plasticity at glutamatergic synapses in principal glutamatergic neurons of the hippocampus and frontal cortex; however, immunohistochemical and genetic analyses strongly suggest these effects are indirect and mediated via ErbB4 receptors on GABAergic interneurons. Here, we used cultured cerebellar granule cells (CGCs) that express ErbB4 to analyze the cell-autonomous effects of NRG1 stimulation on glutamatergic function. These cultures have the advantage that they are relatively homogenous and consist primarily of granule neurons that express ErbB4. We show that acute NRG1 treatment does not affect whole-cell AMPA or NMDA receptor (NMDAR) mediated currents in CGCs at 10-12 days in vitro. NRG1 also does not affect the frequency or amplitude of spontaneous AMPAR or NMDAR mediated miniature excitatory post-synaptic currents (mEPSCs). To further investigate the effects of NRG1 on activity-dependent plasticity of glutamatergic synapses in CGCs, we characterized the effects of high-glyine/0 Mg2+ (which activates synaptic NMDARs) on AMPAR-mEPSC frequency and amplitude. We show that high-glycine induces a form of chemical long-term potentiation (chemLTP) in CGCs characterized by an increase in AMPAR-mEPSC frequency but not amplitude. Moreover, NRG1 induces a decrease in AMPAR-mEPSC frequency following chemLTP, but does not affect AMPAR-mEPSC amplitude. CGCs in our cultures conditions express low levels of GluR1, in contrast to dissociated hippocampal cultures, but do express the long isoform of GluR4. This study provides first evidence that (1) high-glycine can induce plasticity at glutamatergic synapses in CGCs, and (2) that acute NRG1/ErbB-signaling can regulate glutamatergic plasticity in CGCs. Taken together with previous reports, our results suggest that, similar to Schaeffer collateral to CA1 synapses, NRG1 effects are activity dependent and mediated via modulation of synaptic AMPARs. (C) 2011 Elsevier Inc. All rights reserved. C1 [Fenster, Catherine] Ashland Univ, Dept Biol Toxicol, Ashland, OH 44805 USA. [Fenster, Catherine; Vullhorst, Detlef; Buonanno, Andres] NICHD, Sect Dev Neurobiol, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Fenster, C (reprint author), Ashland Univ, Dept Biol Toxicol, 401 Coll Ave, Ashland, OH 44805 USA. EM cfenste1@ashland.edu; vullhord@mail.nih.gov; buonanno@mail.nih.gov FU Henry Luce III Endowment award for distinguished scholarship FX This study was supported through a Henry Luce III Endowment award for distinguished scholarship. We thank Zhanyan Fu and Stefano Vicini for guidance regarding neuronal cell culture, electrophysiological recording and data analysis. NR 48 TC 6 Z9 7 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 EI 1873-2747 J9 BRAIN RES BULL JI Brain Res. Bull. PD JAN 4 PY 2012 VL 87 IS 1 BP 21 EP 29 DI 10.1016/j.brainresbull.2011.10.011 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 891DY UT WOS:000300198600003 PM 22044943 ER PT J AU Waldron-Roby, E Ratovitski, T Wang, XF Jiang, ML Watkin, E Arbez, N Graham, RK Hayden, MR Hou, ZP Mori, S Swing, D Pletnikov, M Duan, WZ Tessarollo, L Ross, CA AF Waldron-Roby, Elaine Ratovitski, Tamara Wang, XiaoFang Jiang, Mali Watkin, Erin Arbez, Nikolas Graham, Rona K. Hayden, Michael R. Hou, Zhipeng Mori, Susumu Swing, Deborah Pletnikov, Mikhail Duan, Wenzhen Tessarollo, Lino Ross, Christopher A. TI Transgenic Mouse Model Expressing the Caspase 6 Fragment of Mutant Huntingtin SO JOURNAL OF NEUROSCIENCE LA English DT Article ID N-TERMINAL FRAGMENTS; KNOCK-IN MICE; INTRANUCLEAR INCLUSIONS; MOTOR DYSFUNCTION; NUCLEAR EXPORT; DISEASE; TOXICITY; AGGREGATION; PROTEIN; NEURODEGENERATION AB Huntington's disease (HD) is caused by a polyglutamine expansion in the Huntingtin (Htt) protein. Proteolytic cleavage of Htt into toxic N-terminal fragments is believed to be a key aspect of pathogenesis. The best characterized putative cleavage event is at amino acid 586, hypothesized to be mediated by caspase 6. A corollary of the caspase 6 cleavage hypothesis is that the caspase 6 fragment should be a toxic fragment. To test this hypothesis, and further characterize the role of this fragment, we have generated transgenic mice expressing the N-terminal 586 aa of Htt with a polyglutamine repeat length of 82 (N586-82Q), under the control of the prion promoter. N586-82Q mice show a clear progressive rotarod deficit by 4 months of age, and are hyperactive starting at 5 months, later changing to hypoactivity before early mortality. MRI studies reveal widespread brain atrophy, and histologic studies demonstrate an abundance of Htt aggregates, mostly cytoplasmic, which are predominantly composed of the N586-82Q polypeptide. Smaller soluble N-terminal fragments appear to accumulate over time, peaking at 4 months, and are predominantly found in the nuclear fraction. This model appears to have a phenotype more severe than current full-length Htt models, but less severe than HD mouse models expressing shorter Htt fragments. These studies suggest that the caspase 6 fragment may be a transient intermediate, that fragment size is a factor contributing to the rate of disease progression, and that short soluble nuclear fragments may be most relevant to pathogenesis. C1 [Waldron-Roby, Elaine; Ratovitski, Tamara; Wang, XiaoFang; Jiang, Mali; Watkin, Erin; Arbez, Nikolas; Pletnikov, Mikhail; Duan, Wenzhen; Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Div Neurobiol, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. [Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Pharmacol, Baltimore, MD 21287 USA. [Pletnikov, Mikhail; Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA. [Watkin, Erin; Pletnikov, Mikhail; Duan, Wenzhen; Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD 21287 USA. [Graham, Rona K.; Hayden, Michael R.] Univ British Columbia, Dept Med Genet, Child & Family Res Inst, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 4H4, Canada. [Hou, Zhipeng; Mori, Susumu] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Swing, Deborah; Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Ross, CA (reprint author), Johns Hopkins Univ, Sch Med, Div Neurobiol, Dept Psychiat & Behav Sci, CMSC 8-121,600 N Wolfe St, Baltimore, MD 21287 USA. EM caross@jhu.edu RI Ross, Christopher/H-8395-2013; Hayden, Michael/D-8581-2011 OI Hayden, Michael/0000-0001-5159-1419 FU NINDS [16375]; Huntington's Disease Society of America (HDSA); Cure Huntington's Disease Initiative (CHDI); NIH; Center for Cancer Research; National Cancer Institute FX This work was supported by NINDS Grant 16375, Huntington's Disease Society of America (HDSA), Cure Huntington's Disease Initiative (CHDI), the Intramural Research Program of the NIH, Center for Cancer Research, and National Cancer Institute (for D.S. and L.T.). We thank Hilda Brown for the generation of the N586-82Q plasmid. We also thank the Behavioral Core at Johns Hopkins and its co-coordinator, Jennifer Yochum for facilities and services. NR 44 TC 20 Z9 23 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 4 PY 2012 VL 32 IS 1 BP 183 EP 193 DI 10.1523/JNEUROSCI.1305-11.2012 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 876PM UT WOS:000299119700018 PM 22219281 ER PT J AU Maison, SF Liu, XP Eatock, RA Sibley, DR Grandy, DK Liberman, MC AF Maison, Stephane F. Liu, Xiao-Ping Eatock, Ruth Anne Sibley, David R. Grandy, David K. Liberman, M. Charles TI Dopaminergic Signaling in the Cochlea: Receptor Expression Patterns and Deletion Phenotypes SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GUINEA-PIG COCHLEA; LATERAL OLIVOCOCHLEAR EFFERENTS; AUDITORY-NERVE FIBERS; RAT SPIRAL GANGLION; OUTER HAIR-CELLS; MOUSE COCHLEA; CAT COCHLEA; QUANTITATIVE-ANALYSIS; TYROSINE-HYDROXYLASE; SERIAL SECTIONS AB Pharmacological studies suggest that dopamine release from lateral olivocochlear efferent neurons suppresses spontaneous and sound-evoked activity in cochlear nerve fibers and helps control noise-induced excitotoxicity; however, the literature on cochlear expression and localization of dopamine receptors is contradictory. To better characterize cochlear dopaminergic signaling, we studied receptor localization using immunohistochemistry or reverse transcriptase PCR and assessed histopathology, cochlear responses and olivocochlear function in mice with targeted deletion of each of the five receptor subtypes. In normal ears, D1, D2, and D5 receptors were detected in microdissected immature (postnatal days 10-13) spiral ganglion cells and outer hair cells but not inner hair cells. D4 was detected in spiral ganglion cells only. In whole cochlea samples from adults, transcripts for D1, D2, D4, and D5 were present, whereas D3 mRNA was never detected. D1 and D2 immunolabeling was localized to cochlear nerve fibers, near the first nodes of Ranvier (D2) and in the inner spiral bundle region (D1 and D2) where presynaptic olivocochlear terminals are found. No other receptor labeling was consistent. Cochlear function was normal in D3, D4, and D5 knock-outs. D1 and D2 knock-outs showed slight, but significant enhancement and suppression, respectively, of cochlear responses, both in the neural output [auditory brainstem response (ABR) wave 1] and in outer hair cell function [distortion product otoacoustic emissions (DPOAEs)]. Vulnerability to acoustic injury was significantly increased in D2, D4 and D5 lines: D1 could not be tested, and no differences were seen in D3 mutants, consistent with a lack of receptor expression. The increased vulnerability in D2 knock-outs was seen in DPOAEs, suggesting a role for dopamine in the outer hair cell area. In D4 and D5 knock-outs, the increased noise vulnerability was seen only in ABRs, consistent with a role for dopaminergic signaling in minimizing neural damage. C1 [Maison, Stephane F.; Liu, Xiao-Ping; Eatock, Ruth Anne; Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Maison, Stephane F.; Eatock, Ruth Anne; Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Maison, Stephane F.; Liu, Xiao-Ping; Eatock, Ruth Anne; Liberman, M. Charles] Harvard MIT, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Sibley, David R.] Natl Inst Neurol Disorders & Stroke, Mol Neuropharmacol Sect, Bethesda, MD 20892 USA. [Grandy, David K.] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97239 USA. RP Maison, SF (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM stephane_maison@meei.harvard.edu RI Eatock, Ruth/F-6404-2013; OI Eatock, Ruth Anne/0000-0001-7547-2051 FU National Institutes of Health [R01 DC0188, R01 DC02290, P30 DC5029] FX This work was supported by National Institutes of Health Grants R01 DC0188 (M. C. L.), R01 DC02290 (R. A. E.), and P30 DC5029 (M. C. L.). We are indebted to Dr. Malcolm Low for his help in guiding us to sources for DR knock-out lines. We thank Ben Winterroth for setting up the protocol used to amplify messenger RNA from small numbers of cells. The skillful assistance of Leslie Dodds and Constance Miller is gratefully acknowledged. NR 58 TC 20 Z9 21 U1 2 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 4 PY 2012 VL 32 IS 1 BP 344 EP 355 DI 10.1523/JNEUROSCI.4720-11.2012 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 876PM UT WOS:000299119700032 PM 22219295 ER PT J AU Bray, GA Smith, SR de Jonge, L Xie, H Rood, J Martin, CK Most, M Brock, C Mancuso, S Redman, LM AF Bray, George A. Smith, Steven R. de Jonge, Lilian Xie, Hui Rood, Jennifer Martin, Corby K. Most, Marlene Brock, Courtney Mancuso, Susan Redman, Leanne M. TI Effect of Dietary Protein Content on Weight Gain, Energy Expenditure, and Body Composition During Overeating A Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID METABOLIC-RATE; YOUNG MEN; THERMOGENESIS; HUMANS; GLUTTONY; FAT; RESTRICTION; MAINTENANCE; PREVALENCE; OBESITY AB Context The role of diet composition in response to overeating and energy dissipation in humans is unclear. Objective To evaluate the effects of overconsumption of low, normal, and high protein diets on weight gain, energy expenditure, and body composition. Design, Setting, and Participants A single-blind, randomized controlled trial of 25 US healthy, weight-stable male and female volunteers, aged 18 to 35 years with a body mass index between 19 and 30. The first participant was admitted to the inpatient metabolic unit in June 2005 and the last in October 2007. Intervention After consuming a weight-stabilizing diet for 13 to 25 days, participants were randomized to diets containing 5% of energy from protein (low protein), 15% (normal protein), or 25% (high protein), which they were overfed during the last 8 weeks of their 10- to 12-week stay in the inpatient metabolic unit. Compared with energy intake during the weight stabilization period, the protein diets provided approximately 40% more energy intake, which corresponds to 954 kcal/d (95% CI, 884-1022 kcal/d). Main Outcome Measures Body composition was measured by dual-energy x-ray absorptiometry biweekly, resting energy expenditure was measured weekly by ventilated hood, and total energy expenditure by doubly labeled water prior to the overeating and weight stabilization periods and at weeks 7 to 8. Results Overeating produced significantly less weight gain in the low protein diet group (3.16 kg; 95% CI, 1.88-4.44 kg) compared with the normal protein diet group (6.05 kg; 95% CI, 4.84-7.26 kg) or the high protein diet group (6.51 kg; 95% CI, 5.23-7.79 kg) (P=.002). Body fat increased similarly in all 3 protein diet groups and represented 50% to more than 90% of the excess stored calories. Resting energy expenditure, total energy expenditure, and body protein did not increase during over-feeding with the low protein diet. In contrast, resting energy expenditure (normal protein diet: 160 kcal/d [95% CI, 102-218 kcal/d]; high protein diet: 227 kcal/d [95% CI, 165-289 kcal/d]) and body protein (lean body mass) (normal protein diet: 2.87 kg [95% CI, 2.11-3.62 kg]; high protein diet: 3.18 kg [95% CI, 2.37-3.98 kg]) increased significantly with the normal and high protein diets. Conclusions Among persons living in a controlled setting, calories alone account for the increase in fat; protein affected energy expenditure and storage of lean body mass, but not body fat storage. C1 [Bray, George A.; Rood, Jennifer; Martin, Corby K.; Brock, Courtney; Mancuso, Susan; Redman, Leanne M.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Smith, Steven R.; Xie, Hui] Florida Hosp, Translat Res Inst Metab & Diabet, Orlando, FL USA. [Smith, Steven R.; Xie, Hui] Sanford Burnham Med Res Inst, Orlando, FL USA. [de Jonge, Lilian] NIH, Bethesda, MD 20892 USA. RP Bray, GA (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM George.bray@pbrc.edu FU US Department of Agriculture [2010-34323-21052]; Louisiana State University FX This study was supported in part by the US Department of Agriculture grant 2010-34323-21052 and by funding from Louisiana State University. NR 34 TC 87 Z9 87 U1 2 U2 41 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 4 PY 2012 VL 307 IS 1 BP 47 EP 55 DI 10.1001/jama.2011.1918 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 872ET UT WOS:000298792300021 PM 22215165 ER PT J AU Henderson, DK AF Henderson, David K. TI Management of Needlestick Injuries A House Officer Who Has a Needlestick SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEALTH-CARE WORKERS; HIV POSTEXPOSURE PROPHYLAXIS; T-LYMPHOCYTE RESPONSES; ACUTE HEPATITIS-C; DRUG USE EXPOSURE; OCCUPATIONAL-EXPOSURE; PERCUTANEOUS INJURY; GLOVE PERFORATIONS; BODY-FLUIDS AB Since its identification in 1985, human immunodeficiency virus (HIV) has challenged several aspects of health care delivery. Because HIV is a blood-borne infectious disease, from the early days of the epidemic, concern was raised about risks of occupational exposures and infections among health care workers. Despite the development of highly active antiretroviral therapy, which has effectively modulated HIV into a chronic disease in many settings, risks of occupational infection with 3 blood-borne pathogens remain in the health care workplace. Using the case of a house officer who has a needlestick during a resuscitation attempt, prevention of needlesticks including universal precautions and postexposure management of occupational HIV, hepatitis B, and hepatitis C exposures is discussed. JAMA. 0;0(1):75-84 C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Henderson, DK (reprint author), NIH, Ctr Clin, 10 Ctr Dr,MSC 1504, Bethesda, MD 20892 USA. EM dkh@nih.gov NR 100 TC 15 Z9 15 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 4 PY 2012 VL 307 IS 1 BP 75 EP 84 DI 10.1001/jama.2011.1828 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 872ET UT WOS:000298792300024 PM 22146902 ER PT J AU Berg, RK Melchjorsen, J Rintahaka, J Diget, E Soby, S Horan, KA Gorelick, RJ Matikainen, S Larsen, CS Ostergaard, L Paludan, SR Mogensen, TH AF Berg, Randi K. Melchjorsen, Jesper Rintahaka, Johanna Diget, Elisabeth Soby, Stine Horan, Kristy A. Gorelick, Robert J. Matikainen, Sampsa Larsen, Carsten S. Ostergaard, Lars Paludan, Soren R. Mogensen, Trine H. TI Genomic HIV RNA Induces Innate Immune Responses through RIG-I-Dependent Sensing of Secondary-Structured RNA SO PLOS ONE LA English DT Article ID DOUBLE-STRANDED-RNA; IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; NF-KAPPA-B; PLASMACYTOID DENDRITIC CELLS; HERPES-SIMPLEX-VIRUS; TOLL-LIKE RECEPTORS; CYTOSOLIC DNA; RECOGNITION; INFECTION AB Background: Innate immune responses have recently been appreciated to play an important role in the pathogenesis of HIV infection. Whereas inadequate innate immune sensing of HIV during acute infection may contribute to failure to control and eradicate infection, persistent inflammatory responses later during infection contribute in driving chronic immune activation and development of immunodeficiency. However, knowledge on specific HIV PAMPs and cellular PRRs responsible for inducing innate immune responses remains sparse. Methods/Principal Findings: Here we demonstrate a major role for RIG-I and the adaptor protein MAVS in induction of innate immune responses to HIV genomic RNA. We found that secondary structured HIV-derived RNAs induced a response similar to genomic RNA. In primary human peripheral blood mononuclear cells and primary human macrophages, HIV RNA induced expression of IFN-stimulated genes, whereas only low levels of type I IFN and tumor necrosis factor alpha were produced. Furthermore, secondary structured HIV-derived RNA activated pathways to NF-kappa B, MAP kinases, and IRF3 and co-localized with peroxisomes, suggesting a role for this organelle in RIG-I-mediated innate immune sensing of HIV RNA. Conclusions/Significance: These results establish RIG-I as an innate immune sensor of cytosolic HIV genomic RNA with secondary structure, thereby expanding current knowledge on HIV molecules capable of stimulating the innate immune system. C1 [Berg, Randi K.; Melchjorsen, Jesper; Diget, Elisabeth; Soby, Stine; Larsen, Carsten S.; Ostergaard, Lars; Mogensen, Trine H.] Aarhus Univ Hosp Skejby, Dept Infect Dis, Aarhus, Denmark. [Rintahaka, Johanna; Matikainen, Sampsa] Finnish Inst Occupat Hlth, Unit Excellence Immunotoxicol, Helsinki, Finland. [Horan, Kristy A.; Paludan, Soren R.] Univ Aarhus, Dept Biomed, Aarhus, Denmark. [Gorelick, Robert J.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD USA. RP Berg, RK (reprint author), Aarhus Univ Hosp Skejby, Dept Infect Dis, Aarhus, Denmark. EM trine.mogensen@dadlnet.dk FU Danish Medical Research Council; Kong Christian IX and Dronning Louises Jubilaeumslegat; Fonden til Laegevidenskabens Fremme; Scandinavian Society of Antimicrobial Chemotherapy; Marie Curie Incoming International Fellowship; Faculty of Health Science, Aarhus University; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; SAIC-Frederick, Inc.; U.S. Government FX This work was supported by The Danish Medical Research Council (THM), Kong Christian IX and Dronning Louises Jubilaeumslegat (THM), Fonden til Laegevidenskabens Fremme (THM), and Scandinavian Society of Antimicrobial Chemotherapy (JM). KAH is recipient of a Marie Curie Incoming International Fellowship and RKB was supported by a PhD Stipend from the Faculty of Health Science, Aarhus University. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E with SAIC-Frederick, Inc. (RJG). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Neither SAIC-Frederick, Inc., nor the funders had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors have the following competing interest: One of the authors (RJG) has an affiliation to SAIC-Frederick, Inc., which is a U.S. Government contractor, thus funding comes from the U.S. Government. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors. NR 55 TC 56 Z9 56 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 3 PY 2012 VL 7 IS 1 AR e29291 DI 10.1371/journal.pone.0029291 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903NK UT WOS:000301123400042 PM 22235281 ER PT J AU Cizza, G Ronsaville, DS Kleitz, H Eskandari, F Mistry, S Torvik, S Sonbolian, N Reynolds, JC Blackman, MR Gold, PW Martinez, PE AF Cizza, Giovanni Ronsaville, Donna S. Kleitz, Hayley Eskandari, Farideh Mistry, Sejal Torvik, Sara Sonbolian, Nina Reynolds, James C. Blackman, Marc R. Gold, Philip W. Martinez, Pedro E. CA POWER Premenopausal Osteopenia TI Clinical Subtypes of Depression Are Associated with Specific Metabolic Parameters and Circadian Endocrine Profiles in Women: The Power Study SO PLOS ONE LA English DT Article ID NUTRITION EXAMINATION SURVEY; NATIONAL COMORBIDITY SURVEY; STAR-ASTERISK-D; ATYPICAL DEPRESSION; MAJOR DEPRESSION; PREMENOPAUSAL WOMEN; INSULIN-RESISTANCE; FEATURES; LEPTIN; PREVALENCE AB Background: Major depressive disorder (MDD) has been associated with adverse medical consequences, including cardiovascular disease and osteoporosis. Patients with MDD may be classified as having melancholic, atypical, or undifferentiated features. The goal of the present study was to assess whether these clinical subtypes of depression have different endocrine and metabolic features and consequently, varying medical outcomes. Methods: Premenopausal women, ages 21 to 45 years, with MDD (N = 89) and healthy controls (N = 44) were recruited for a prospective study of bone turnover. Women with MDD were classified as having melancholic (N = 51), atypical (N = 16), or undifferentiated (N = 22) features. Outcome measures included: metabolic parameters, body composition, bone mineral density (BMD), and 24 hourly sampling of plasma adrenocorticotropin (ACTH), cortisol, and leptin. Results: Compared with control subjects, women with undifferentiated and atypical features of MDD exhibited greater BMI, waist/hip ratio, and whole body and abdominal fat mass. Women with undifferentiated MDD characteristics also had higher lipid and fasting glucose levels in addition to a greater prevalence of low BMD at the femoral neck compared to controls. Elevated ACTH levels were demonstrated in women with atypical features of depression, whereas higher mean 24-hour leptin levels were observed in the melancholic subgroup. Conclusions: Pre-menopausal women with various features of MDD exhibit metabolic, endocrine, and BMD features that may be associated with different health consequences. C1 [Cizza, Giovanni; Eskandari, Farideh; Mistry, Sejal; Torvik, Sara; Sonbolian, Nina] NIDDKD, Sect Neuroendocrinol Obes, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Ronsaville, Donna S.; Kleitz, Hayley; Gold, Philip W.; Martinez, Pedro E.] NIMH, Behav Endocrinol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Reynolds, James C.] NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Dept Hlth & Human Serv, Bethesda, MD USA. [Blackman, Marc R.] Vet Affairs Med Ctr, Res Serv, Washington, DC 20422 USA. RP Cizza, G (reprint author), NIDDKD, Sect Neuroendocrinol Obes, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM cizzag@intra.niddk.nih.gov FU National Institutes of Health FX This study was fully supported by the Intramural Program of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There were no current external funding sources for this study. NR 46 TC 27 Z9 28 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 3 PY 2012 VL 7 IS 1 AR e28912 DI 10.1371/journal.pone.0028912 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903NK UT WOS:000301123400013 PM 22235252 ER PT J AU Milla, LA Cortes, CR Christian, Q Onate, MG Cambiazo, V Burgess, SM Palma, V AF Milla, Luis A. Cortes, Claudio R. Hodar, Christian Q. Onate, Maritza G. Cambiazo, Veronica Burgess, Shawn M. Palma, Veronica TI Yeast-based assay identifies novel Shh/Gli target genes in vertebrate development SO BMC GENOMICS LA English DT Article DE Hh/Gli targets; zebrafish; purmorphamine; cyclopamine; neogenin 1; c-myc; sfrp2 ID SONIC HEDGEHOG; CEREBELLUM DEVELOPMENT; BINDING-AFFINITY; ZEBRAFISH; EXPRESSION; GENOME; PROTEINS; DISTINCT; CLONING; PATHWAY AB Background: The increasing number of developmental events and molecular mechanisms associated with the Hedgehog (Hh) pathway from Drosophila to vertebrates, suggest that gene regulation is crucial for diverse cellular responses, including target genes not yet described. Although several high-throughput, genome-wide approaches have yielded information at the genomic, transcriptional and proteomic levels, the specificity of Gli binding sites related to direct target gene activation still remain elusive. This study aims to identify novel putative targets of Gli transcription factors through a protein-DNA binding assay using yeast, and validating a subset of targets both in-vitro and in-vivo. Testing in different Hh/Gli gain-and loss-of-function scenarios we here identified known (e.g., ptc1) and novel Hh-regulated genes in zebrafish embryos. Results: The combined yeast-based screening and MEME/MAST analysis were able to predict Gli transcription factor binding sites, and position mapping of these sequences upstream or in the first intron of promoters served to identify new putative target genes of Gli regulation. These candidates were validated by qPCR in combination with either the pharmacological Hh/Gli antagonist cyc or the agonist pur in Hh-responsive C3H10T1/2 cells. We also used small-hairpin RNAs against Gli proteins to evaluate targets and confirm specific Gli regulation their expression. Taking advantage of mutants that have been identified affecting different components of the Hh/Gli signaling system in the zebrafish model, we further analyzed specific novel candidates. Studying Hh function with pharmacological inhibition or activation complemented these genetic loss-of-function approaches. We provide evidence that in zebrafish embryos, Hh signaling regulates sfrp2, neo1, and c-myc expression in-vivo. Conclusion: A recently described yeast-based screening allowed us to identify new Hh/Gli target genes, functionally important in different contexts of vertebrate embryonic development. C1 [Milla, Luis A.; Cortes, Claudio R.; Onate, Maritza G.; Palma, Veronica] Univ Chile, Fac Sci, Santiago, Chile. [Hodar, Christian Q.; Cambiazo, Veronica] Univ Chile, INTA, Lab Bioinformat Expres Gen, Santiago, Chile. [Milla, Luis A.; Cortes, Claudio R.; Hodar, Christian Q.; Onate, Maritza G.; Cambiazo, Veronica; Palma, Veronica] Univ Chile, Fac Ciencias, FONDAP Ctr Genome Regulat, Santiago, Chile. [Burgess, Shawn M.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Palma, V (reprint author), Univ Chile, Fac Sci, Santiago, Chile. EM vpalma@uchile.cl RI Hodar, Christian/I-1055-2013; Hodar, Christian/I-6399-2016; OI Hodar, Christian/0000-0001-8617-7998; Hodar, Christian/0000-0001-8617-7998; Cortes, Claudio/0000-0003-2255-7806; Burgess, Shawn/0000-0003-1147-0596 FU FONDAP [15090007]; Fondecyt [1070248, 1110237, 3100045, 1090211]; National Human Genome Research Institute, National Institutes of Health FX We would like to thank Catalina Lafourcade for technical assistance, Dr. Miguel Allende for kindly providing access to zebrafish embryos and the zebrafish community for reagents and Hh mutant lines. We are particularly grateful to the PEW foundation for their continuous support. This work was supported by FONDAP 15090007 (VP, VC), Fondecyt grant 1070248, 1110237 (VP), Fondecyt Postdoctoral 3100045 (LAM), Fondecyt 1090211 (VC) and Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (SB). NR 43 TC 7 Z9 7 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JAN 3 PY 2012 VL 13 AR 2 DI 10.1186/1471-2164-13-2 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 898IW UT WOS:000300737000001 PM 22214306 ER PT J AU Hsieh, YC Seshadri, S Chung, WT Hsieh, FI Hsu, YH Lin, HJ Tseng, HP Lien, LM Bai, CH Hu, CJ Jeng, JS Tang, SC Chen, CI Yu, CC Chiou, HY AF Hsieh, Yi-Chen Seshadri, Sudha Chung, Wen-Ting Hsieh, Fang-I Hsu, Yi-Hsiang Lin, Huey-Juan Tseng, Hung-Pin Lien, Li-Ming Bai, Chyi-Huey Hu, Chaur-Jong Jeng, Jiann-Shing Tang, Sung-Chun Chen, Chin-I Yu, Chia-Chen Chiou, Hung-Yi CA FSGC TI Association between genetic variant on chromosome 12p13 and stroke survival and recurrence: a one year prospective study in Taiwan SO JOURNAL OF BIOMEDICAL SCIENCE LA English DT Article DE stroke; single nucleotide polymorphisms; survival ID ISCHEMIC-STROKE; ADHESION MOLECULE; POLYMORPHISMS; METAANALYSIS; POPULATION; NERVE AB Background: The association between ischemic stroke and 2 single nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579 appears inconsistent across different samples. These SNPs are close to the ninjurin2 gene which may alter the risk of stroke by affecting brain response to ischemic injury. The purpose of this study was to investigate the association between these two SNPs and ischemic stroke risk, as well as prognostic outcomes in a Taiwanese sample. Methods: We examined the relations of these two SNPs to the odds of new-onset ischemic stroke, ischemic stroke subtypes, and to the one year risk of stroke-related death or recurrent stroke following initial stroke in a case-control study. A total of 765 consecutive patients who had first-ever ischemic stroke were compared to 977 stroke-free, age-matched controls. SNPs were genotyped by Taqman fluorescent allelic discrimination assay. The association between ischemic stroke and SNPs were analyzed by multivariate logistic regression. Cox proportional hazard model was used to assess the effect of individual SNPs on stroke-related mortality or recurrent stroke. Results: There was no significant association between SNP rs12425791 and rs11833579 and ischemic stroke after multiple testing corrections. However, the marginal significant association was observed between SNP rs12425791 and large artery atherosclerosis under recessive model (OR, 2.30; 95% CI, 1.22-4.34; q-value = 0.062). Among the 765 ischemic stroke patients, 59 died or developed a recurrent stroke. After adjustment for age, sex, vascular risk factors and baseline stroke severity, Cox proportional hazard analysis indicated that the hazard ratios were 2.76 (95% CI, 1.34-5.68; q-value, 0.02) and 2.15 (95% CI, 1.15-4.02; q-value, 0.03) for individuals with homozygous variant allele of rs12425791 and rs11833579, respectively. Conclusions: This is a precedent study that found genetic variants of rs12425791 and rs11833579 on chromosome 12p13 are independent predictors of stroke-related mortality or stroke recurrence in patients with incident ischemic stroke in Taiwan. Further study is needed to explore the details of the physiological function and the molecular mechanisms underlying the association of this genetic locus with ischemic stroke. C1 [Hsieh, Yi-Chen; Hsieh, Fang-I; Bai, Chyi-Huey; Yu, Chia-Chen; Chiou, Hung-Yi] Taipei Med Univ, Sch Publ Hlth, Taipei, Taiwan. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Framingham Heart Study, Boston, MA 02118 USA. [Seshadri, Sudha] NHLBI, Framingham Heart Study, Framingham, MA USA. [Chung, Wen-Ting; Chen, Chin-I] Taipei Med Univ, Wanfang Hosp, Dept Neurol, Taipei, Taiwan. [Chung, Wen-Ting] Taipei Med Univ, Grad Inst Clin Med, Taipei, Taiwan. [Hsieh, Fang-I; Chiou, Hung-Yi] Taipei Med Univ, Dr Chi Hsing Huang Stroke Res Ctr, Taipei, Taiwan. [Hsu, Yi-Hsiang] Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA. [Hsu, Yi-Hsiang] Harvard Univ, Sch Med, Boston, MA 02131 USA. [Hsu, Yi-Hsiang] Harvard Univ, Sch Publ Hlth, Mol & Integrat Physiol Sci Program, Boston, MA 02131 USA. [Lin, Huey-Juan] Chi Mei Med Ctr, Dept Neurol, Tainan, Taiwan. [Tseng, Hung-Pin] Lotung Poh Ai Hosp, Dept Neurol, Ilan, Taiwan. [Lien, Li-Ming] Shin Kong Wu Ho Su Mem Hosp, Dept Neurol, Taipei, Taiwan. [Bai, Chyi-Huey] Shin Kong Wu Ho Su Mem Hosp, Cent Lab, Taipei, Taiwan. [Hu, Chaur-Jong] Taipei Med Univ Hosp, Dept Neurol, Taipei, Taiwan. [Hu, Chaur-Jong] Shuang Ho Hosp, Taipei, Taiwan. [Jeng, Jiann-Shing; Tang, Sung-Chun] Natl Taiwan Univ Hosp, Stroke Ctr, Taipei, Taiwan. [Jeng, Jiann-Shing; Tang, Sung-Chun] Natl Taiwan Univ Hosp, Dept Neurol, Taipei, Taiwan. RP Chiou, HY (reprint author), Taipei Med Univ, Sch Publ Hlth, Taipei, Taiwan. EM hychiou@tmu.edu.tw OI Seshadri, Sudha/0000-0001-6135-2622; Jeng, Jiann-Shing/0000-0002-1456-3686; Tang, Sung-Chun/0000-0003-3731-5973 FU National Science Council of Taiwan [NSC97-2321-B-038-002, NSC98-2321-B-038-001, NSC99-2321-B-038-001, NSC99-2314-B-038-022-MY3]; Ministry of Education Topnotch Stroke Research Center; Department of Health Center of Excellence for Clinical Trial and Research in Neuroscience [DOH99-TD-B-111-003, DOH100-TD-B-111-003, DOH101-TD-B-111-003] FX This work was supported by grants from the National Science Council of Taiwan (NSC97-2321-B-038-002, NSC98-2321-B-038-001 and NSC99-2321-B-038-001 and NSC99-2314-B-038-022-MY3). Additional supports were received from a Ministry of Education Topnotch Stroke Research Center grant and the Department of Health Center of Excellence for Clinical Trial and Research in Neuroscience (DOH99-TD-B-111-003, DOH100-TD-B-111-003, DOH101-TD-B-111-003), Dr. Chi-Chin Huang Stroke Research Center, and Taipei Medical University-Wan Fang Hospital (95TMU-WFH-07). NR 17 TC 14 Z9 16 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1021-7770 J9 J BIOMED SCI JI J. Biomed. Sci. PD JAN 3 PY 2012 VL 19 AR 1 DI 10.1186/1423-0127-19-1 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 892XX UT WOS:000300320000001 PM 22212150 ER PT J AU Galon, J Pages, F Marincola, FM Thurin, M Trinchieri, G Fox, BA Gajewski, TF Ascierto, PA AF Galon, Jerome Pages, Franck Marincola, Francesco M. Thurin, Magdalena Trinchieri, Giorgio Fox, Bernard A. Gajewski, Thomas F. Ascierto, Paolo A. TI The Immune Score as a New Possible Approach for the Classification of Cancer SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material ID COLORECTAL-CANCER; IMMUNOTHERAPY BIOMARKERS; RECOMMENDATIONS; DISCOVERY; WORKSHOP; MARKERS; MEMORY; TUMORS; CELLS AB The outcome prediction in cancer is usually achieved by evaluating tissue samples obtained during surgical removal of the primary tumor focusing on their histopathological characteristics. Tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N), and evidence for metastases (M). However, this classification provides limited prognostic information in estimating the outcome in cancer and does not predict response to therapy. It is recognized that cancer outcomes can vary significantly among patients within the same stage. Recently, many reports suggest that cancer development is controlled by the host's immune system underlying the importance of including immunological biomarkers for the prediction of prognosis and response to therapy. Data collected from large cohorts of human cancers demonstrated that the immune-classification has a prognostic value that may be superior to the AJCC/UICC TNM-classification. Thus, it is imperative to begin incorporating immune scoring as a prognostic factor and to introduce this parameter as a marker to classify cancers, as part of the routine diagnostic and prognostic assessment of tumors. At the same time, the inherent complexity of quantitative immunohistochemistry, in conjunction with variable assay protocols across laboratories, the different immune cell types analyzed, different region selection criteria, and variable ways to quantify immune infiltration underscore the urgent need to reach assay harmonization. In an effort to promote the immunoscore in routine clinical settings worldwide, the Society for Immunotherapy of Cancer (SITC), the European Academy of Tumor Immunology, the Cancer and Inflammation Program, the National Cancer Institute, National Institutes of Health, USA and "La Fondazione Melanoma" will jointly initiate a task force on Immunoscoring as a New Possible Approach for the Classification of Cancer that will take place in Naples, Italy, February 13th, 2012. The expected outcome will include a concept manuscript that will be distributed to all interested participants for their contribution before publication outlining the goal and strategy to achieve this effort; a preliminary summary to be presented during the "Workshop on Tumor Microenvironment" prior to the SITC annual meeting on October 24th - 25th 2012 in Bethesda, Maryland, USA and finally a " Workshop on Immune Scoring" to be held in Naples in December of 2012 leading to the preparation of a summary document providing recommendations for the harmonization and implementation of the Immune Score as a new component for the classification of cancer. C1 [Galon, Jerome; Pages, Franck] INSERM, U872, Lab Integrat Canc Immunol, F-75006 Paris, France. [Galon, Jerome; Pages, Franck] Univ Paris 05, F-75006 Paris, France. [Galon, Jerome; Pages, Franck] Univ Paris 06, Ctr Rech Cordeliers, F-75006 Paris, France. [Galon, Jerome; Pages, Franck] Assistance Publ Hop Paris, HEGP, F-75015 Paris, France. [Galon, Jerome; Marincola, Francesco M.; Fox, Bernard A.; Gajewski, Thomas F.] Soc ImmunoTherapy Canc, Milwaukee, WI 53202 USA. [Marincola, Francesco M.] NIH, IDIS, Ctr Clin, Bethesda, MD 20892 USA. [Marincola, Francesco M.] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. [Thurin, Magdalena] NCI, Canc Diag Program, NIH, Rockville, MD 20852 USA. [Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Expt Immunol Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Fox, Bernard A.] Providence Portland Med Ctr, Lab Mol & Tumor Immunol, Earle A Chiles Res Inst, Robert W Franz Canc Ctr, Portland, OR 97213 USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. [Gajewski, Thomas F.] Univ Chicago, Dept Pathol, Chicago, IL USA. [Gajewski, Thomas F.] Univ Chicago, Dept Med, Sect Hematol Oncol, Chicago, IL USA. [Ascierto, Paolo A.] Fdn G Pascale, Med Oncol & Innovat Therapies Unit, Ist Nazl Studio & Cura Tumori, I-80131 Naples, Italy. [Ascierto, Paolo A.] Fdn Melanoma Onlus, I-80131 Naples, Italy. RP Galon, J (reprint author), INSERM, U872, Lab Integrat Canc Immunol, 15 Rue Ecole Med, F-75006 Paris, France. EM jerome.galon@crc.jussieu.fr NR 22 TC 132 Z9 135 U1 5 U2 27 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JAN 3 PY 2012 VL 10 AR 1 DI 10.1186/1479-5876-10-1 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 893HN UT WOS:000300347000001 PM 22214470 ER PT J AU Pili, R Salumbides, B Zhao, M Altiok, S Qian, D Zwiebel, J Carducci, MA Rudek, MA AF Pili, R. Salumbides, B. Zhao, M. Altiok, S. Qian, D. Zwiebel, J. Carducci, M. A. Rudek, M. A. TI Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours SO BRITISH JOURNAL OF CANCER LA English DT Article DE histone deacetylase inhibitor; retinoic acid receptor; solid tumours ID RENAL-CELL-CARCINOMA; ACUTE PROMYELOCYTIC LEUKEMIA; RECEPTOR BETA-2; BREAST-CANCER; TRIAL; MS-275; GENE; PHARMACOKINETICS; BIOAVAILABILITY; PHENYLBUTYRATE AB BACKGROUND: Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumour sensitivity to retinoids. The objective of this study was to determine the safety, tolerability, and the pharmacokinetic (PK)/ pharmacodynamic (PD) profiles of the HDAC inhibitor entinostat in combination with 13-cis retinoic acid (CRA) in patients with solid tumours. METHODS: Patients with advanced solid tumours were treated with entinostat orally once weekly and with CRA orally twice daily x 3 weeks every 4 weeks. The starting dose for entinostat was 4 mgm(-2) with a fixed dose of CRA at 1 mg kg(-1) per day. Entinostat dose was escalated by 1mgm(-2) increments. Pharmacokinetic concentrations of entinostat and CRA were determined by LC/MS/MS. Western blot analysis of peripheral blood mononuclear cells and tumour samples were performed to evaluate target inhibition. RESULTS: A total of 19 patients were enroled. The maximum tolerated dose (MTD) was exceeded at the entinostat 5 mgm(-2) dose level (G3 hyponatremia, neutropenia, and anaemia). Fatigue (G1 or G2) was a common side effect. Entinostat exhibited substantial variability in clearance (147%) and exposure. CRA trough concentrations were consistent with prior reports. No objective responses were observed, however, prolonged stable disease occurred in patients with prostate, pancreatic, and kidney cancer. Data further showed increased tumour histone acetylation and decreased phosphorylated ERK protein expression. CONCLUSION: The combination of entinostat with CRA was reasonably well tolerated. The recommended phase II doses are entinostat 4 mgm(-2) once weekly and CRA 1mg kg(-1) per day. Although no tumour responses were seen, further evaluation of this combination is warranted. British Journal of Cancer (2012) 106, 77-84. doi: 10.1038/bjc.2011.527 www.bjcancer.com Published online 1 December 2011 (C) 2012 Cancer Research UK C1 [Pili, R.; Salumbides, B.; Zhao, M.; Altiok, S.; Qian, D.; Carducci, M. A.; Rudek, M. A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21231 USA. [Zwiebel, J.] NCI CTEP, Bethesda, MD USA. RP Pili, R (reprint author), Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, 1650 Orleans St,CRB1 Room 1M52, Baltimore, MD 21231 USA. EM Roberto.Pili@RoswellPark.org; mrudek2@jhmi.edu FU NCI-CTEP; The Maryland Cigarette Restitution Research Fund; The Flight Attendant Medical Research Institute; The Translational Research Initiative CTEP-NCI; The Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins [P30 CA006973, U01 CA 70095] FX We thank NCI-CTEP for supporting the study and Schering AG for purchasing Accutane. We also thank Dr Sharyn Baker for his scientific input, Ping He for her technical support, and Susan Davidson for her quality assurance of the data. This work was supported in part by The Maryland Cigarette Restitution Research Fund, The Flight Attendant Medical Research Institute, The Translational Research Initiative CTEP-NCI (RP), The Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins (P30 CA006973), and U01 CA 70095 (MAC). NR 35 TC 56 Z9 60 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 3 PY 2012 VL 106 IS 1 BP 77 EP 84 DI 10.1038/bjc.2011.527 PG 8 WC Oncology SC Oncology GA 877HL UT WOS:000299168300012 PM 22134508 ER PT J AU Chang, J Varghese, DS Gillam, MC Peyton, M Modi, B Schiltz, RL Girard, L Martinez, ED AF Chang, J. Varghese, D. S. Gillam, M. C. Peyton, M. Modi, B. Schiltz, R. L. Girard, L. Martinez, E. D. TI Differential response of cancer cells to HDAC inhibitors trichostatin A and depsipeptide SO BRITISH JOURNAL OF CANCER LA English DT Article DE trichostatin A; depsipeptide; HDAC inhibitors; cancer cell viability; drug sensitivity ID HISTONE DEACETYLASE INHIBITORS; BRONCHIAL EPITHELIAL-CELLS; REFRACTORY SOLID TUMORS; LUNG-CANCER; ANTITUMOR-ACTIVITY; BREAST-CANCER; PHASE-I; EPIGENETIC THERAPY; UVEAL MELANOMA; ACETYLATION AB BACKGROUND: Over the last decade, several drugs that inhibit class I and/or class II histone deacetylases (HDACs) have been identified, including trichostatin A, the cyclic depsipeptide FR901228 and the antibiotic apicidin. These compounds have had immediate application in cancer research because of their ability to reactivate aberrantly silenced tumour suppressor genes and/or block tumour cell growth. Although a number of HDAC inhibitors are being evaluated in preclinical cancer models and in clinical trials, little is known about the differences in their specific mechanism of action and about the unique determinants of cancer cell sensitivity to each of these inhibitors. METHODS: Using a combination of cell viability assays, HDAC enzyme activity measurements, western blots for histone modifications, microarray gene expression analysis and qRT-PCR, we have characterised differences in trichostatin A vs depsipeptide-induced phenotypes in lung cancer, breast cancer and skin cancer cells and in normal cells and have then expanded these studies to other HDAC inhibitors. RESULTS: Cell viability profiles across panels of lung cancer, breast cancer and melanoma cell lines showed distinct sensitivities to the pan-inhibitor TSA compared with the class 1 selective inhibitor depsipeptide. In several instances, the cell lines most sensitive to one inhibitor were most resistant to the other inhibitor, demonstrating these drugs act on at least some non-overlapping cellular targets. These differences were not explained by the HDAC selectivity of these inhibitors alone since apicidin, which is a class 1 selective compound similar to depsipeptide, also showed a unique drug sensitivity profile of its own. TSA had greater specificity for cancer vs normal cells compared with other HDAC inhibitors. In addition, at concentrations that blocked cancer cell viability, TSA effectively inhibited purified recombinant HDACs 1, 2 and 5 and moderately inhibited HDAC8, while depsipeptide did not inhibit the activity of purified HDACs in vitro but did in cellular extracts, suggesting a potentially indirect action of this drug. Although both depsipeptide and TSA increased levels of histone acetylation in cancer cells, only depsipeptide decreased global levels of transcriptionally repressive histone methylation marks. Analysis of gene expression profiles of an isogenic cell line pair that showed discrepant sensitivity to depsipeptide, suggested that resistance to this inhibitor may be mediated by increased expression of multidrug resistance genes triggered by exposure to chemotherapy as was confirmed by verapamil studies. CONCLUSION: Although generally thought to have similar activities, the HDAC modulators trichostatin A and depsipeptide demonstrated distinct phenotypes in the inhibition of cancer cell viability and of HDAC activity, in their selectivity for cancer vs normal cells, and in their effects on histone modifications. These differences in mode of action may bear on the future therapeutic and research application of these inhibitors. British Journal of Cancer (2012) 106, 116-125. doi:10.1038/bjc.2011.532 www.bjcancer.com Published online 8 December 2011 (C) 2012 Cancer Research UK C1 [Chang, J.; Varghese, D. S.; Gillam, M. C.; Peyton, M.; Modi, B.; Girard, L.; Martinez, E. D.] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. [Schiltz, R. L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Girard, L.; Martinez, E. D.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. RP Martinez, ED (reprint author), Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, 6000 Harry Hines Blvd, Dallas, TX 75390 USA. EM elisabeth.martinez@utsouthwestern.edu FU NCI [K22CA11871703, R01CA12526901]; Galderma; Doctors Cancer Foundation FX We are grateful to Drs John Minna and Adi Gazdar for sharing a large collection of non- small cell lung cancer cells and bronchial epithelial cells, and to Shelley Sheridan for immortalising epithelial cells. We thank MK Hyland for technical assistance with MDR western blots. We are indebted to Dr David Schrump for the generous gift of depsipeptide. Human breast cancer cells and immortalised mammary epithelial cells were the kind gift of Drs Cheryl Lewis and David Euhus. Melanoma cell lines were received from the NCI and uveal melanoma lines were generously provided by Jerry Niederkorn. This study was supported by the NCI (K22CA11871703 and R01CA12526901 to EDM), by Galderma (grant to EDM) and by the Doctors Cancer Foundation (Nolan Miller Lung Cancer grant to EDM). NR 52 TC 45 Z9 47 U1 1 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 3 PY 2012 VL 106 IS 1 BP 116 EP 125 DI 10.1038/bjc.2011.532 PG 10 WC Oncology SC Oncology GA 877HL UT WOS:000299168300017 PM 22158273 ER PT J AU Chang, CM Yu, KJ Hsu, WL Major, JM Chen, JY Lou, PJ Liu, MY Diehl, SR Goldstein, AM Chen, CJ Hildesheim, A AF Chang, C. M. Yu, K. J. Hsu, W. L. Major, J. M. Chen, J. Y. Lou, P. J. Liu, M. Y. Diehl, S. R. Goldstein, A. M. Chen, C. J. Hildesheim, A. TI Correlates of anti-EBV EBNA1 IgA positivity among unaffected relatives from nasopharyngeal carcinoma multiplex families SO BRITISH JOURNAL OF CANCER LA English DT Article DE Epstein-Barr virus; EBNA1; VCA; IgA; DNase; nasopharyngeal carcinoma ID ARECA NUT EXTRACT; FOLLOW-UP; RISK; TAIWAN; INDIVIDUALS; CANCER; CHINA; CELLS AB BACKGROUND: To determine whether non-viral nasopharyngeal carcinoma (NPC) risk factors might be associated with (and mediated through) Epstein-Barr virus (EBV) serological responses linked to NPC risk, we evaluated predictors of risk of anti-EBNA1 IgA seropositivity and other markers among unaffected relatives from a large NPC family study in Taiwan. METHODS: Multivariate logistic regression conditioned on family was used to examine the associations between sociodemographic, dietary, lifestyle, and occupational variables and risk of anti-EBV EBNA1 IgA positivity, anti-VCA IgA, and anti-DNase positivity. RESULTS: Among 2393 unaffected relatives from 319 multiplex families, 1180 (49.3%) were anti-EBV EBNA1 IgA seropositive. None of the associations with anti-EBNA1 IgA were statistically significant, except for being 31-50 years of age (vs <30, adjusted ORs 0.51-0.57). For one or more EBV serological markers, there were suggestive associations for older age, GuangDong firm salted fish, betel use, current alcohol use, and male gender. CONCLUSION: Overall, we found little evidence to suggest that non-viral NPC risk factors significantly alter EBV serological patterns, suggesting that non-viral NPC risk factors act through pathways independent of EBV serological responses. British Journal of Cancer (2012) 106, 206-209. doi:10.1038/bjc.2011.502 www.bjcancer.com Published online 17 November 2011 & 2012 Cancer Research UK C1 [Chang, C. M.; Yu, K. J.; Major, J. M.; Goldstein, A. M.; Hildesheim, A.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. [Hsu, W. L.; Chen, C. J.] Natl Taiwan Univ, Coll Publ Hlth, Grad Inst Epidemiol, Taipei 10764, Taiwan. [Hsu, W. L.; Chen, C. J.] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan. [Chen, J. Y.] Natl Hlth Res Inst, Natl Inst Canc Res, Zhunan Town 350, Miaoli County, Taiwan. [Lou, P. J.] Natl Taiwan Univ Hosp, Dept Otolaryngol, Taipei, Taiwan. [Lou, P. J.] Natl Taiwan Univ, Coll Med, Taipei, Taiwan. [Liu, M. Y.] Natl Taipei Univ Nursing & Hlth Sci, Ctr Gen Educ, Taipei, Taiwan. [Diehl, S. R.] Univ Med & Dent New Jersey, New Jersey Dent Sch, Ctr Pharmacogen & Complex Dis Res, Newark, NJ 07103 USA. RP Chang, CM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, 6120 Execut Blvd,EPS 7073, Rockville, MD USA. EM changcm@mail.nih.gov RI Chen, Chien-Jen/C-6976-2008; Chen, Jen-Yang/D-2085-2010; Hildesheim, Allan/B-9760-2015; OI Hildesheim, Allan/0000-0003-0257-2363; LOU, PEI-JEN/0000-0002-3383-8593 FU National Cancer Institute, National Institutes of Health FX We thank the NPC Study team and study participants for making this study possible. We also thank Ruth Pfeiffer and Fatma Shebl for help with the analysis. This study was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 18 TC 1 Z9 1 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 3 PY 2012 VL 106 IS 1 BP 206 EP 209 DI 10.1038/bjc.2011.502 PG 4 WC Oncology SC Oncology GA 877HL UT WOS:000299168300028 PM 22095229 ER PT J AU Murphy, TP Cutlip, DE Regensteiner, JG Mohler, ER Cohen, DJ Reynolds, MR Massaro, JM Lewis, BA Cerezo, J Oldenburg, NC Thum, CC Goldberg, S Jaff, MR Steffes, MW Comerota, AJ Ehrman, J Treat-Jacobson, D Walsh, ME Collins, T Badenhop, DT Bronas, U Hirsch, AT AF Murphy, Timothy P. Cutlip, Donald E. Regensteiner, Judith G. Mohler, Emile R. Cohen, David J. Reynolds, Matthew R. Massaro, Joseph M. Lewis, Beth A. Cerezo, Joselyn Oldenburg, Niki C. Thum, Claudia C. Goldberg, Suzanne Jaff, Michael R. Steffes, Michael W. Comerota, Anthony J. Ehrman, Jonathan Treat-Jacobson, Diane Walsh, M. Eileen Collins, Tracie Badenhop, Dalynn T. Bronas, Ulf Hirsch, Alan T. CA CLEVER Study Investigators TI Supervised Exercise Versus Primary Stenting for Claudication Resulting From Aortoiliac Peripheral Artery Disease Six-Month Outcomes From the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) Study SO CIRCULATION LA English DT Article DE claudication; comparative effectiveness research; peripheral artery disease; vascular diseases ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; INTERMITTENT CLAUDICATION; ENDOVASCULAR REVASCULARIZATION; FUNCTIONAL STATUS; LOWER-EXTREMITY; LONG; ANGIOPLASTY; PERFORMANCE; PLACEMENT AB Background-Claudication is a common and disabling symptom of peripheral artery disease that can be treated with medication, supervised exercise (SE), or stent revascularization (ST). Methods and Results-We randomly assigned 111 patients with aortoiliac peripheral artery disease to receive 1 of 3 treatments: optimal medical care (OMC), OMC plus SE, or OMC plus ST. The primary end point was the change in peak walking time on a graded treadmill test at 6 months compared with baseline. Secondary end points included free-living step activity, quality of life with the Walking Impairment Questionnaire, Peripheral Artery Questionnaire, Medical Outcomes Study 12-Item Short Form, and cardiovascular risk factors. At the 6-month follow-up, change in peak walking time (the primary end point) was greatest for SE, intermediate for ST, and least with OMC (mean change versus baseline, 5.8 +/- 4.6, 3.7 +/- 4.9, and 1.2 +/- 2.6 minutes, respectively; P < 0.001 for the comparison of SE versus OMC, P = 0.02 for ST versus OMC, and P = 0.04 for SE versus ST). Although disease-specific quality of life as assessed by the Walking Impairment Questionnaire and Peripheral Artery Questionnaire also improved with both SE and ST compared with OMC, for most scales, the extent of improvement was greater with ST than SE. Free-living step activity increased more with ST than with either SE or OMC alone (114 +/- 274 versus 73 +/- 139 versus -6 +/- 109 steps per hour), but these differences were not statistically significant. Conclusions-SE results in superior treadmill walking performance than ST, even for those with aortoiliac peripheral artery disease. The contrast between better walking performance for SE and better patient-reported quality of life for ST warrants further study. C1 [Murphy, Timothy P.] Rhode Isl Hosp, Vasc Dis Res Ctr, Providence, RI 02903 USA. [Cutlip, Donald E.; Reynolds, Matthew R.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Cutlip, Donald E.; Reynolds, Matthew R.; Thum, Claudia C.] Harvard Clin Res Inst, Boston, MA USA. [Regensteiner, Judith G.] Univ Colorado, Sch Med, Aurora, CO USA. [Mohler, Emile R.] Univ Penn, Philadelphia, PA 19104 USA. [Cohen, David J.] Univ Missouri, Kansas City, KS USA. [Massaro, Joseph M.] Boston Univ, Boston, MA 02215 USA. [Lewis, Beth A.] Univ Minnesota, Sch Kinesiol, Minneapolis, MN USA. [Oldenburg, Niki C.; Steffes, Michael W.; Collins, Tracie; Hirsch, Alan T.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Goldberg, Suzanne] NHLBI, Bethesda, MD 20892 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Comerota, Anthony J.] Jobst Vasc Ctr, Toledo, OH USA. Henry Ford Hosp, Detroit, MI 48202 USA. [Treat-Jacobson, Diane; Bronas, Ulf] Univ Minnesota, Sch Nursing, Minneapolis, MN 55455 USA. [Walsh, M. Eileen] Univ Toledo, Coll Nursing, Toledo, OH 43606 USA. RP Murphy, TP (reprint author), Rhode Isl Hosp, Vasc Dis Res Ctr, Gerry 337,593 Eddy St, Providence, RI 02903 USA. EM tmurphy@lifespan.org OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute [HL77221, HL081656]; Cordis/Johnson & Johnson (Warren, NJ); eV3 (Plymouth, MN); Boston Scientific (Natick, MA); Abbott Vascular; Cordis/Johnson Johnson; Otsuka Pharmaceuticals; Microvention/Terumo, Inc.; Medtronic; Boston Scientific; Medrad; Medtronic, Inc.; Aastrom; Baxter; BMS; Boehringer Ingelheim; BSN; Colorado Prevention Center; CVRx; Daiichi Sankyo; EV3; Johnson Johnson; Lombard Medical; National Institutes of Health; Pfizer; Sanofi/Aventis; Schering Plough; Talecris; National Heart, Lung, and Blood Institute; Cytokinetics; Viromed; Merck; Pozen; Novartis; AstraZeneca FX The CLEVER study was sponsored mostly by the National Heart, Lung, and Blood Institute (grants HL77221 and HL081656) and received financial support from Cordis/Johnson & Johnson (Warren, NJ), eV3 (Plymouth, MN), and Boston Scientific (Natick, MA). Otsuka America, Inc, (San Francisco, CA) donated cilostazol for all study participants throughout the study. Omron Healthcare Inc, Lake Forest, IL, donated pedometers. Krames Staywell, San Bruno, CA, donated print materials for study participants on exercise and diet.; Dr Murphy has received research grant support from Abbott Vascular, Cordis/Johnson & Johnson, and Otsuka Pharmaceuticals and consultant fees from Microvention/Terumo, Inc. Dr Cohen has received research grant support from Medtronic, Boston Scientific, Abbott Vascular, and Medrad and consultant fees from Medtronic, Inc. Dr Reynolds has received consultant fees from Medtronic, Inc. Dr Jaff has equity in Micell, Inc and PQ Bypass; has board membership at VIVA Physicians, Inc; and is a consultant for Becker Venture Services Group, Abbott Vascular, Cordis Corp, Covidien/eV3, and Medtronic Vascular. Dr Comerota serves on the advisory committee for BMS Aastrom, Covidien, AngioDynamics, Otsuka, Convatec, Sanofi/Aventis, Cook, Inc, Servier, ZymoGenetics, and Vessix Vascular (formerly Minnow Medical); has been a consultant to Aastrom, AngioDynamics, Convatec, Cook, Covidien, BMS, Sanofi/Aventis, and Talecris; and has received grant/research support from Aastrom, Abbott Vascular, Baxter, BMS, Boehringer Ingelheim, BSN, Colorado Prevention Center, CVRx, Daiichi Sankyo, EV3, Johnson & Johnson, Lombard Medical, Medtronic, National Institutes of Health, Pfizer, Sanofi/Aventis, Schering Plough, and Talecris. Dr Treat-Jacobson has received research grant support from the National Heart, Lung, and Blood Institute/Exercise Training for Claudication: Arm Ergometry Versus Treadmill Walking Study. Dr Collins has been a Data Safety Monitoring Board member for Viromed BioPharma/Synteract. Dr Hirsch has received research grant support from Cytokinetics, Viromed, and Abbott Vascular and consultant fees from Merck, Pozen, Novartis, and AstraZeneca. The other authors report no conflicts. NR 34 TC 143 Z9 146 U1 4 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 3 PY 2012 VL 125 IS 1 BP 130 EP 139 DI 10.1161/CIRCULATIONAHA.111.075770 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 877HT UT WOS:000299169100026 PM 22090168 ER PT J AU Palmore, TN Henderson, DK AF Palmore, Tara N. Henderson, David K. TI Fortune Favors a Prepared Health Care System SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Henderson, David K.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Henderson, DK (reprint author), NIH, Ctr Clin, Bldg 10,Room 6-1480,10 Ctr Dr, Bethesda, MD 20892 USA. EM dkh@nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 3 PY 2012 VL 156 IS 1 BP 54 EP U101 DI 10.7326/0003-4819-156-1-201201030-00011 PN 1 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 872VK UT WOS:000298837600009 PM 22213496 ER PT J AU Ross, JS Tse, T Zarin, DA Xu, H Zhou, L Krumholz, HM AF Ross, Joseph S. Tse, Tony Zarin, Deborah A. Xu, Hui Zhou, Lei Krumholz, Harlan M. TI Publication of NIH funded trials registered in ClinicalTrials.gov: cross sectional analysis SO BRITISH MEDICAL JOURNAL LA English DT Article ID OUTCOME REPORTING BIAS; RANDOMIZED-TRIALS; EMPIRICAL-EVIDENCE; CLINICAL-RESEARCH; REGISTRATION; COMMITTEE; PROTOCOLS; EFFICACY; COHORT AB Objective To review patterns of publication of clinical trials funded by US National Institutes of Health (NIH) in peer reviewed biomedical journals indexed by Medline. Design Cross sectional analysis. Setting Clinical trials funded by NIH and registered within ClinicalTrials.gov (clinicaltrials.gov), a trial registry and results database maintained by the US National Library of Medicine, after 30 September 2005 and updated as having been completed by 31 December 2008, allowing at least 30 months for publication after completion of the trial. Main outcome measures Publication and time to publication in the biomedical literature, as determined through Medline searches, the last of which was performed in June 2011. Results Among 635 clinical trials completed by 31 December 2008, 294 (46%) were published in a peer reviewed biomedical journal, indexed by Medline, within 30 months of trial completion. The median period of follow-up after trial completion was 51 months (25th-75th centiles 40-68 months), and 432 (68%) were published overall. Among published trials, the median time to publication was 23 months (14-36 months). Trials completed in either 2007 or 2008 were more likely to be published within 30 months of study completion compared with trials completed before 2007 (54% (196/366) v 36% (98/269); P<0.001). Conclusions Despite recent improvement in timely publication, fewer than half of trials funded by NIH are published in a peer reviewed biomedical journal indexed by Medline within 30 months of trial completion. Moreover, after a median of 51 months after trial completion, a third of trials remained unpublished. C1 [Ross, Joseph S.] Yale Univ, Sch Med, Gen Internal Med Sect, Dept Med, New Haven, CT 06520 USA. [Ross, Joseph S.; Krumholz, Harlan M.] Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, New Haven, CT 06504 USA. [Tse, Tony; Zarin, Deborah A.] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bethesda, MD 20892 USA. [Xu, Hui; Zhou, Lei] Chinese Acad Med Sci, Fuwai Hosp, Beijing 100730, Peoples R China. [Xu, Hui; Zhou, Lei] Chinese Acad Med Sci, Cardiovasc Inst, Beijing 100730, Peoples R China. [Xu, Hui; Zhou, Lei] Peking Union Med Coll, Beijing 100021, Peoples R China. [Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Med, Robert Wood Johnson Clin Scholars Program, New Haven, CT USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Med, Sect Cardiovasc Med, New Haven, CT USA. [Krumholz, Harlan M.] Yale Univ, Sch Epidemiol & Publ Hlth, Sect Hlth Policy & Adm, New Haven, CT USA. RP Ross, JS (reprint author), Yale Univ, Sch Med, Gen Internal Med Sect, Dept Med, POB 208093, New Haven, CT 06520 USA. EM joseph.ross@yale.edu RI Zhou, Lei/E-6314-2012 FU US National Library of Medicine, National Institutes of Health, Department of Health and Human Services [HHSN276201000788P]; Medtronic; Centers of Medicare and Medicaid Services (CMS); National Institute on Aging [K08 AG032886]; American Federation for Aging Research; National Institutes of Health, National Library of Medicine; National Heart, Lung, and Blood Institute Cardiovascular Outcomes Center [1U01HL105270-02] FX The analyses on which this publication is based were performed under Contract No. HHSN276201000788P, entitled "Evaluating Time-to-Publication Following Completion of Clinical Trials and Related Factors," funded by the US National Library of Medicine, National Institutes of Health, Department of Health and Human Services. The ideas and opinions expressed are those of the authors. The content of this publication does not necessarily reflect the views or policies of the US National Institutes of Health, Public Health Service, or Department of Health and Human Services. The authors assume full responsibility for the accuracy and completeness of the ideas presented. JSR and HMK receive support from Medtronic and from the Centers of Medicare and Medicaid Services (CMS) to develop and maintain performance measures that are used for public reporting. JSR is supported by the National Institute on Aging (K08 AG032886) and by the American Federation for Aging Research through the Paul B Beeson Career Development Award Program. DAZ and TT are supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. HMK is supported by a National Heart, Lung, and Blood Institute Cardiovascular Outcomes Center Award (1U01HL105270-02). NR 32 TC 120 Z9 120 U1 0 U2 20 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JAN 3 PY 2012 VL 344 AR d7292 DI 10.1136/bmj.d7292 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 874UE UT WOS:000298982800005 PM 22214755 ER PT J AU Batra, VK Shock, DD Beard, WA McKenna, CE Wilson, SH AF Batra, Vinod K. Shock, David D. Beard, William A. McKenna, Charles E. Wilson, Samuel H. TI Binary complex crystal structure of DNA polymerase beta reveals multiple conformations of the templating 8-oxoguanine lesion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE oxidative DNA lesion; X-ray crystallography ID STEADY-STATE KINETICS; HIGH-FIDELITY; TRIPHOSPHATE INCORPORATION; ACTIVE-SITE; 8-HYDROXYGUANINE; DAMAGE; REPAIR; MYH; MECHANISM; OPPOSITE AB Oxidation of genomic DNA forms the guanine lesion 7,8-dihydro-8-oxoguanine (8-oxoG). When in the template base position during DNA synthesis the 8-oxoG lesion has dual coding potential by virtue of its anti-and syn-conformations, base pairing with cytosine and adenine, respectively. This impacts mutagenesis, because insertion of adenine opposite template 8-oxoG can result in a G to T transversion. DNA polymerases vary by orders of magnitude in their preferences for mutagenic vs. error-free 8-oxoG lesion bypass. Yet, the structural basis for lesion bypass specificity is not well understood. The DNA base excision repair enzyme DNA polymerase (pol) beta is presented with gap-filling synthesis opposite 8-oxoG during repair and has similar insertion efficiencies for dCTP and dATP. We report the structure of pol beta in binary complex with template 8-oxoG in a base excision repair substrate. The structure reveals both the syn- and anti-conformations of template 8-oxoG in the confines of the polymerase active site, consistent with the dual coding observed kinetically for this enzyme. A ternary complex structure of pol beta with the syn-8-oxoG:anti-A Hoogsteen base pair in the closed fully assembled preinsertion active site is also reported. The syn-conformation of 8-oxoG is stabilized by minor groove hydrogen bonding between the side chain of Arg283 and O8 of 8-oxoG. An adjustment in the position of the phosphodiester backbone 5'-phosphate enables 8-oxoG to adopt the syn-conformation. C1 [Batra, Vinod K.; Shock, David D.; Beard, William A.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [McKenna, Charles E.] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU National Institutes of Health (NIH), National Institute of Environmental Health Sciences [Z01-ES050158]; NIH [1U19CA105010] FX We thank Thomas Upton for synthesis of dCMP(CF2)PP, Lars Pedersen and Bret Freudenthal for comments on the manuscript, and Bonnie Mesmer for editorial assistance. We thank Rajen Prasad and Esther Hou for purifying the enzyme. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (Z01-ES050158) and in association with NIH Grant 1U19CA105010. NR 44 TC 29 Z9 29 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 3 PY 2012 VL 109 IS 1 BP 113 EP 118 DI 10.1073/pnas.1112235108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 873IV UT WOS:000298876500028 PM 22178760 ER PT J AU Galperin, MY Koonin, EV AF Galperin, Michael Y. Koonin, Eugene V. TI Divergence and Convergence in Enzyme Evolution SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID ALKALINE-PHOSPHATASE SUPERFAMILY; N-TERMINAL NUCLEOPHILE; COMMON STRUCTURAL ELEMENTS; ESCHERICHIA-COLI; ACTIVE-SITES; RIBONUCLEOTIDE SYNTHETASE; MOONLIGHTING PROTEINS; CYSTEINE DIOXYGENASE; ENOLASE SUPERFAMILY; ANALOGOUS ENZYMES AB Comparative analysis of the sequences of enzymes encoded in a variety of prokaryotic and eukaryotic genomes reveals convergence and divergence at several levels. Functional convergence can be inferred when structurally distinct and hence non-homologous enzymes show the ability to catalyze the same biochemical reaction. In contrast, as a result of functional diversification, many structurally similar enzyme molecules act on substantially distinct substrates and catalyze diverse biochemical reactions. Here, we present updates on the ATP-grasp, alkaline phosphatase, cupin, HD hydrolase, and N-terminal nucleophile (Ntn) hydrolase enzyme superfamilies and discuss the patterns of sequence and structural conservation and diversity within these superfamilies. Typically, enzymes within a superfamily possess common sequence motifs and key active site residues, as well as (predicted) reaction mechanisms. These observations suggest that the strained conformation (the entatic state) of the active site, which is responsible for the substrate binding and formation of the transition complex, tends to be conserved within enzyme superfamilies. The subsequent fate of the transition complex is not necessarily conserved and depends on the details of the structures of the enzyme and the substrate. This variability of reaction outcomes limits the ability of sequence analysis to predict the exact enzymatic activities of newly sequenced gene products. Nevertheless, sequence-based (super) family assignments and generic functional predictions, even if imprecise, provide valuable leads for experimental studies and remain the best approach to the functional annotation of uncharacterized proteins from new genomes. C1 [Galperin, Michael Y.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013; Zhang, Ning/F-1387-2014 OI Galperin, Michael/0000-0002-2265-5572; FU National Institutes of Healtha at the National Library of Medicine FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program at the National Library of Medicine. This is the third article in the Thematic Minireview Series on Enzyme Evolution in the Post-genomic Era. NR 85 TC 57 Z9 58 U1 3 U2 45 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 2 PY 2012 VL 287 IS 1 BP 21 EP 28 DI 10.1074/jbc.R111.241976 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 870PW UT WOS:000298682400004 PM 22069324 ER PT J AU Wildling, L Rankl, C Haselgrubler, T Gruber, HJ Holy, M Newman, AH Zou, MF Zhu, R Freissmuth, M Sitte, HH Hinterdorfer, P AF Wildling, Linda Rankl, Christian Haselgruebler, Thomas Gruber, Hermann J. Holy, Marion Newman, Amy Hauck Zou, Mu-Fa Zhu, Rong Freissmuth, Michael Sitte, Harald H. Hinterdorfer, Peter TI Probing Binding Pocket of Serotonin Transporter by Single Molecular Force Spectroscopy on Living Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEUROTRANSMITTER TRANSPORTERS; DOPAMINE TRANSPORTER; MONOAMINE TRANSPORTERS; BACTERIAL HOMOLOG; MICROSCOPE TIPS; AMPHETAMINES; LEUT; RECOGNITION; RECEPTORS; ATTACHMENT AB The serotonin transporter (SERT) terminates neurotransmission by removing serotonin from the synaptic cleft. In addition, it is the site of action of antidepressants (which block the transporter) and of amphetamines (which induce substrate efflux). The interaction energies involved in binding of such compounds to the transporter are unknown. Here, we used atomic force microscopy (AFM) to probe single molecular interactions between the serotonin transporter and MFZ2-12 (a potent cocaine analog) in living CHOK1 cells. For the AFM measurements, MFZ2-12 was immobilized on AFM tips by using a heterobifunctional cross-linker. By varying the pulling velocity in force distance cycles drug-transporter complexes were ruptured at different force loadings allowing for mapping of the interaction energy landscape. We derived chemical rate constants from these recordings and compared them with those inferred from inhibition of transport and ligand binding: k(off) values were in good agreement with those derived from uptake experiments; in contrast, the k(on) values were scaled down when determined by AFM. Our observations generated new insights into the energy landscape of the interaction between SERT and inhibitors. They thus provide a useful framework for molecular dynamics simulations by exploring the range of forces and energies that operate during the binding reaction. C1 [Wildling, Linda; Gruber, Hermann J.; Zhu, Rong; Hinterdorfer, Peter] Johannes Kepler Univ Linz, Inst Biophys, A-4040 Linz, Austria. [Rankl, Christian] Austria GmbH, Agilent Technol, A-4040 Linz, Austria. [Haselgruebler, Thomas; Hinterdorfer, Peter] Ctr Adv Bioanal, A-4020 Linz, Austria. [Holy, Marion; Freissmuth, Michael; Sitte, Harald H.] Med Univ Vienna, Ctr Physiol & Pharmacol, A-1090 Vienna, Austria. [Newman, Amy Hauck; Zou, Mu-Fa] Natl Inst Drug Abuse, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Hinterdorfer, P (reprint author), Johannes Kepler Univ Linz, Inst Biophys, Altenbergerstr 69, A-4040 Linz, Austria. EM peter.hinterdorfer@jku.at RI Sitte, Harald/N-2681-2013; Hinterdorfer, Peter/C-4235-2013; Gruber, Hermann/C-4234-2013 OI Sitte, Harald/0000-0002-1339-7444; FU Austrian Science Fund [F35]; National Institute on Drug Abuse-NIH FX This work was supported by Austrian Science Fund Grant F35 and the National Institute on Drug Abuse-Intramural Research Program, NIH (to A. H. N. and M.-F. Z.). NR 49 TC 31 Z9 31 U1 2 U2 44 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 2 PY 2012 VL 287 IS 1 BP 105 EP 113 DI 10.1074/jbc.M111.304873 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 870PW UT WOS:000298682400013 PM 22033932 ER PT J AU Ghosh, AK Rossi, ML Singh, DK Dunn, C Ramamoorthy, M Croteau, DL Liu, Y Bohr, VA AF Ghosh, Avik K. Rossi, Marie L. Singh, Dharmendra Kumar Dunn, Christopher Ramamoorthy, Mahesh Croteau, Deborah L. Liu, Yie Bohr, Vilhelm A. TI RECQL4, the Protein Mutated in Rothmund-Thomson Syndrome, Functions in Telomere Maintenance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SINGLE-STRANDED-DNA; MAMMALIAN TELOMERES; HOMOLOGOUS RECOMBINATION; CANCER PREDISPOSITION; SYNDROME HELICASE; GENOTOXIC AGENTS; BLM HELICASE; REPLICATION; TRF1; INITIATION AB Telomeres are structures at the ends of chromosomes and are composed of long tracks of short tandem repeat DNA sequences bound by a unique set of proteins (shelterin). Telomeric DNA is believed to form G-quadruplex and D-loop structures, which presents a challenge to the DNA replication and repair machinery. Although the RecQ helicases WRN and BLM are implicated in the resolution of telomeric secondary structures, very little is known about RECQL4, the RecQ helicase mutated in Rothmund-Thomson syndrome (RTS). Here, we report that RTS patient cells have elevated levels of fragile telomeric ends and that RECQL4-depleted human cells accumulate fragile sites, sister chromosome exchanges, and double strand breaks at telomeric sites. Further, RECQL4 localizes to telomeres and associates with shelterin proteins TRF1 and TRF2. Using recombinant proteins we showed that RECQL4 resolves telomeric D-loop structures with the help of shelterin proteins TRF1, TRF2, and POT1. We also found a novel functional synergistic interaction of this protein with WRN during D-loop unwinding. These data implicate RECQL4 in telomere maintenance. C1 [Ghosh, Avik K.; Rossi, Marie L.; Singh, Dharmendra Kumar; Dunn, Christopher; Ramamoorthy, Mahesh; Croteau, Deborah L.; Liu, Yie; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Biomed Res Ctr, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Ramamoorthy, Mahesh/0000-0002-2359-5647 FU National Institutes of Health NIA FX This work was supported, in whole or in part, by the National Institutes of Health NIA Intramural Program. NR 62 TC 35 Z9 36 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 2 PY 2012 VL 287 IS 1 BP 196 EP 209 DI 10.1074/jbc.M111.295063 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 870PW UT WOS:000298682400021 PM 22039056 ER PT J AU Clark, VP Coffman, BA Mayer, AR Weisend, MP Lane, TDR Calhoun, VD Raybourn, EM Garcia, CM Wassermann, EM AF Clark, Vincent P. Coffman, Brian A. Mayer, Andy R. Weisend, Michael P. Lane, Terran D. R. Calhoun, Vince D. Raybourn, Elaine M. Garcia, Christopher M. Wassermann, Eric M. TI TDCS guided using fMRI significantly accelerates learning to identify concealed objects SO NEUROIMAGE LA English DT Article DE Perception; Attention; Memory; Functional magnetic resonance imaging; Expertise; Training; Transcranial direct current stimulation; Frontal cortex; Parietal cortex; Medial temporal lobe; Cingulate cortex ID DIRECT-CURRENT STIMULATION; PRIMATE PREFRONTAL CORTEX; HUMAN VISUAL-CORTEX; HUMAN MOTOR CORTEX; ILLUSORY CONTOURS; NEURAL MECHANISMS; FALSE MEMORIES; WORKING-MEMORY; HUMAN BRAIN; ATTENTION AB The accurate identification of obscured and concealed objects in complex environments was an important skill required for survival during human evolution, and is required today for many forms of expertise. Here we used transcranial direct current stimulation (tDCS) guided using neuroimaging to increase learning rate in a novel, minimally guided discovery-learning paradigm. Ninety-six subjects identified threat-related objects concealed in naturalistic virtual surroundings used in real-world training. A variety of brain networks were found using functional magnetic resonance imaging (fMRI) data collected at different stages of learning, with two of these networks focused in right inferior frontal and right parietal cortex. Anodal 2.0 mA tDCS performed for 30 min over these regions in a series of single-blind, randomized studies resulted in significant improvements in learning and performance compared with 0.1 mA tDCS. This difference in performance increased to a factor of two after a one-hour delay. A dose response effect of current strength on learning was also found. Taken together, these brain imaging and stimulation studies suggest that right frontal and parietal cortex are involved in learning to identify concealed objects in naturalistic surroundings. Furthermore, they suggest that the application of anodal tDCS over these regions can greatly increase learning, resulting in one of the largest effects on learning yet reported. The methods developed here may be useful to decrease the time required to attain expertise in a variety of settings. (C) 2010 Elsevier Inc. All rights reserved. C1 [Clark, Vincent P.; Coffman, Brian A.; Mayer, Andy R.; Weisend, Michael P.; Calhoun, Vince D.; Garcia, Christopher M.] Mind Res Network, Albuquerque, NM 87106 USA. [Clark, Vincent P.; Coffman, Brian A.; Garcia, Christopher M.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Lane, Terran D. R.; Calhoun, Vince D.] Univ New Mexico, Dept Comp Sci, Albuquerque, NM 87131 USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. [Raybourn, Elaine M.] Sandia Natl Labs, Albuquerque, NM 87123 USA. [Wassermann, Eric M.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. RP Clark, VP (reprint author), Mind Res Network, 1101 Yale Blvd NE, Albuquerque, NM 87106 USA. EM vclark@unm.edu RI Calhoun, Vince/H-7146-2013; Clark, Vincent/B-3343-2010 OI Calhoun, Vince/0000-0001-9058-0747; Clark, Vincent/0000-0002-9151-2102 FU Defense Advanced Research Projects Agency [NBCHC070103]; Department of Energy [DE-FG02-99ER62764]; United States Department of Energy's National Nuclear Security Administration [DEAC04-94AL85000] FX This work was supported by the Defense Advanced Research Projects Agency (Government contract NBCHC070103) and the Department of Energy (Government contract DE-FG02-99ER62764). Special thanks to Dr. Richard E. Clark and Dr. Raja Parasuraman and anonymous referees for comments on this manuscript, to Dr. Amy Kruse for many helpful suggestions, and to Brian Clark, Kyle Kenny, Neal Miller, Ron Denny and Alan Rolli, Ranee Flores, Jeremy Bockholt, Elizabeth Browning, Andre van der Merwe, Michael Doty, Megan Schendel, Dae II Kim, Josef Ling, Jing Xu, Mark Skully, Jill Fries, Arvind Caprihan, Claudia Tesche, Sergey Plis, Diane Oyen, Blake Anderson and Francesca McIntire for help in experiment development, data collection and data analysis. Sandia is a multi-program laboratory operated by Sandia Corporation, a Lockheed Martin Company, for the United States Department of Energy's National Nuclear Security Administration under Contract DEAC04-94AL85000. The views, opinions, and/or findings contained in this article/presentation are those of the author/presenter and should not be interpreted as representing the official views or policies, either expressed or implied, of the Defense Advanced Research Projects Agency, the Department of Defense, or the Department of Energy. Approved for public release, distribution unlimited. NR 88 TC 65 Z9 67 U1 4 U2 30 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 2 PY 2012 VL 59 IS 1 SI SI BP 117 EP 128 DI 10.1016/j.neuroimage.2010.11.036 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 838CX UT WOS:000296265500013 PM 21094258 ER PT J AU Thambisetty, M An, Y Kinsey, A Koka, D Saleem, M Guntert, A Kraut, M Ferrucci, L Davatzikos, C Lovestone, S Resnick, SM AF Thambisetty, Madhav An, Yang Kinsey, Anna Koka, Deepthi Saleem, Muzamil Guentert, Andreas Kraut, Michael Ferrucci, Luigi Davatzikos, Christos Lovestone, Simon Resnick, Susan M. TI Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment SO NEUROIMAGE LA English DT Article DE Clusterin; Mild cognitive impairment (MCI); Alzheimer's disease (26); Plasma; Atrophy; Biomarker ID GENOME-WIDE ASSOCIATION; ALZHEIMERS-DISEASE; IDENTIFIES VARIANTS; CLU; THERAPIES; DEMENTIA; MODEL; RISK AB Recent genetic and proteomic studies demonstrate that clusterin/apolipoprotein-J is associated with risk, pathology, and progression of Alzheimer's disease (AD). Our main aim was to examine associations between plasma clusterin concentration and longitudinal changes in brain volume in normal aging and mild cognitive impairment (MCI). A secondary objective was to examine associations between peripheral concentration of clusterin and its concentration in the brain within regions that undergo neuropathological changes in AD. Non-demented individuals (N=139; mean baseline age 70.5 years) received annual volumetric MRI (912 MRI scans in total) over a mean six-year interval. Sixteen participants (92 MRI scans in total) were diagnosed during the course of the study with amnestic MCI. Clusterin concentration was assayed by ELISA in plasma samples collected within a year of the baseline MRI. Mixed effects regression models investigated whether plasma clusterin concentration was associated with rates of brain atrophy for control and MCI groups and whether these associations differed between groups. In a separate autopsy sample of individuals with AD (N = 17) and healthy controls (N = 4), we examined the association between antemortem clusterin concentration in plasma and postmortem levels in the superior temporal gyrus, hippocampus and cerebellum. The associations of plasma clusterin concentration with rates of change in brain volume were significantly different between MCI and control groups in several volumes including whole brain, ventricular CSF, temporal gray matter as well as parahippocampal, superior temporal and cingulate gyri. Within the MCI but not control group, higher baseline concentration of plasma clusterin was associated with slower rates of brain atrophy in these regions. In the combined autopsy sample of AD and control cases, representing a range of severity in AD pathology, we observed a significant association between clusterin concentration in the plasma and that in the superior temporal gyrus. Our findings suggest that clusterin, a plasma protein with roles in amyloid clearance, complement inhibition and apoptosis, is associated with rate of brain atrophy in MCI. Furthermore, peripheral concentration of clusterin also appears to reflect its concentration within brain regions vulnerable to AD pathology. These findings in combination suggest an influence of this multi-functional protein on early stages of progression in AD pathology. Published by Elsevier Inc. C1 [Thambisetty, Madhav; An, Yang; Resnick, Susan M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Kinsey, Anna; Saleem, Muzamil; Guentert, Andreas; Lovestone, Simon] Kings Coll London, London WC2R 2LS, England. [Koka, Deepthi; Davatzikos, Christos] Univ Penn, Sch Med, Dept Radiol, Philadelphia, PA 19104 USA. [Kraut, Michael] Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21205 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Thambisetty, M (reprint author), NIA, Lab Behav Neurosci, NIH, Room 48-317,251 Bayview Blvd, Baltimore, MD 21224 USA. EM thambisettym@mail.nih.gov; anya@grc.nia.nih.gov; anna.kinsey@kcl.ac.uk; deepumich@gmail.com; mkraut1@jhmi.edu; ferruccilu@grc.nia.nih.gov; Christos.Davatzikos@uphs.upenn.edu; simon.lovestone@kcl.ac.uk; resnicks@grc.nia.nih.gov OI Kinsey, Anna/0000-0001-8987-5353 FU NIH, National Institute on Aging and by Research and Development [N01-AG-3-2124]; National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust (SLaM); Institute of Psychiatry, King's College London; MedStar Research Institute FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging and by Research and Development Contract N01-AG-3-2124 together with funding from the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust (SLaM) and Institute of Psychiatry, King's College London. Partial support was also through a R&D contract with MedStar Research Institute. We are grateful to the BLSA participants and neuroimaging staff for their dedication to these studies and the staff of the Johns Hopkins PET facility for their assistance. NR 32 TC 55 Z9 57 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 2 PY 2012 VL 59 IS 1 SI SI BP 212 EP 217 DI 10.1016/j.neuroimage.2011.07.056 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 838CX UT WOS:000296265500022 PM 21824521 ER PT J AU Johnson, B Zhang, K Gay, M Horovitz, S Hallett, M Sebastianelli, W Slobounov, S AF Johnson, Brian Zhang, Kai Gay, Michael Horovitz, Silvina Hallett, Mark Sebastianelli, Wayne Slobounov, Semyon TI Alteration of brain default network in subacute phase of injury in concussed individuals: Resting-state fMRI study SO NEUROIMAGE LA English DT Article DE Default mode network; Resting state fMRI; Sub-acute mTBI ID FUNCTIONAL CONNECTIVITY; WORKING-MEMORY; MODE NETWORK; FOOTBALL PLAYERS; CINGULATE CORTEX; MILD; DYSFUNCTION; MRI; ABNORMALITIES; DEFICITS AB There are a number of symptoms, both neurological and behavioral, associated with a single episode of r mild traumatic brain injury (mTBI). Neuropsychological testing and conventional neuroimaging techniques are not sufficiently sensitive to detect these changes, which adds to the complexity and difficulty in relating symptoms from mTBI to their underlying structural or functional deficits. With the inability of traditional brain imaging techniques to properly assess the severity of brain damage induced by mTBI, there is hope that more advanced neuroimaging applications will be more sensitive, as well as specific, in accurately assessing mTBI. In this study, we used resting state functional magnetic resonance imaging to evaluate the default mode network (DMN) in the subacute phase of mTBI. Fourteen concussed student-athletes who were asymptomatic based upon clinical symptoms resolution and clearance for aerobic exercise by medical professionals were scanned using resting state functional magnetic resonance imaging. Nine additional asymptomatic yet not medically cleared athletes were recruited to investigate the effect of a single episode of mTBI versus multiple mTBIs on the resting state DMN. In concussed individuals the resting state DMN showed a reduced number of connections and strength of connections in the posterior cingulate and lateral parietal cortices. An increased number of connections and strength of connections was seen in the medial prefrontal cortex. Connections between the left dorso-lateral prefrontal cortex and left lateral parietal cortex showed a significant reduction in magnitude as the number of concussions increased. Regression analysis also indicated an overall loss of connectivity as the number of mTBI episodes increased. Our findings indicate that alterations in the brain resting state default mode network in the subacute phase of injury may be of use clinically in assessing the severity of mTBI and offering some insight into the pathophysiology of the disorder. (C) 2011 Elsevier Inc. All rights reserved. C1 [Johnson, Brian; Zhang, Kai; Gay, Michael; Slobounov, Semyon] Penn State Univ, Dept Kinesiol, University Pk, PA 16802 USA. [Horovitz, Silvina; Hallett, Mark; Slobounov, Semyon] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Sebastianelli, Wayne; Slobounov, Semyon] Penn State Univ, Dept Orthopaed & Med Rehabil, HMC, University Pk, PA 16802 USA. RP Slobounov, S (reprint author), Penn State Univ, Dept Kinesiol, 19 Recreat Bldg, University Pk, PA 16802 USA. EM sms18@psu.edu FU National Institutes of Health [RO1 NS056227-01A2] FX This work was supported by National Institutes of Health Grant RO1 NS056227-01A2 "Identification of Athletes at Risk for Traumatic Brain Injury" awarded to Dr. Slobounov, PI. NR 63 TC 89 Z9 90 U1 2 U2 25 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 2 PY 2012 VL 59 IS 1 SI SI BP 511 EP 518 DI 10.1016/j.neuroimage.2011.07.081 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 838CX UT WOS:000296265500050 PM 21846504 ER PT B AU Choi, HJ Jung, HY Yang, HC Zheng, F Shung, KK AF Choi, Hojong Jung, Hayong Yang, Hao-Chung Zheng, Fan Shung, K. Kirk GP IEEE TI New Modified Butterworth Van-Dyke Model for High Frequency Ultrasonic Imaging SO 2012 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) SE IEEE International Ultrasonics Symposium LA English DT Proceedings Paper CT IEEE International Ultrasonics Symposium (IUS) CY OCT 07-10, 2012 CL Dresden, GERMANY SP IEEE DE Protection Devices; Butterworth Van Dyke; Ultrasonic Transducers; Equivalent Circuit Model ID TRANSDUCER AB For ultrasonic transducers, a number of equivalent circuit models including KLM, Mason and Butterworth Van Dyke (BVD) have been developed. To allow them to be incorporated into design tools for complex integrated circuits, KLM or Mason models are not practical because the discrete components of the equivalent circuits have negative values. Therefore, BVD model appears to be more appropriate but it needs to be improved because the resolution of a high frequency ultrasound system may be severely affected by impedance mismatching between the transducer and the system, as well as attenuation due to parasitic impedances of the systems. A new modified BVD model has been developed and the results demonstrate its usefulness in modeling high frequency ultrasonic transducer and its imaging systems. C1 [Choi, Hojong; Jung, Hayong; Yang, Hao-Chung; Zheng, Fan; Shung, K. Kirk] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP Choi, HJ (reprint author), Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. NR 21 TC 2 Z9 2 U1 2 U2 4 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4673-4562-0; 978-1-4673-4561-3 J9 IEEE INT ULTRA SYM PY 2012 BP 576 EP 579 DI 10.1109/ULTSYM.2012.0143 PG 4 WC Engineering, Electrical & Electronic SC Engineering GA BHX71 UT WOS:000326960200127 ER PT B AU Choi, H Kim, M Shung, KK AF Choi, Hojong Kim, Mingon Shung, K. Kirk GP IEEE TI New MOSFET-Based Expander for High Frequency Ultrasound Systems SO 2012 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) SE IEEE International Ultrasonics Symposium LA English DT Proceedings Paper CT IEEE International Ultrasonics Symposium (IUS) CY OCT 07-10, 2012 CL Dresden, GERMANY SP IEEE DE Protection Devices; Expander; Power MOSFET; High Frequency Ultrasound Systems; Ultrasonic Transducers AB Diode-based expanders (expanders with single-crossed diodes) are widely used for pulse-echo measurements and in imaging systems. The function of the diode-based expander is to obstruct the noise from the transmitted output signals of the pulser and block the returned signals from the ultrasonic transducers to the pulser. It may also degrade the performance of the transducer and electronic components on the imaging side of the system because of non-linearity and attenuation at higher voltages. A new type of expander using power MOSFETs for high frequency ultrasound systems is proposed and studied. Compared to diode-based expander, this device is shown to yield lower insertion loss and total harmonic distortion, and faster reverse recovery time. C1 [Choi, Hojong; Kim, Mingon; Shung, K. Kirk] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP Choi, HJ (reprint author), Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. NR 11 TC 2 Z9 2 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4673-4562-0; 978-1-4673-4561-3 J9 IEEE INT ULTRA SYM PY 2012 BP 623 EP 626 DI 10.1109/ULTSYM.2012.0155 PG 4 WC Engineering, Electrical & Electronic SC Engineering GA BHX71 UT WOS:000326960200137 ER PT B AU Yang, HC Chiu, CT Choi, HJ Zheng, F Liu, CG Qiu, WB Kim, HH Shung, KK AF Yang, Hao-Chung Chiu, Chi Tat Choi, Hojong Zheng, Fan Liu, Changgeng Qiu, Weibao Kim, Hyung Ham Shung, K. Kirk GP IEEE TI Low Cross-talk Kerfless Annular Array Ultrasound Transducers using 1-3 Piezocomposites with Pseudo-Random Pillars SO 2012 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) SE IEEE International Ultrasonics Symposium LA English DT Proceedings Paper CT IEEE International Ultrasonics Symposium (IUS) CY OCT 07-10, 2012 CL Dresden, GERMANY SP IEEE DE Pseudo-Random; Annular Array; Pillar; Lateral Interference; Cross-Talk; Piezocomposite ID FABRICATION; COMPOSITE; DESIGN AB This paper describes the design and fabrication of a high-frequency kerfless annular array transducer utilizing a novel 1-3 piezocomposite which was designed to reduce inter-element cross-talk. 1-3 piezocomposites have significant advantages over bulk piezoelectric materials and other types of piezocomposites; however, their benefits come at the expense of introducing more undesired interpillar resonances. At high frequencies, this is especially detrimental to kerfless annular array transducers. We have previously shown that this unwanted coupling effect (high inter-element crosstalk), can be further reduced by employing a pseudo-random pillar geometry. Utilizing the 1-3 composites with the pseudo-random pillars, a 40 MHz annular array transducer was fabricated. Each annular array was designed to have six equal-area elements and a center frequency of 40 MHz. The average center frequency estimated from the measured pulse-echo responses of array elements was 38.7 MHz and the -6 dB bandwidth was 51 %. The average insertion loss recorded was 23.1 dB, and the maximum combined crosstalk between the adjacent elements was less than -31 dB. These results demonstrate that the 1-3 piezocomposite with the pseudo-random pillars may be a better choice for fabricating enhanced high frequency linear array ultrasound transducers; especially when mechanical dicing is used. C1 [Yang, Hao-Chung; Chiu, Chi Tat; Choi, Hojong; Zheng, Fan; Liu, Changgeng; Kim, Hyung Ham; Shung, K. Kirk] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP Yang, HC (reprint author), Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM yangh@usc.edu NR 10 TC 0 Z9 0 U1 0 U2 6 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4673-4562-0; 978-1-4673-4561-3 J9 IEEE INT ULTRA SYM PY 2012 BP 1560 EP 1563 DI 10.1109/ULTSYM.2012.0390 PG 4 WC Engineering, Electrical & Electronic SC Engineering GA BHX71 UT WOS:000326960201082 ER PT B AU Lam, KH Li, Y Lee, C Zhou, QF Shung, KK AF Lam, Kwok Ho Li, Ying Lee, Changyang Zhou, Qifa Shung, K. Kirk GP IEEE TI Ultrahigh Frequency Ultrasound Microbeam for Biomedical Applications SO 2012 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) SE IEEE International Ultrasonics Symposium LA English DT Proceedings Paper CT IEEE International Ultrasonics Symposium (IUS) CY OCT 07-10, 2012 CL Dresden, GERMANY SP IEEE DE Ultrasonic transducer; microbeam; biomedical ID SINGLE; TWEEZERS; FORCE AB Several 200-MHz lithium niobate (LN) single crystal single-element press-focused ultrasonic transducers were developed for biomedical applications. Micro-particle trapping experiments were carried out to demonstrate that the acoustic device can manipulate a single microbead as small as 5 mu m within the range of hundreds of micrometers in distilled water. As the result suggests that the 200-MHz microbeam device is capable of manipulating particles two-dimensionally at the cellular level, the device was used for studying red blood cell (RBC) mechanical deformation. It was found that by attaching the trapped microbead to a RBC, the RBC could be stretched by moving the trapped microbead. This preliminary result demonstrates the acoustic microbeam may be promising tool for studying the RBC membrane elastic properties. C1 [Lam, Kwok Ho] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP Lam, KH (reprint author), Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. RI Lam, K.H./B-7765-2014; OI Lam, K.H./0000-0003-1456-9049; Lee, Changyang/0000-0002-3746-7304 NR 10 TC 3 Z9 3 U1 1 U2 8 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4673-4562-0; 978-1-4673-4561-3 J9 IEEE INT ULTRA SYM PY 2012 BP 1994 EP 1997 DI 10.1109/ULTSYM.2012.0499 PG 4 WC Engineering, Electrical & Electronic SC Engineering GA BHX71 UT WOS:000326960201169 ER PT J AU Sheng, ZH Chu, CT AF Sheng, Zu-Hang Chu, Charleen T. BE Yue, Z Chu, CT TI NEURONAL MITOCHONDRIAL TRANSPORT AND TURNOVER VIA MITOPHAGY SO AUTOPHAGY OF THE NERVOUS SYSTEM: CELLULAR SELF-DIGESTION IN NEURONS AND NEUROLOGICAL DISEASES LA English DT Article; Book Chapter ID NERVE GROWTH-FACTOR; AXONAL-TRANSPORT; IN-VIVO; PINK1/PARKIN-MEDIATED MITOPHAGY; SYNAPTIC-TRANSMISSION; CYTOPLASMIC DYNEIN; FOREBRAIN NEURONS; PINK1 FUNCTION; AUTOPHAGY; PARKIN AB Mitochondria are essential organelles for neuronal survival and function due to their key roles in ATP generation, calcium buffering, and apoptotic signalling. As neurons are highly polarized cells, the complex mechanisms of mitochondrial transport and docking are particularly important for neuronal development and synaptic function. Mitochondria are transported to and dock in areas with high demand for ATP and calcium homeostasis. Conversely, effete, or damaged mitochondria are transported for lysosomal degradation through the process of macroautophagy. Axonal mitochondria display complex mobility patterns and undergo saltatory and bidirectional movement. At any given time, approximately one-third of axonal mitochondria are mobile in cultured neurons. The balance between mobile and stationary mitochondria, however, is dynamic and responds quickly to changes in axonal and synaptic physiology. Defects in mitochondrial transport and turnover have been implicated in the pathologic processes of amyotrophic lateral sclerosis, Huntington's disease and Parkinson's disease. Further investigation into the mechanisms that regulate axonal mitochondrial transport, docking, and targeting for autophagy will provide important insight into these disease processes. Here, we highlight recent advances in our understanding of the motor-adaptor complexes and docking machinery that mediate mitochondrial transport and distribution along axons. We will also discuss new mechanisms underlying cargo recognition and autophagic turnover of damaged mitochondria, with particular reference to Parkinson's disease. The potential effects of altered mitochondrial transport or mitophagy on neuronal health and cell death reflect the particular dependence of neurons on mitochondrial metabolism. C1 [Sheng, Zu-Hang] NINDS, Synapt Funct Sect, NIH, Bethesda, MD 20892 USA. [Chu, Charleen T.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Sect, NIH, 35 Convent Dr,Bldg 35,Room 2B-215, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov; ctc4@pitt.edu NR 100 TC 0 Z9 0 U1 0 U2 1 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4350-44-0 PY 2012 BP 375 EP 405 D2 10.1142/8150 PG 31 WC Neurosciences SC Neurosciences & Neurology GA BHZ39 UT WOS:000327076800017 ER PT B AU Clerici, M Biasin, M Shearer, GM AF Clerici, Mario Biasin, Mara Shearer, Gene M. BE Pancino, G Silvestri, G Fowke, KR TI Are Some People Protected Against HIV Infection? SO MODELS OF PROTECTION AGAINST HIV/SIV: AVOIDING AIDS IN HUMANS AND MONKEYS LA English DT Article; Book Chapter ID EXPOSED SERONEGATIVE INDIVIDUALS; T-LYMPHOCYTE RESPONSES; PERIPHERAL-BLOOD; HOMOSEXUAL-MEN; DRUG-USERS; CLASS-I; RESISTANCE; TYPE-1; WORKERS; TRANSMISSION C1 [Clerici, Mario; Biasin, Mara] Univ Milan, Milan, Italy. [Clerici, Mario] ONLUS, Fdn Don Gnocchi, Milan, Italy. [Shearer, Gene M.] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Clerici, M (reprint author), Univ Milan, Milan, Italy. NR 43 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-387716-1; 978-0-12-387715-4 PY 2012 BP 135 EP 143 DI 10.1016/B978-0-12-387715-4.00004-6 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA BHU09 UT WOS:000326658900005 ER PT J AU Merikangas, KR Cravchik, A AF Merikangas, Kathleen Ries Cravchik, Anibal BE Nurnberger, JI Berrettini, WH TI Contribution of genetic epidemiology to our understanding of psychiatric disorders SO PRINCIPLES OF PSYCHIATRIC GENETICS LA English DT Article; Book Chapter ID OBSESSIVE-COMPULSIVE DISORDER; GENERALIZED ANXIETY DISORDER; POPULATION-BASED SAMPLE; SUBSTANCE USE DISORDERS; COPY-NUMBER VARIATIONS; ENVIRONMENT INTERACTION; FAMILIAL AGGREGATION; FEMALE TWINS; BIPOLAR DISORDER; PANIC DISORDER C1 [Merikangas, Kathleen Ries; Cravchik, Anibal] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. NR 139 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-0-521-89649-8 PY 2012 BP 1 EP 12 D2 10.1017/CBO9781139025997 PG 12 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA BHV51 UT WOS:000326744300002 ER PT J AU Murphy, DL Moya, PR Wendland, JR Timpano, K AF Murphy, Dennis L. Moya, Pablo R. Wendland, Jens R. Timpano, Kiara BE Nurnberger, JI Berrettini, WH TI Genetic contributions to obsessive-compulsive disorder (OCD) and OCD-related disorders SO PRINCIPLES OF PSYCHIATRIC GENETICS LA English DT Article; Book Chapter ID SEROTONIN TRANSPORTER GENE; POSTTRAUMATIC-STRESS-DISORDER; COMPLEX SEGREGATION ANALYSIS; MYOCLONUS-DYSTONIA SYNDROME; FAMILY-BASED ASSOCIATION; CARDIO-FACIAL SYNDROME; LA-TOURETTE-SYNDROME; OPEN-LABEL TRIAL; PSYCHIATRIC-DISORDERS; COLLABORATIVE GENETICS C1 [Murphy, Dennis L.; Moya, Pablo R.; Wendland, Jens R.] NIMH, Clin Sci Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Wendland, Jens R.] NIMH, Genet Basis Mood & Anxiety Disorders Sect, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Timpano, Kiara] Univ Miami, Coral Gables, FL 33124 USA. RP Murphy, DL (reprint author), NIMH, Clin Sci Lab, Intramural Res Program, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 145 TC 0 Z9 1 U1 2 U2 2 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-0-521-89649-8 PY 2012 BP 121 EP 133 D2 10.1017/CBO9781139025997 PG 13 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA BHV51 UT WOS:000326744300012 ER PT S AU Clore, M Potts, J AF Clore, Marius Potts, Jennifer BE Clore, M Potts, J TI Recent Developments in Biomolecular NMR Preface SO RECENT DEVELOPMENTS IN BIOMOLECULAR NMR SE RSC Biomolecular Sciences LA English DT Editorial Material; Book Chapter C1 [Clore, Marius] NIDDKD, NIH, Bethesda, MD 20892 USA. [Potts, Jennifer] Univ York, Dept Biol, York YO10 5DD, N Yorkshire, England. [Potts, Jennifer] Univ York, Dept Chem, York YO10 5DD, N Yorkshire, England. RP Clore, M (reprint author), NIDDKD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, CAMBRIDGE CB4 4WF, CAMBS, ENGLAND SN 1757-7152 BN 978-1-84973-539-1; 978-1-84973-120-1 J9 RSC BIOMOL SCI JI RSC Biomol. Sci. PY 2012 VL 25 BP V EP VII DI 10.1039/9781849735391-FP005 D2 10.1039/9781849735391 PG 3 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA BHW84 UT WOS:000326878600001 ER PT J AU Dworkin, G AF Dworkin, Gerald BE Paul, EF Miller, FD Paul, J TI HARM AND THE VOLENTI PRINCIPLE SO NEW ESSAYS IN POLITICAL AND SOCIAL PHILOSOPHY LA English DT Article; Book Chapter C1 [Dworkin, Gerald] Univ Calif Davis, Davis, CA 95616 USA. RP Dworkin, G (reprint author), NIH, Dept Bioeth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-139-09681-2 PY 2012 BP 309 EP 321 DI 10.1017/S0265052511000057 PG 13 WC Philosophy; Political Science SC Philosophy; Government & Law GA BHR72 UT WOS:000326503800013 ER PT S AU Tomasiewicz, HG Liu, XC Tassone, C North, P Thometz, J AF Tomasiewicz, H. G. Liu, X. C. Tassone, C. North, P. Thometz, J. BE Kotwicki, T Grivas, TB TI A Line of Zebrafish with Increased Incidence of Spinal Deformities SO RESEARCH INTO SPINAL DEFORMITIES 8 SE Studies in Health Technology and Informatics LA English DT Meeting Abstract CT 9th Biennial Meeting of the International-Research-Society-of-Spinal-Deformities (IRSSD) CY JUL, 2012 CL Poznan, POLAND SP Int Res Soc Spinal Deformities, Ortopedia Polska, Rynek Zdrowia, Medycyna Praktyczna C1 [Tomasiewicz, H. G.] Univ Wisconsin, NIEHS Childrens Environm Hlth Sci Core Ctr, Milwaukee, WI 53201 USA. NR 0 TC 0 Z9 1 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0926-9630 BN 978-1-61499-067-3 J9 STUD HEALTH TECHNOL PY 2012 VL 176 BP 454 EP 454 PG 1 WC Orthopedics SC Orthopedics GA BHL20 UT WOS:000325768100094 ER PT S AU Schug, TT Erlebacher, A Leibowitz, S Ma, L Muglia, LJ Rando, OJ Rogers, JM Romero, R vom Saal, FS Wise, DL AF Schug, Thaddeus T. Erlebacher, Adrian Leibowitz, Sarah Ma, Liang Muglia, Louis J. Rando, Oliver J. Rogers, John M. Romero, Roberto vom Saal, Frederick S. Wise, David L. GP Annals NY Acad Sci TI Fetal programming and environmental exposures: implications for prenatal care and preterm birth SO ANNALS MEETING REPORTS 2013 SE Annals of the New York Academy of Sciences LA English DT Article DE genetic and epigenetic programming; fetal development; toxicity ID BISPHENOL-A; STEM-CELLS; PREGNANCY; INTERFACE; MODEL; DIET; PLACENTATION; DISORDERS; RESPONSES; OBESITY AB Sponsored by the New York Academy of Sciences and Cincinnati Children's Hospital Medical Center, with support from the National Institute of Environmental Health Sciences (NIEHS), the National Institute on Drug Abuse (NIDA), and Life Technologies, "Fetal Programming and Environmental Exposures: Implications for Prenatal Care and Preterm Birth" was held on June 11-12, 2012 at the New York Academy of Sciences in New York City. The meeting, comprising individual talks and panel discussions, highlighted basic, clinical, and translational research approaches, and highlighted the need for specialized testing of drugs, consumer products, and industrial chemicals, with a view to the unique impacts these can have during gestation. Speakers went on to discuss many other factors that affect prenatal development, from genetics to parental diet, revealing the extraordinary sensitivity of the developing fetus. C1 [Schug, Thaddeus T.] NIEHS, Res Triangle Pk, NC 27709 USA. [Erlebacher, Adrian] NYU, Sch Med, New York, NY USA. [Leibowitz, Sarah] Rockefeller Univ, New York, NY 10021 USA. [Ma, Liang] Washington Univ, Sch Med, Dept Med, Div Dermatol, St Louis, MO 63110 USA. [Muglia, Louis J.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Muglia, Louis J.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Rando, Oliver J.] Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA USA. [Rogers, John M.] US EPA, Tox Assessment Div, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [vom Saal, Frederick S.] Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. [Wise, David L.] Merck Res Labs, West Point, PA USA. RP Schug, TT (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM schugt@niehs.nih.gov FU Cincinnati Children's Hospital Medical Center and Academy Friend Sponsors; Abcam Inc.; Quartzy; Watson Pharmaceuticals, Inc.; Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Weill Cornell Medical College; Burroughs Wellcome Fund; March of Dimes Foundation [4-FY12-545]; National Institute of Environmental Health Sciences (NIEHS) [1R13ES021699-01]; National Institute on Drug Abuse (NIDA) FX This meeting report presents research featured at the June 11-12, 2012 Fetal Programming and Environmental Exposures: Implications for Prenatal Care and Preterm Birth conference, presented by the New York Academy of Sciences and Cincinnati Children's Hospital Medical Center. The conference was supported by Cincinnati Children's Hospital Medical Center and Academy Friend Sponsors, Abcam Inc., Quartzy, Watson Pharmaceuticals, Inc., and the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Weill Cornell Medical College. The conference was also supported by educational grants from the Burroughs Wellcome Fund and the March of Dimes Foundation (Grant No. 4-FY12-545). Funding for this conference was also made possible, in part, by Grant number 1R13ES021699-01 from the National Institute of Environmental Health Sciences (NIEHS) and the National Institute on Drug Abuse (NIDA). The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services, nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. government. NR 46 TC 2 Z9 2 U1 1 U2 12 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1276 BP 37 EP 46 DI 10.1111/nyas.12003 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA BHO44 UT WOS:000326095100003 PM 23278645 ER PT S AU Kaminski, HJ Kusner, LL Wolfe, GI Aban, I Minisman, G Conwit, R Cutter, G AF Kaminski, Henry J. Kusner, Linda L. Wolfe, Gil I. Aban, Inmaculada Minisman, Greg Conwit, Robin Cutter, Gary BE Wolfe, GI Meriggioli, MN Ciafaloni, E Ruff, RL TI Biomarker development for myasthenia gravis SO MYASTHENIA GRAVIS AND RELATED DISORDERS II SE Annals of the New York Academy of Sciences LA English DT Article; Proceedings Paper CT 12th International Conference on Myasthenia Gravis and Related Disorders CY MAY 21-23, 2012 CL New York Acad Sci, New York, NY SP Myasthenia Gravis Fdn Amer, CSL Behring, IBL Int, KRONUS, Athena Diagnost, Terumo BCT HO New York Acad Sci DE biomarkers; myasthenia gravis; surrogate end point; Prentice criteria ID DRUG DEVELOPMENT; CLINICAL-TRIALS; DISEASE; RECOMMENDATIONS; COMPLEMENT AB Biomarkers are defined as characteristics (e. g., proteins, RNA, single nucleotide polymorphisms, imaging) that are objectively measured and evaluated as indicators of pathogenic processes or pharmacologic responses to therapeutic intervention. Biomarkers are important in clinical trials where the robust biomarker reflects the underlying disease process in a sensitive and reliable manner. For myasthenia gravis (MG), acetylcholine receptor and muscle-specific kinase antibodies, as well as single-fiber electromyography, serve as excellent biomarkers for diagnosis but do not adequately substitute for clinical evaluations to predict treatment response. Newtechnologies are emerging that enable broad biomarker discovery in biological fluids. Biomarker evaluation is ideally done in the context of longitudinal clinical trials. The MGTX trial has collected plasma and serum for RNA and protein analysis and thymus, which will allow robust biomarker discovery. The ultimate goal will be to identify candidates for a reliable substitute for a clinically meaningful end point that is a direct measure of the effectiveness of a therapy in the context of a continuum of disease natural history and a patient's overall well-being. C1 [Kaminski, Henry J.] George Washington Univ, Dept Neurol, Washington, DC 20037 USA. [Kaminski, Henry J.; Kusner, Linda L.] George Washington Univ, Dept Pharmacol, Washington, DC 20037 USA. [Kaminski, Henry J.; Kusner, Linda L.] George Washington Univ, Dept Physiol, Washington, DC 20037 USA. [Wolfe, Gil I.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Neurol, Buffalo, NY 14260 USA. [Aban, Inmaculada; Minisman, Greg; Cutter, Gary] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [Conwit, Robin] NINDS, Div Extramural Res, NIH, Bethesda, MD 20892 USA. RP Kaminski, HJ (reprint author), George Washington Univ, Dept Neurol, 2150 Penn Ave, Washington, DC 20037 USA. EM HKaminski@mfa.gwu.edu OI Kusner, Linda/0000-0002-5530-2140 FU NINDS [U01 NS042685] FX This work was supported by NINDS Grant U01 NS042685. NR 30 TC 6 Z9 6 U1 1 U2 9 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 BN 978-1-57331-911-9 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1275 BP 101 EP 106 DI 10.1111/j.1749-6632.2012.06787.x PG 6 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA BHO21 UT WOS:000326037400016 PM 23278584 ER PT B AU Chootong, C Sornil, O AF Chootong, Chalothon Sornil, Ohm GP ASME TI COMBINING CHART PATTERNS AND INDICATORS FOR IDENTIFYING STOCK TRADING SIGNALS SO 4TH INTERNATIONAL CONFERENCE ON SOFTWARE TECHNOLOGY AND ENGINEERING (ICSTE 2012) LA English DT Proceedings Paper CT 4th International Conference on Software Technology and Engineering (ICSTE 2012) CY SEP 01-02, 2012 CL Univ Madras, Phuket, THAILAND SP Singapore Int Assoc Comp Sci & Informat Technol, Polytechn Univ Puerto Rico, Univ Putra Malaysia HO Univ Madras DE Stock Trading; Price Movement; Candlestick Chart; Indicators; Neural Network AB Chat patterns and indicators are popularly used to make investment decisions. This paper presents a trading strategy combining price movement patterns, candlestick chart patterns, and trading indicators including MA, EMA, BB, OVB, RSI, MACD, and Stochastic Oscillator with the aim to increase the return on investment. A neural network model is employed to determine buy and sell signals on the next trading day. Stocks in three different industries from Stock Exchange of Thailand are used as case studies. The experimental results show that the proposed strategy yields higher returns than traditional means of trading. C1 [Chootong, Chalothon] NIDA, Dept Comp Sci, Grad Sch Appl Stat, Bethesda, MD USA. RP Chootong, C (reprint author), NIDA, Dept Comp Sci, Grad Sch Appl Stat, Bethesda, MD USA. EM chalothon.cs@gmail.com; osornil@as.nida.ac.th NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MECHANICAL ENGINEERS PI NEW YORK PA THREE PARK AVENUE, NEW YORK, NY 10016-5990 USA BN 978-0-7918-6015-1 PY 2012 BP 429 EP 435 PG 7 WC Computer Science, Software Engineering SC Computer Science GA BGU12 UT WOS:000324148400068 ER PT J AU Muneyyirci-Delale, O Charles, C Anopa, J Osei-Tutu, N Dalloul, M Weedon, J Muney, A Stratton, P AF Muneyyirci-Delale, O. Charles, C. Anopa, J. Osei-Tutu, N. Dalloul, M. Weedon, J. Muney, A. Stratton, P. TI Changes in bone density in women with symptomatic endometriosis during treatment SO HUMAN REPRODUCTION LA English DT Meeting Abstract CT 28th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE) CY JUL 01-04, 2012 CL Istanbul, TURKEY SP European Soc Human Reprod & Embryol C1 [Muneyyirci-Delale, O.; Charles, C.; Anopa, J.; Osei-Tutu, N.; Dalloul, M.; Weedon, J.; Muney, A.] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Stratton, P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Program Reprod & Adult Endocrinol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PY 2012 VL 27 SU 2 MA P-265 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 229WW UT WOS:000325299600552 ER PT J AU Yu, B DeCherney, A Segars, J Russanova, V Howard, B AF Yu, B. DeCherney, A. Segars, J. Russanova, V. Howard, B. TI Distinctive DNA methylome changes in human ovarian granulosa cells are associated with diminished ovarian function SO HUMAN REPRODUCTION LA English DT Meeting Abstract CT 28th Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE) CY JUL 01-04, 2012 CL Istanbul, TURKEY SP European Soc Human Reprod & Embryol C1 [Yu, B.; DeCherney, A.; Segars, J.] NICHD, Program Adult & Reprod Endocrinol, Bethesda, MD USA. [Russanova, V.; Howard, B.] NICHD, Program Genom Dev, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PY 2012 VL 27 SU 2 MA P-441 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 229WW UT WOS:000325299600719 ER PT J AU Quiroz, JA Chen, G Drevets, WC Henter, ID Manji, HK AF Quiroz, Jorge A. Chen, Guang Drevets, Wayne C. Henter, Ioline D. Manji, Husseini K. BE Barrett, JE Coyle, JT Williams, M TI Mood disorders SO TRANSLATIONAL NEUROSCIENCE: APPLICATIONS IN PSYCHIATRY, NEUROLOGY, AND NEURODEVELOPMENTAL DISORDERS LA English DT Article; Book Chapter ID MAJOR DEPRESSIVE DISORDER; GLYCOGEN-SYNTHASE KINASE-3; MEDIAL PREFRONTAL CORTEX; ANTERIOR CINGULATE CORTEX; METABOTROPIC GLUTAMATE RECEPTORS; D-ASPARTATE ANTAGONIST; NECROSIS-FACTOR-ALPHA; TREATMENT-RESISTANT DEPRESSION; FORCED SWIM TEST; OPEN-LABEL TRIAL C1 [Quiroz, Jorge A.] Hoffmann La Roche, Pharma Res & Early Dev, Neurosci, Nutley, NJ USA. [Chen, Guang; Manji, Husseini K.] Johnson & Johnson Pharmaceut Res & Dev, San Diego, CA USA. [Drevets, Wayne C.] Univ Oklahoma, Laureate Inst Brain Res, Coll Med, Tulsa, OK USA. [Drevets, Wayne C.] Univ Oklahoma, Dept Psychiat, Coll Med, Tulsa, OK USA. [Henter, Ioline D.] NIMH, NIH, Bethesda, MD 20892 USA. RP Quiroz, JA (reprint author), Hoffmann La Roche, Pharma Res & Early Dev, Neurosci, Nutley, NJ USA. RI Chen, Guang/A-2570-2017 NR 482 TC 1 Z9 1 U1 5 U2 7 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-0-521-51976-2 PY 2012 BP 27 EP 79 D2 10.1017/CBO9780511980053 PG 53 WC Neurosciences SC Neurosciences & Neurology GA BHB34 UT WOS:000324875800004 ER PT J AU Mikkilineni, S Cantuti-Castelvetri, I Cahill, CM Balliedier, A Greig, NH Rogers, JT AF Mikkilineni, Sohan Cantuti-Castelvetri, Ippolita Cahill, Catherine M. Balliedier, Amelie Greig, Nigel H. Rogers, Jack T. TI The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5 ' Untranslated-Region-Directed Translation Blockers of the Parkinson's Alpha Synuclein Expression SO PARKINSONS DISEASE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; IRON-RESPONSIVE ELEMENT; ALZHEIMERS-DISEASE; 5'-UNTRANSLATED REGION; MESSENGER-RNA; NEURODEGENERATIVE DISEASES; ANTIPODAL ISOMERS; NONMOTOR SYMPTOMS; DEMENTIA; BETA AB There is compelling support for limiting expression of alpha-synuclein (alpha-syn) in the brains of Parkinson's disease (PD) patients. An increase of SNCA gene copy number can genetically cause familial PD where increased dose of this pathogenic protein correlates with severity of symptoms (triplication of the SNCA gene causes dementia in PD patients). Gene promoter polymorphisms were shown to increase alpha-synuclein expression as a risk for PD. Cholinesterase inhibitors can clinically slow cognitive decline in the later stages of PD etiology similar to their widespread use in Alzheimer's disease (AD). Pertinent to this, we identified that the well-tolerated anticholinesterase, phenserine, blocked neural SNCA mRNA translation and tested for targeting via its 5'untranslated region (5'UTR) in a manner similar to its action to limit the expression of the AD-specific amyloid precursor protein (APP). Posiphen, its better-tolerated (+) enantiomer (devoid of anticholinesterase action), repressed neural alpha-synuclein translation. Primary metabolic analogs of posiphen were, likewise, characterized using primary fetal neurons grown ex vivo from the brains of Parkinson's transgenic mice expressing the human SNCA gene. C1 [Mikkilineni, Sohan; Cahill, Catherine M.; Balliedier, Amelie; Rogers, Jack T.] Massachusetts Gen Hosp East, Neurochem Lab, Charlestown, MA 02129 USA. [Cantuti-Castelvetri, Ippolita] Massachusetts Gen Hosp, MIND, Charlestown, MA 02129 USA. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Rogers, JT (reprint author), Massachusetts Gen Hosp East, Neurochem Lab, CNY2,149,13th St, Charlestown, MA 02129 USA. EM jrogers@partners.org FU Michael J. Fox Foundation Novel Drug Discoveries Award; National Institute of Aging [R01 AG20181]; NINDS [R21NS059434]; Alzheimer's Association Zenith Award [09-131352]; Intramural Research Program, National Institute on Aging, National Institutes of Health; I. Cantuti-Caselvetri: the MGH/MIT Morris Udall Center of Excellence in PD Research [NIH NS38372]; APDA Advanced Center for Parkinson Research at MGH; NIH [HD012437 29 S-1] FX The authors thank Prof. Robert Nussbaum and Dr. Yien-Ming Kuo (UCSF) for their PAC-Tg(SNCA) mice. This research was supported (i) for J. T. Rogers by the Michael J. Fox Foundation Novel Drug Discoveries Award, National Institute of Aging R01 AG20181, NINDS R21NS059434, Alzheimer's Association Zenith Award 09-131352 and ISOA (ii) for N. H. Greig by the Intramural Research Program, National Institute on Aging, National Institutes of Health, (iii) for I. Cantuti-Caselvetri: the MGH/MIT Morris Udall Center of Excellence in PD Research (NIH NS38372) and the APDA Advanced Center for Parkinson Research at MGH, and (iv) for C. M. Cahill by NIH HD012437 29 S-1. NR 62 TC 4 Z9 4 U1 0 U2 0 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 2090-8083 J9 PARKINSONS DIS-US JI Parkinsons Dis. PY 2012 AR UNSP 142372 DI 10.1155/2012/142372 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA 214CP UT WOS:000324108600001 ER PT J AU Pequegnat, W AF Pequegnat, Willo CA NIMH Consortium Families HIV AIDS BE Pequegnat, W Bell, CC TI Family and HIV/AIDS: First Line of Health Promotion and Disease Prevention SO FAMILY AND HIV/AIDS: CULTURAL AND CONTEXTUAL ISSUES IN PREVENTION AND TREATMENT LA English DT Article; Book Chapter ID RISKY SEXUAL-BEHAVIOR; AFRICAN-AMERICAN ADOLESCENTS; HIV-POSITIVE MOTHERS; PSYCHIATRIC-CARE; SOCIAL SUPPORT; MENTAL-HEALTH; SUBSTANCE USE; PSYCHOLOGICAL DISTRESS; HISPANIC ADOLESCENTS; PARENTAL INVOLVEMENT AB This chapter provides an overview of both the field of family-based research and of this book. The epidemiology of HIV affecting family members is briefly described to indicate the severity of the problem. We use the NIMH Consortium on HIV/AIDS definition of family which is "a network of mutual commitment" and we describe the different configurations of families. There is a description of what has been documented in the literature about family process, stigma, disclosure, social capital and social support, and psychological distress of families and HIV/AIDS. This chapter also addresses the multiple roles of parents and family members: (1) as AIDS educators; (2) as monitors, (3) as providers of warmth and support; and (4) as communicators about sex and relationships. There is a description of the role of families in adapting to HIV infection in family members and negotiating other family issues, such as homosexuality, high-risk sexual behavior, and alcohol and substance abuse. There is a discussion of issues about stigma and disclosure, family dynamics, stress and coping, handling complex medical regimes, and maintaining custody of children in families experiencing HIV infection. Other chapters in this book are referenced so that a more in-depth review of the issues can be explored. C1 [Pequegnat, Willo] NIMH, Div AIDS Res, NIH, Bethesda, MD 20892 USA. RP Pequegnat, W (reprint author), NIMH, Div AIDS Res, NIH, Bethesda, MD 20892 USA. EM wpequegn@mail.nih.gov NR 178 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-1-4614-0439-2 PY 2012 BP 3 EP 45 DI 10.1007/978-1-4614-0439-2_1 D2 10.1007/978-1-4614-0439-2 PG 43 WC Family Studies; Public, Environmental & Occupational Health SC Family Studies; Public, Environmental & Occupational Health GA BGJ68 UT WOS:000323234400003 ER PT J AU Pequegnat, W Bell, CC AF Pequegnat, Willo Bell, Carl C. BE Pequegnat, W Bell, CC TI Family and HIV/AIDS Cultural and Contextual Issues in Prevention and Treatment Preface SO FAMILY AND HIV/AIDS: CULTURAL AND CONTEXTUAL ISSUES IN PREVENTION AND TREATMENT LA English DT Editorial Material; Book Chapter C1 [Pequegnat, Willo] NIMH, Div AIDS Res, NIH, Bethesda, MD 20892 USA. [Bell, Carl C.] Univ Illinois, Chicago, IL USA. [Bell, Carl C.] Univ Illinois, Inst Juvenile Res, Chicago, IL USA. [Bell, Carl C.] Community Mental Hlth Council CMHC & Fdn Inc, Chicago, IL USA. RP Pequegnat, W (reprint author), NIMH, Div AIDS Res, NIH, Bethesda, MD 20892 USA. EM wpequegn@mail.nih.gov; carlcbell@pol.net NR 2 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-1-4614-0439-2 PY 2012 BP IX EP XII D2 10.1007/978-1-4614-0439-2 PG 4 WC Family Studies; Public, Environmental & Occupational Health SC Family Studies; Public, Environmental & Occupational Health GA BGJ68 UT WOS:000323234400002 ER PT J AU Allison, S AF Allison, Susannah BE Pequegnat, W Bell, CC TI The Role of Families Among Orphans and Vulnerable Children in Confronting HIV/AIDS in Sub-Saharan Africa SO FAMILY AND HIV/AIDS: CULTURAL AND CONTEXTUAL ISSUES IN PREVENTION AND TREATMENT LA English DT Article; Book Chapter ID REPRODUCTIVE HEALTH-RISK; YOUTH-HEADED HOUSEHOLDS; AIDS ORPHANS; SOUTH-AFRICA; PROTECTIVE FACTORS; PARENTAL DEATH; HIV-INFECTION; MENTAL-HEALTH; RURAL UGANDA; PSYCHOLOGICAL DISTRESS AB This chapter provides an overview of the impact of the HIV/AIDS epidemic on vulnerable children and families in sub-Saharan Africa. There is a discussion of the terms used to describe HIV-affected vulnerable children. As a result of the generalized epidemic and widespread poverty, many children and families are in need of services. This chapter covers the research on the impact of HIV/AIDS on children and their families in four key areas: (1) care arrangements, (2) educational opportunities, (3) mental health, and (4) HIV risk behaviors. This is followed by a review of the emerging literature on services and programs. The chapter concludes with a discussion of the shortcomings of the research and what has been learned from the studies and programs to date. C1 NIMH, Infants Children & Adolescents Res Program, Ctr Mental Hlth Res AIDS, Bethesda, MD 20892 USA. RP Allison, S (reprint author), NIMH, Infants Children & Adolescents Res Program, Ctr Mental Hlth Res AIDS, Bethesda, MD 20892 USA. NR 134 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-1-4614-0439-2 PY 2012 BP 173 EP 194 DI 10.1007/978-1-4614-0439-2_8 D2 10.1007/978-1-4614-0439-2 PG 22 WC Family Studies; Public, Environmental & Occupational Health SC Family Studies; Public, Environmental & Occupational Health GA BGJ68 UT WOS:000323234400010 ER PT J AU Mustanski, B Hunter, J AF Mustanski, Brian Hunter, Joyce BE Pequegnat, W Bell, CC TI Parents as Agents of HIV Prevention for Gay, Lesbian, and Bisexual Youth SO FAMILY AND HIV/AIDS: CULTURAL AND CONTEXTUAL ISSUES IN PREVENTION AND TREATMENT LA English DT Article; Book Chapter ID YOUNG MEN; UNITED-STATES; BEHAVIORAL INTERVENTIONS; IDENTITY DEVELOPMENT; SEXUAL ORIENTATION; HEALTH-PROBLEMS; SELF-ESTEEM; COMING-OUT; PREVALENCE; RISK AB Young men who have sex with men (MSM) account for the majority of HIV infections among young people in the United States and young women who have sex with women and men can also become infected with HIV. While family-based approaches have been established for other groups of youth, very few have been developed and tested with sexual minority youth. This chapter reviews evidence for the feasibility of developing family-based programs for these youth as well some of the factors that should be incorporated into such an approach. C1 [Mustanski, Brian] Northwestern Univ, Evanston, IL 60208 USA. [Mustanski, Brian] Northwestern Univ, IMPACT LGBT Hlth & Dev Program, Evanston, IL 60208 USA. [Mustanski, Brian] NIH, Bethesda, MD USA. [Mustanski, Brian] Natl Sci Fdn, Arlington, VA 22230 USA. [Hunter, Joyce] Columbia Univ, New York State Psychiat Inst, HIV Ctr Clin & Behav Studies, New York, NY 10027 USA. [Hunter, Joyce] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY 10027 USA. [Hunter, Joyce] Columbia Univ, New York, NY 10027 USA. RP Mustanski, B (reprint author), Northwestern Univ, Evanston, IL 60208 USA. NR 55 TC 2 Z9 2 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-1-4614-0439-2 PY 2012 BP 249 EP 260 DI 10.1007/978-1-4614-0439-2_12 D2 10.1007/978-1-4614-0439-2 PG 12 WC Family Studies; Public, Environmental & Occupational Health SC Family Studies; Public, Environmental & Occupational Health GA BGJ68 UT WOS:000323234400014 ER PT B AU Bell, CC Pequegnat, W AF Bell, Carl C. Pequegnat, Willo BE Pequegnat, W Bell, CC TI Future Directions for Family-Based Prevention and Treatment Research: Challenges and Emerging Issues SO FAMILY AND HIV/AIDS: CULTURAL AND CONTEXTUAL ISSUES IN PREVENTION AND TREATMENT LA English DT Article; Book Chapter ID ADULT PSYCHIATRIC-DISORDERS; CHILDHOOD ADVERSITIES; VACCINE AB This chapter reviews the emerging issues in family-based prevention programs and future research directions. Despite the fact that there are many universal family attributes, there are some important cultural and contextual issues that require "tailor made" approach for some issues. However, the culturally tailored intervention must be grounded in core behavior change principles or they will not have the intended benefit for families. This chapter reviews the challenges of family-based combination and multilevel intervention which combine biomedical and behavioral approaches that optimize the HIV prevention benefits for families. There are some challenges in research strategies that must be addressed. For example, the current studies have a short follow-up period and if we are going to learn how the family impacts the long-term protective factors, we must have cohorts that are followed while children age into more risky periods of social development. Strategies need to be identified that ensure sustainability of effective family-based programs. If family based programs are going to be adopted by public health agencies, it is important to generate cost effectiveness data. There are also challenges in new settings that need to be explored; for example, foster care and juvenile systems, African American and Hispanic churches, and workplaces. There are also some populations that would benefit from family-based prevention program such as mentally ill children, young men who have sex with men (YMSM), rural families, and children in blended families. Researchers are challenged by the promising new directions of the third decade of the HIV epidemic. C1 [Bell, Carl C.] Univ Illinois, Chicago, IL 60607 USA. [Bell, Carl C.] Univ Illinois, Inst Juvenile Res, Chicago, IL USA. [Bell, Carl C.] Community Mental Hlth Council CMHC & Fdn Inc, Chicago, IL USA. [Pequegnat, Willo] NIMH, Div AIDS Res, NIH, Bethesda, MD 20892 USA. RP Bell, CC (reprint author), Univ Illinois, Chicago, IL 60607 USA. EM carlcbell@pol.net; wpequegn@mail.nih.gov NR 15 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-1-4614-0439-2; 978-1-4614-0438-5 PY 2012 BP 331 EP 339 DI 10.1007/978-1-4614-0439-2_16 D2 10.1007/978-1-4614-0439-2 PG 9 WC Family Studies; Public, Environmental & Occupational Health SC Family Studies; Public, Environmental & Occupational Health GA BGJ68 UT WOS:000323234400018 ER PT S AU Peddada, SD Umbach, DM Harris, S AF Peddada, Shyamal D. Umbach, David M. Harris, Shawn BE Rao, CR Chakraborty, R Sen, PK TI Statistical Analysis of Gene Expression Studies with Ordered Experimental Conditions SO BIOINFORMATICS IN HUMAN HEALTH AND HEREDITY SE Handbook of Statistics LA English DT Article; Book Chapter DE gene expression; microarray; time-course; dose-response; order-restricted inference; multiple comparisons; cell cycle ID TIME-COURSE MICROARRAY; CYCLE-REGULATED GENES; FALSE DISCOVERY RATE; FUNCTIONAL DATA-ANALYSIS; YEAST-CELL CYCLE; CDNA MICROARRAY; TRANSCRIPTIONAL PROGRAM; SAMPLE CLASSIFICATION; RESTRICTED INFERENCE; COEXPRESSED GENES AB In the past decade, the availability of microarray technology for monitoring the expression of thousands of genes simultaneously has enhanced the ability of scientists to probe fundamental biological processes. Interest often focuses on comparisons across experimental conditions that exhibit a characteristic ordering, such as time-course or dose-response experiments. Although many methods for analyzing microarray data exist, relatively few of them are tailored for maximal efficiency with ordered experimental conditions. This chapter provides an overview of the range of methods available for analyzing such studies. We consider methods appropriate with "short-series" data that involves relatively few time points as well as those appropriate with "long-series" data for the study of the cell cycle or developmental processes. The number of available methods makes an exhaustive review impractical; instead, we have tried to illustrate selectively the spectrum of available methods. C1 [Peddada, Shyamal D.; Umbach, David M.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Harris, Shawn] SRA Int Inc, Publ Hlth Programs, Durham, NC 27713 USA. RP Peddada, SD (reprint author), NIEHS, Biostat Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM peddada@niehs.nih.gov NR 97 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-7161 BN 978-0-08-093098-5 J9 HANDB STAT PY 2012 VL 28 BP 39 EP 66 DI 10.1016/B978-0-44-4518750.00003-8 PG 28 WC Medical Informatics; Statistics & Probability SC Medical Informatics; Mathematics GA BGH53 UT WOS:000323006600004 ER PT J AU Onyshchenko, MI Panyutin, IG Panyutin, IV Neumann, RD AF Onyshchenko, Mykola I. Panyutin, Igor G. Panyutin, Irina V. Neumann, Ronald D. TI Stimulation of Cultured H9 Human Embryonic Stem Cells with Thyroid Stimulating Hormone Does Not Lead to Formation of Thyroid-Like Cells SO STEM CELLS INTERNATIONAL LA English DT Article ID SODIUM/IODIDE SYMPORTER NIS; DEFINITIVE ENDODERM; GENE-EXPRESSION; BREAST-CANCER; RADIOIODINE THERAPY; IN-VITRO; DIFFERENTIATION; LINES AB The sodium-iodine symporter (NIS) is expressed on the cell membrane of many thyroid cancer cells, and is responsible for the radioactive iodine accumulation. However, treatment of anaplastic thyroid cancer is ineffective due to the low expression of NIS on cell membranes of these tumor cells. Human embryonic stem cells (ESCs) provide a potential vehicle to study the mechanisms of NIS expression regulation during differentiation. Human ESCs were maintained on feeder-independent culture conditions. RT-qPCR and immunocytochemistry were used to study differentiation marker expression, I-125 uptake to study NIS function. We designed a two-step protocol for human ESC differentiation into thyroid-like cells, as was previously done for mouse embryonic stem cells. First, we obtained definitive endoderm from human ESCs. Second, we directed differentiation of definitive endoderm cells into thyroid-like cells using various factors, with thyroid stimulating hormone (TSH) as the main differentiating factor. Expression of pluripotency, endoderm and thyroid markers and I-125 uptake were monitored throughout the differentiation steps. These approaches did not result in efficient induction of thyroid-like cells. We conclude that differentiation of human ESCs into thyroid cells cannot be induced by TSH media supplementation alone and most likely involves complicated developmental patterns that are yet to be understood. C1 [Onyshchenko, Mykola I.] NIH, Imaging Sci Training Program, Ctr Clin, Bethesda, MD 20892 USA. [Onyshchenko, Mykola I.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Panyutin, Igor G.; Panyutin, Irina V.; Neumann, Ronald D.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Onyshchenko, MI (reprint author), NIH, Imaging Sci Training Program, Ctr Clin, Bethesda, MD 20892 USA. EM onyshchenkom@mail.nih.gov OI Onyshchenko, Mykola/0000-0003-4663-0991 FU Imaging Sciences Training Program; Radiology and Imaging Sciences Department, Clinical Center; Intramural Research Program at the National Institute of Biomedical Imaging and Bioengineering, NIH FX The paper was sponsored by the Imaging Sciences Training Program, the Radiology and Imaging Sciences Department, Clinical Center, and the Intramural Research Program at the National Institute of Biomedical Imaging and Bioengineering, NIH. The authors would like to thank Dr. Manimekalai Saravanan for the samples of normal human thyroid tissue from the Laboratory of Pathology for Human Biological Materials, NIH. NR 32 TC 0 Z9 0 U1 2 U2 3 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1687-966X J9 STEM CELLS INT JI Stem Cells Int. PY 2012 AR UNSP 634914 DI 10.1155/2012/634914 PG 8 WC Cell & Tissue Engineering SC Cell Biology GA 209RB UT WOS:000323776400001 ER PT J AU Pal, R Rao, M Vemuri, MC Verma, P Dinnyes, A AF Pal, Rajarshi Rao, Mahendra Vemuri, Mohan C. Verma, Paul Dinnyes, Andras TI Advances in Induced Pluripotent Stem Cell Technologies SO STEM CELLS INTERNATIONAL LA English DT Editorial Material C1 [Pal, Rajarshi] Manipal Univ, Manipal Inst Regenerat Med, Bangalore 560071, Karnataka, India. [Rao, Mahendra] NIH Ctr Regenerat Med, Bethesda, MD 20892 USA. [Vemuri, Mohan C.] Life Technol, Frederick, MD 21704 USA. [Verma, Paul] Monash Univ, Monash Inst Med Res, Ctr Reprod & Dev, Clayton, Vic 33168, Australia. [Dinnyes, Andras] BioTalentum Ltd, H-2100 Godollo, Hungary. RP Pal, R (reprint author), Manipal Univ, Manipal Inst Regenerat Med, Branch Campus, Bangalore 560071, Karnataka, India. EM rajarshi.pal@manipal.edu OI Dinnyes, Andras/0000-0003-3791-2583 NR 0 TC 0 Z9 0 U1 1 U2 2 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1687-966X J9 STEM CELLS INT JI Stem Cells Int. PY 2012 AR UNSP 850201 DI 10.1155/2012/850201 PG 1 WC Cell & Tissue Engineering SC Cell Biology GA 209TD UT WOS:000323782000001 ER PT J AU Sokolov, MV Neumann, RD AF Sokolov, Mykyta V. Neumann, Ronald D. TI Human Embryonic Stem Cell Responses to Ionizing Radiation Exposures: Current State of Knowledge and Future Challenges SO STEM CELLS INTERNATIONAL LA English DT Review ID NORMAL HUMAN FIBROBLASTS; DOUBLE-STRAND BREAKS; GENE-EXPRESSION; INTERCELLULAR COMMUNICATION; HOMOLOGOUS RECOMBINATION; SELF-RENEWAL; DNA-DAMAGE; CYCLE; REPAIR; LINES AB Human embryonic stem cells, which are derived from the inner cell mass of the blastocyst, have become an object of intense study over the last decade. They possess two unique properties that distinguish them from many other cell types: (i) the ability to self-renew indefinitely in culture under permissive conditions, and (ii) the pluripotency, defined as the capability of giving rise to all cell types of embryonic lineage under the guidance of the appropriate developmental cues. The focus of many recent efforts has been on the elucidating the signaling pathways and molecular networks operating in human embryonic stem cells. These cells hold great promise in cell-based regenerative therapies, disease modeling, drug screening and testing, assessing genotoxic and mutagenic risks associated with exposures to a variety of environmental factors, and so forth. Ionizing radiation is ubiquitous in nature, and it is widely used in diagnostic and therapeutic procedures in medicine. In this paper, our goal is to summarize the recent progress in understanding how human embryonic stem cells respond to ionizing radiation exposures, using novel methodologies based on "omics" approaches, and to provide a critical discussion of what remains unknown; thus proposing a roadmap for the future research in this area. C1 [Sokolov, Mykyta V.; Neumann, Ronald D.] NIH, Ctr Clin, Radiol & Imaging Sci Dept, Div Nucl Med, Bethesda, MD 20892 USA. RP Sokolov, MV (reprint author), NIH, Ctr Clin, Radiol & Imaging Sci Dept, Div Nucl Med, 9000 Rockville Pike,Bldg 10,Room 4D49, Bethesda, MD 20892 USA. EM sokolovm@mail.nih.gov NR 91 TC 2 Z9 2 U1 0 U2 3 PU HINDAWI PUBLISHING CORP PI NEW YORK PA 315 MADISON AVE 3RD FLR, STE 3070, NEW YORK, NY 10017 USA SN 1687-966X EI 1687-9678 J9 STEM CELLS INT JI Stem Cells Int. PY 2012 AR UNSP 579104 DI 10.1155/2012/579104 PG 11 WC Cell & Tissue Engineering SC Cell Biology GA 209QJ UT WOS:000323774200001 ER PT J AU Waheed, AA Freed, EO AF Waheed, Abdul A. Freed, Eric O. TI HIV Type 1 Gag as a Target for Antiviral Therapy SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; MATURATION INHIBITOR BEVIRIMAT; MURINE LEUKEMIA-VIRUS; AMINO-ACID SUBSTITUTIONS; GP41 CYTOPLASMIC TAIL; LATE-BUDDING DOMAINS; TRIM5-ALPHA RESTRICTION FACTOR; NUCLEOCAPSID PROTEIN NCP7; SMALL-MOLECULE INHIBITION; MAJOR HOMOLOGY REGION AB The Gag proteins of HIV-1 are central players in virus particle assembly, release, and maturation, and also function in the establishment of a productive infection. Despite their importance throughout the replication cycle, there are currently no approved antiretroviral therapies that target the Gag precursor protein or any of the mature Gag proteins. Recent progress in understanding the structural and cell biology of HIV-1 Gag function has revealed a number of potential Gag-related targets for possible therapeutic intervention. In this review, we summarize our current understanding of HIV-1 Gag and suggest some approaches for the development of novel antiretroviral agents that target Gag. C1 [Waheed, Abdul A.; Freed, Eric O.] NCI, HIV Drug Resistance Program, Virus Cell Interact Sect, Frederick, MD 21702 USA. RP Waheed, AA (reprint author), NCI, HIV Drug Resistance Program, Virus Cell Interact Sect, Bldg 535,Room 108,1050 Boyles St, Frederick, MD 21702 USA. EM waheedab@mail.nih.gov; efreed@nih.gov FU NIH; National Cancer Institute; Center for Cancer Research; Intramural AIDS Targeted Antiviral Program FX We thank L. Henderson for providing the image shown in Fig. 1 and M. Summers for Fig. 3. Wealso thank W. Sundquist, M. Summers, E. Wright, A. Steven, M. Yeager, J. Hurley, and G. Jensen for permission to reproduce figures and members of Freed laboratory for helpful discussions and critical reading of the manuscript. Research in Freed laboratory is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and the Intramural AIDS Targeted Antiviral Program. NR 279 TC 30 Z9 30 U1 0 U2 15 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JAN PY 2012 VL 28 IS 1 BP 54 EP 75 DI 10.1089/aid.2011.0230 PG 22 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 876WB UT WOS:000299137300005 PM 21848364 ER PT J AU Sharon, E Zhang, JL Hollevoet, K Steinberg, SM Pastan, I Onda, M Gaedcke, J Ghadimi, BM Ried, T Hassan, R AF Sharon, Elad Zhang, Jingli Hollevoet, Kevin Steinberg, Seth M. Pastan, Ira Onda, Masanori Gaedcke, Jochen Ghadimi, B. Michael Ried, Thomas Hassan, Raffit TI Serum mesothelin and megakaryocyte potentiating factor in pancreatic and biliary cancers SO CLINICAL CHEMISTRY AND LABORATORY MEDICINE LA English DT Article DE biliary cancer; megakaryocyte potentiating factor; mesothelin; pancreatic cancer ID MALIGNANT PLEURAL MESOTHELIOMA; TUMOR-MARKER; SOLUBLE MESOTHELIN; ADENOCARCINOMAS; DIAGNOSIS; CA125 AB Background: Tumor mesothelin overexpression is present in different malignancies, including the majority of patients with pancreatic or biliary cancers. The objective of this study was to evaluate the use of shed serum mesothelin and megakaryocyte potentiating factor (MPF) concentrations as biomarkers for these cancers. Methods: A total of 151 individuals, divided into five groups, were retrospectively analyzed: healthy donors (n=15), patients with benign non-pancreatic conditions (n=52), benign pancreatic conditions (n=33), biliary carcinoma (n=9), and pancreatic ductal adenocarcinoma (n=42). Mesothelin and MPF concentrations were measured in serum with the Mesomark (TM) and Human MPF ELISA, respectively. Results: Mesothelin and MPF concentrations did not significantly differ among the five individual participant groups (p=0.34, p=0.33, respectively), nor did any other combination and pair-wise comparison of the participant groups demonstrated a significant difference in biomarker concentrations. In patients with pancreatic cancer, mesothelin or MPF concentrations were not associated with tumor stage (p=0.87, p=0.48, respectively) or differentiation grade (p=0.73, p=0.52, respectively). Conclusions: Serum mesothelin and MPF concentrations, measured with standard available ELISAs, were not specific for benign or pancreatic disease. Both biomarkers were not elevated in patients with pancreatic or biliary cancers, and consequently do not appear to be useful biomarkers for these malignancies. C1 [Sharon, Elad; Zhang, Jingli; Hollevoet, Kevin; Pastan, Ira; Onda, Masanori; Hassan, Raffit] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gaedcke, Jochen; Ghadimi, B. Michael] Univ Med Ctr Goettingen, Dept Gen & Visceral Surg, Gottingen, Germany. [Ried, Thomas] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5116, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank all study participants and the investigators involved in this study. David J. Liewehr provided technical assistance with the statistical analysis and presentation of data. Yoshiro Kishi and colleagues (Medical & Biological Laboratories Co., Ltd., Japan) provided the Human MPF ELISA kits. NR 25 TC 5 Z9 5 U1 1 U2 4 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 1434-6621 J9 CLIN CHEM LAB MED JI Clin. Chem. Lab. Med. PY 2012 VL 50 IS 4 BP 721 EP 725 DI 10.1515/CCLM.2011.816 PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 946FO UT WOS:000304337100020 PM 22149739 ER PT J AU Resnik, DB AF Resnik, David B. BE Chapman, AR TI Ethical issues in human genomic databases in addiction research SO GENETIC RESEARCH ON ADDICTION: ETHICS, THE LAW, AND PUBLIC HEALTH LA English DT Article; Book Chapter ID INFORMED-CONSENT; SUSCEPTIBILITY; PARTICIPANTS; BIOBANKS; ICELAND; LESSONS; SCIENCE; PRIVACY; SAMPLES; RULES C1 Natl Inst Environm Hlth, NIH, Bethesda, MD USA. RP Resnik, DB (reprint author), Natl Inst Environm Hlth, NIH, Bethesda, MD USA. NR 47 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-107-65334-4 PY 2012 BP 108 EP 121 D2 10.1017/CBO9781139058971 PG 14 WC Genetics & Heredity; Medical Ethics SC Genetics & Heredity; Medical Ethics GA BFS53 UT WOS:000321148000009 ER PT B AU Diana, A AF Diana, Augusto BE Meyer, AL Gullotta, TP TI Physical Activity: Definitional Issues and Knowledge Gaps SO PHYSICAL ACTIVITY ACROSS THE LIFESPAN: PREVENTION AND TREATMENT FOR HEALTH AND WELL-BEING SE Issues in Childrens and Families Lives LA English DT Article; Book Chapter ID POSITIVE YOUTH DEVELOPMENT; LIVING RESEARCH-PROGRAM; EXTRACURRICULAR ACTIVITIES; COLLEGE-STUDENTS; ALCOHOL-USE; EXERCISE; HEALTH; LEISURE; PARTICIPATION; ADOLESCENTS C1 NIDA, Div Epidemiol Serv & Prevent Res, Prevent Res Branch, Bethesda, MD 20892 USA. RP Diana, A (reprint author), NIDA, Div Epidemiol Serv & Prevent Res, Prevent Res Branch, 6001 Execut Blvd,Room 5163,MSC 9589, Bethesda, MD 20892 USA. EM dianaa@nida.nih.gov NR 95 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-1-4614-3606-5; 978-1-4614-3605-8 J9 ISSUES CHILD FAM LIV PY 2012 BP 1 EP 22 DI 10.1007/978-1-4614-3606-5_1 D2 10.1007/978-1-4614-3606-5 PG 22 WC Family Studies; Public, Environmental & Occupational Health SC Family Studies; Public, Environmental & Occupational Health GA BFW95 UT WOS:000321718900002 ER PT J AU Meyer, AL Diana, A Robertson, E AF Meyer, Aleta L. Diana, Augusto Robertson, Elizabeth BE Meyer, AL Gullotta, TP TI Physical Activity for the Prevention of Child and Adolescent Drug Abuse SO PHYSICAL ACTIVITY ACROSS THE LIFESPAN: PREVENTION AND TREATMENT FOR HEALTH AND WELL-BEING SE Issues in Childrens and Families Lives LA English DT Article; Book Chapter ID EXECUTIVE COGNITIVE FUNCTION; SOCIAL-DEVELOPMENT; DEVELOPMENTAL SCIENCE; SELF-REGULATION; SUBSTANCE USE; FOOD-INTAKE; INTERVENTION; BEHAVIOR; MOTIVATION; PROGRAM C1 [Meyer, Aleta L.] Adm Children & Families, Off Planning Res & Evaluat, Washington, DC 20447 USA. [Diana, Augusto] NIDA, Div Epidemiol Serv & Prevent Res, Prevent Res Branch, Bethesda, MD 20892 USA. [Robertson, Elizabeth] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20852 USA. RP Meyer, AL (reprint author), Adm Children & Families, Off Planning Res & Evaluat, 370 Enfant Plaza Promenade SW, Washington, DC 20447 USA. EM aleta.meyer@acf.hhs.gov NR 61 TC 0 Z9 0 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-1-4614-3606-5 J9 ISSUES CHILD FAM LIV PY 2012 BP 193 EP 212 DI 10.1007/978-1-4614-3606-5_10 D2 10.1007/978-1-4614-3606-5 PG 20 WC Family Studies; Public, Environmental & Occupational Health SC Family Studies; Public, Environmental & Occupational Health GA BFW95 UT WOS:000321718900011 ER PT J AU Aguilera, G AF Aguilera, Greti BE Fink, G Pfaff, DW Levine, JE TI The Hypothalamic-Pituitary-Adrenal Axis and Neuroendocrine Responses to Stress SO HANDBOOK OF NEUROENDOCRINOLOGY LA English DT Article; Book Chapter ID CORTICOTROPIN-RELEASING-HORMONE; MESSENGER-RNA EXPRESSION; RAT ANTERIOR-PITUITARY; SENSORY CIRCUMVENTRICULAR ORGANS; PARAVENTRICULAR NUCLEUS; GLUCOCORTICOID-RECEPTOR; ARGININE-VASOPRESSIN; LUTEINIZING-HORMONE; GENE-EXPRESSION; INDUCED SUPPRESSION AB External or internal stressful stimuli threatening homeostasis induce coordinated responses, including behavioral, autonomic nervous system and endocrine changes, aimed at restoring the internal equilibrium. The major neuroendocrine stress response occurs via activation of the hypothalamic pituitary adrenal axis, initiated by corticotropin-releasing hormone (CRH) secretion, leading ultimately to increased adrenal glucocorticoid production. Acting through receptors in the brain, CRH and glucocorticoids play a critical role in coordinating the stress response. This includes not only behavioral and autonomic responses but also alterations in the activity of other neuroendocrine systems, such as the hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid and hypothalamic-growth hormone axes. Acute stress responses are transient and beneficial, but chronic stress or inadequate stress responses often lead to pathology. This chapter describes the neuroendocrine mechanisms regulating the HPA axis responses to stress, and its contribution to the integrated adaptive responses. C1 NIH, Program Dev Endocrinol & Genet, Eunice Kennedy Shiver Inst Child Hlth & Human Dev, Bethesda, MD 20892 USA. RP Aguilera, G (reprint author), NIH, Program Dev Endocrinol & Genet, Eunice Kennedy Shiver Inst Child Hlth & Human Dev, Bldg 10, Bethesda, MD 20892 USA. NR 149 TC 2 Z9 2 U1 2 U2 7 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-378554-1 PY 2012 BP 175 EP 196 DI 10.1016/B978-0-12-375097-6.10008-3 PG 22 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA BFX77 UT WOS:000321820500009 ER PT B AU Clarke, IJ Campbell, R Smith, JT Prevot, V Wray, S AF Clarke, Iain J. Campbell, Rebecca Smith, Jeremy T. Prevot, Vincent Wray, Susan BE Fink, G Pfaff, DW Levine, JE TI Neuroendocrine Control of Reproduction SO HANDBOOK OF NEUROENDOCRINOLOGY LA English DT Article; Book Chapter ID GONADOTROPIN-RELEASING-HORMONE; FOLLICLE-STIMULATING-HORMONE; ESTROGEN-RECEPTOR-ALPHA; RFAMIDE-RELATED PEPTIDE-3; ELEMENT-BINDING PROTEIN; MESSENGER-RNA LEVELS; RIBONUCLEIC-ACID EXPRESSION; PLASMA LUTEINIZING-HORMONE; POSITIVE FEEDBACK ACTION; FEMALE RHESUS-MONKEYS AB In this chapter the operation of the hypothalamic-pituitary gonadal axis is considered, with special reference to the way that gonadotropin-releasing hormone (GnRH) and gonadotropin secretion is controlled by gonadal hormones. The nature of GnRH neurons and how they function is considered, especially with respect to the way that GnRH secretion is controlled by the feedback effects of gonadal steroids. Feedback effects are also important at the level of the gonadotropes, and this too is covered in detail. With this background, a working model of the female estrous/menstrual cycle is presented. C1 [Clarke, Iain J.; Smith, Jeremy T.] Monash Univ, Dept Physiol, Clayton, Vic 3168, Australia. [Campbell, Rebecca] Univ Otago, Dept Physiol, Sch Med Sci, Dunedin, New Zealand. [Prevot, Vincent] INSERM, U837, Jean Pierre Aubert Res Ctr, F-59045 Lille, France. [Prevot, Vincent] Univ Nord France, Lille, France. [Prevot, Vincent] UDSL, Anat Lab, Sch Med, Lille, France. [Prevot, Vincent] Hop Roger Salengro, CHRU Lille, Dept Neurosurg, Lille, France. [Wray, Susan] NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Clarke, IJ (reprint author), Monash Univ, Dept Physiol, Clayton, Vic 3168, Australia. OI Prevot, Vincent/0000-0001-7185-3615; wray, susan/0000-0001-7670-3915 NR 238 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-378554-1; 978-0-12-375097-6 PY 2012 BP 197 EP 235 DI 10.1016/B978-0-12-375097-6.10009-5 PG 39 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA BFX77 UT WOS:000321820500010 ER PT B AU Kino, T Charmandari, E Chrousos, GP AF Kino, Tomoshige Charmandari, Evangelia Chrousos, George P. BE Fink, G Pfaff, DW Levine, JE TI Disorders of the Hypothalamic-Pituitary-Adrenocortical System SO HANDBOOK OF NEUROENDOCRINOLOGY LA English DT Article; Book Chapter ID GLUCOCORTICOID-RECEPTOR GENE; LIGAND-BINDING DOMAIN; CORTICOTROPIN-RELEASING HORMONE; CONGENITAL ADRENAL-HYPERPLASIA; PRIMARY CORTISOL RESISTANCE; PRADER-WILLI-SYNDROME; CUSHINGS-SYNDROME; POINT MUTATION; ER22/23EK POLYMORPHISM; HOMOZYGOUS MUTATION AB The hypothalamic-pituitary-adrenocortical (HPA) system is essential for the maintenance of internal homeostasis and a major mediator component of the body's adaptive response to internal or external stressors. This system consists of three components, the hypothalamus, the pituitary gland and the adrenal cortex, which respectively secrete their signaling molecules: the corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), the adrenocorticotropic hormone (ACTH), and the glucocorticoid steroid cortisol. Importantly, various pathologic conditions affecting any of the three components, whether hereditary or acquired, result in dysfunction in this system. The clinical manifestations of impaired function of the HPA system are evident either as glucocorticoid excess or as glucocorticoid insufficiency, and may have detrimental effects on several organs and systems. In this chapter, we describe the pathologic origins, the clinical manifestations and the management of the most common disorders of the HPA system. C1 [Kino, Tomoshige] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Charmandari, Evangelia; Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, Aghia Sophia Childrens Hosp, GR-11527 Athens, Greece. [Charmandari, Evangelia; Chrousos, George P.] Acad Athens, Div Endocrinol & Metab, Biomed Res Fdn, Athens, Greece. RP Kino, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 129 TC 1 Z9 2 U1 1 U2 2 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-378554-1; 978-0-12-375097-6 PY 2012 BP 639 EP 657 DI 10.1016/B978-0-12-375097-6.10029-0 PG 19 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA BFX77 UT WOS:000321820500030 ER PT J AU Rubinow, DR Crowder, VL Schmidt, PJ Rubinow, KB AF Rubinow, David R. Crowder, Virginia L. Schmidt, Peter J. Rubinow, Katya B. BE Fink, G Pfaff, DW Levine, JE TI Psychoneuroendocrinology SO HANDBOOK OF NEUROENDOCRINOLOGY LA English DT Article; Book Chapter ID CORTICOTROPIN-RELEASING HORMONE; GLUCOCORTICOID-RECEPTOR GENE; POSITRON-EMISSION-TOMOGRAPHY; PITUITARY-ADRENAL-FUNCTION; FORCED SWIM TEST; CUSHINGS-SYNDROME; DEPRESSED-PATIENTS; GONADAL-STEROIDS; MENSTRUAL-CYCLE; PREMENSTRUAL-SYNDROME AB The basic principles of psychoneuroendocrinology can be extracted from the efforts to characterize the complex interactions among the central nervous system, hormones, and behavior. The first set of principles derives from traditional psychoneuroendocrine studies: (1) hormonal disruption can effect behavioral change; (2) exogenously administered hormones can confer psychoactive effects; (3) endocrine dysfunction and psychiatric symptoms may co-occur in both primary endocrinopathies and primary psychiatric disorders. The second set of principles incorporates a more recent, nuanced, and contextual view of physiology in general and the physiological basis of behavioral regulation in particular: (4) altered endocrine function generates behavioral abnormalities in only a subset of individuals; (5) behavioral abnormalities can be etiologically linked to normal endocrine function; and (6) environmental context can modulate this relationship between endocrine function and behavior. The observations giving rise to these latter principles suggest that despite the clear relevance of endocrine function to a variety of affective-behavioral experiences (as implied by the term "psychoneuroendocrinology"), the etiological role of hormones in these experiences is highly context-dependent. Further, identification of the determinants of context dependency is far more likely to inform us about the biological constituents of behavior than is exclusive attention to hormone exposure and level. C1 [Rubinow, David R.; Crowder, Virginia L.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA. [Schmidt, Peter J.] NIMH, Sect Behav Endocrinol, Bethesda, MD 20892 USA. [Rubinow, Katya B.] Univ Washington, Sch Med, Dept Med, Div Endocrinol, Seattle, WA 98195 USA. RP Rubinow, DR (reprint author), Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA. NR 79 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-378554-1 PY 2012 BP 779 EP 790 DI 10.1016/B978-0-12-375097-6.10036-8 PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA BFX77 UT WOS:000321820500037 ER PT J AU Muyembe-Tamfum, JJ Mulangu, S Masumu, J Kayembe, JM Kemp, A Paweska, JT AF Muyembe-Tamfum, J. J. Mulangu, S. Masumu, Justin Kayembe, J. M. Kemp, A. Paweska, Janusz T. TI Ebola virus outbreaks in Africa: Past and present SO ONDERSTEPOORT JOURNAL OF VETERINARY RESEARCH LA English DT Article; Proceedings Paper CT Conference of the Southern-African-Centre-for-Infectious-Diseases-Surveillance One Health CY JUL 14-15, 2011 CL Natl Inst Communicable Dis, Johannesburg, SOUTH AFRICA SP So African Ctr Infect Dis Surveillance HO Natl Inst Communicable Dis ID HEMORRHAGIC-FEVER EPIDEMIC; IGG ANTIBODIES; MARBURG VIRUS; GABON; CONGO; PREVALENCE; SUDAN; ZAIRE; TRANSMISSION; REEMERGENCE AB Ebola haemorrhagic fever (EHF) is a zoonosis affecting both human and non-human primates (NHP). Outbreaks in Africa occur mainly in the Congo and Nile basins. The first outbreaks of EHF occurred nearly simultaneously in 1976 in the Democratic Republic of the Congo (DRC, former Zaire) and Sudan with very high case fatality rates of 88% and 53%, respectively. The two outbreaks were caused by two distinct species of Ebola virus named Zaire ebolavirus (ZEBOV) and Sudan ebolavirus (SEBOV). The source of transmission remains unknown. After a long period of silence (1980-1993), EHF outbreaks in Africa caused by the two species erupted with increased frequency and new species were discovered, namely Cote d'Ivoire ebolavirus (CIEBOV) in 1994 in the Ivory Coast and Bundibugyo ebolavirus (BEBOV) in 2007 in Uganda. The re-emergence of EHF outbreaks in Gabon and Republic of the Congo were concomitant with an increase in mortality amongst gorillas and chimpanzees infected with ZEBOV. The human outbreaks were related to multiple, unrelated index cases who had contact with dead gorillas or chimpanzees. However, in areas where NHP were rare or absent, as in Kikwit (DRC) in 1995, Mweka (DRC) in 2007, Gulu (Uganda) in 2000 and Yambio (Sudan) in 2004, the hunting and eating of fruit bats may have resulted in the primary transmission of Ebola virus to humans. Human-to-human transmission is associated with direct contact with body fluids or tissues from an infected subject or contaminated objects. Despite several, often heroic field studies, the epidemiology and ecology of Ebola virus, including identification of its natural reservoir hosts, remains a formidable challenge for public health and scientific communities. C1 [Muyembe-Tamfum, J. J.; Masumu, Justin] Inst Natl Rech Biomed, Kinshasa 1, Zaire. [Muyembe-Tamfum, J. J.; Kayembe, J. M.] Univ Kinshasa, Kinshasa 11, Zaire. [Mulangu, S.; Masumu, Justin] Southern African Ctr Infect Dis, Chuo Kiikuu, Tanzania. [Mulangu, S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Masumu, J (reprint author), POB 3297, Morogoro, Tanzania. EM justin.masumu@sacids.org NR 40 TC 34 Z9 37 U1 8 U2 136 PU ONDERSTEPOORT VETERINARY INST, AGRICULTURAL RESEARCH COUNCIL PI ONDERSTEPOORT PA PRIVATE BAG X5, ONDERSTEPOORT 0110, SOUTH AFRICA SN 0030-2465 EI 2219-0635 J9 ONDERSTEPOORT J VET JI Onderstepoort J. Vet. Res. PY 2012 VL 79 IS 2 SU 3 AR 451 DI 10.4102/ojvr.v79i2.451 PG 8 WC Veterinary Sciences SC Veterinary Sciences GA 189OF UT WOS:000322275800003 PM 23327370 ER PT S AU Pedoto, G Santaniello, S Fiengo, G Glielmo, L Hallett, M Zhuang, P Sarma, SV AF Pedoto, Gilda Santaniello, Sabato Fiengo, Giovanni Glielmo, Luigi Hallett, Mark Zhuang, Ping Sarma, Sridevi V. GP IEEE TI Towards Automated Navigation of Deep Brain Stimulating Electrodes: Analyzing Neuronal Activity Near the Target SO 2012 IEEE INTERNATIONAL CONFERENCE ON CONTROL APPLICATIONS (CCA) SE IEEE International Conference on Control Applications LA English DT Proceedings Paper CT IEEE International Conference on Control Applications (CCA) Part of 6th IEEE Multi-Conference on Systems and Control (IEEE MSC) CY OCT 03-05, 2012 CL Dubrovnik, CROATIA SP IEEE, IEEE Control Syst Soc (CSS), IEEE Conf Control Applicat (CCA), IEEE Int Syposium Intelligent Control (ISIC) ID PARKINSONS-DISEASE PATIENTS; SUBTHALAMIC NUCLEUS; SPIKE DETECTION; SYNCHRONIZATION; OSCILLATIONS; MOVEMENT; SURGERY AB Deep brain stimulation (DBS) is a highly promising therapy for Parkinson's disease (PD). However, most patients do not get full therapeutic benefit from DBS yet, due to its critical dependence on electrode location. For this reason, we believe that the investigation of a neural modeling, estimation and control framework for the STN is an interesting research problem. This would pave the way for the development of a novel surgical tool for the DBS placement standardization, i.e., an automated intraoperative closed-loop DBS localization system. A fundamental problem to be solved for the realization of a such framework is the neurophysiologic characterization of the STN activity. Indeed, this would allow to understand if the modeling of the sweet spot is feasible. In this paper an effort towards the modeling of the neuronal activity near the stimulation target is made: first we analyze single unit spiking activity of 120 STN neurons collected from four PD patients at different distances from the sweet spot and, for each neuron, we estimate a point process model (PPM). Then, we see that PPMs capture the stochastic effects of the distance from the sweet spot on the STN spiking activity, and characterize the impact of local neuronal networks on the single neurons. Our results suggest that PPMs might be an effective tool for modeling of the STN neuronal activities accounting for the depth within it. C1 [Pedoto, Gilda] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Santaniello, Sabato; Sarma, Sridevi V.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. [Fiengo, Giovanni; Glielmo, Luigi] Univ Sannio, Dept Engn, Benevento, Italy. [Hallett, Mark] Natl Inst Hlth, NINDS, Human Motor Control Sect, Bethesda, MD USA. [Zhuang, Ping] Capital Med Univ, Xuanwu Hosp, Beijing Inst Funct Neurosurg, Beijing, Peoples R China. RP Pedoto, G (reprint author), Johns Hopkins Univ, Baltimore, MD 21218 USA. EM gpedota1@jhu.edu; ssantan5@jhu.edu; gifiengo@unisannio.it; glielmo@unisannio.it; hallettm@ninds.nih.gov; zhuangp@vip.sina.com; sree@jhu.edu OI Santaniello, Sabato/0000-0002-2133-9471 NR 28 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1085-1992 BN 978-1-4673-4505-7 J9 IEEE INTL CONF CONTR PY 2012 BP 782 EP 787 PG 6 WC Automation & Control Systems; Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Automation & Control Systems; Computer Science; Engineering GA BFK99 UT WOS:000320336200111 ER PT S AU Chen, K Tjandra, N AF Chen, Kang Tjandra, Nico BE Zhu, G TI The Use of Residual Dipolar Coupling in Studying Proteins by NMR SO NMR OF PROTEINS AND SMALL BIOMOLECULES SE Topics in Current Chemistry LA English DT Review; Book Chapter DE RDC; Alignment medium; Ensemble; Dynamics; Oligomer ID LIQUID-CRYSTALLINE MEDIUM; CHEMICAL-SHIFT ANISOTROPY; HIGH-RESOLUTION NMR; MOLECULAR-STRUCTURE DETERMINATION; ORIENTED PHOSPHOLIPID MICELLES; TENSOR PRINCIPAL COMPONENTS; MULTIPLE ALIGNMENT MEDIA; SMALL ALPHA/BETA PROTEIN; MODEL-FREE ANALYSIS; WEAK ALIGNMENT AB The development of residual dipolar coupling (RDC) in protein NMR spectroscopy, over a decade ago, has become a useful and almost routine tool for accurate protein solution structure determination. RDCs provide orientation information of magnetic dipole-dipole interaction vectors within a common reference frame. Its measurement requires a nonisotropic orientation, through a direct or indirect magnetic field alignment, of the protein in solution. There has been recent progress in the developments of alignment methods to allow the measurement of RDC and of methods to analyze the resulting data. In this chapter we briefly go through the mathematical expressions for the RDC and common descriptions of the alignment tensor, which may be represented using either Saupe order or the principal order matrix. Then we review the latest developments in alignment media. In particular we looked at the lipid-compatible media that allow the measurement of RDCs for membrane proteins. Other methods including conservative surface residue mutation have been invented to obtain up to five orthogonal alignment tensors that provide a potential for de novo structure and dynamics study using RDCs exclusively. We then discuss approximations assumed in RDC interpretations and different views on dynamics uncovered from the RDC method. In addition to routine usage of RDCs in refining a single structure, novel applications such as ensemble refinement against RDCs have been implemented to represent protein structure and dynamics in solution. The RDC application also extends to the study of protein-substrate interaction as well as to solving quaternary structure of oligomer in equilibrium with a monomer, opening an avenue for RDCs in high-order protein structure determination. C1 [Chen, Kang; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 50,Room 3503, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov FU Intramural NIH HHS [ZIA HL001048-16] NR 90 TC 18 Z9 18 U1 5 U2 42 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0340-1022 BN 978-3-642-28917-0 J9 TOP CURR CHEM JI Top. Curr. Chem. PY 2012 VL 326 BP 47 EP 67 DI 10.1007/128_2011_215 D2 10.1007/978-3-642-28917-0 PG 21 WC Chemistry, Multidisciplinary; Chemistry, Organic SC Chemistry GA BFW20 UT WOS:000321618300004 PM 21952837 ER PT S AU Izquierdo, A Belcher, AM AF Izquierdo, Alicia Belcher, Annabelle M. BE Kobeissy, FH TI Rodent Models of Adaptive Decision Making SO PSYCHIATRIC DISORDER: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Reward; Rat; Cognitive flexibility; Effort; Choice behavior; Addiction ID MEDIAL FRONTAL-CORTEX; PREFRONTAL CORTEX; REVERSAL; DISCRIMINATION; AMPHETAMINE; MICE; RAT; DYSFUNCTION; MODULATION; DEFICITS AB Adaptive decision making affords the animal the ability to respond quickly to changes in a dynamic environment: one in which attentional demands, cost or effort to procure the reward, and reward contingencies change frequently. The more flexible the organism is in adapting choice behavior, the more command and success the organism has in navigating its environment. Maladaptive decision-making is at the heart of much neuropsychiatric disease, including addiction. Thus, a better understanding of the mechanisms that underlie normal, adaptive decision making helps achieve a better understanding of certain diseases that incorporate maladaptive decision making as a core feature. This chapter presents three general domains of methods that the experimenter can manipulate in animal decision-making tasks: attention, effort, and reward contingency. Here, we present detailed methods of rodent tasks frequently employed within these domains: the Attentional Set-Shift Task, Effortful T-maze Task, and Visual Discrimination Reversal Learning. These tasks all recruit regions within the frontal cortex and the striatum, and performance is heavily modulated by the neurotransmitter dopamine, making these assays highly valid measures in the study of psychostimulant addiction. C1 [Izquierdo, Alicia] Calif State Univ Los Angeles, Dept Psychol, Cognit Neurosci Lab, Los Angeles, CA 90032 USA. [Belcher, Annabelle M.] NIDA, Neuroimaging Res Program, NIH, Baltimore, MD USA. RP Izquierdo, A (reprint author), Calif State Univ Los Angeles, Dept Psychol, Cognit Neurosci Lab, Los Angeles, CA 90032 USA. FU NIMH NIH HHS [1SC2MH087974] NR 23 TC 6 Z9 6 U1 0 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-457-5 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 829 BP 85 EP 101 DI 10.1007/978-1-61779-458-2_5 D2 10.1007/978-1-61779-458-2 PG 17 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA BFY26 UT WOS:000321877300007 PM 22231808 ER PT S AU Cohen, T Widdows, D Schvaneveldt, RW Rindflesch, TC AF Cohen, Trevor Widdows, Dominic Schvaneveldt, Roger W. Rindflesch, Thomas C. BE Gao, J Dubitzky, W Wu, C Liebman, M Alhaij, R Ungar, L Christianson, A Hu, X TI Discovery at a Distance: Farther Journeys in Predication Space SO 2012 IEEE INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND BIOMEDICINE WORKSHOPS (BIBMW) SE IEEE International Conference on Bioinformatics and Biomedicine Workshop-BIBMW LA English DT Proceedings Paper CT IEEE International Conference on Bioinformatics and Biomedicine Workshops (BIBMW) CY OCT 04-07, 2012 CL Philadelphia, PA SP IEEE, IEEE Comp Soc (CS), Natl Sci Fdn (NSF), Omic Soft Corp, IEEE Comp Soc Tech Comm Bioinformat ID KNOWLEDGE AB In this paper we extend the Predication-based Semantic Indexing (PSI) approach to search efficiently across triple-predicate pathways in a database of predications extracted from the biomedical literature by the SemRep system. PSI circumvents the combinatorial explosion of possible pathways by converting the task of traversing individual predications into the task of measuring the similarity between composite concept vectors. Consequently, search time for single, double or triple predicate paths is identical once the relevant concept vectors have been constructed. This paper describes the application of PSI to infer double and triple predicate pathways connecting example pairs of therapeutically related drugs and diseases; and to use these inferred pathways to guide search for treatments for other diseases. In an evaluation of the utility of vector-based dual-and triple-predicate path search in a simulated discovery experiment, these approaches are found to be complementary, with best performance obtained through their application in combination. C1 [Cohen, Trevor] Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Houston, TX 77030 USA. [Widdows, Dominic] Microsofr Bing, Houston, TX USA. [Schvaneveldt, Roger W.] Arizona State Univ, Tempe, AZ 85287 USA. [Rindflesch, Thomas C.] Natl Lib Med, Bethesda, MD USA. RP Cohen, T (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Houston, TX 77030 USA. FU US National Library of Medicine [R21 LMOI0826]; Intramural Research Program of the NIH; National Library of Medicine FX This research was supported by the US National Library of Medicine grant R21 LMOI0826, and the Intramural Research Program of the NIH, National Library of Medicine. NR 26 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2163-6966 BN 978-1-4673-2746-6; 978-1-4673-2745-9 J9 IEEE INT C BIO BIO W PY 2012 PG 8 WC Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Mathematical & Computational Biology; Medical Informatics GA BFL42 UT WOS:000320379600031 ER PT S AU Jaeger, S AF Jaeger, Stefan BE Gao, J Dubitzky, W Wu, C Liebman, M Alhaij, R Ungar, L Christianson, A Hu, X TI An Information-Theoretic Neural Model Based on Concepts in Chinese Medicine SO 2012 IEEE INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND BIOMEDICINE WORKSHOPS (BIBMW) SE IEEE International Conference on Bioinformatics and Biomedicine Workshop-BIBMW LA English DT Proceedings Paper CT IEEE International Conference on Bioinformatics and Biomedicine Workshops (BIBMW) CY OCT 04-07, 2012 CL Philadelphia, PA SP IEEE, IEEE Comp Soc (CS), Natl Sci Fdn (NSF), Omic Soft Corp, IEEE Comp Soc Tech Comm Bioinformat AB This paper presents a linear information-theoretic model for neural signal processing using Chinese philosophical ideas, in particular Yin and Yang. The main goal is to provide a mathematical model that can explain neural activity in accordance with concepts in traditional Chinese medicine. As yet, the lack of such models has prevented a more formal explanation of the efficacy of traditional treatments related to the nervous system, such as acupuncture. According to the proposed model, a synapse performs a linear operation on its input. This operation, when plotted in polar coordinates, follows the shape of a Yin-Yang symbol. Synaptic learning becomes synonymous with adapting the size and rotation of the Yin-Yang symbol. The model distinguishes between the perceived input and the actual input. Both, perception and reality, coincide in the golden ratio. Learning thus becomes a process of aligning perception with reality, which is a novel learning concept. C1 NIH, Natl Lib Med, Bethesda, MD 20894 USA. RP Jaeger, S (reprint author), NIH, Natl Lib Med, Bethesda, MD 20894 USA. EM stefan.jaeger@nih.gov NR 20 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2163-6966 BN 978-1-4673-2746-6; 978-1-4673-2745-9 J9 IEEE INT C BIO BIO W PY 2012 PG 7 WC Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Mathematical & Computational Biology; Medical Informatics GA BFL42 UT WOS:000320379600090 ER PT S AU Luo, XZJ AF Luo, Xiao-zhong James BE Gao, J Dubitzky, W Wu, C Liebman, M Alhaij, R Ungar, L Christianson, A Hu, X TI Nanomaterial Registry A resource for biological and environmental interactions of nanomaterials SO 2012 IEEE INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND BIOMEDICINE WORKSHOPS (BIBMW) SE IEEE International Conference on Bioinformatics and Biomedicine Workshop-BIBMW LA English DT Proceedings Paper CT IEEE International Conference on Bioinformatics and Biomedicine Workshops (BIBMW) CY OCT 04-07, 2012 CL Philadelphia, PA SP IEEE, IEEE Comp Soc (CS), Natl Sci Fdn (NSF), Omic Soft Corp, IEEE Comp Soc Tech Comm Bioinformat DE Nanomaterial registry; effects of nanomaterials; human health; environment AB This paper introduces the Nanomaterial Registry, a resource for biological and environmental interactions of well-characterized nanomaterials. The registry also provides links to associated publications, modeling tools, computational results, and relevant manufacturing guidance. C1 Natl Inst Biomed Imaging & Bioengn, Biomed Informat Programs, NIH, Bethesda, MD USA. RP Luo, XZJ (reprint author), Natl Inst Biomed Imaging & Bioengn, Biomed Informat Programs, NIH, Bethesda, MD USA. EM luoja@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2163-6966 BN 978-1-4673-2746-6; 978-1-4673-2745-9 J9 IEEE INT C BIO BIO W PY 2012 PG 4 WC Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Mathematical & Computational Biology; Medical Informatics GA BFL42 UT WOS:000320379600158 ER PT S AU Saeed, F Pisitkun, T Hoffert, JD Wang, GH Gucek, M Knepper, MA AF Saeed, Fahad Pisitkun, Trairak Hoffert, Jason D. Wang, Guanghui Gucek, Marjan Knepper, Mark A. BE Gao, J Dubitzky, W Wu, C Liebman, M Alhaij, R Ungar, L Christianson, A Hu, X TI An Efficient Dynamic Programming Algorithm for Phosphorylation Site Assignment of Large-Scale Mass Spectrometry Data SO 2012 IEEE INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND BIOMEDICINE WORKSHOPS (BIBMW) SE IEEE International Conference on Bioinformatics and Biomedicine Workshop-BIBMW LA English DT Proceedings Paper CT IEEE International Conference on Bioinformatics and Biomedicine Workshops (BIBMW) CY OCT 04-07, 2012 CL Philadelphia, PA SP IEEE, IEEE Comp Soc (CS), Natl Sci Fdn (NSF), Omic Soft Corp, IEEE Comp Soc Tech Comm Bioinformat ID QUANTITATIVE PHOSPHOPROTEOMIC ANALYSIS; PROTEIN IDENTIFICATION; NETWORKS; SPECTRA; PEPTIDE; LOCALIZATION; DISCOVERY; PATHWAY; CELLS AB Phosphorylation site assignment of large-scale data from high throughput tandem mass spectrometry (LC-MS/MS) data is an important aspect of phosphoproteomics. Correct assignment of phosphorylated residue(s) is important for functional interpretation of the data within a biological context. Common search algorithms (Sequest etc.) for mass spectrometry data are not designed for accurate site assignment; thus, additional algorithms are needed. In this paper, we propose a linear-time and linear-space dynamic programming strategy for phosphorylation site assignment. The algorithm, referred to as PhosSA, optimizes the objective function defined as the summation of peak intensities that are associated with theoretical phosphopeptide fragmentation ions. Quality control is achieved through the use of a post-processing criteria whose value is indicative of the signal-to-noise (SIN) properties and redundancy of the fragmentation spectra. The algorithm is tested using experimentally generated data sets of peptides with known phosphorylation sites while varying the fragmentation strategy (CID or HCD) and molar amounts of the peptides, The algorithm is also compatible with various peptide labeling strategies including SILAC and iTRAQ. PhosSA is shown to achieve > 99% accuracy with a high degree of sensitivity. The algorithm is extremely fast and scalable (able to process up to 0.5 million peptides in an hour). The implemented algorithm is freely available at http://helixweb.nih.gov/ESBL/PhosSA/ for academic purposes. C1 [Saeed, Fahad; Pisitkun, Trairak; Hoffert, Jason D.; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wang, Guanghui; Gucek, Marjan] Natl Inst Hlth NIH, Natl Heart Lung & Blood Inst NHLBI, Bethesda, MD USA. RP Saeed, F (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM fahad.saeed@nih.gov FU operating budget of Division of Intramural Research; National Heart, Lung and Blood Institute,; National Insitutes of Health (NIH) [ZOI-HLOOI285] FX The comments and suggestions by anonymous referees have helped improve the manuscript. This work was funded by the operating budget of Division of Intramural Research, National Heart, Lung and Blood Institute, National Insitutes of Health (NIH), Project ZOI-HLOOI285. NR 33 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2163-6966 BN 978-1-4673-2746-6; 978-1-4673-2745-9 J9 IEEE INT C BIO BIO W PY 2012 PG 8 WC Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Mathematical & Computational Biology; Medical Informatics GA BFL42 UT WOS:000320379600110 ER PT J AU Brady, ST Siegel, GJ Albers, RW Price, D Benjamins, J Fisher, S Hall, A Bazan, N Coyle, J Sisodia, S AF Brady, Scott T. Siegel, George J. Albers, R. Wayne Price, Donald Benjamins, Joyce Fisher, Stephen Hall, Alison Bazan, Nicolas Coyle, Joseph Sisodia, Sangram BE Brady, ST Siegel, GJ Albers, RW Price, DL TI Eighth Edition Acknowledgments and History SO BASIC NEUROCHEMISTRY: PRINCIPLES OF MOLECULAR, CELLULAR, AND MEDICAL NEUROBIOLOGY, 8THEDITION LA English DT Editorial Material; Book Chapter C1 [Brady, Scott T.] Univ Illinois, Dept Anat & Cell Biol, Chicago, IL 60612 USA. [Siegel, George J.] Loyola Univ, Chicago Stritch Sch Med, Dept Neurol & Cell Biol, Maywood, IL 60153 USA. [Siegel, George J.] Loyola Univ, Chicago Stritch Sch Med, Dept Neurobiol, Maywood, IL 60153 USA. [Siegel, George J.] Loyola Univ, Chicago Stritch Sch Med, Dept Anat, Maywood, IL 60153 USA. [Siegel, George J.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Neurol Serv, Hines, IL 60141 USA. [Albers, R. Wayne] NINDS, Sect Enzymes, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Price, Donald] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. [Price, Donald] Johns Hopkins Univ, Sch Med, Dept Neurol, Div Neuropathol, Baltimore, MD 21205 USA. [Price, Donald] Johns Hopkins Univ, Sch Med, Dept Neurosci, Div Neuropathol, Baltimore, MD 21205 USA. [Benjamins, Joyce] Wayne State Univ, Dept Neurol, Detroit Med Ctr, Univ Hlth Ctr, Detroit, MI 48201 USA. [Fisher, Stephen] Univ Michigan, Ann Arbor, MI 48109 USA. [Fisher, Stephen] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Hall, Alison] Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA. [Hall, Alison] Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. [Bazan, Nicolas] Louisiana State Univ, Hlth Sci Ctr, Neurosci Ctr Excellence, New Orleans, LA 70112 USA. [Coyle, Joseph] Harvard Univ, Sch Med, McLean Hosp, Belmont, MA 02478 USA. RP Brady, ST (reprint author), Univ Illinois, Dept Anat & Cell Biol, 808 S Wood St,Room 578,M-C 512, Chicago, IL 60612 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS BN 978-0-08-095901-6 PY 2012 BP XXI EP XXI PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA BFN78 UT WOS:000320652300001 ER PT J AU Albers, RW AF Albers, R. Wayne BE Brady, ST Siegel, GJ Albers, RW Price, DL TI Cell Membrane Structures and Functions SO BASIC NEUROCHEMISTRY: PRINCIPLES OF MOLECULAR, CELLULAR, AND MEDICAL NEUROBIOLOGY, 8THEDITION LA English DT Article; Book Chapter ID CENTRAL-NERVOUS-SYSTEM; GLIA-DERIVED CHOLESTEROL; LIPID RAFTS; APOLIPOPROTEIN-E; SPECTRIN; DOMAINS; BRAIN; SYNAPTOGENESIS; PROTEINS; NEURONS C1 NINDS, Sect Enzymes, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Albers, RW (reprint author), NINDS, Sect Enzymes, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NR 46 TC 0 Z9 0 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS BN 978-0-08-095901-6 PY 2012 BP 26 EP 39 PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA BFN78 UT WOS:000320652300005 ER PT J AU Albers, RW Siegel, GJ Xie, ZJ AF Albers, R. Wayne Siegel, George J. Xie, Zi-Jian BE Brady, ST Siegel, GJ Albers, RW Price, DL TI Membrane Transport SO BASIC NEUROCHEMISTRY: PRINCIPLES OF MOLECULAR, CELLULAR, AND MEDICAL NEUROBIOLOGY, 8THEDITION LA English DT Article; Book Chapter ID ACTIVATED ADENOSINE-TRIPHOSPHATASE; NA+,K+-ATPASE ALPHA-SUBUNIT; K+-ATPASE; NA/K-ATPASE; AQUAPORIN 4; NA,K-ATPASE; BRAIN; NA+; TRAFFICKING; RECEPTOR C1 [Albers, R. Wayne] NINDS, Sect Enzymes, Neurochem Lab, NIH, Bethesda, MD 20892 USA. [Siegel, George J.] Loyola Univ, Dept Neurol & Cell Biol, Chicago Stritch Sch Med, Maywood, IL 60153 USA. [Siegel, George J.] Loyola Univ, Dept Neurobiol, Chicago Stritch Sch Med, Maywood, IL 60153 USA. [Siegel, George J.] Loyola Univ, Dept Anat, Chicago Stritch Sch Med, Maywood, IL 60153 USA. [Xie, Zi-Jian] Univ Toledo, Dept Physiol & Pharmacol, Coll Med, Toledo, OH 43614 USA. RP Albers, RW (reprint author), NINDS, Sect Enzymes, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NR 79 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS BN 978-0-08-095901-6 PY 2012 BP 40 EP 62 PG 23 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA BFN78 UT WOS:000320652300007 ER PT J AU Mattson, MP Bazan, NG AF Mattson, Mark P. Bazan, Nicolas G. BE Brady, ST Siegel, GJ Albers, RW Price, DL TI Apoptosis and Necrosis SO BASIC NEUROCHEMISTRY: PRINCIPLES OF MOLECULAR, CELLULAR, AND MEDICAL NEUROBIOLOGY, 8THEDITION LA English DT Article; Book Chapter ID EPITHELIAL-CELL SURVIVAL; NEURODEGENERATIVE DISORDERS; NEUROPROTECTIN D1; DOCOSAHEXAENOIC ACID; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; AUTOPHAGY; HORMESIS; TARGETS; MECHANISMS C1 [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Bazan, Nicolas G.] Louisiana State Univ, Hlth Sci Ctr, Neurosci Ctr Excellence, New Orleans, LA 70112 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 38 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS BN 978-0-08-095901-6 PY 2012 BP 663 EP 676 PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA BFN78 UT WOS:000320652300058 ER PT S AU Mukouyama, YS James, J Nam, J Uchida, Y AF Mukouyama, Yoh-suke James, Jennifer Nam, Joseph Uchida, Yutaka BE Peng, X Antonyak, M TI Whole-Mount Confocal Microscopy for Vascular Branching Morphogenesis SO CARDIOVASCULAR DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Confocal microscopy; Whole-mount immunohistochemistry; Mouse embryo; Blood vessel; Lymphatic vessel; Fluorescence; Antibody; Patterning ID EPHRIN-B2 AB We introduce a whole-mount immunohistochemistry method for analyzing intricate vascular network formation in mouse embryonic tissues. Laser scanning confocal microscopy with multiple labeling allows for robust imaging of blood and lymphatic vessel branching morphogenesis with excellent resolution. C1 [Mukouyama, Yoh-suke; James, Jennifer; Nam, Joseph; Uchida, Yutaka] NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Mukouyama, YS (reprint author), NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA HL005702-07] NR 4 TC 5 Z9 5 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-522-0 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 843 BP 69 EP 78 DI 10.1007/978-1-61779-523-7_7 D2 10.1007/978-1-61779-523-7 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Developmental Biology SC Biochemistry & Molecular Biology; Developmental Biology GA BFY22 UT WOS:000321875600008 PM 22222522 ER PT S AU Govind, CK Ginsburg, D Hinnebusch, AG AF Govind, Chhabi K. Ginsburg, Daniel Hinnebusch, Alan G. BE Morse, RH TI Measuring Dynamic Changes in Histone Modifications and Nucleosome Density during Activated Transcription in Budding Yeast SO CHROMATIN REMODELING: METTHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Activated transcription; RNA polymerase II; Histone modifications; Acetylation; Gcn4; Gal4; Saccharomyces cerevisiae; Histone acetyltransferase; Histone deacetylase complexes ID RNA-POLYMERASE-II; CODING REGIONS; IN-VIVO; CHROMATIN; METHYLATION; DEACETYLATION; RECRUITS; ELONGATION; EVICTION; COMPLEX AB Chromatin immunoprecipitation is widely utilized to determine the in vivo binding of factors that regulate transcription. This procedure entails formaldehyde-mediated cross-linking of proteins and isolation of soluble chromatin followed by shearing. The fragmented chromatin is subjected to immunoprecipitation using antibodies against the protein of interest and the associated DNA is identified using quantitative PCR. Since histones are posttranslationally modified during transcription, this technique can be effectively used to determine the changes in histone modifications that occur during transcription. In this paper, we describe a detailed methodology to determine changes in histone modifications in budding yeast that takes into account reductions in nucleosome. C1 [Govind, Chhabi K.] Oakland Univ, Dept Biol Sci, Rochester, MI 48063 USA. [Ginsburg, Daniel] Long Isl Univ, Dept Biomed Sci, Brookville, NY USA. [Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD USA. RP Govind, CK (reprint author), Oakland Univ, Dept Biol Sci, Rochester, MI 48063 USA. FU NIGMS NIH HHS [R01 GM095514] NR 18 TC 4 Z9 4 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-476-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 833 BP 15 EP 27 DI 10.1007/978-1-61779-477-3_2 D2 10.1007/978-1-61779--477-3 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BFY94 UT WOS:000321932900003 PM 22183585 ER PT S AU Kiefer, CM Dean, A AF Kiefer, Christine M. Dean, Ann BE Morse, RH TI Monitoring the Effects of Chromatin Remodelers on Long-Range Interactions In Vivo SO CHROMATIN REMODELING: METTHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Long-range gene activation; Locus control regions; Chromatin immunoprecipitation; Chromatin remodeling; DNase I hypersensitivity; Chromosome conformation capture ID BETA-GLOBIN LOCUS; ERYTHROID-DIFFERENTIATION; GENE-EXPRESSION; CONTROL REGION; TRANSCRIPTION; REQUIRES; PCR AB In metazoans transcriptional enhancers and their more complex relatives, locus control regions, are often located at great linear distances from their target genes. In addition, these elements frequently activate different members of gene families in temporal sequence or in different tissues. These issues have complicated understanding the mechanisms underlying long-range gene activation. Advances in primarily technical approaches, such as chromosome conformation capture (3C) and its derivatives have now solidified the idea that distant regulatory elements achieve proximity with their target genes when they are activating them. Furthermore, these approaches are now allowing genome-wide views of chromosome interactions that are likely to include regulatory, structural, and organization aspects from which we will be able to understand more about nuclear structure. At the base of these advances are experimental approaches to localize protein-binding sites in chromatin, to assess remodeling of chromatin and to measure interaction frequency between distant sites. Examples of these approaches comprise this review. C1 [Kiefer, Christine M.; Dean, Ann] NIH, Lab Cellular & Dev Biol, Bethesda, MD 20892 USA. RP Kiefer, CM (reprint author), NIH, Lab Cellular & Dev Biol, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 14 TC 1 Z9 1 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-476-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 833 BP 29 EP 45 DI 10.1007/978-1-61779-477-3_3 D2 10.1007/978-1-61779--477-3 PG 17 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BFY94 UT WOS:000321932900004 PM 22183586 ER PT S AU Trotter, KW Archer, TK AF Trotter, Kevin W. Archer, Trevor K. BE Morse, RH TI Assaying Chromatin Structure and Remodeling by Restriction Enzyme Accessibility SO CHROMATIN REMODELING: METTHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Chromatin; Restriction enzyme; Hypersensitivity; BRG1; SWI/SNF; Transcription ID POSITIONED NUCLEOSOMES; NUCLEAR RECEPTORS; IN-VIVO; TRANSCRIPTION; PROMOTER; ACTIVATION AB The packaging of eukaryotic DNA into nucleosomes, the fundamental unit of chromatin, creates a barrier to nuclear processes, such as transcription, DNA replication, recombination, and repair. This obstructive nature of chromatin can be overcome by the enzymatic activity of chromatin remodeling complexes, which create a more favorable environment for the association of essential factors and regulators to sequences within target genes. Here, we describe a detailed approach for analyzing chromatin architecture and remodeling by restriction endonuclease hypersensitivity assay. This procedure uses restriction endonucleases to characterize changes in chromatin that accompany nucleosome remodeling. The specific experimental example described in this article is the BRG1 complex-dependent chromatin remodeling of the steroid hormone-responsive mouse mammary tumor virus promoter. Through the use of these methodologies one is able to quantify changes at specific nucleosomes in response to regulatory signals. C1 [Trotter, Kevin W.; Archer, Trevor K.] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Trotter, KW (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. FU Intramural NIH HHS [ZIA ES071006-12] NR 21 TC 3 Z9 3 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-476-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 833 BP 89 EP 102 DI 10.1007/978-1-61779-477-3_6 D2 10.1007/978-1-61779--477-3 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BFY94 UT WOS:000321932900007 PM 22183589 ER PT S AU Mueller, F Karpova, TS Mazza, D McNally, JG AF Mueller, Florian Karpova, Tatiana S. Mazza, Davide McNally, James G. BE Morse, RH TI Monitoring Dynamic Binding of Chromatin Proteins In Vivo by Fluorescence Recovery After Photobleaching SO CHROMATIN REMODELING: METTHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE FRAP; Binding; Modeling; Chromatin; Microscopy ID NUCLEAR PROTEINS; TRANSCRIPTION FACTOR; FRAP ANALYSIS; DNA-BINDING; DIFFUSION; CELLS; KINETICS AB Fluorescence recovery after photobleaching (FRAP) has now become widely used to investigate nuclear protein binding to chromatin in live cells. FRAP can be applied qualitatively to assess if chromatin binding interactions are altered by various biological perturbations. It can also be applied semi-quantitatively to allow numerical comparisons between FRAP curves, and even fully quantitatively to yield estimates of in vivo diffusion constants and nuclear protein binding rates to chromatin. Here we describe how FRAP data should be collected and processed for these qualitative, semi-quantitative, and quantitative analyses. C1 [Mueller, Florian] Inst Pasteur, Grp Imagerie & Modelisat, CNRS, URA 2582, Paris, France. [Karpova, Tatiana S.; Mazza, Davide; McNally, James G.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Mueller, F (reprint author), Inst Pasteur, Grp Imagerie & Modelisat, CNRS, URA 2582, Paris, France. RI Mueller, Florian/C-9075-2012; Mazza, Davide/R-5340-2016 OI Mueller, Florian/0000-0002-9622-4396; Mazza, Davide/0000-0003-2776-4142 NR 22 TC 15 Z9 15 U1 0 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-476-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 833 BP 153 EP 176 DI 10.1007/978-1-61779-477-3_11 D2 10.1007/978-1-61779--477-3 PG 24 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BFY94 UT WOS:000321932900012 PM 22183594 ER PT S AU Mazza, D Stasevich, TJ Karpova, TS McNally, JG AF Mazza, Davide Stasevich, Timothy J. Karpova, Tatiana S. McNally, James G. BE Morse, RH TI Monitoring Dynamic Binding of Chromatin Proteins In Vivo by Fluorescence Correlation Spectroscopy and Temporal Image Correlation Spectroscopy SO CHROMATIN REMODELING: METTHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Fluorescence correlation spectroscopy; Temporal image correlation spectroscopy; Binding; Nuclear protein; In vivo ID LIVING CELLS; FRAP AB Live-cell microscopy has demonstrated that many nuclear proteins bind transiently to target sites in chromatin These binding interactions can be detected and quantified by two related live-cell imaging techniques, Fluorescence Correlation Spectroscopy (FCS) and Temporal Image Correlation Spectroscopy (TICS). With proper quantitative modeling, it is possible to obtain estimates from FCS and TICS data of the association and dissociation rates of nuclear protein binding to chromatin. These binding rates permit calculating the fractions of free and bound protein in the nucleus, plus the time required to diffuse from one binding site to the next and the dwell time on a chromatin target. In this protocol, we summarize the underlying principles of FCS and TICS, and then describe how these data should be collected and analyzed to extract estimates of in vivo binding. C1 [Mazza, Davide; Karpova, Tatiana S.; McNally, James G.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Stasevich, Timothy J.] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka, Japan. RP Mazza, D (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RI Mazza, Davide/R-5340-2016 OI Mazza, Davide/0000-0003-2776-4142 NR 21 TC 7 Z9 7 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-476-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 833 BP 177 EP 200 DI 10.1007/978-1-61779-477-3_12 D2 10.1007/978-1-61779--477-3 PG 24 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BFY94 UT WOS:000321932900013 PM 22183595 ER PT S AU Cui, KR Zhao, KJ AF Cui, Kairong Zhao, Keji BE Morse, RH TI Genome-Wide Approaches to Determining Nucleosome Occupancy in Metazoans Using MNase-Seq SO CHROMATIN REMODELING: METTHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Nucleosome mapping; MNase-Seq; Chromatin structure ID CHROMATIN; TRANSCRIPTION AB The precise location of nucleosomes in functional regulatory regions in chromatin is critical to the regulation of transcription. The nucleosome structure protects DNA from microccocal nuclease (MNase) digestion and leaves a footprint on DNA that indicates the position of nucleosomes. Short sequence reads (25-36 bp) from ends of mononucleosome-sized DNA generated from MNase digestion of chromatin can be determined using next-generation sequencing techniques. Mapping of these short reads to the genome provides a powerful genome-wide approach to precisely define the nucleosome positions in any genome with known genomic sequence. This chapter outlines the reagents and experimental procedures of MNase-Seq for mapping nucleosome positions in the human genome. C1 [Cui, Kairong; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Cui, KR (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA HL005801-08] NR 9 TC 17 Z9 17 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-476-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 833 BP 413 EP 419 DI 10.1007/978-1-61779-477-3_24 D2 10.1007/978-1-61779--477-3 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BFY94 UT WOS:000321932900025 PM 22183607 ER PT S AU Baek, S Sung, MH Hager, GL AF Baek, Songjoon Sung, Myong-Hee Hager, Gordon L. BE Morse, RH TI Quantitative Analysis of Genome-Wide Chromatin Remodeling SO CHROMATIN REMODELING: METTHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Chromatin; Chromatin remodeling; DNaseI hypersensitivity; Global DHS-seq analysis; Global ChIP-seq analysis; Genome-wide; High-throughput deep sequencing; Computational methods; Footprinting ID IN-VIVO; DNA; MICROARRAYS; DYNAMICS; MOTIFS AB Recent high-throughput sequencing technologies have opened the door for genome-wide characterization of chromatin features at an unprecedented resolution. Chromatin accessibility is an important property that regulates protein binding and other nuclear processes. Here, we describe computational methods to analyze chromatin accessibility using DNaseI hypersensitivity by sequencing (DNaseI-seq). Although there are numerous bioinformatic tools to analyze ChIP-seq data, our statistical algorithm was developed specifically to identify significantly accessible genomic regions by handling features of DNaseI hypersensitivity. Without prior knowledge of relevant protein factors, one can discover genome-wide chromatin remodeling events associated with specific conditions or differentiation stages from quantitative analysis of DNaseI hypersensitivity. By performing appropriate subsequent computational analyses on a select subset of remodeled sites, it is also possible to extract information about putative factors that may bind to specific DNA elements within DNaseI hypersensitive sites. These approaches enabled by DNaseI-seq represent a powerful new methodology that reveals mechanisms of transcriptional regulation. C1 [Baek, Songjoon; Sung, Myong-Hee; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Baek, S (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. NR 15 TC 16 Z9 16 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-476-6 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 833 BP 433 EP 441 DI 10.1007/978-1-61779-477-3_26 D2 10.1007/978-1-61779--477-3 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BFY94 UT WOS:000321932900027 PM 22183609 ER PT S AU Boucheron, C Baxendale, V AF Boucheron, Catherine Baxendale, Vanessa BE Chan, WY Bloomberg, LA TI Isolation and Purification of Murine Male Germ Cells SO GERMLINE DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Germ cell; Testis; Spermatogonia; Gradient; Albumin ID SPERMATOGENIC CELLS; MOUSE AB Seminiferous tubules of the male testis contain somatic cells (Sertoli and Leydig cells) and germ cells at different stages of spermatogenesis (spermatogonia, spermatocytes and spermatids). Germ cells at different stages of differentiation migrate toward the central lumen via cell junctions formed by Sertoli cells. The protocol described herein consists of the dissection and decapsulation of the testes, disruption of the structure of the seminiferous tubules, and the breaking of cell junctions to release all the cells in suspension. Germ cells are then separated from Sertoli cells by overnight plating of the suspension on plastic to which the germ cells preferentially adhere. And finally, a BSA gradient allows a high-purity separation of the various types of germ cells according to size. C1 [Boucheron, Catherine; Baxendale, Vanessa] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Boucheron, C (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. FU Intramural NIH HHS NR 3 TC 4 Z9 4 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-435-3 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 825 BP 59 EP 66 DI 10.1007/978-1-61779-436-0_5 D2 10.1007/978-1-61779-436-0 PG 8 WC Biochemistry & Molecular Biology; Developmental Biology SC Biochemistry & Molecular Biology; Developmental Biology GA BFY90 UT WOS:000321932500006 PM 22144236 ER PT S AU Lee, TL Rennert, OM Chan, WY AF Lee, Tin-Lap Rennert, Owen M. Chan, Wai-Yee BE Chan, WY Bloomberg, LA TI Revealing the Transcriptome Landscape of Mouse Spermatogonial Cells by Tiling Microarray SO GERMLINE DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Male germ cells; Development; Transcriptome; Tiling microarray; Expression profiling ID MALE GERM-CELLS; GENE-EXPRESSION; EMBRYONIC GONAD; GENOME; SPERMATOGENESIS; TECHNOLOGY; DISCOVERY; ARRAYS AB In the past decade, the advent of microarray technologies has allowed functional genomic studies of male germ cell development, resulting in the identification of genes governing various processes. A major limitation with conventional gene expression microarray is that results obtained are biased due to gene probe design. The gene probes for expression microarrays are usually represented by a small number of probes located at the 3' end of a transcript. Tiling microarrays eliminate such issue by interrogating the genome in an unbiased fashion through probes tiled across the entire genome. These arrays provide higher genomic resolution and allow the identification of novel transcripts. To reveal the complexity of the genomic landscape of developing male germ cells, we applied tiling microarray to evaluate the transcriptome in spermatogonial cells. Over 50% of all known mouse genes are expressed during testicular development. More than 47% of the transcripts are uncharacterized. The results suggested that the transcription machinery in spermaotogonial cells is more complex than previously envisioned. C1 [Lee, Tin-Lap; Chan, Wai-Yee] Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Lee, Tin-Lap; Rennert, Owen M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Clin & Dev Genom, Bethesda, MD USA. RP Lee, TL (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Intramural NIH HHS [Z01 HD008726-08] NR 15 TC 5 Z9 5 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-435-3 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 825 BP 75 EP 92 DI 10.1007/978-1-61779-436-0_7 D2 10.1007/978-1-61779-436-0 PG 18 WC Biochemistry & Molecular Biology; Developmental Biology SC Biochemistry & Molecular Biology; Developmental Biology GA BFY90 UT WOS:000321932500008 PM 22144238 ER PT S AU Pang, ALY AF Pang, Alan Lap-Yin BE Chan, WY Bloomberg, LA TI Biochemical Characterization of a Testis-Predominant Isoform of N-Alpha Acetyltransferase SO GERMLINE DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Testis; Male germ cells; N-alpha acetyltransferase; Arrest defective 1; Co-immunoprecipitation; Protein-protein interaction AB N-alpha protein acetylation, catalyzed by N-alpha acetyltransferase complex, is a common protein modification process in eukaryotic cells. Despite its widespread occurrence, the biological significance of this modification process is still unclear. We recently discovered a novel testis-predominant isoform of the catalytic subunit of the enzyme complex. Here, we describe the biochemical characterization of this testis-predominant N-alpha acetyltransferase complex, which includes protein protein interaction study by co-immunoprecipitation experiment and functional study by N-alpha acetyltransferase assay. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Clin Genom, Lab Clin & Dev Genom, NIH, Bethesda, MD USA. RP Pang, ALY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Clin Genom, Lab Clin & Dev Genom, NIH, Bethesda, MD USA. FU Intramural NIH HHS NR 9 TC 0 Z9 0 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-435-3 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 825 BP 93 EP 104 DI 10.1007/978-1-61779-436-0_8 D2 10.1007/978-1-61779-436-0 PG 12 WC Biochemistry & Molecular Biology; Developmental Biology SC Biochemistry & Molecular Biology; Developmental Biology GA BFY90 UT WOS:000321932500009 PM 22144239 ER PT S AU Lee, TL Xiao, A Rennert, OM AF Lee, Tin-Lap Xiao, Amy Rennert, Owen M. BE Chan, WY Bloomberg, LA TI Identification of Novel Long Noncoding RNA Transcripts in Male Germ Cells SO GERMLINE DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Long noncoding RNA; Male germ cells; Development; SAGE ID COMPREHENSIVE SAGE DATABASE; EMBRYONIC GONAD; COMPLEXITY; DISCOVERY AB Emerging evidence from these studies suggested that the male germ cell transcriptome is more complex than previously envisioned. In addition to protein-coding genes, the transcriptome also encodes a significant number of nonprotein-coding transcripts. These noncoding (nc) RNAs appear to be involved in a variety of cellular activities, ranging from simple housekeeping to complex regulatory functions. A class of ncRNAs known as long ncRNAs (lncRNAs) were recently shown to be expressed in a developmentally regulated manner during brain and embryonic stem cell development. This protocol aims to predict and identify potential lncRNA candidates using Serial Analysis of Gene Expression (SAGE) data. We also illustrate how to validate the potential lncRNAs by expression analyses using real-time PCR and Northern Blot. Potential lncRNA candidates in male germ cells are identified using our previously established male germ cell SAGE database (GermSAGE). C1 [Lee, Tin-Lap] Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Lee, Tin-Lap; Rennert, Owen M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Clin & Dev Genom, Bethesda, MD USA. [Xiao, Amy] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Clin & Dev Genom, NIH, Bethesda, MD USA. RP Lee, TL (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Intramural NIH HHS [ZIA HD008817-03] NR 11 TC 12 Z9 13 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-435-3 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 825 BP 105 EP 114 DI 10.1007/978-1-61779-436-0_9 D2 10.1007/978-1-61779-436-0 PG 10 WC Biochemistry & Molecular Biology; Developmental Biology SC Biochemistry & Molecular Biology; Developmental Biology GA BFY90 UT WOS:000321932500010 PM 22144240 ER PT S AU Cheung, HH Lee, TL Rennert, OM Chan, WY AF Cheung, Hoi-Hung Lee, Tin-Lap Rennert, Owen M. Chan, Wai-Yee BE Chan, WY Bloomberg, LA TI Methylation Profiling Using Methylated DNA Immunoprecipitation and Tiling Array Hybridization SO GERMLINE DEVELOPMENT: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE MeDIP; DNA methylation; Tiling arrays ID GENOME; ARABIDOPSIS; CELLS; WIDE AB DNA methylation is an important epigenetic modification that regulates development and plays a role in the pathophysiology of many diseases. It is dynamically changed during germline development. Methylated DNA immunoprecipitation (MeDIP) is an efficient, cost-effective method for locus-specific and genome-wide analysis. Methylated DNA fragments are enriched by a 5-methylcytidine-recognizing antibody, therefore allowing the analysis of both CpG and non-CpG methylation. The enriched DNA fragments can be amplified and hybridized to tiling arrays covering CpG islands, promoters, or the entire genome. Comparison of different methylomes permits the discovery of differentially methylated regions that might be important in disease- or tissue-specific expression. Here, we describe an established MeDIP protocol and tiling array hybridization method for profiling methylation of testicular germ cells. C1 [Cheung, Hoi-Hung; Lee, Tin-Lap; Rennert, Owen M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Clin & Dev Genom, Bethesda, MD USA. [Lee, Tin-Lap; Chan, Wai-Yee] Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. RP Cheung, HH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Clin & Dev Genom, Bethesda, MD USA. RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Intramural NIH HHS [Z01 HD008821-01] NR 6 TC 2 Z9 2 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-435-3 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 825 BP 115 EP 126 DI 10.1007/978-1-61779-436-0_10 D2 10.1007/978-1-61779-436-0 PG 12 WC Biochemistry & Molecular Biology; Developmental Biology SC Biochemistry & Molecular Biology; Developmental Biology GA BFY90 UT WOS:000321932500011 PM 22144241 ER PT B AU Satwani, P Wayne, AS AF Satwani, Prakash Wayne, Alan S. BE Cairo, MS Perkins, SL TI Antibody-Targeted Therapy for Children, Adolescents and Young Adults with Hematological Malignancies SO HEMATOLOGICAL MALIGNANCIES IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS LA English DT Article; Book Chapter ID ACUTE LYMPHOBLASTIC-LEUKEMIA; B-CELL LYMPHOMA; NON-HODGKINS-LYMPHOMA; ACUTE MYELOID-LEUKEMIA; IMMUNOTOXIN RFB4(DSFV)-PE38 BL22; HUMANIZED ANTI-CD22 ANTIBODY; I CLINICAL-TRIAL; ONCOLOGY GROUP; GEMTUZUMAB OZOGAMICIN; PEDIATRIC-PATIENTS C1 [Satwani, Prakash] Columbia Univ, Morgan Stanley Childrens Hosp New York Presbyteri, New York, NY 10027 USA. [Wayne, Alan S.] NCI, Hematol Dis Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Satwani, P (reprint author), Columbia Univ, Morgan Stanley Childrens Hosp New York Presbyteri, New York, NY 10027 USA. NR 50 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4299-60-2; 978-981-4299-61-9 PY 2012 BP 403 EP 419 PG 17 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA BFP07 UT WOS:000320848700021 ER PT J AU Seibel, NL Smith, MA AF Seibel, Nita L. Smith, Malcolm A. BE Cairo, MS Perkins, SL TI Novel Therapeutics in Hematologic Malignancies in Children, Adolescents and Young Adults SO HEMATOLOGICAL MALIGNANCIES IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS LA English DT Article; Book Chapter ID PRECLINICAL TESTING PROGRAM; ACUTE LYMPHOBLASTIC-LEUKEMIA; PROTEASOME INHIBITOR BORTEZOMIB; ACUTE MYELOID-LEUKEMIA; CANCER-THERAPY; RAPAMYCIN INHIBITOR; PEDIATRIC-PATIENTS; APOPTOSIS PROTEIN; MAMMALIAN TARGET; MTOR INHIBITORS C1 [Seibel, Nita L.] NCI, Pediat Sect, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Seibel, Nita L.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Seibel, Nita L.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Seibel, NL (reprint author), NCI, Pediat Sect, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. NR 47 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4299-60-2 PY 2012 BP 421 EP 435 PG 15 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA BFP07 UT WOS:000320848700022 ER PT J AU Rouault, TA AF Rouault, Tracey A. BE Anderson, GJ McLaren, GD TI Regulation of Iron Metabolism in Mammalian Cells SO IRON PHYSIOLOGY AND PATHOPHYSIOLOGY IN HUMANS SE Nutrition and Health Series LA English DT Article; Book Chapter DE Ferritin; Ferroportin; IRE; IRP1; IRP2; Posttranscriptional regulation; TfR ID SULFUR CLUSTER BIOGENESIS; ELEMENT-BINDING PROTEIN; FE-S CLUSTER; RESPONSIVE ELEMENT; MESSENGER-RNA; TRANSLATIONAL REGULATION; NEURODEGENERATIVE DISEASE; MITOCHONDRIAL ACONITASE; 5-UNTRANSLATED REGION; HEPCIDIN EXPRESSION C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. EM rouault@mail.nih.gov NR 74 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 978-1-60327-485-2 J9 NUTR HEALTH SER JI Nutr. Health Ser. PY 2012 BP 51 EP 62 DI 10.1007/978-1-60327-485-2_3 D2 10.1007/978-1-60327-485-2 PG 12 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA BFW51 UT WOS:000321676100003 ER PT J AU Philpott, CC AF Philpott, Caroline C. BE Anderson, GJ McLaren, GD TI Yeast Iron Metabolism SO IRON PHYSIOLOGY AND PATHOPHYSIOLOGY IN HUMANS SE Nutrition and Health Series LA English DT Article; Book Chapter DE Copper; Hem; Iron; Iron sulfur cluster; Siderophore; Transport; Yeast ID MAJOR FACILITATOR SUPERFAMILY; UBIQUITIN-DEPENDENT TRAFFICKING; TRANSCRIPTION FACTOR AFT1P; METAL-ION TRANSPORTERS; SACCHAROMYCES-CEREVISIAE; FERRICHROME TRANSPORTER; COPPER TRAFFICKING; SIDEROPHORE-IRON; GENE ENCODES; FET3 PROTEIN C1 NIDDK, Genet & Metab Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Philpott, CC (reprint author), NIDDK, Genet & Metab Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM carolinep@intra.niddk.nih.gov NR 101 TC 0 Z9 0 U1 1 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 978-1-60327-485-2 J9 NUTR HEALTH SER JI Nutr. Health Ser. PY 2012 BP 653 EP 667 DI 10.1007/978-1-60327-485-2_30 D2 10.1007/978-1-60327-485-2 PG 15 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA BFW51 UT WOS:000321676100030 ER PT S AU Ji, JF Wang, XW AF Ji, Junfang Wang, Xin Wei BE Ochiya, T TI Identification of Cancer Stem Cell-Related MicroRNAs in Hepatocellular Carcinoma SO LIVER STEM CELLS: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Hepatic cancer stem cells; MicroRNAs; Hepatocellular carcinoma; EpCAM; Fluorescence-activated cell sorting; MicroRNA microarray; Quantitative reverse transcription-polymerase chain reaction; Transfection; Spheroid assay; Tumorigenicity assay ID TUMOR-INITIATING CELLS; LIVER-CANCER; EXPRESSION; DIFFERENTIATION; EPCAM; DIVISION; RNAS AB Cancer Stem cells (CSCs) are the source of many solid tumor types including hepatocellular carcinoma. MicroRNAs (miRNAs) are small noncoding RNAs and have been showed to be associated with hepatic CSCs. Here, we described methods to screen hepatic CSC-related miRNAs, and to validate and examine their expressions and functions in vitro and in vivo, which contribute to the maintenance of sternness and differentiation of hepatic CSCs. C1 [Ji, Junfang; Wang, Xin Wei] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Ji, JF (reprint author), NCI, Human Carcinogenesis Lab, Bldg 37, Bethesda, MD 20892 USA. RI Wang, Xin/B-6162-2009 FU Intramural NIH HHS NR 31 TC 4 Z9 5 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-467-4 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 826 BP 163 EP 175 DI 10.1007/978-1-61779-468-1_14 D2 10.1007/978-1-61779-468-1 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Cell & Tissue Engineering; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA BFY91 UT WOS:000321932600015 PM 22167648 ER PT J AU Zhang, CL Hu, FB AF Zhang, Cuilin Hu, Frank B. BE Gillman, MW Poston, L TI Determinants of obesity SO MATERNAL OBESITY LA English DT Article; Book Chapter ID POSTPARTUM WEIGHT RETENTION; GENOME-WIDE ASSOCIATION; LONG-TERM OBESITY; BODY-MASS INDEX; WAIST-HIP RATIO; MATERNAL METABOLISM; PHYSICAL-ACTIVITY; LACTATING WOMEN; MILK-PRODUCTION; DIETARY-FAT C1 [Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Med, Boston, MA USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. NR 70 TC 1 Z9 1 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-107-00396-5 PY 2012 BP 8 EP 19 D2 10.1017/CBO9780511782466 PG 12 WC Nutrition & Dietetics; Obstetrics & Gynecology SC Nutrition & Dietetics; Obstetrics & Gynecology GA BFS07 UT WOS:000321114100003 ER PT J AU Chen, XY AF Chen, Xiaoyuan BE Chen, X TI MOLECULAR IMAGING PROBES FOR CANCER RESEARCH Preface SO MOLECULAR IMAGING PROBES FOR CANCER RESEARCH LA English DT Editorial Material; Book Chapter C1 Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4293-67-9 PY 2012 BP XV EP XVIII D2 10.1142/7605 PG 4 WC Biochemical Research Methods; Oncology; Medicine, Research & Experimental; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Oncology; Research & Experimental Medicine; Radiology, Nuclear Medicine & Medical Imaging GA BFO57 UT WOS:000320761300001 ER PT J AU Lang, LX Chen, XY AF Lang, Lixin Chen, Xiaoyuan BE Chen, X TI PET Chemistry SO MOLECULAR IMAGING PROBES FOR CANCER RESEARCH LA English DT Article; Book Chapter ID 5-HT1A RECEPTOR RADIOLIGAND; IN-VIVO; EPIBATIDINE; ANALOG C1 [Lang, Lixin; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. EM shawn.chen@nih.gov NR 15 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4293-67-9 PY 2012 BP 151 EP 164 D2 10.1142/7605 PG 14 WC Biochemical Research Methods; Oncology; Medicine, Research & Experimental; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Oncology; Research & Experimental Medicine; Radiology, Nuclear Medicine & Medical Imaging GA BFO57 UT WOS:000320761300006 ER PT B AU Niu, G Chen, XY AF Niu, Gang Chen, Xiaoyuan BE Chen, X TI Molecular Imaging of Apoptosis in Cancer SO MOLECULAR IMAGING PROBES FOR CANCER RESEARCH LA English DT Article; Book Chapter ID PROGRAMMED CELL-DEATH; ACTIVITY-BASED PROBES; IN-VIVO EVALUATION; MEMBRANE PHOSPHOLIPID ASYMMETRY; ACUTE MYOCARDIAL-INFARCTION; RADIATION-INDUCED APOPTOSIS; GAMMA-CARBOXYGLUTAMIC ACID; PHOTODYNAMIC THERAPY AGENT; FLOW-CYTOMETRIC DETECTION; RED FLUORESCENT PEPTIDE C1 [Niu, Gang] Ctr Clin, Imaging Sci Training Program, Bethesda, MD USA. [Niu, Gang; Chen, Xiaoyuan] NIBIB, NIH, Bethesda, MD USA. RP Niu, G (reprint author), Ctr Clin, Imaging Sci Training Program, Bethesda, MD USA. EM niug@mail.nih.gov; shawn.chen@nih.gov NR 154 TC 0 Z9 0 U1 0 U2 3 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4293-67-9; 978-981-4293-68-6 PY 2012 BP 257 EP 284 D2 10.1142/7605 PG 28 WC Biochemical Research Methods; Oncology; Medicine, Research & Experimental; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Oncology; Research & Experimental Medicine; Radiology, Nuclear Medicine & Medical Imaging GA BFO57 UT WOS:000320761300010 ER PT J AU Chen, K Chen, XY AF Chen, Kai Chen, Xiaoyuan BE Chen, X TI PET and SPECT Imaging of Tumor Vasculature SO MOLECULAR IMAGING PROBES FOR CANCER RESEARCH LA English DT Article; Book Chapter ID ENDOTHELIAL GROWTH-FACTOR; POSITRON-EMISSION-TOMOGRAPHY; INTEGRIN ALPHA(V)BETA(3) EXPRESSION; MEMBRANE ANTIGEN PSMA; MATRIX-METALLOPROTEINASE EXPRESSION; CANCER ALPHA(V)-INTEGRIN EXPRESSION; FACTOR RECEPTOR EXPRESSION; TETRAMERIC RGD PEPTIDE; BLOOD-VESSEL FORMATION; PROSTATE-CANCER C1 [Chen, Kai] Univ So Calif, Mol Imaging Ctr, Dept Radiol, Keck Sch Med, Los Angeles, CA 90033 USA. [Chen, Kai; Chen, Xiaoyuan] NIBIB, NIH, Bethesda, MD 20892 USA. RP Chen, K (reprint author), Univ So Calif, Mol Imaging Ctr, Dept Radiol, Keck Sch Med, Los Angeles, CA 90033 USA. EM chenkai@usc.edu; shawn.chen@nih.gov NR 146 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4293-67-9 PY 2012 BP 341 EP 371 D2 10.1142/7605 PG 31 WC Biochemical Research Methods; Oncology; Medicine, Research & Experimental; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Oncology; Research & Experimental Medicine; Radiology, Nuclear Medicine & Medical Imaging GA BFO57 UT WOS:000320761300013 ER PT B AU Lee, S Chen, XY AF Lee, Seulki Chen, Xiaoyuan BE Chen, X TI Activatable Optical Probes for Cancer Imaging SO MOLECULAR IMAGING PROBES FOR CANCER RESEARCH LA English DT Article; Book Chapter ID RESONANCE ENERGY-TRANSFER; MATRIX METALLOPROTEINASE-7 ACTIVITY; PHOTODYNAMIC MOLECULAR BEACON; INFRARED FLUORESCENT-PROBES; CELL-PENETRATING PEPTIDES; IN-VIVO CHARACTERIZATION; PROTEASE ACTIVITY; GOLD NANOPARTICLES; QUANTUM DOTS; DIAGNOSTIC APPLICATIONS C1 [Lee, Seulki; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Lee, S (reprint author), NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, 31 Ctr Dr Suite 1C14, Bethesda, MD 20892 USA. EM lees8@mail.nih.gov; Shawn.Chen@nih.gov NR 85 TC 0 Z9 0 U1 1 U2 5 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4293-67-9; 978-981-4293-68-6 PY 2012 BP 519 EP 543 D2 10.1142/7605 PG 25 WC Biochemical Research Methods; Oncology; Medicine, Research & Experimental; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Oncology; Research & Experimental Medicine; Radiology, Nuclear Medicine & Medical Imaging GA BFO57 UT WOS:000320761300018 ER PT J AU Neumaier, CE Baio, G AF Neumaier, Carlo Emanuele Baio, Gabriella BE Chen, X TI Ultrasound Probes for Imaging Tumor Vasculature SO MOLECULAR IMAGING PROBES FOR CANCER RESEARCH LA English DT Article; Book Chapter ID MYOCARDIAL CONTRAST ECHOCARDIOGRAPHY; ACOUSTIC RADIATION FORCE; ENDOTHELIAL GROWTH-FACTOR; GAS-FILLED MICROBUBBLES; IN-VIVO; P-SELECTIN; CELL-ADHESION; LYMPH-NODES; ACTIVATED LEUKOCYTES; ECHOGENIC LIPOSOMES C1 [Neumaier, Carlo Emanuele; Baio, Gabriella] IRCCS Azienda Osped Univ San Martino, IST, Natl Canc Inst, Dept Diagnost Imaging, I-16100 Genoa, Italy. RP Neumaier, CE (reprint author), IRCCS Azienda Osped Univ San Martino, IST, Natl Canc Inst, Dept Diagnost Imaging, Largo Rosanna Benzi 10, I-16100 Genoa, Italy. EM carlo.neumaier@istge.it; gabriella.baio@istge.it RI Baio, Gabriella/M-7621-2015 OI Baio, Gabriella/0000-0002-8397-5318 NR 135 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4293-67-9 PY 2012 BP 733 EP 767 D2 10.1142/7605 PG 35 WC Biochemical Research Methods; Oncology; Medicine, Research & Experimental; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Oncology; Research & Experimental Medicine; Radiology, Nuclear Medicine & Medical Imaging GA BFO57 UT WOS:000320761300026 ER PT J AU Hancock, H Frenkel, V AF Hancock, Hilary Frenkel, Victor BE Chen, X TI Ultrasound Mediated Drug and Gene Delivery for the Treatment of Solid Tumors SO MOLECULAR IMAGING PROBES FOR CANCER RESEARCH LA English DT Article; Book Chapter ID INTENSITY FOCUSED ULTRASOUND; BLOOD-BRAIN-BARRIER; TEMPERATURE-SENSITIVE LIPOSOMES; LOCALIZED PROSTATE-CANCER; PLASMID DNA DELIVERY; MR CONTRAST AGENT; IN-VIVO; RADIATION-FORCE; THERMOSENSITIVE LIPOSOMES; THERAPEUTIC ULTRASOUND C1 [Hancock, Hilary] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Frenkel, Victor] Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA. RP Hancock, H (reprint author), NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 139 TC 1 Z9 1 U1 1 U2 2 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4293-67-9 PY 2012 BP 769 EP 794 D2 10.1142/7605 PG 26 WC Biochemical Research Methods; Oncology; Medicine, Research & Experimental; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Oncology; Research & Experimental Medicine; Radiology, Nuclear Medicine & Medical Imaging GA BFO57 UT WOS:000320761300027 ER PT J AU Liu, G Chen, XY Ai, H AF Liu, Gang Chen, Xiaoyuan Ai, Hua BE Chen, X TI Multifunctional Probes for Multimodality Imaging of Cancer SO MOLECULAR IMAGING PROBES FOR CANCER RESEARCH LA English DT Article; Book Chapter ID POSITRON-EMISSION-TOMOGRAPHY; IRON-OXIDE NANOPARTICLES; REPORTER GENE-EXPRESSION; FLUORESCENT SILICA NANOPARTICLES; SEMICONDUCTOR QUANTUM DOTS; TYPE-1 THYMIDINE KINASE; SENTINEL LYMPH-NODE; IN-VIVO; MAGNETIC-RESONANCE; BREAST-CANCER C1 [Liu, Gang; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. [Liu, Gang; Ai, Hua] Sichuan Univ, Natl Engn Res Ctr Biomat, Chengdu 610064, Peoples R China. [Liu, Gang] North Sichuan Med Coll, Affiliated Hosp, Sichuan Key Lab Med Imaging, Nanchong 637007, Peoples R China. [Ai, Hua] Sichuan Univ, West China Hosp, Dept Radiol, Chengdu 610064, Peoples R China. RP Liu, G (reprint author), NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. NR 174 TC 1 Z9 1 U1 0 U2 1 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4293-67-9 PY 2012 BP 863 EP 903 D2 10.1142/7605 PG 41 WC Biochemical Research Methods; Oncology; Medicine, Research & Experimental; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Oncology; Research & Experimental Medicine; Radiology, Nuclear Medicine & Medical Imaging GA BFO57 UT WOS:000320761300030 ER PT J AU Lin, X Xie, J Chen, XY AF Lin, Xin Xie, Jin Chen, Xiaoyuan BE Chen, X TI Molecular Imaging in Early Detection of Cancer SO MOLECULAR IMAGING PROBES FOR CANCER RESEARCH LA English DT Article; Book Chapter ID CELL LUNG-CANCER; POSITRON-EMISSION-TOMOGRAPHY; PROSTATE-SPECIFIC ANTIGEN; COLOR DOPPLER SONOGRAPHY; LYMPH-NODE METASTASES; HIGH FAMILIAL RISK; BREAST-CANCER; ENDORECTAL MR; COMPUTED-TOMOGRAPHY; HELICAL CT C1 [Lin, Xin; Xie, Jin; Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. RP Chen, XY (reprint author), NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. EM shawn.chen@nih.gov NR 145 TC 3 Z9 3 U1 0 U2 2 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4293-67-9 PY 2012 BP 951 EP 978 D2 10.1142/7605 PG 28 WC Biochemical Research Methods; Oncology; Medicine, Research & Experimental; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Oncology; Research & Experimental Medicine; Radiology, Nuclear Medicine & Medical Imaging GA BFO57 UT WOS:000320761300032 ER PT J AU Sharov, AA AF Sharov, Alexei A. BE Maran, T Lindstrom, K Magnus, R Tonnessen, M TI THE ORIGIN OF MIND SO SEMIOTICS IN THE WILD: ESSAYS IN HONOUR OF KALEVI KULL ON THE OCCASION OF HIS 60TH BIRTHDAY LA English DT Article; Book Chapter C1 [Sharov, Alexei A.] NIA, Genet Lab, Baltimore, MD 21224 USA. RP Sharov, AA (reprint author), 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sharoval@mail.nih.gov NR 16 TC 1 Z9 1 U1 0 U2 0 PU UNIV TARTU PRESS PI TARTU PA 1 W STRUVE ST, TARTU, 50091, ESTONIA BN 978-9949-32-041-7 PY 2012 BP 63 EP 70 PG 8 WC Communication; Language & Linguistics SC Communication; Linguistics GA BFL77 UT WOS:000320440000008 ER PT S AU Burroughs, AM Iyer, LM Aravind, L AF Burroughs, A. Maxwell Iyer, Lakshminarayan M. Aravind, L. BE Dohmen, RJ Scheffner, M TI Structure and Evolution of Ubiquitin and Ubiquitin-Related Domains SO UBIQUITIN FAMILY MODIFIERS AND THE PROTEASOME: REVIEWS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Ubiquitin; Prokaryotic ubiquitin conjugation; Nonribosomal peptide ligases; SUMO; RNA modification; Beta-grasp fold ID PROTEIN CONJUGATION SYSTEM; TRANSFER-RNA SYNTHETASES; CASPASE-ACTIVATED DNASE; X-RAY CRYSTALLOGRAPHY; INITIATION-FACTOR IF3; NUCLEAR-PORE COMPLEX; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; DEUBIQUITINATING ENZYMES; BACILLUS-SUBTILIS AB Since its discovery over three decades ago, it has become abundantly clear that the ubiquitin (Ub) system is a quintessential feature of all aspects of eulcaryotic biology. At the heart of the system lies the conjugation and deconjugation of Ub and Ub-like (Ubls) proteins to proteins or lipids drastically altering the biochemistry of the targeted molecules. In particular, it represents the primary mechanism by which protein stability is regulated in eukaryotes. Ub/Ubls are typified by the beta-grasp fold (beta-GF) that has additionally been recruited for a strikingly diverse range of biochemical functions. These include catalytic roles (e.g., NUDIX phosphohydrolases), scaffolding of iron sulfur clusters, binding of RNA and other biomolecules such as co-factors, sulfur transfer in biosynthesis of diverse metabolites, and as mediators of key protein protein interactions in practically every conceivable cellular context. In this chapter, we present a synthetic overview of the structure, evolution, and natural classification of Ub, Ubls, and other members of the beta-GE. The beta-GF appears to have differentiated into at least seven clades by the time of the last universal common ancestor of all extant organisms, encompassing much of the structural diversity observed in extant versions. The beta-GF appears to have first emerged in the context of translation-related RNA-interactions and subsequently exploded to occupy various functional niches. Most biochemical diversification of the fold occurred in prokaryotes, with the eukaryotic phase of its evolution mainly marked by the expansion of the Ubl clade of the beta-GE. Consequently, at least 70 distinct Ubl families are distributed across eukaryotes, of which nearly 20 families were already present in the eukaryotic common ancestor. These included multiple protein and one lipid conjugated forms and versions that functions as adapter domains in multimodule polypeptides. The early diversification of the Ubl families in eukaryotes played a major role in the emergence of characteristic eukaryotic cellular substructures and systems pertaining to nucleo-cytoplasmic compartmentalization, vesicular trafficking, lysosomal targeting, protein processing in the endoplasmic reticulum, and chromatin dynamics. Recent results from comparative genomics indicate that precursors of the eukaryotic Ub-system were already present in prokaryotes. The most basic versions are those combining an Ubl and an El-like enzyme involved in metabolic pathways related to metallopterin, thiamine, cysteine, siderophore and perhaps modified base biosynthesis. Some of these versions also appear to have given rise to simple protein-tagging systems such as Sampylation in archaea and Urmylation in eukaryotes. However, other prokaryotic systems with Ubls of the YukD and other families, including one very close to Ub itself, developed additional elements that more closely resemble the eukaryotic state in possessing an E2, a RING-type E3, or both of these components. Additionally, prokaryotes have evolved conjugation systems that are independent of Ub ligases, such as the Pup system. C1 [Burroughs, A. Maxwell] RIKEN Yokohama Inst, OSC, Yokohama, Kanagawa, Japan. [Iyer, Lakshminarayan M.; Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Burroughs, AM (reprint author), RIKEN Yokohama Inst, OSC, Yokohama, Kanagawa, Japan. FU Intramural NIH HHS NR 154 TC 16 Z9 16 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-61779-473-5 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2012 VL 832 BP 15 EP 63 DI 10.1007/978-1-61779-474-2_2 D2 10.1007/978-1-61779-474-2 PG 49 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BFY93 UT WOS:000321932800003 PM 22350875 ER PT J AU Pearce, LD Hardie, JH AF Pearce, Lisa D. Hardie, Jessica Halliday BE Trommsdorff, G Chen, X TI Religion's Role in the Development of Girls' Occupational Aspirations SO VALUES, RELIGION, AND CULTURE IN ADOLESCENT DEVELOPMENT SE Jacobs Foundation Series on Adolescence LA English DT Article; Book Chapter ID EDUCATIONAL EXPECTATIONS; HIGH-SCHOOL; LIFE GOALS; GENDER; ADOLESCENTS; ATTAINMENT; ADULTHOOD; FAMILY; VALUES; CONSERVATISM AB In this chapter we explore the influence of religion on female adolescents through the use of both nationally representative, longitudinal survey data and semi-structured, in-person interviews from the National Study of Youth and Religion. Our results suggest that growing up in a religious family, especially those involved in religious institutions, may result in an increased identification with femininity and a heightened emphasis on care, leading to preference for more female-dominated jobs like teaching, nursing, and other medical assistant type work. Adolescent girls (ages 16-21) express a preference for these careers over business, science, or other male-dominated (and more highly paid) professions while directly referring to a personal desire for an altruistic, rewarding, and "family friendly" career track. These gendered career aspirations sort girls into limited career tracks early in their educational lives and often well before family formation processes begin, likely contributing to continued gender inequality in educational and career attainment. Although occupational aspirations are thought to be primarily products of social class and ability, we argue that cultural forces such as religion provide a system of meaning and values that shape how girls imagine their futures. C1 [Pearce, Lisa D.] Univ N Carolina, Chapel Hill, NC 27515 USA. [Hardie, Jessica Halliday] Penn State Univ, NICHD, University Pk, PA 16802 USA. RP Pearce, LD (reprint author), Univ N Carolina, Chapel Hill, NC 27515 USA. NR 42 TC 1 Z9 1 U1 1 U2 3 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-107-01425-1 J9 JACOBS FOUND SER ADO PY 2012 BP 271 EP 289 D2 10.1017/CBO9781139013659 PG 19 WC Psychology, Developmental SC Psychology GA BFN59 UT WOS:000320646800013 ER PT S AU Kayaalp, M AF Kayaalp, Mehmet BE Murray, A TI ICU Outcome Predictions using Physiologic Trends in the First Two Days SO 2012 COMPUTING IN CARDIOLOGY (CINC), VOL 39 SE Computers in Cardiology Series LA English DT Proceedings Paper CT 39th Conference on Computing in Cardiology CY SEP 09-12, 2012 CL AGH Univ Sci & Technol, Krakow, POLAND SP European Soc Cardiol, EMB, IEEE, PhysioNet, Silvermedia, Mortara, Drager, GE, Aspel, itAm, Physiol Measurement, Zoll, IBM HO AGH Univ Sci & Technol ID NETWORKS; CARE AB Aims: This study aims to accurately predict patient mortality in the ICU Given all physiologic measurements in the first 48 hours of the ICU stay, the Bayesian model of the study predicts outcome with a posterior probability. Methods: This study modeled the outcome as a binary random variable dependent on trends of daily physiologic measures of the patient, where trends were conditionally independent given the outcome. A two-day trend is a sequence of two discrete values, one for each day. Each value (low, medium, high or unmeasured) is a function of the arithmetic mean of that measure on the corresponding day. Results: The prediction performance of the model was measured as the minimum of sensitivity and positive predictive values. The model yielded a score of 0.39 along with a Hosmer-Lemeshow H statistic of 36, which measures calibration. The perfect scores would be 1.0 and 0, respectively. Conclusion: The prediction performance of the study was an improvement over the established ICU scoring metric SAPS-L whose score was 0.32. Calibration of the model outputs was comparable to that of SAPS-I. C1 NIH, Lister Hill Natl Ctr Biomed Commun, US Natl Lib Med, Bethesda, MD 20894 USA. RP Kayaalp, M (reprint author), NIH, Lister Hill Natl Ctr Biomed Commun, US Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM mehmet@kayaalp.us NR 13 TC 0 Z9 0 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 0276-6574 BN 978-1-4673-2074-0 J9 COMPUT CARDIOL PY 2012 BP 977 EP 980 PG 4 WC Cardiac & Cardiovascular Systems; Computer Science, Interdisciplinary Applications SC Cardiovascular System & Cardiology; Computer Science GA BFK65 UT WOS:000320270700245 ER PT J AU Rebois, RV Ray, K AF Rebois, R. Victor Ray, Kausik BE Gupta, RC TI Ionizing radiation and radioactive materials in health and disease SO VETERINARY TOXICOLOGY: BASIC AND CLINICAL PRINCIPLES, 2ND EDITION LA English DT Article; Book Chapter ID ADAPTIVE RESPONSE; MICE; IRRADIATION; HORMESIS; LATENCY C1 [Rebois, R. Victor] Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. [Rebois, R. Victor] NINDS, NIH, Bethesda, MD 20892 USA. [Ray, Kausik] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. RP Rebois, RV (reprint author), Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. NR 19 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-385927-3 PY 2012 BP 391 EP 405 DI 10.1016/B978-0-12-385926-6.00025-9 PG 15 WC Toxicology; Veterinary Sciences SC Toxicology; Veterinary Sciences GA BER41 UT WOS:000317854000026 ER PT S AU Karargyris, A Karargyris, O Pantelopoulos, A AF Karargyris, Alexandros Karargyris, Orestis Pantelopoulos, Alexandros GP IEEE TI DERMA/care: An advanced image-processing mobile application for monitoring skin cancer SO 2012 IEEE 24TH INTERNATIONAL CONFERENCE ON TOOLS WITH ARTIFICIAL INTELLIGENCE (ICTAI 2012), VOL 2 SE Proceedings-International Conference on Tools With Artificial Intelligence LA English DT Proceedings Paper CT IEEE 24th International Conference on Tools with Artificial Intelligence (ICTAI) CY NOV 07-09, 2012 CL Athens, GREECE SP IEEE, IEEE Comp Soc, Biol & Artificial Intelligence Fdn (BAIF), Hellen Artificial Intelligence Soc (EETN), Univ Piraeus, Univ Piraeus Res Ctr DE Mobile; health; microscope; image; machine learning; iPhone; iOS; melanomas; skin cancer prevention ID SPATIAL-FREQUENCY; FILTERS; TEXTURE AB This paper describes a mobile hardware/software system (DERMA/care) to help with screening of skin cancer (melanomas). Our system uses an inexpensive apparatus (microscope) and a smartphone (iPhone). These two components standalone are sufficient to capture highly detailed images for use by experts with medical background. However the novelty of our system lies in the fact that we further improved the efficiency of the system by implementing an advanced image-processing framework to detect suspicious areas and help with skin cancer prevention. Our main goal was to demonstrate how smartphones could turn into powerful and intelligent machines and help large populations without expertise in low-resource settings. C1 [Karargyris, Alexandros] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Karargyris, A (reprint author), NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM akarargyris@gmail.com; okarargyris@gmail.com; alekospant@gmail.com NR 8 TC 11 Z9 11 U1 6 U2 8 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1082-3409 BN 978-0-7695-4915-6 J9 PROC INT C TOOLS ART PY 2012 BP 1 EP 7 DI 10.1109/ICTAI.2012.180 PG 7 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BFP41 UT WOS:000320865800001 ER PT J AU Calado, RT Young, NS AF Calado, Rodrigo T. Young, Neal S. BA Friedberg, EC Castrillon, DH Galindo, RL Wharton, KA BF Friedberg, EC Castrillon, DH Galindo, RL Wharton, KA TI Telomeropathies SO NEW -OPATHIES: AN EMERGING MOLECULAR RECLASSIFICATION OF HUMAN DISEASE LA English DT Article; Book Chapter ID NODULAR REGENERATIVE HYPERPLASIA; IDIOPATHIC PULMONARY-FIBROSIS; GENOME-WIDE ASSOCIATION; DYSKERATOSIS-CONGENITA; TELOMERE LENGTH; APLASTIC-ANEMIA; GENETIC-VARIATION; LIVER-CIRRHOSIS; CANCER; MUTATIONS C1 [Calado, Rodrigo T.; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Calado, RT (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10 CRC,Rm 3E-5140, Bethesda, MD 20892 USA. EM calado@nhlbi.nih.gov; youngns@nhlbi.nih.gov NR 45 TC 0 Z9 0 U1 0 U2 3 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA PO BOX 128 FARRER RD, SINGAPORE 9128, SINGAPORE BN 978-981-4355-68-1 PY 2012 BP 169 EP 187 PG 19 WC Biochemistry & Molecular Biology; Pathology SC Biochemistry & Molecular Biology; Pathology GA BFM38 UT WOS:000320509000006 ER PT J AU Marotta, M Chen, XF Inoshita, A Stephens, R Budd, GT Crowe, JP Lyons, J Kondratova, A Tubbs, R Tanaka, H AF Marotta, Michael Chen, Xiongfong Inoshita, Ayako Stephens, Robert Budd, G. Thomas Crowe, Joseph P. Lyons, Joanne Kondratova, Anna Tubbs, Raymond Tanaka, Hisashi TI A common copy-number breakpoint of ERBB2 amplification in breast cancer colocalizes with a complex block of segmental duplications SO BREAST CANCER RESEARCH LA English DT Article ID TOPOISOMERASE-II-ALPHA; COMPARATIVE GENOMIC HYBRIDIZATION; MITOTIC HOMOLOGOUS RECOMBINATION; HOMOGENEOUSLY STAINING REGIONS; DNA-DAMAGE CHECKPOINT; DOUBLE-STRAND BREAK; GENE AMPLIFICATION; INVERTED REPEATS; LUNG-CANCER; CELL-LINES AB Introduction: Segmental duplications (low-copy repeats) are the recently duplicated genomic segments in the human genome that display nearly identical (> 90%) sequences and account for about 5% of euchromatic regions. In germline, duplicated segments mediate nonallelic homologous recombination and thus cause both non-disease-causing copy-number variants and genomic disorders. To what extent duplicated segments play a role in somatic DNA rearrangements in cancer remains elusive. Duplicated segments often cluster and form genomic blocks enriched with both direct and inverted repeats (complex genomic regions). Such complex regions could be fragile and play a mechanistic role in the amplification of the ERBB2 gene in breast tumors, because repeated sequences are known to initiate gene amplification in model systems. Methods: We conducted polymerase chain reaction (PCR)-based assays for primary breast tumors and analyzed publically available array-comparative genomic hybridization data to map a common copy-number breakpoint in ERBB2-amplified primary breast tumors. We further used molecular, bioinformatics, and population-genetics approaches to define duplication contents, structural variants, and haplotypes within the common breakpoint. Results: We found a large (> 300-kb) block of duplicated segments that was colocalized with a common-copy number breakpoint for ERBB2 amplification. The breakpoint that potentially initiated ERBB2 amplification localized in a region 1.5 megabases (Mb) on the telomeric side of ERBB2. The region is very complex, with extensive duplications of KRTAP genes, structural variants, and, as a result, a paucity of single-nucleotide polymorphism (SNP) markers. Duplicated segments are varied in size and degree of sequence homology, indicating that duplications have occurred recurrently during genome evolution. Conclusions: Amplification of the ERBB2 gene in breast tumors is potentially initiated by a complex region that has unusual genomic features and thus requires rigorous, labor-intensive investigation. The haplotypes we provide could be useful to identify the potential association between the complex region and ERBB2 amplification. C1 [Marotta, Michael; Inoshita, Ayako; Kondratova, Anna; Tanaka, Hisashi] Cleveland Clin Lerner Res Inst, Dept Mol Genet, Cleveland, OH 44195 USA. [Budd, G. Thomas] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44195 USA. [Crowe, Joseph P.; Lyons, Joanne] Cleveland Clin, Dept Gen Surg, Cleveland, OH 44195 USA. [Chen, Xiongfong; Stephens, Robert] SAIC Frederick Inc, Adv Biomed Comp Ctr, Natl Canc Inst, Frederick, MD 21702 USA. [Tubbs, Raymond] Cleveland Clin, Dept Mol Pathol, Cleveland, OH 44195 USA. [Tanaka, Hisashi] Case Western Reserve Univ, Cleveland Clin Lerner Coll Med, Dept Mol Med, Cleveland, OH 44195 USA. RP Tanaka, H (reprint author), Cleveland Clin Lerner Res Inst, Dept Mol Genet, Cleveland, OH 44195 USA. EM tanakah@ccf.org FU Cleveland Clinic; American Cancer Society; National Cancer Institute [R01CA149385] FX We thank Drs George Stark, Charis Eng, and Scott Diede for comments on the manuscript. This work is supported by the funding from Cleveland Clinic, American Cancer Society, and National Cancer Institute (R01CA149385). NR 143 TC 7 Z9 8 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X J9 BREAST CANCER RES JI Breast Cancer Res. PY 2012 VL 14 IS 6 AR R150 DI 10.1186/bcr3362 PG 19 WC Oncology SC Oncology GA 160YO UT WOS:000320156600021 PM 23181561 ER PT S AU Meinertzhagen, IA Lee, CH AF Meinertzhagen, Ian A. Lee, Chi-Hon BE Friedmann, T Dunlap, JC Goodwin, SF TI The Genetic Analysis of Functional Connectomics in Drosophila SO ADVANCES IN GENETICS, VOL 80 SE Advances in Genetics LA English DT Review; Book Chapter ID METABOTROPIC GLUTAMATE-RECEPTOR; GAP-JUNCTION PROTEINS; LARVAL VISUAL-SYSTEM; CHLORIDE CHANNEL SUBUNITS; SHAW POTASSIUM CHANNEL; CENTRAL-NERVOUS-SYSTEM; IN-VIVO; SYNAPTIC-TRANSMISSION; ANTENNAL LOBE; NEURAL CIRCUITS AB Fly and vertebrate nervous systems share many organizational features, such as layers, columns and glomeruli, and utilize similar synaptic components, such as ion channels and receptors. Both also exhibit similar network features. Recent technological advances, especially in electron microscopy, now allow us to determine synaptic circuits and identify pathways cell-by-cell, as part of the fly's connectome. Genetic tools provide the means to identify synaptic components, as well as to record and manipulate neuronal activity, adding function to the connectome. This review discusses technical advances in these emerging areas of functional connectomics, offering prognoses in each and identifying the challenges in bridging structural connectomics to molecular biology and synaptic physiology, thereby determining fundamental mechanisms of neural computation that underlie behavior. C1 [Meinertzhagen, Ian A.] Dalhousie Univ, Dept Psychol & Neurosci, Life Sci Ctr, Halifax, NS B3H 4R2, Canada. [Meinertzhagen, Ian A.] Dalhousie Univ, Dept Biol, Life Sci Ctr, Halifax, NS B3H 4R2, Canada. [Lee, Chi-Hon] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Meinertzhagen, IA (reprint author), Dalhousie Univ, Dept Psychol & Neurosci, Life Sci Ctr, Halifax, NS B3H 4R2, Canada. EM iam@dal.ca; leechih@mail.nih.gov FU Howard Hughes Medical Institute; Intramural NIH HHS [ZIA HD008776-06]; NEI NIH HHS [EY-03592, R01 EY003592]; NICHD NIH HHS [HD008776-08, Z01 HD008776] NR 297 TC 17 Z9 17 U1 2 U2 20 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-2660 BN 978-0-12-404742-6 J9 ADV GENET JI Adv. Genet. PY 2012 VL 80 BP 99 EP 151 PG 53 WC Genetics & Heredity SC Genetics & Heredity GA BEW75 UT WOS:000318445700003 PM 23084874 ER PT B AU Dunleavy, K Grant, C Wilson, WH AF Dunleavy, Kieron Grant, Cliona Wilson, Wyndham H. BE Sweetenham, JW TI Novel Pathways and Therapeutic Strategies for Aggressive B-Cell Lymphoma SO LYMPHOMAS SE Emerging Cancer Therapeutics LA English DT Article; Book Chapter DE lymphoma; molecular subtypes; DLBCL; activated B-cell like; germinal center B-cell like; ABC; GCB; NF-kappa B pathway; B-cell receptor signaling; Bruton's tyrosine kinase; primary mediastinal B-cell lymphoma; PMBL ID NON-HODGKINS-LYMPHOMA; 3-WEEKLY CHOP CHEMOTHERAPY; NF-KAPPA-B; GERMINAL-CENTER; MOLECULAR SUBTYPES; ANTITUMOR-ACTIVITY; YOUNG-PATIENTS; IN-VIVO; MACOP-B; CANCER AB Over recent years, there has been significant progress in understanding and elucidating the molecular biology and pertinent signaling pathways of aggressive B-cell lymphoma, particularly diffuse large B-cell lymphoma (DLBCL). This has facilitated a switch in the focus of drug discovery from classical cytotoxic agents to molecules that target specific pathways involved in signal transduction, apoptosis, and cell differentiation, to name a few. These efforts in novel drug discovery have been greatly aided by insights into the structure of proteins and the ability to design specific inhibitors using small molecules or monoclonal antibodies. The discovery of new signaling pathways, critical to lymphomagenesis, through gene-expression profiling (GEP) and RNA interference (RNAi) screening has produced an array of new targets for the treatment of lymphomas. Specifically, GEP has revealed that DLBCL consists of at least three major subtypes: germinal center B-cell-like (GCB), activated B-cell-like (ABC), and primary mediastinal B-cell (PMBL) DLBCL, which are derived from B-cells at different stages of differentiation and are each characterized by distinct mechanisms of oncogenesis. ABC DLBCL shows high expression of target genes of the NF-kappa B/Rel family of transcription factors and may benefit from NF-kappa B inhibition. In GCB DLBCL, studies raise the hypothesis that inhibition of the Bcl-6 transcription factor may be therapeutically important, whereas PMBL, like its biological cousin nodular sclerosis Hodgkin lymphoma (HL), may benefit from dose-intensity approaches and inhibition of the Janus Kinases. In this review, We focus particularly on DLBCL, which makes up the majority of aggressive B-cell lymphomas, and discuss novel therapies in the context of molecular subtypes of this disease. C1 [Dunleavy, Kieron; Grant, Cliona; Wilson, Wyndham H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dunleavy, K (reprint author), NCI, Metab Branch, Bldg 10,Room 4N-115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dunleavk@mail.nih.gov; wilsonw@mail.nih.gov NR 88 TC 0 Z9 0 U1 0 U2 1 PU DEMOS MEDICAL PUBLICATIONS PI NEW YORK PA 11 WEST 42ND STREET, 15TH FLOOR, NEW YORK, NY 10036 USA BN 978-1-936287-78-9 J9 EMERG CANCER THER PY 2012 VL 3 IS 2 BP 279 EP 302 DI 10.5003/2151-4194.3.2.279 PG 24 WC Oncology SC Oncology GA BEW16 UT WOS:000318375100007 ER PT J AU Hanebrink, JR Smith, AJ AF Hanebrink, Julia R. Smith, Alanya J. BE Ensor, MO TI PAINTING A PICTURE OF CREATIVE ARTS THERAPY FOR WAR-AFFECTED YOUTH IN NORTHERN UGANDA SO AFRICAN CHILDHOODS: EDUCATION, DEVELOPMENT, PEACEBUILDING, AND THE YOUNGEST CONTINENT LA English DT Article; Book Chapter C1 [Hanebrink, Julia R.; Smith, Alanya J.] Christian Bros Univ, Natl Inst Hlth, Minor Hlth Int Res Training Program, Memphis, TN 38104 USA. [Hanebrink, Julia R.] Christian Bros Univ, Memphis, TN USA. [Hanebrink, Julia R.] Univ Tennessee, Knoxville, TN USA. [Smith, Alanya J.] Aurora Behav Hlth, Tempe, AZ USA. RP Hanebrink, JR (reprint author), Christian Bros Univ, Natl Inst Hlth, Minor Hlth Int Res Training Program, Memphis, TN 38104 USA. NR 29 TC 0 Z9 0 U1 0 U2 0 PU PALGRAVE PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, ENGLAND BN 978-1-137-02470-1 PY 2012 BP 219 EP 233 D2 10.1057/9781137024701 PG 15 WC Area Studies; Social Sciences, Interdisciplinary SC Area Studies; Social Sciences - Other Topics GA BES13 UT WOS:000317917300015 ER PT J AU MacLachlan, AJ AF MacLachlan, Anne J. BE HintonSmith, T TI Women and Students of Colour as Non-Traditional Students: The Difficulties of Inclusion in the United States SO WIDENING PARTICIPATION IN HIGHER EDUCATION: CASTING THE NET WIDE? SE Issues in Higher Education LA English DT Article; Book Chapter C1 [MacLachlan, Anne J.] Univ Calif Berkeley, Ctr Studies Higher Educ, Berkeley, CA 94720 USA. [MacLachlan, Anne J.] NIH, Bethesda, MD USA. [MacLachlan, Anne J.] Natl Sci Fdn, Arlington, VA 22230 USA. [MacLachlan, Anne J.] Amer Assoc Advancement Sci, Washington, DC USA. RP MacLachlan, AJ (reprint author), Univ Calif Berkeley, Ctr Studies Higher Educ, Berkeley, CA 94720 USA. NR 50 TC 0 Z9 0 U1 0 U2 1 PU PALGRAVE PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, ENGLAND BN 978-1-137-28341-2 J9 ISSUES HIGH EDUC PY 2012 BP 263 EP 279 D2 10.1057/9781137283412 PG 17 WC Education & Educational Research SC Education & Educational Research GA BEQ04 UT WOS:000317666200016 ER PT J AU Hunsberger, JG Fessler, EB Wang, ZF Elkahloun, AG Chuang, DM AF Hunsberger, Joshua G. Fessler, Emily B. Wang, Zhifei Elkahloun, Abdel G. Chuang, De-Maw TI Post-insult valproic acid-regulated microRNAs: potential targets for cerebral ischemia SO AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH LA English DT Article DE Cerebral ischemia; valproic acid; microRNA; oxygen-glucose deprivation; neuroprotection ID HISTONE DEACETYLASE INHIBITION; PROTEIN-TYROSINE-PHOSPHATASE; GENE-EXPRESSION; ARTERY OCCLUSION; PROSTATE-CANCER; CELL-DEATH; STROKE; NEUROPROTECTION; BINDING; BRAIN AB Stroke is a devastating brain injury that is a leading cause of adult disability with limited treatment options. Using a rat model of middle cerebral artery occlusion (MCAO) to induce cerebral ischemia, we profiled microRNAs (miRNAs), small non-protein coding RNAs, in the ischemic cortex. Many miRNAs were confirmed by qPCR to be robustly upregulated 24 hours following MCAO surgery including miR-155, miR-297a, miR-466f, miR-466h, and miR-1224. In addition, we treated MCAO rats with valproic acid (VPA), a mood stabilizer and histone deacetylase inhibitor. This post-insult treatment was shown to improve neurological deficits and motor performance following MCAO. To provide mechanistic insight into the potential targets and pathways that may underlie these benefits, we profiled miRNAs regulated following this VPA treatment. Two promising post-insult VPA-regulated candidates were miR-331 and miR-885-3p. miR-331 was also regulated by VPA pre-treatment in rat cortical neuronal cultures subjected to oxygen-glucose deprivation, an in vitro ischemic model. The predicted targets of these miRNAs analyzed by Ingenuity Pathway Analysis (IPA) identified networks involved in hematological system development, cell death, and nervous system development. These predicted networks were further filtered using IPA and showed significant associations with neurological diseases including movement disorders, neurodegenerative disorders, damage to cerebral cortex, and seizure disorders among others. Collectively, these data support common disease mechanisms that may be under miRNA control and provide exciting directions for further investigations aimed at elucidating the miRNA mechanisms and targets that may yield new therapies for neurological disorders. C1 [Hunsberger, Joshua G.; Fessler, Emily B.; Wang, Zhifei; Chuang, De-Maw] NIMH, Sect Mol Neurobiol, NIH, Bethesda, MD 20892 USA. [Elkahloun, Abdel G.] NHGRI, Microarray Core Facil, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Sect Mol Neurobiol, NIH, Bethesda, MD 20892 USA. EM hunsbergerj@mail.nih.gov; chuang@mail.nih.gov RI Wang, Zhifei/I-2787-2013 FU NIMH, NIH; Hsu family foundation FX We would like to acknowledge the support of the Intramural Research Program of the NIMH, NIH, and by the Hsu family foundation. We would also like to acknowledge the technical support kindly provided by Weiwei Wu for microRNA array processing and the editorial suggestions by Peter Leeds. NR 42 TC 29 Z9 30 U1 0 U2 4 PU E-CENTURY PUBLISHING CORP PI MADISON PA 40 WHITE OAKS LN, MADISON, WI 53711 USA SN 1943-8141 J9 AM J TRANSL RES JI Am. J. Transl. Res. PY 2012 VL 4 IS 3 BP 316 EP 332 PG 17 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA 135HP UT WOS:000318279500007 PM 22937209 ER PT J AU Burbelo, PD Bayat, A Wagner, J Nutman, TB Baraniuk, JN Iadarola, MJ AF Burbelo, Peter D. Bayat, Ahmad Wagner, Jason Nutman, Thomas B. Baraniuk, James N. Iadarola, Michael J. TI No serological evidence for a role of HHV-6 infection in chronic fatigue syndrome SO AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH LA English DT Article DE Chronic Fatigue Syndrome (CFS); Human Herpes Virus-6 (HHV6); luciferase immunoprecipitation systems (LIPS) ID HUMAN-HERPESVIRUS 6; MULTIPLE-SCLEROSIS; VARIANT-B; UNITED-STATES; HUMAN-HERPESVIRUS-6; IDENTIFICATION; ENCEPHALITIS; ANTIBODIES; ANTIGENS; DISEASE AB Human herpesvirus 6A (HHV-6A) and human herpesvirus 6B (HHV-6B) are associated with a variety of conditions including rash, fever, and encephalitis and may play a role in several neurological diseases. Here luciferase immunoprecipitation systems (LIPS) was used to develop HHV-6 serologic diagnostic tests using antigens encoded by the U11 gene from HHV-6A (p100) and HHV-6B (p101). Analysis of the antibody responses against Renilla luciferase fusions with different HHV-6B p101 fragments identified an antigenic fragment (amino acids 389 to 858) that demonstrated similar to 86% seropositivity in serum samples from healthy US blood donors. Additional experiments detected a HHV-6A antigenic fragment (amino acids 751-870) that showed similar to 48% antibody seropositivity in samples from Mali, Africa, a known HHV-6A endemic region. In contrast to the high levels of HHV-6A immunoreactivity seen in the African samples, testing of US blood donors with the HHV-6A p100 antigenic fragment revealed little immunoreactivity. To potentially explore the role of HHV-6 infection in human disease, a blinded cohort of controls (n=59) and chronic fatigue syndrome (CFS) patients (n=72) from the US was examined for serum antibodies. While only a few of the controls and CFS patients showed high level immunoreactivity with HHV-6A, a majority of both the controls and CFS patients showed significant immunoreactivity with HHV-6B. However, no statistically significant differences in antibody levels or frequency of HHV-6A or HHV-6B infection were detected between the controls and CFS patients. These findings highlight the utility of LIPS for exploring the seroepidemiology of HHV-6A and HHV-6B infection, but suggest that these viruses are unlikely to play a role in the pathogenesis of CFS. C1 [Burbelo, Peter D.; Bayat, Ahmad; Wagner, Jason; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, NIH, Bethesda, MD USA. [Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Baraniuk, James N.] Georgetown Univ, Div Rheumatol Immunol & Allergy, Washington, DC 20007 USA. RP Baraniuk, JN (reprint author), Georgetown Univ, Div Rheumatol Immunol & Allergy, Room 3004F,3rd Floor,PHC Bldg,3800 Reservoir Rd,N, Washington, DC 20007 USA. EM baraniuj@georgetown.edu FU Intramural Research Program of the National Institute of Dental and Craniofacial Research; National Institute of Allergy and Infectious Diseases; Center for Neuroscience and Regenerative Medicine; U.S. Public Health Service from the National Institute of Environmental and Health Science [R01 ES015382]; Congressionally Directed Medical Research Program (CDMRP) [W81XWH-07-1-0618] FX This study was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, the National Institute of Allergy and Infectious Diseases, and from the Center for Neuroscience and Regenerative Medicine. Additional funding for the CFS subproject was from U.S. Public Health Service Award R01 ES015382 from the National Institute of Environmental and Health Science; and the Congressionally Directed Medical Research Program (CDMRP) Award W81XWH-07-1-0618. NR 36 TC 6 Z9 6 U1 0 U2 0 PU E-CENTURY PUBLISHING CORP PI MADISON PA 40 WHITE OAKS LN, MADISON, WI 53711 USA SN 1943-8141 J9 AM J TRANSL RES JI Am. J. Transl. Res. PY 2012 VL 4 IS 4 BP 443 EP 451 PG 9 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA 135HW UT WOS:000318280200008 PM 23145212 ER PT J AU Shuch, B Vourganti, S Friend, JC Zehngebot, LM Linehan, WM Srinivasan, R AF Shuch, Brian Vourganti, Srinivas Friend, Julia C. Zehngebot, Lee M. Linehan, W. Marston Srinivasan, Ramaprasad TI Targeting the mTOR pathway in Chromophobe Kidney Cancer SO JOURNAL OF CANCER LA English DT Article DE mTOR inhibitors; Chromophobe Kidney Cancer ID RENAL-CELL CARCINOMA; SORAFENIB; TEMSIROLIMUS; INTERFERON; ACTIVATION; EFFICACY AB Chromophobe kidney cancer accounts for approximately 5% of cases of renal cell carcinoma (RCC). While the genetics of clear cell RCC has been a major focus of research, little is known about the biology of chromophobe tumors. There is ample preclinical rationale for the use of targeted therapy in clear cell tumors, and agents targeting the VHL/HIF pathway are now widely used in clinical practice. However, there is limited experience with targeted agents in non-clear cell tumors. Recently, a few case reports have emerged which report the use of mTOR inhibitors in chromophobe tumors. Here, we report our experience with targeted therapy in a patient with advanced chromophobe RCC who had a durable partial response to temsirolimus. We also include a literature review summarizing the published experience with targeted therapeutic approaches in chromophobe RCC. Additionally, the preclinical rationale for the use of mTOR inhibitors in this population based on our characterization of the hereditary form of chromophobe kidney cancer, Birt-Hogg-Dube syndrome, is discussed. C1 [Shuch, Brian; Vourganti, Srinivas; Friend, Julia C.; Linehan, W. Marston; Srinivasan, Ramaprasad] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Zehngebot, Lee M.] Orlando Oncol, Orlando, FL 32804 USA. RP Srinivasan, R (reprint author), NCI, Urol Oncol Branch, 10 Ctr Dr,CRC 2-5950, Bethesda, MD 20892 USA. EM ramasrin@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We would like to acknowledge Rabindra Gautam for his assistance with film review and administrative support. A special thanks goes to Dr. Sheldon Shuch and Maria Kwon for manuscript and figure editing. NR 14 TC 8 Z9 9 U1 0 U2 0 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1837-9664 J9 J CANCER JI J. Cancer PY 2012 VL 3 BP 152 EP 157 DI 10.7150/jca.4378 PG 6 WC Oncology SC Oncology GA 135PD UT WOS:000318299800021 PM 22481981 ER PT J AU Langan, RC Ripley, RT Davis, JL Prieto, PA Datrice, N Stein-Berg, SM Bratslavsky, G Rudloff, U Kammula, US Stojadinovic, A Avital, I AF Langan, Russell C. Ripley, R. Taylor Davis, Jeremy L. Prieto, Peter A. Datrice, Nicole Stein-Berg, Seth M. Bratslavsky, Gennady Rudloff, Udo Kammula, Udai S. Stojadinovic, Alexander Avital, Itzhak TI Liver Directed Therapy for Renal Cell Carcinoma SO JOURNAL OF CANCER LA English DT Article DE liver resection; metastatic renal cell carcinoma; liver metastases; radiofrequency ablation ID HEPATIC RESECTION; METASTASES; HEPATECTOMY; SURVIVAL AB Background: Metastatic renal cell carcinoma (RCC) to the liver portrays a poor prognosis and liver directed therapy remains controversial. We aimed to determine potential selection criteria for patients who might benefit from this strategy. Materials and Methods: We evaluated 247 consecutive patients with RCC metastatic to the liver from a prospectively maintained database. Results: Eighteen patients received liver directed therapy (18/247, 7%). Ten patients underwent liver resection (10/247, 4%) and eight patients underwent radiofrequency ablation (RFA, 8/247, 3%). All were rendered free of disease in the liver. Five had synchronous liver disease and underwent synchronous resections with their primary. Mortality was 0%. Fourteen had single (surgery 7, RFA 7) and four (surgery 3, RFA 1) had multiple liver lesions, respectively. Median size of lesions was 5cm (0.5 - 10cm) and 2.5cm (1 - 6cm) in the surgery and RFA groups, respectively. Median DFI was 10 months, and no difference was observed in those with a longer vs. shorter than median DFI (p = 0.95); liver specific progression free survival for the surgery and RFA groups were 4 and 6 months, respectively (p= 0.93). 1, 3 and 5-year actuarial survivals for the whole group were 89%, 40%, 27%. Median survival for the surgery group was 24 (3 to 254+) months, and for the RFA group 15.6 (7-56+) months (p = 0.56). Metachronous liver disease was associated with prolonged survival (p = 0.02). Conclusions: Liver directed therapy for RCC is safe. For highly selected patients with metachronous liver RCC metastases, liver directed therapy should be considered in a multidisciplinary manner. C1 [Langan, Russell C.; Ripley, R. Taylor; Davis, Jeremy L.; Prieto, Peter A.; Datrice, Nicole; Rudloff, Udo; Kammula, Udai S.; Avital, Itzhak] NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. [Stein-Berg, Seth M.] NCI, NIH, Ctr Canc Res, Off Clin Director,Biostatist & Data Management Se, Bethesda, MD 20892 USA. [Bratslavsky, Gennady] NCI, NIH, Ctr Canc Res, Urol Oncol Branch, Bethesda, MD 20892 USA. [Stojadinovic, Alexander] Dept Surg, Div Surg Oncol, Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Avital, Itzhak] Bon Secours Canc Inst, Richmond, VA USA. RP Langan, RC (reprint author), NCI, NIH, Surg Branch, Bldg 10-Hatfield CRC,Room 3-3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM Russell.Langan@gmail.com FU NIH, National Cancer Institute FX This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute. NR 13 TC 8 Z9 8 U1 0 U2 1 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1837-9664 J9 J CANCER JI J. Cancer PY 2012 VL 3 BP 184 EP 190 DI 10.7150/jca.4456 PG 7 WC Oncology SC Oncology GA 135PD UT WOS:000318299800025 PM 22558019 ER PT J AU Ray, S Langan, RC Mullinax, JE Koizumi, T Xin, HW Wiegand, GW Anderson, AJ Stojadinovic, A Thorgeirsson, S Rudloff, U Avital, I AF Ray, Satyajit Langan, Russell C. Mullinax, John E. Koizumi, Tomotake Xin, Hong-Wu Wiegand, Gordon W. Anderson, Andrew J. Stojadinovic, Alexander Thorgeirsson, Snorri Rudloff, Udo Avital, Itzhak TI Establishment of Human Ultra-Low Passage Colorectal Cancer Cell Lines Using Spheroids from Fresh Surgical Specimens Suitable for In Vitro and In Vivo Studies SO JOURNAL OF CANCER LA English DT Article DE Colon cancer; Fresh Tumor; Cell lines; Spheroids; Cancer Stem Cells ID CULTURE MODEL; STEM-CELLS; INVITRO AB Colorectal cancer (CRC) holds the third highest incidence and cancer related mortality rate among men and women in the United States. Unfortunately, there has been little progression made in the treatment of this deadly disease once it has spread beyond the colon. It has been hypothesize that colon cancer stem cells are implicated in CRC carcinogenesis, metastasis, and therapeutic resistance. One of the difficulties in testing these hypotheses is the current use of established high-passage cancer cell lines. Long term, high-passage established cell lines have cells with stem like properties as they propagate almost indefinitely. These cells are thought to be different than the original cancer stem cells in fresh tumors. In order to investigate cancer stem cells, and molecularly profiling tumors with high fidelity to the original primary tumor, one needs to establish suitable primary ultra-low passage cell lines from fresh surgical specimens. Here we report the establishment of tumor initiating colon cancer ultra-low passage cell lines by a combination of gentle mechanical, enzymatic dissociation, spheroid formation, and followed by two generation xenografts from fresh tumors obtained at time of operation. Tumors generated were characterized by morphology, flow cytometry, immunofluorescence, and by gene expression. In the future, such a technology can be used to produce expeditiously enough material to test for mutations, genetic signatures and molecular subtyping readily available for clinical therapeutic decision making. C1 [Ray, Satyajit; Langan, Russell C.; Mullinax, John E.; Koizumi, Tomotake; Xin, Hong-Wu; Wiegand, Gordon W.; Anderson, Andrew J.; Rudloff, Udo; Avital, Itzhak] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stojadinovic, Alexander] Walter Reed Natl Mil Med Ctr, Dept Surg, Div Surg Oncol, Bethesda, MD USA. [Stojadinovic, Alexander] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD 20814 USA. [Thorgeirsson, Snorri] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Avital, Itzhak] Bon Secours Canc Inst, Richmond, VA USA. RP Thorgeirsson, S (reprint author), NCI, Ctr Excellence Integrat Canc Biol, NIH, 37 Convent Dr MSC 4262, Bethesda, MD 20892 USA. EM snor-ri_thorgeirsson@nih.gov; itzhak.avital@gmail.com RI Mullinax, John/L-2509-2014 FU NIH [1ZIABC011005-03] FX This study was supported by the NIH grant 1ZIABC011005-03. NR 13 TC 5 Z9 5 U1 0 U2 1 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1837-9664 J9 J CANCER JI J. Cancer PY 2012 VL 3 BP 196 EP 206 DI 10.7150/jca.4484 PG 11 WC Oncology SC Oncology GA 135PD UT WOS:000318299800027 PM 22606209 ER PT J AU Langan, RC Mullinax, JE Ray, S Raiji, MT Schaub, N Xin, HW Koizumi, T Steinberg, SM Anderson, A Wiegand, G Butcher, D Anver, M Bilchik, AJ Stojadinovic, A Rudloff, U Avital, I AF Langan, Russell C. Mullinax, John E. Ray, Satyajit Raiji, Manish T. Schaub, Nicholas Xin, Hong-Wu Koizumi, Tomotake Steinberg, Seth M. Anderson, Andrew Wiegand, Gordon Butcher, Donna Anver, Miriam Bilchik, Anton J. Stojadinovic, Alexander Rudloff, Udo Avital, Itzhak TI A Pilot Study Assessing the Potential Role of non-CD133 Colorectal Cancer Stem Cells as Biomarkers SO JOURNAL OF CANCER LA English DT Article DE colon cancer; staging; lymph node; cancer recurrence; overall survival; prognosis; biomarkers; cancer stem cells ID TUMOR MICROSATELLITE-INSTABILITY; SHORTENED PATIENT SURVIVAL; COLON-CANCER; ADHESION MOLECULE; PROGNOSTIC IMPACT; MARKERS CD133; EP-CAM; EXPRESSION; CARCINOMA; CD24 AB Introduction: Over 50% of patients with colorectal cancer (CRC) will progress and/or develop metastases. Biomarkers capable of predicting progression, risk stratification and therapeutic benefit are needed. Cancer stem cells are thought to be responsible for tumor initiation, dissemination and treatment failure. Therefore, we hypothesized that CRC cancer stem cell markers (CRCSC) will identify a group of patients at high risk for progression. Methods: Paraffin-embedded tissue cores of normal (n=8), and histopathologically well-defined primary (n=30) and metastatic (n=10) CRC were arrayed in duplicate on tissue microarrays (TMAs). Expression profiles of non-CD133 CRCSC (CD29, CD44, ALDH1A1, ALDH1B1, EpCam, and CD166) were detected by immunohistochemistry and the association with clinicopathological data and patient outcomes was determined using standard statistical methodology. An independent pathologist, blinded to the clinical data scored the samples. Scoring included percent positive cells (0 to 4, 0 = <10%, 1 = 10 - 24%, 2 = 25 - 49%, 3 = 50 - 74%, 4 = 75 - 100%), and the intensity of positively stained cells (0 to 4; 0 = no staining, 1 = diminutive intensity, 2 = low intensity, 3 = intermediate intensity, 4 = high intensity). The pathologic score represents the sum of these two values, reported in this paper as a combined IHC staining score (CSS). Results: Of 30 patients 7 were AJCC stage IIA, 10 stage IIIB, 7 stage IIIC and 6 stage IV. Median follow-up was 113 months. DFI was 17 months. Median overall survival (OS) was not reached. Stage-specific OS was: II - not reached; III - not reached; IV - 11 months. In a univariate analysis, poor OS was associated with loss of CD29 expression; median OS, 32 months vs. not reached for CSS 3-7 vs. >7.5, respectively; p=0.052 comparing entire curves, after adjustment. In a Cox model analysis, loss of CD29 exhibited a trend toward association with survival (p=0.098) after adjusting for the effect of stage (p=0.0076). Greater expression of ALDH1A1 was associated with increasing stage (p=0.042 over stages 2, 3b, 3c, and 4) while loss of CD29 expression exhibited a trend toward being associated with stages 3 and 4 (p=0.08). Compared to normal colon tissue, primary tumors were associated with increased expression of ALDH1B1 (p=0.008). ALD1H1B1 expression level differed according to whether the tumor was moderately or poorly differentiated, well differentiated, or mucinous; the highest expression levels were associated with moderately or poorly differentiated tumors (p=0.011). Lymph node metastases were associated with a trend toward decreased expression of EpCAM (p=0.06) when comparing 0 vs. 1 vs. 2+ positive lymph nodes, as was CD29 (p=0.08) when comparing 0 vs. any positive lymph nodes. Compared to normal colon tissue metastatic colon cancers from different patients were associated with increased ALDH1B1 expression (p=0.001) whereas CD29 expression was higher in normal colonic tissue (p=0.014). Conclusion: CD29 may be associated with survival as well as clinical stage and number of lymph nodes. ALDH1B1 expression was associated with differentiation as well as type of tissue evaluated. ALDH1A1 was associated with clinical stage, and decreased EpCAM expression was found in patients with advanced lymph node stage. CRCSCs may be useful biomarkers to risk stratify, and estimate outcomes in CRC. Larger prospective studies are required to validate the current findings. C1 [Langan, Russell C.; Mullinax, John E.; Ray, Satyajit; Raiji, Manish T.; Schaub, Nicholas; Xin, Hong-Wu; Koizumi, Tomotake; Anderson, Andrew; Wiegand, Gordon; Rudloff, Udo] NCI, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Butcher, Donna; Anver, Miriam] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Pathol Histotechnol Lab, Frederick, MD USA. [Bilchik, Anton J.] John Wayne Canc Inst, Santa Monica, CA USA. [Stojadinovic, Alexander] Walter Reed Natl Mil Med Ctr, Div Surg Oncol, Dept Surg, Bethesda, MD USA. [Stojadinovic, Alexander] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD 20814 USA. [Avital, Itzhak] Bon Secours Canc Inst, Richmond, VA USA. RP Rudloff, U (reprint author), NCI, NIH, 10 Ctr Dr,CRC3-5950, Bethesda, MD 20892 USA. EM rudloffu@mail.nih.gov; Itzhak_Avital@BSHSI.com RI Mullinax, John/L-2509-2014 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. NR 42 TC 22 Z9 22 U1 0 U2 0 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1837-9664 J9 J CANCER JI J. Cancer PY 2012 VL 3 BP 231 EP 240 DI 10.7150/jca.4542 PG 10 WC Oncology SC Oncology GA 135PD UT WOS:000318299800031 PM 22670157 ER PT J AU Kamel, M Shouman, S El-Merzebany, M Kilic, G Veenstra, T Saeed, M Wagih, M Diaz-Arrastia, C Patel, D Salama, S AF Kamel, Marwa Shouman, Samia El-Merzebany, Mahmoud Kilic, Gokhan Veenstra, Timothy Saeed, Muhammad Wagih, Mohamed Diaz-Arrastia, Concepcion Patel, Deepa Salama, Salama TI Effect of Tumour Necrosis Factor-Alpha on Estrogen Metabolic Pathways in Breast Cancer Cells SO JOURNAL OF CANCER LA English DT Article DE Breast cancer; Tumor necrosis factor-alpha; Estrogen metabolites; Estrogen metabolizing genes and enzymes; DNA adducts ID ENDOGENOUS ESTROGENS; MAMMARY-GLAND; TNF-ALPHA; INFLAMMATION; EXPRESSION; CYTOKINES; RISK; MICE; 2-METHOXYESTRADIOL; STEROIDOGENESIS AB Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that has been linked to breast cancer development. Estrogen metabolic pathway is also involved in breast carcinogenesis and DNA adducts formation. In this study we investigated the effect of TNF-alpha on the estrogen metabolic pathway in MCF-7, a breast cancer cell line. Capillary liquid chromatography/mass spectrometry (LC/MS) and High performance liquid chromatography (HPLC) were used for analysis of estrogen metabolites and estrogen-DNA adducts levels respectively. Reporter gene assay, Real time reverse transcription polymerase chain reaction (real time RT-PCR) and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes. TNF-alpha significantly increased the total EM and decreased the estrone (E1) / 17-beta estradiol (E2) ratio. Moreover, it altered the expression of genes and enzymes involved in E2 activation and deactivation pathways e.g. Cytochrome P-450 1A1 (CYP1A1), Cytochrome P-450 1B1 (CYP1B1), Catechol-O-methyl transferase (COMT) and Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1 (NQO1). In addition, there were increased levels of some catechol estrogens e.g. 4-hydroxy-estrone (4-OHE1) and 2-hydroxyestradiol (2-OHE2) with decreased levels of methylated catechols e.g. 2-methoxy estradiol (2-MeOE2). DNA adducts especially 4-OHE1-[2]-1-N3 Adenine was significantly increased. TNF-alpha directs the estrogen metabolism into more hormonally active and carcinogenic products in MCF-7. This may implicate a new possible explanation for inflammation associated breast cancer. C1 [Kamel, Marwa; Shouman, Samia; El-Merzebany, Mahmoud] Cairo Univ, Natl Canc Inst, Dept Canc Biol, Pharmacol Unit, Cairo, Egypt. [Kilic, Gokhan] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Veenstra, Timothy] NCI Frederick, SAIC Frederick Inc, Adv Technol Program, Lab Prote & Analyt Technol, Frederick, MD 21702 USA. [Saeed, Muhammad] Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. [Wagih, Mohamed] Beni Suef Univ, Dept Pathol, Fac Med, Bani Suwayf, Egypt. [Diaz-Arrastia, Concepcion; Patel, Deepa; Salama, Salama] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. RP Salama, S (reprint author), Baylor Coll Med, Dept Obstet & Gynecol, 1Baylor Plaza MS BCM 610, Houston, TX 77030 USA. EM salama@bcm.edu OI Kilic, Gokhan/0000-0002-7926-7458 NR 50 TC 15 Z9 16 U1 0 U2 3 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1837-9664 J9 J CANCER JI J. Cancer PY 2012 VL 3 BP 310 EP 321 DI 10.7150/jca.4584 PG 12 WC Oncology SC Oncology GA 135PD UT WOS:000318299800040 PM 22866165 ER PT J AU Mo, MH Chen, L Fu, YB Wang, W Fu, SW AF Mo, Meng-Hsuan Chen, Liang Fu, Yebo Wang, Wendy Fu, Sidney W. TI Cell-free Circulating miRNA Biomarkers in Cancer SO JOURNAL OF CANCER LA English DT Review DE serum; cancer; miRNA; biomarker ID HUMAN HEPATOCELLULAR-CARCINOMA; POTENTIAL DIAGNOSTIC MARKER; TUMOR-SUPPRESSOR GENES; BLOOD-BASED MARKERS; BREAST-CANCER; MICRORNA EXPRESSION; LUNG-CANCER; DOWN-REGULATION; COLORECTAL-CANCER; PROSTATE-CANCER AB Considerable attention and an enormous amount of resources have been dedicated to cancer biomarker discovery and validation. However, there are still a limited number of useful biomarkers available for clinical use. An ideal biomarker should be easily assayed with minimally invasive medical procedures but possess high sensitivity and specificity. Commonly used circulating biomarkers are proteins in serum, most of which require labor-intensive analysis hindered by low sensitivity in early tumor detection. Since the deregulation of microRNA (miRNA) is associated with cancer development and progression, profiling of circulating miRNAs has been used in a number of studies to identify novel minimally invasive miRNA biomarkers. In this review, we discuss the origin of the circulating cell-free miRNAs and their carriers in blood. We summarize the clinical use and function of potentially promising miRNA biomarkers in a variety of different cancers, along with their downstream target genes in tumor initiation and development. Additionally, we analyze some technical challenges in applying miRNA biomarkers to clinical practice. C1 [Mo, Meng-Hsuan; Chen, Liang; Fu, Yebo; Fu, Sidney W.] George Washington Univ, Sch Med & Hlth Sci, Dept Med, Div Genom Med, Washington, DC 20037 USA. [Mo, Meng-Hsuan; Chen, Liang; Fu, Yebo; Fu, Sidney W.] George Washington Univ, Sch Med & Hlth Sci, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA. [Wang, Wendy] NCI, Canc Biomarkers Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Fu, SW (reprint author), George Washington Univ, Med Ctr, Dept Med, Dept Microbiol Immunol & Trop Med,Div Genom Med, 2300 1 St,NW Room 443B, Washington, DC 20037 USA. EM sfu@gwu.edu OI Chen, Liang/0000-0002-3605-8883 FU Wendy Will Case award; NCI/NIH [R21CA159103] FX This work was supported by the Wendy Will Case award and the NCI/NIH award (R21CA159103) to S. W. Fu. We thank Ms. Danielle Soberman for her edits and comments. NR 182 TC 59 Z9 69 U1 4 U2 30 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1837-9664 J9 J CANCER JI J. Cancer PY 2012 VL 3 BP 432 EP 448 DI 10.7150/jca.4919 PG 17 WC Oncology SC Oncology GA 135PD UT WOS:000318299800052 PM 23074383 ER PT J AU Carcoforo, P Raiji, MT Palini, GM Pedriali, M Maestroni, U Soliani, G Detroia, A Zanzi, MV Manna, AL Crompton, JG Langan, RC Stojadinovic, A Avital, I AF Carcoforo, P. Raiji, M. T. Palini, G. M. Pedriali, M. Maestroni, U. Soliani, G. Detroia, A. Zanzi, M. V. Manna, A. L. Crompton, J. G. Langan, R. C. Stojadinovic, A. Avital, I. TI Primary Anorectal Melanoma: An Update SO JOURNAL OF CANCER LA English DT Review DE anorectal mucosal melanoma ID PRIMARY MALIGNANT-MELANOMA; ANAL-CANAL EPITHELIUM; BRAF MUTATIONS; ULTRAVIOLET-RADIATION; WAARDENBURG-SYNDROME; SURGICAL-MANAGEMENT; MELANOCYTIC LESIONS; CUTANEOUS MELANOMA; MUCOSAL MELANOMAS; LOCAL EXCISION AB The anorectum is a rare anatomic location for primary melanoma. Mucosal melanoma is a distinct biological and clinical entity from the more common cutaneous melanoma. It portrays worse prognosis than cutaneous melanoma, with distant metastases being the overwhelming cause of morbidity and mortality. Surgery is the treatment of choice, but significant controversy exists over the extent of surgical resection. We present an update on the state of the art of anorectal mucosal melanoma. To illustrate the multimodality approach to anorectal melanoma, we present a typical patient. C1 [Carcoforo, P.; Pedriali, M.; Soliani, G.; Detroia, A.; Zanzi, M. V.; Manna, A. L.] Univ Ferrara, Dept Surg Anaesthesiol & Radiol Sci, Sect Gen Surg, I-44100 Ferrara, Italy. [Raiji, M. T.; Langan, R. C.] Georgetown Univ Hosp, Dept Gen Surg, Washington, DC 20007 USA. [Palini, G. M.] Univ Ferrara, Dept Expt & Diagnost Med, Sect Pathol, I-44100 Ferrara, Italy. [Maestroni, U.] Univ Hosp Parma, Dept Surg, Parma, Italy. [Crompton, J. G.] Univ Calif Los Angeles, Ctr Med, Dept Surg, Los Angeles, CA 90024 USA. [Avital, I.] Walter Reed Natl Mil Med Ctr, Dept Surg, Div Surg Oncol, Bethesda, MD USA. [Avital, I.] Bon Secours Natl Canc Inst, Richmond, VA USA. RP Avital, I (reprint author), Walter Reed Natl Mil Med Ctr, Dept Surg, Div Surg Oncol, Bethesda, MD USA. EM itzhakavital@gmail.com NR 67 TC 9 Z9 10 U1 2 U2 3 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1837-9664 J9 J CANCER JI J. Cancer PY 2012 VL 3 BP 449 EP 453 DI 10.7150/jca.5187 PG 5 WC Oncology SC Oncology GA 135PD UT WOS:000318299800053 PM 23193431 ER PT J AU Coleman, K Bloomsmith, MA Crockett, CM Weed, JL Schapiro, SJ AF Coleman, Kristine Bloomsmith, Mollie A. Crockett, Carolyn M. Weed, James L. Schapiro, Steven J. BE Abee, CR Mansfield, K Tardif, S Morris, T TI Behavioral Management, Enrichment, and Psychological Well-being of Laboratory Nonhuman Primates SO NONHUMAN PRIMATES IN BIOMEDICAL RESEARCH, VOL 1: BIOLOGY AND MANAGEMENT, 2ND EDITION SE American College of Laboratory Animal Medicine Series LA English DT Article; Book Chapter ID MACAQUES MACACA-MULATTA; SELF-INJURIOUS-BEHAVIOR; CHIMPANZEES PAN-TROGLODYTES; HOUSED RHESUS MACAQUES; BIOMEDICAL-RESEARCH FACILITIES; URINARY CORTISOL RESPONSES; ENVIRONMENTAL ENRICHMENT; CAPTIVE CHIMPANZEES; LONGTAILED MACAQUES; ABNORMAL BEHAVIORS C1 [Coleman, Kristine] Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Bloomsmith, Mollie A.] Yerkes Natl Primate Res Ctr, Atlanta, GA USA. [Crockett, Carolyn M.] Washington Natl Primate Res Ctr, Seattle, WA USA. [Weed, James L.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. [Schapiro, Steven J.] Univ Texas MD Anderson Canc Ctr, Bastrop, TX USA. RP Coleman, K (reprint author), Oregon Natl Primate Res Ctr, Beaverton, OR USA. NR 206 TC 5 Z9 5 U1 3 U2 11 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-12-397837-0 J9 AM COLL LAB PY 2012 BP 149 EP 176 DI 10.1016/B978-0-12-381365-7.00006-6 PG 28 WC Veterinary Sciences SC Veterinary Sciences GA BEO91 UT WOS:000317610300007 ER PT J AU Oh, SY Kwon, HC Kim, SH Lee, S Lee, JH Graves, CA Camphausen, K Kirn, HJ AF Oh, Sung Yong Kwon, Hyuk-Chan Kim, Sung Hyun Lee, Suee Lee, Ji Hyun Graves, Christian A. Camphausen, Kevin Kirn, Hyo-Jin TI Prognostic Significance of Serum Levels of Vascular Endothelial Growth Factor and Insulin-Like Growth Factor-1 in Advanced Gastric Cancer Patients Treated with FOLFOX Chemotherapy SO CHEMOTHERAPY LA English DT Article DE Vascular endothelial growth factor; Insulin-like growth factor-1; FOLFOX; Gastric carcinoma ID GLUTATHIONE-S-TRANSFERASE; FACTOR EXPRESSION; LUNG-CANCER; THYMIDYLATE-SYNTHASE; FACTOR (IGF)-1; COLON-CANCER; IGF-I; METAANALYSIS; CARCINOMA; 5-FLUOROURACIL AB Background: Tumor vascular endothelial growth factor (VEGF) is a key angiogenic factor and may have an impact on tumor progression and response to chemotherapy. The insulin-like growth factor (IGF) system is related to cell proliferation and tumor growth. However, there is limited available data regarding the clinical and prognostic significance of VEGF or IGF-1 in advanced gastric cancer. The aim of this study was to evaluate the prognostic significance of serum VEGF and IGF-1 levels in advanced gastric cancer patients who were treated with oxaliplatin/5-fluorouracil (FOLFOX). Methods: The study population consisted of 100 advanced gastric cancer patients (median age 56 years). Patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1 plus leucovorin 20 mg/m(2) over 10 min, followed by a 5-fluorouracil (5-FU) bolus 400 mg/m(2) and 22 h of continuous infusion of 600 mg/m(2) on days 1-2. Treatment was repeated in 2-week intervals. The levels of serum VEGF and IGF-1 were measured using enzyme-linked immunoassays. Results: There was a significant correlation between the serum level of VEGF and Lauren's classification (p = 0.030) and previous operations (p = 0.010). IGF-1 was associated with the number of metastases (p = 0.012). The median level of serum VEGF was decreased after FOLFOX chemotherapy (p = 0.034). However, none of the measured serum markers were significantly correlated with response. In univariate analysis, overall survival (p < 0.001) was significantly shorter in patients with high serum levels of VEGF. Multivariate analysis revealed that VEGF was an independent factor for overall survival (HR 2.221; 95% Cl 1.377-3.583, p = 0.001). Furthermore, IGF-1 had no significant influence on the clinical outcome. Conclusion: A high level of serum VEGF is an independent prognostic factor in patients with advanced gastric cancer treated with chemotherapy. This may help to identify the patients who are more sensitive to the FOLFOX regimen. Copyright (C) 2013 S. Karger AG, Basel C1 [Oh, Sung Yong; Kwon, Hyuk-Chan; Kim, Sung Hyun; Lee, Suee; Lee, Ji Hyun; Kirn, Hyo-Jin] Dong A Univ, Dept Internal Med, Coll Med, Pusan 602715, South Korea. [Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Kirn, HJ (reprint author), Dong A Univ, Dept Internal Med, Coll Med, 3-1 Dongdaeshin Dong, Pusan 602715, South Korea. EM kimhj@dau.ac.kr FU Dong-A University Research Fund FX This paper was supported by the Dong-A University Research Fund. NR 34 TC 6 Z9 7 U1 0 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0009-3157 J9 CHEMOTHERAPY JI Chemotherapy PY 2012 VL 58 IS 6 BP 426 EP 434 DI 10.1159/000345918 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 129AB UT WOS:000317809700002 PM 23295255 ER PT J AU Wayne, AS AF Wayne, Alan S. BE Pui, CH TI Antibody-targeted therapy SO CHILDHOOD LEUKEMIAS, 3RD EDITION LA English DT Article; Book Chapter ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; NON-HODGKINS-LYMPHOMA; B-CELL LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; ANTI-CD20 MONOCLONAL-ANTIBODY; CHILDRENS ONCOLOGY GROUP; PHASE-I TRIAL; IMMUNOTOXIN RFB4(DSFV)-PE38 BL22; VERSUS-HOST-DISEASE C1 NCI, Hematol Dis Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Wayne, AS (reprint author), NCI, Hematol Dis Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NR 189 TC 1 Z9 1 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-0-521-19661-1 PY 2012 BP 563 EP 581 D2 10.1017/CBO9780511977633 PG 19 WC Oncology; Hematology SC Oncology; Hematology GA BDE99 UT WOS:000312990000025 ER PT J AU Abhyankar, S Leishear, K Callaghan, FM Demner-Fushman, D McDonald, CJ AF Abhyankar, Swapna Leishear, Kira Callaghan, Fiona M. Demner-Fushman, Dina McDonald, Clement J. TI Lower short- and long-term mortality associated with overweight and obesity in a large cohort study of adult intensive care unit patients SO CRITICAL CARE LA English DT Article ID BODY-MASS INDEX; ACUTE PHYSIOLOGY SCORE; BLUNT TRAUMA PATIENTS; CRITICAL ILLNESS; ADIPOSE-TISSUE; HOSPITAL MORTALITY; ORGAN FAILURE; OUTCOMES; IMPACT; INFLAMMATION AB Introduction: Two thirds of United States adults are overweight or obese, which puts them at higher risk of developing chronic diseases and of death compared with normal-weight individuals. However, recent studies have found that overweight and obesity by themselves may be protective in some contexts, such as hospitalization in an intensive care unit (ICU). Our objective was to determine the relation between body mass index (BMI) and mortality at 30 days and 1 year after ICU admission. Methods: We performed a cohort analysis of 16,812 adult patients from MIMIC-II, a large database of ICU patients at a tertiary care hospital in Boston, Massachusetts. The data were originally collected during the course of clinical care, and we subsequently extracted our dataset independent of the study outcome. Results: Compared with normal-weight patients, obese patients had 26% and 43% lower mortality risk at 30 days and 1 year after ICU admission, respectively (odds ratio (OR), 0.74; 95% confidence interval (CI), 0.64 to 0.86) and 0.57 (95% CI, 0.49 to 0.67)); overweight patients had nearly 20% and 30% lower mortality risk (OR, 0.81; 95% CI, 0.70 to 0.93) and OR, 0.68 (95% CI, 0.59 to 0.79)). Severely obese patients (BMI >= 40 kg/m(2)) did not have a significant survival advantage at 30 days (OR, 0.94; 95% CI, 0.74 to 1.20), but did have 30% lower mortality risk at 1 year (OR, 0.70 (95% CI, 0.54 to 0.90)). No significant difference in admission acuity or ICU and hospital length of stay was found across BMI categories. Conclusion: Our study supports the hypothesis that patients who are overweight or obese have improved survival both 30 days and 1 year after ICU admission. C1 [Abhyankar, Swapna; Leishear, Kira; Callaghan, Fiona M.; Demner-Fushman, Dina; McDonald, Clement J.] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Bethesda, MD 20894 USA. RP Abhyankar, S (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, 8600 Rockville Pike,Bldg 38A-7N707, Bethesda, MD 20894 USA. EM swapna.abhyankar@nih.gov FU Intramural Research Program of the National Library of Medicine, National Institutes of Health, under NIH IRB exemption FX This research was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health, under NIH IRB exemption. NR 42 TC 29 Z9 30 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1466-609X J9 CRIT CARE JI Crit. Care PY 2012 VL 16 IS 6 AR R235 DI 10.1186/cc11903 PG 14 WC Critical Care Medicine SC General & Internal Medicine GA 125UI UT WOS:000317566500021 PM 23249446 ER PT S AU Neogi, N Hagen, G Herencia-Zapana, H AF Neogi, Natasha Hagen, George Herencia-Zapana, Heber GP IEEE TI Comparison of Aircraft Models and Integration Schemes for Interval Management in the Terminal Radar Control (TRACON) SO 2012 IEEE/AIAA 31ST DIGITAL AVIONICS SYSTEMS CONFERENCE (DASC) SE IEEE-AIAA Digital Avionics Systems Conference LA English DT Proceedings Paper CT IEEE/AIAA 31st Digital Avionics Systems Conference (DASC) CY OCT 14-18, 2012 CL Williamsburg, VA SP IEEE, AIAA, Avionics, AESS, DATC, Boeing C1 [Neogi, Natasha; Herencia-Zapana, Heber] NIA, Bethesda, MD 20892 USA. RP Neogi, N (reprint author), NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2155-7195 BN 978-1-4673-1700-9 J9 IEEEAAIA DIGIT AVION PY 2012 PG 35 WC Engineering, Aerospace SC Engineering GA BEJ49 UT WOS:000316917206034 ER PT J AU Sheets, L Callaghan, F Gavino, A Liu, F Fontelo, P AF Sheets, L. Callaghan, F. Gavino, A. Liu, F. Fontelo, P. TI Usability of Selected Databases for Low-Resource Clinical Decision Support SO APPLIED CLINICAL INFORMATICS LA English DT Article DE Library information systems; handheld devices; ambulatory care; general healthcare providers; economic barriers AB Background: Smartphones are increasingly important for clinical decision support, but smartphone and Internet use are limited by cost or coverage in many settings. txt2MEDLINE provides access to published medical evidence by text messaging. Previous studies have evaluated this approach, but we found no comparisons with other tools in this format. Objectives: To compare txt2MEDLINE with other databases for answering clinical queries by text messaging in low-resource settings. Methods: Using varied formats, we searched txt2MEDLINE and five other search portals (askMEDLINE, Cochrane, DynaMed, PubMed PICO, and UpToDate) to develop optimal strategies for each. We then searched each database again with five benchmark queries, using the customized search-optimization formats. We truncated the results to less than 480 characters each to simulate delivering them to a maximum of three text messages. Clinicians with practice experience in low-resource areas scored the results on a 5-point Likert scale. Results: Median scores and standard deviations from 17 reviewers were: txt2MEDLINE, 3.2 +/- 0.82 (control); askMEDLINE, 3.2 +/- 0.90 (p = 0.918); Cochrane, 3.8 +/- 0.58 (p = 0.073); DynaMed, 3.6 +/- 0.65 (p = 0.105); PubMed PICO, 3.6 +/- 0.82 (p = 0.005); and UpToDate, 4.0 +/- 0.52 (p = 0.002). Our sample size was sufficiently powered to find differences of 1.0 point. Conclusions: Comparing several possible sources for texting-based clinical-decision-support information, our results did not demonstrate one-point differences in usefulness on a scale of 1 to 5. PubMed PICO and UpToDate were significantly better than txt2MEDLINE, but with relatively small improvements in Likert score (0.4 and 0.8, respectively). In a texting-only setting, txt2MEDLINE is comparable to simulated alternatives based on established reference sources. C1 [Sheets, L.] Univ Missouri, Inst Informat, Columbia, MO 65211 USA. [Sheets, L.; Callaghan, F.; Gavino, A.; Liu, F.; Fontelo, P.] Natl Lib Med, Bethesda, MD 20894 USA. RP Sheets, L (reprint author), Univ Missouri, Inst Informat, EBW 241, Columbia, MO 65211 USA. EM lincolnsheets@gmail.com OI Sheets, Lincoln/0000-0002-1586-1474 FU NLM Research Participation Program; National Institutes of Health (NIH), National Library of Medicine (NLM); Lister Hill Center for Biomedical Communications (LHNCBC) FX This research was supported in part by an appointment to the NLM Research Participation Program. This program is administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the National Library of Medicine. This research was also supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM), and Lister Hill Center for Biomedical Communications (LHNCBC). NR 17 TC 3 Z9 3 U1 0 U2 3 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 1869-0327 J9 APPL CLIN INFORM JI Appl. Clin. Inform. PY 2012 VL 3 IS 3 BP 326 EP 333 DI 10.4338/ACI-06-RA-0024 PG 8 WC Medical Informatics SC Medical Informatics GA 120PR UT WOS:000317183900007 PM 23646080 ER PT J AU Cimino, JJ AF Cimino, J. J. TI The False Security of Blind Dates Chrononymization's Lack of Impact on Data Privacy of Laboratory Data SO APPLIED CLINICAL INFORMATICS LA English DT Article DE Patient data privacy; data adjustments; clinical research; clinical informatics; health policy; anonymizatoin; de-identification; dates ID GENOMIC DATA PRIVACY; RECORD LINKAGE; DE-IDENTIFICATION; ANONYMITY; ACCURACY; STATE; MODEL AB Background: The reuse of clinical data for research purposes requires methods for the protection of personal privacy. One general approach is the removal of personal identifiers from the data. A frequent part of this anonymization process is the removal of times and dates, which we refer to as "chrononymization." While this step can make the association with identified data (such as public information or a small sample of patient information) more difficult, it comes at a cost to the usefulness of the data for research. Objectives: We sought to determine whether removal of dates from common laboratory test panels offers any advantage in protecting such data from re-identification. Methods: We obtained a set of results for 5.9 million laboratory panels from the National Institutes of Health's (NIH) Biomedical Translational Research Information System (BTRIS), selected a random set of 20,000 panels from the larger source sets, and then identified all matches between the sets. Results: We found that while removal of dates could hinder the re-identification of a single test result, such removal had almost no effect when entire panels were used. Conclusions: Our results suggest that reliance on chrononymization provides a false sense of security for the protection of laboratory test results. As a result of this study, the NIH has chosen to rely on policy solutions, such as strong data use agreements, rather than removal of dates when reusing clinical data for research purposes. C1 [Cimino, J. J.] NIH, NIH Clin Ctr, Bethesda, MD 20814 USA. RP Cimino, JJ (reprint author), NIH, Lab Informat Dev, NIH Clin Ctr, 10 Ctr Dr, Bethesda, MD 20814 USA. EM ciminoj@mail.nih.gov OI Cimino, James/0000-0003-4101-1622 FU Intramural NIH HHS NR 20 TC 4 Z9 4 U1 0 U2 4 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 1869-0327 J9 APPL CLIN INFORM JI Appl. Clin. Inform. PY 2012 VL 3 IS 4 BP 392 EP 403 DI 10.4338/ACI-2012-07-RA-0028 PG 12 WC Medical Informatics SC Medical Informatics GA 120PS UT WOS:000317184000004 PM 23646086 ER PT J AU Bailey, RL Mills, JL Yetley, EA Gahche, JJ Pfeiffer, CM Dwyer, JT Dodd, KW Sempos, CT Betz, JM Picciano, MF AF Bailey, Regan L. Mills, James L. Yetley, Elizabeth A. Gahche, Jaime J. Pfeiffer, Christine M. Dwyer, Johanna T. Dodd, Kevin W. Sempos, Christopher T. Betz, Joseph M. Picciano, Mary Frances TI Serum unmetabolized folic acid in a nationally representative sample of adults >= 60 years in the United States, 2001-2002 SO FOOD & NUTRITION RESEARCH LA English DT Editorial Material DE folic acid; folate; NHANES; folic acid fortification ID FOLATE INTAKE; BLOOD FOLATE; CANCER-RISK; FORTIFICATION; TRIAL; VITAMIN-B-12; SUPPLEMENTS; WOMEN C1 [Bailey, Regan L.; Yetley, Elizabeth A.; Dwyer, Johanna T.; Sempos, Christopher T.; Betz, Joseph M.; Picciano, Mary Frances] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child & Human De, NIH, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Gahche, Jaime J.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Pfeiffer, Christine M.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. [Dodd, Kevin W.] NCI, NIH, Bethesda, MD 20892 USA. RP Bailey, RL (reprint author), NIH, RD Off Dietary Supplements, 6100 Execut Blvd,Rm 3B01, Bethesda, MD 20892 USA. EM baileyr@mail.nih.gov NR 16 TC 2 Z9 2 U1 1 U2 5 PU CO-ACTION PUBLISHING PI JARFALLA PA RIPVAGEN 7, JARFALLA, SE-175 64, SWEDEN SN 1654-6628 J9 FOOD NUTR RES JI Food Nutr. Res. PY 2012 VL 56 SU S AR 5616 DI 10.3402/fnr.v56i0.5616 PG 3 WC Food Science & Technology; Nutrition & Dietetics SC Food Science & Technology; Nutrition & Dietetics GA 119ZL UT WOS:000317138700012 ER PT J AU Pfeiffer, CM Schleicher, RL Johnson, CL Coates, PM AF Pfeiffer, Christine M. Schleicher, Rosemary L. Johnson, Clifford L. Coates, Paul M. TI Assessing vitamin status in large population surveys by measuring biomarkers and dietary intake - two case studies: folate and vitamin D SO FOOD & NUTRITION RESEARCH LA English DT Article DE nutrition survey; NHANES; monitoring; trend; biochemical indicator; nutrition status; food intake; dietary questionnaire; folate; vitamin D ID NUTRITION EXAMINATION SURVEY; SERUM 25-HYDROXYVITAMIN D; 3RD NATIONAL-HEALTH; UNITED-STATES; FOLIC-ACID; TOTAL HOMOCYSTEINE; US POPULATION; BLOOD FOLATE; FORTIFICATION; QUESTIONNAIRE AB The National Health and Nutrition Examination Survey (NHANES) provides the most comprehensive assessment of the health and nutrition status of the US population. Up-to-date reference intervals on biomarkers and dietary intake inform the scientific and public health policy communities on current status and trends over time. The main purpose of dietary assessment methods such as the food-frequency questionnaire, food record (or diary), and 24-hr dietary recall is to estimate intake of nutrients and, together with supplement usage information, describe total intake of various foods or nutrients. As with all self-reporting methods, these tools are challenging to use and interpret. Yet, they are needed to establish dietary reference intake recommendations and to evaluate what proportion of the population meets these recommendations. While biomarkers are generally expensive and, to some degree, invasive, there is no question as to their ability to assess nutrition status. In some cases biomarkers can also be used to assess intake or function, although rarely can one biomarker fulfill all these purposes. For example, serum folate is a good indicator of folate intake, red blood cell (RBC) folate is a good status indicator, and plasma total homocysteine is a good functional indicator of one-carbon metabolism. Using folate and vitamin D - two vitamins that are currently hotly debated in the public health arena - as two case studies, we discuss the complexities of using biomarkers and total intake information to assess nutrition status. These two examples also show how biomarkers and intake provide different information and how both are needed to evaluate and set public health policy. We also provide guidance on general requirements for using nutrition biomarkers and food and supplement intake information in longitudinal, population-based surveys. C1 [Pfeiffer, Christine M.; Schleicher, Rosemary L.] Ctr Dis Control & Prevent CDC, Natl Ctr Environm Hlth, Atlanta, GA USA. [Johnson, Clifford L.] CDC, Natl Ctr Hlth Stat, Hyattsville, MD USA. [Coates, Paul M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Pfeiffer, CM (reprint author), Ctr Dis Control & Prevent, 4770 Buford Highway MS F55, Chamblee, GA 30341 USA. EM cpfeiffer@cdc.gov NR 37 TC 8 Z9 8 U1 1 U2 6 PU CO-ACTION PUBLISHING PI JARFALLA PA RIPVAGEN 7, JARFALLA, SE-175 64, SWEDEN SN 1654-6628 J9 FOOD NUTR RES JI Food Nutr. Res. PY 2012 VL 56 SU S AR 5944 DI 10.3402/fnr.v56i0.5944 PG 10 WC Food Science & Technology; Nutrition & Dietetics SC Food Science & Technology; Nutrition & Dietetics GA 119ZL UT WOS:000317138700017 ER PT B AU Hessman, CJ Stewart, AA Miller, AD Yang, JC Rosenberg, SA AF Hessman, Crystal J. Stewart, Ashley A. Miller, Akemi D. Yang, James C. Rosenberg, Steven A. BE Sharfman, WH TI Adoptive Cell Transfer Immunotherapy for Patients With Metastatic Melanoma SO MELANOMA SE Emerging Cancer Therapeutics LA English DT Article; Book Chapter DE adoptive cell therapy; tumor infiltrating lymphocytes; immunotherapy; metastatic melanoma ID TUMOR-INFILTRATING LYMPHOCYTES; CHIMERIC-ANTIGEN-RECEPTOR; ACTIVATED KILLER-CELLS; IN-VIVO PERSISTENCE; T-CELLS; AUTOLOGOUS TUMOR; ENGINEERED LYMPHOCYTES; CANCER/TESTIS ANTIGENS; CANCER-IMMUNOTHERAPY; TRANSFER THERAPY AB Cancer immunotherapy using adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes (TIL) has emerged as one of the most effective therapies for patients with metastatic melanoma, resulting in objective tumor regression in 49% to 72% of patients when administered in combination with a lymphodepleting preparative regimen. With increased lymphodepletion, complete tumor regression has been achieved in up to 40% of patients with ongoing durable responses beyond 3 to 7 years. New approaches to cell transfer using genetically engineered peripheral blood lymphocytes (PBL) that express conventional or chimeric T-cell receptors (TCRs) have increased the applicability of ACT and mediated significant regression in patients with metastatic melanoma, synovial sarcoma, and refractory lymphoma. This chapter will discuss the development of ACT and the more recent advances that are currently under investigation. C1 [Hessman, Crystal J.; Stewart, Ashley A.; Miller, Akemi D.; Yang, James C.; Rosenberg, Steven A.] NCI, Surg Branch, Bethesda, MD USA. RP Hessman, CJ (reprint author), NCI, Surg Branch, CRC, 10 Ctr Dr,Bldg 10,Room 3-1730, Bethesda, MD USA. EM crystal.hessman@gmail.com NR 56 TC 0 Z9 0 U1 0 U2 1 PU DEMOS MEDICAL PUBLICATIONS PI NEW YORK PA 11 WEST 42ND STREET, 15TH FLOOR, NEW YORK, NY 10036 USA BN 978-1-936287-79-6 J9 EMERG CANCER THER PY 2012 VL 3 IS 3 BP 531 EP 546 DI 10.5003/2151-4194.3.3.531 PG 16 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA BEA11 UT WOS:000315828500010 ER PT B AU Conlon, K AF Conlon, Kevin BE Sharfman, WH TI Immunotherapies for Metastatic Melanoma SO MELANOMA SE Emerging Cancer Therapeutics LA English DT Article; Book Chapter DE interleukin-7; interleukin-21; interleukin-15; class I cytokines; common gamma chain cytokines; anti-PD-1; anti-PD-L1 ID RENAL-CELL CARCINOMA; RECOMBINANT HUMAN INTERLEUKIN-21; ACTIVATED KILLER-CELLS; RECEPTOR-BETA CHAIN; CD8(+) T-CELLS; PHASE-I TRIAL; PROGRAMMED DEATH-1; ESTABLISHED TUMORS; IMMUNE ACTIVATION; B7-H1 EXPRESSION AB During the last several years, a number of promising new immunotherapeutic agents for the treatment of advanced or metastatic melanoma have emerged. Continuing the seeming momentum generated by the positive phase III registration trials for ipilimumab and vemurafenib, publication of the results of several phase I trials evaluating antibodies directed at programmed death 1 (anti-PD-1) or 1 of its physiologic ligands, PD ligand 1 (PD-L1), demonstrated striking efficacy in the early clinical trials. Treatment with recombinant human (rh) Interleukin 21 (IL-21) has shown response rates (RRs) as high as 24% for melanoma patients in early phase I/II single-agent trials. Recently, the first-in-human (FIH) clinical trials with rhIL-15 have been initiated, and there are clinical trials currently assessing the reformulated glycosylated rhIL-7, which is now produced in mammalian cell lines. Results from clinical trials evaluating these 2 promising cytokines with potential activity are eagerly awaited. After a period when interest immunotherapeutic strategies had plateaued and new cytokines were not as efficacious in human cancer patients as the preclinical animal models indicated, a palpable enthusiasm is evident for the clinical evaluation of these promising new agents and in combination with the active cellular therapies or immunotherapy drugs. C1 NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Conlon, K (reprint author), NCI, Metab Branch, Ctr Canc Res, Bldg 10,Room 4E-5322,9000 Rockville Pike, Bethesda, MD 20892 USA. EM conlonkc@mail.nih.gov NR 82 TC 0 Z9 0 U1 0 U2 1 PU DEMOS MEDICAL PUBLICATIONS PI NEW YORK PA 11 WEST 42ND STREET, 15TH FLOOR, NEW YORK, NY 10036 USA BN 978-1-936287-79-6 J9 EMERG CANCER THER PY 2012 VL 3 IS 3 BP 547 EP 581 DI 10.5003/2151-4194.3.3.547 PG 35 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA BEA11 UT WOS:000315828500011 ER PT J AU Auld, DS Thorne, N AF Auld, Douglas S. Thorne, Natasha BE Fu, H TI Molecular Sensors for Transcriptional and Post-Transcriptional Assays SO CHEMICAL GENOMICS LA English DT Article; Book Chapter ID GREEN-FLUORESCENT PROTEIN; RESONANCE ENERGY-TRANSFER; ENZYME FRAGMENT COMPLEMENTATION; REPORTER-GENE ASSAYS; THROUGHPUT SCREENING ASSAYS; LIVE MAMMALIAN-CELLS; KAPPA-B ACTIVATION; FIREFLY LUCIFERASE; BETA-LACTAMASE; DRUG DISCOVERY C1 [Auld, Douglas S.] Novartis Inst Biomed Res, Ctr Prote Chem, Cambridge, MA USA. [Thorne, Natasha] NIH, NIH Chem Genom Ctr, Bethesda, MD 20892 USA. RP Auld, DS (reprint author), Novartis Inst Biomed Res, Ctr Prote Chem, Cambridge, MA USA. NR 182 TC 2 Z9 2 U1 2 U2 2 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-0-521-88948-3 PY 2012 BP 173 EP 197 PG 25 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA BEA25 UT WOS:000315876900014 ER PT J AU Bornstein, MH Colombo, J AF Bornstein, Marc H. Colombo, John BE Pauen, SM TI Infant Cognitive Functioning and Mental Development SO EARLY CHILDHOOD DEVELOPMENT AND LATER OUTCOME SE Jacobs Foundation Series on Adolescence LA English DT Article; Book Chapter ID PAIRED-COMPARISON PARADIGM; LOCAL STIMULUS PROPERTIES; INDIVIDUAL-DIFFERENCES; VISUAL HABITUATION; RECOGNITION-MEMORY; PROCESSING SPEED; PRETERM INFANTS; INSPECTION TIME; EARLY-CHILDHOOD; SHORT-TERM C1 [Bornstein, Marc H.] NICHHD, Bethesda, MD 20892 USA. [Colombo, John] Univ Kansas, Lawrence, KS 66045 USA. RP Bornstein, MH (reprint author), NICHHD, Bethesda, MD 20892 USA. NR 121 TC 4 Z9 4 U1 2 U2 2 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-0-521-76550-3 J9 JACOBS FOUND SER ADO PY 2012 BP 118 EP 147 PG 30 WC Psychology, Developmental; Psychology; Psychology, Multidisciplinary SC Psychology GA BEB51 UT WOS:000315994800006 ER PT S AU Mattsson, N Zetterberg, H Bianconi, S Yanjanin, NM Fu, R Mansson, JE Porter, FD Blennow, K AF Mattsson, Niklas Zetterberg, Henrik Bianconi, Simona Yanjanin, Nicole M. Fu, Rao Mansson, Jan-Eric Porter, Forbes D. Blennow, Kaj GP SSIEM TI Miglustat Treatment May Reduce Cerebrospinal Fluid Levels of the Axonal Degeneration Marker Tau in Niemann-Pick Type C SO JIMD REPORTS - CASE AND RESEARCH REPORTS, 2011/3 SE JIMD Reports LA English DT Article; Book Chapter ID DISEASE TYPE-C; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; CSF BIOMARKERS; CELL-SURFACE; CHOLESTEROL; TRIAL; STABILITY; THERAPY; NEURONS AB Introduction: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder that leads to progressive neurodegeneration. The glucosylceramide synthase blocker miglustat is being used to treat NPC, but monitoring of disease progression and treatment response is difficult. NPC patients have elevated cerebrospinal fluid (CSF) levels of total-tau (T-tau) indicating axonal degeneration, and increased CSF amyloid beta (A beta) indicating abnormal brain amyloid metabolism, but it is unknown if start of miglustat treatment affects these biomarker levels. Methods: Biomarkers were measured in serial CSF samples from NPC patients who started miglustat between samplings (N = 5), were untreated at both samplings (N = 5) or received treatment during the whole study (N = 6) (median time between samplings 309 days [range 175-644]). CSF was analyzed for A beta(38), A beta(40), A beta(42), alpha-cleaved soluble APP, beta-cleaved soluble APP, T-tau and phospho-tau. Results: T-tau levels decreased in patients who started miglustat treatment (median 955 [range 338-1,271] ng/L at baseline vs. 382 [187-736] ng/L at follow-up, p = 0.043). Untreated patients and continuously treated patients had stable levels (p > 0.05). No changes were seen in the other biomarkers. Conclusion: Reduced CSF T-tau suggests that miglustat treatment might affect axonal degeneration in NPC. However, the results must be interpreted with caution and verified in future studies, since this pilot study was small, treatment was not randomized, and patients starting treatment had higher baseline CSF T-tau than untreated patients. C1 [Mattsson, Niklas; Zetterberg, Henrik; Mansson, Jan-Eric; Blennow, Kaj] Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden. [Bianconi, Simona; Yanjanin, Nicole M.; Fu, Rao; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, DHHS, Bethesda, MD USA. RP Mattsson, N (reprint author), Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden. EM Henrik.zetterberg@clinchem.gu.se; biancons@mail.nih.gov; nyanjanin@mail.nih.gov; fur@mail.nih.gov; jan-eric.mansson@vgregion.se; fdporter@mail.nih.gov; kaj.blennow@neuro.gu.se NR 40 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 2192-8304 BN 978-3-642-24936-5 J9 JIMD REP PY 2012 VL 3 BP 45 EP 52 DI 10.1007/8904_2011_47 D2 10.1007/978-3-642-24936-5 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA BEB08 UT WOS:000315963200007 PM 23430872 ER PT J AU Jiang, Q Weiss, JM Wiltrout, RH AF Jiang, Qun Weiss, Jonathan M. Wiltrout, Robert H. TI A matched couple Combining kinase inhibitors with immunotherapy for cancer treatment SO ONCOIMMUNOLOGY LA English DT Editorial Material DE mTOR; MAP Kinase; small molecule inhibitors; immunotherapy; PI3 Kinase; AKT; CD40 ID IMMUNE; CELLS; ACTIVATION AB Small-molecule kinase inhibitors targeting oncogenic signaling pathways have been explored as cancer therapeutic agents due to their strong anti-tumor activity and manageable toxicity. Accumulating evidence shows that many kinase inhibitors also profoundly modulate immune cell functions, suggesting they may be promising candidates for combination with immunotherapeutic agents for the improved treatment of cancer. C1 [Jiang, Qun; Weiss, Jonathan M.; Wiltrout, Robert H.] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. RP Wiltrout, RH (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. EM wiltrour@mail.nih.gov RI Jiang, Qun/A-1358-2014 NR 9 TC 2 Z9 2 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 J9 ONCOIMMUNOLOGY JI OncoImmunology PD JAN-FEB PY 2012 VL 1 IS 1 BP 115 EP 117 DI 10.4161/onci.1.1.18036 PG 3 WC Oncology; Immunology SC Oncology; Immunology GA 107YR UT WOS:000316257500026 ER PT J AU Seelan, RS Mukhopadhyay, P Pisano, MM Greene, RM AF Seelan, Ratnam S. Mukhopadhyay, Partha Pisano, M. Michele Greene, Robert M. TI Developmental Epigenetics of the Murine Secondary Palate SO ILAR JOURNAL LA English DT Article DE cleft palate; CpG islands; DMR; methylation promoter arrays; methylome; microRNAs; secondary palate ID EMBRYONIC STEM-CELLS; GENE-ENVIRONMENT INTERACTION; NONSYNDROMIC CLEFT-PALATE; TREACHER-COLLINS-SYNDROME; GROWTH-FACTOR-BETA; CPG ISLAND SHORES; DNA METHYLATION; NEURAL CREST; GENOME-WIDE; MICRORNA EXPRESSION AB Orofacial clefts occur with a frequency of 1 to 2 per 1000 live births. Cleft palate, which accounts for 30% of orofacial clefts, is caused by the failure of the secondary palatal processes-medially directed, oral projections of the paired embryonic maxillary processes-to fuse. Both gene mutations and environmental effects contribute to the complex etiology of this disorder. Although much progress has been made in identifying genes whose mutations are associated with cleft palate, little is known about the mechanisms by which the environment adversely influences gene expression during secondary palate development. An increasing body of evidence, however, implicates epigenetic processes as playing a role in adversely influencing orofacial development. Epigenetics refers to inherited changes in phenotype or gene expression caused by processes other than changes in the underlying DNA sequence. Such processes include, but are not limited to, DNA methylation, microRNA effects, and histone modifications that alter chromatin conformation. In this review, we describe our current understanding of the possible role epigenetics may play during development of the secondary palate. Specifically, we present the salient features of the embryonic palatal methylome and profile the expression of numerous microRNAs that regulate protein-encoding genes crucial to normal orofacial ontogeny. C1 [Seelan, Ratnam S.; Mukhopadhyay, Partha; Pisano, M. Michele] Univ Louisville, ULSD, Birth Defects Ctr, Dept Mol Cellular & Craniofacial Biol, Louisville, KY 40202 USA. [Pisano, M. Michele; Greene, Robert M.] Univ Louisville, ULSD, Dept Mol Cellular & Craniofacial Biol, Louisville, KY 40202 USA. [Pisano, M. Michele; Greene, Robert M.] Univ Louisville, ULSD, Birth Defects Ctr, Louisville, KY 40202 USA. [Pisano, M. Michele; Greene, Robert M.] Univ Louisville, ULSD, NIH, Ctr Biomed Res Excellence, Louisville, KY 40202 USA. RP Pisano, MM (reprint author), Univ Louisville, ULSD, Birth Defects Ctr, Dept Mol Cellular & Craniofacial Biol, 501 S Preston St, Louisville, KY 40202 USA. EM pisano@louisville.edu FU National Institute of Health [HD053509, DE018215]; Cleft Palate Foundation; Centers of Biomedical Research Excellence program of the National Institute of General Medical Sciences [P20 RR017702] FX This research was supported in part by grants from the National Institute of Health (grants HD053509 and DE018215); the Cleft Palate Foundation; and the Centers of Biomedical Research Excellence program of the National Institute of General Medical Sciences (P20 RR017702). The authors are indebted to Dr. Guy N. Brock and Ms. Savitri N. Appana, School of Public Health, University of Louisville, for their help in the biostatistic analysis of the microarray data. NR 161 TC 4 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1084-2020 J9 ILAR J JI ILAR J. PY 2012 VL 53 IS 3-4 BP 240 EP 252 DI 10.1093/ilar.53.3-4.240 PG 13 WC Veterinary Sciences SC Veterinary Sciences GA 103WN UT WOS:000315950300003 PM 23744964 ER PT J AU Mandrup, S Hager, GL AF Mandrup, Susanne Hager, Gordon L. TI Modulation of chromatin access during adipocyte differentiation SO NUCLEUS-AUSTIN LA English DT Article DE adipocyte differentiation; chromatin structure; C/EBPbeta; ChIP-seq; DNase I hypersensitive sites; DHS-seq; hotspot ID GLUCOCORTICOID-RECEPTOR BINDING; TRANSCRIPTION; ACCESSIBILITY; ADIPOGENESIS AB Cellular development requires reprogramming of the genome to modulate the gene program of the undifferentiated cell and allow expression of the gene program unique to differentiated cells. A number of key transcription factors involved in this reprogramming of preadipocytes to adipocytes have been identified; however, it is not until recently that we have begun to understand how these factors act at a genome-wide scale. In a recent publication we have mapped the genome-wide changes in chromatin structure during differentiation of 3T3-L1 preadipocytes and shown that a major reorganization of the chromatin landscape occurs within few hours following the addition of the adipogenic cocktail. In addition, we have mapped the genome-wide profiles of several of the early adipogenic transcription factors and shown that they act in a highly cooperative manner to drive this dramatic remodeling process. C1 [Mandrup, Susanne] Univ Southern Denmark, Dept Biochem & Mol Biol, Odense, Denmark. [Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Mandrup, S (reprint author), Univ Southern Denmark, Dept Biochem & Mol Biol, Odense, Denmark. EM s.mandrup@bmb.sdu.dk; hagerg@exchange.nih.gov OI Mandrup, Susanne/0000-0002-0961-5787 FU Danish Natural Science Research Council; Novo Nordisk Foundation; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by grants from the Danish Natural Science Research Council, the Novo Nordisk Foundation, and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 10 TC 3 Z9 3 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1949-1034 J9 NUCLEUS-AUSTIN JI Nucleus-Austin PD JAN-FEB PY 2012 VL 3 IS 1 BP 12 EP 15 DI 10.4161/nucl.3.1.18928 PG 4 WC Cell Biology SC Cell Biology GA 103OF UT WOS:000315926800008 PM 22540022 ER PT J AU Jirsa, V Huys, R Pillai, A Perdikis, D Woodman, M AF Jirsa, Viktor Huys, Raoul Pillai, Ajay Perdikis, Dionysios Woodman, Marmaduke BE Rabinovich, MI Friston, KJ Varona, P TI Connectivity and Dynamics of Neural Information Processing SO PRINCIPLES OF BRAIN DYNAMICS: GLOBAL STATE INTERACTIONS SE Computational Neuroscience-MIT LA English DT Article; Book Chapter ID COORDINATION DYNAMICS; RHYTHMICAL MOVEMENTS; COGNITIVE SCIENCE; MODEL; BRAIN; INTEGRATION; COMPLEXITY; EXCITATOR; NETWORKS; STATES AB Brain function arises from the complex interactions of brain networks, in which neural activity needs to be tightly coordinated. How this coordination is achieved is largely unknown, although various proposals thereof have been made. Here, we review some of the approaches to neural information processing in brain networks and propose a novel concept termed structured flows on manifolds (SFMs) describing function as a low-dimensional dynamic process emerging from coupled neurons. Initially, we develop this concept and demonstrate its validity in networks of coupled populations. In a second step, we provide proof of concept for this formalism in networks of spiking neurons. Then, we show how sets of SFMs can capture the dynamic repertoire of complex behaviors and develop novel forms of functional architectures based on hierarchies of timescales. We illustrate these concepts using the example of handwriting. C1 [Jirsa, Viktor; Huys, Raoul; Perdikis, Dionysios; Woodman, Marmaduke] CNRS, Inst Sci Mouvement, Theoret Neurosci Grp, Unite Mixte Rech 6233, Marseille, France. [Pillai, Ajay] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, NIH, Bethesda, MD USA. RP Jirsa, V (reprint author), CNRS, Inst Sci Mouvement, Theoret Neurosci Grp, Unite Mixte Rech 6233, Marseille, France. NR 66 TC 1 Z9 1 U1 2 U2 2 PU MIT PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA BN 978-0-262-30649-2 J9 COMPUT NEUROSCI-MIT JI Comput. Neurosci. MIT PY 2012 BP 209 EP 231 PG 23 WC Neurosciences SC Neurosciences & Neurology GA BDW30 UT WOS:000315291000012 ER PT J AU Leroy, G Chepelev, I DiMaggio, PA Blanco, MA Zee, BM Zhao, K Garcia, BA AF LeRoy, Gary Chepelev, Iouri DiMaggio, Peter A. Blanco, Mario A. Zee, Barry M. Zhao, Keji Garcia, Benjamin A. TI Proteogenomic characterization and mapping of nucleosomes decoded by Brd and HP1 proteins SO GENOME BIOLOGY LA English DT Article ID HOMEOTIC GENE; HUMAN GENOME; HISTONE H3; STRUCTURAL BASIS; MAMMALIAN-CELLS; CHROMATIN; HETEROCHROMATIN; BROMODOMAIN; DIFFERENTIATION; EXPRESSION AB Background: Histone post-translational modifications (PTMs) constitute a branch of epigenetic mechanisms that can control the expression of eukaryotic genes in a heritable manner. Recent studies have identified several PTM-binding proteins containing diverse specialized domains whose recognition of specific PTM sites leads to gene activation or repression. Here, we present a high-throughput proteogenomic platform designed to characterize the nucleosomal make-up of chromatin enriched with a set of histone PTM binding proteins known as histone PTM readers. We support our findings with gene expression data correlating to PTM distribution. Results: We isolated human mononucleosomes bound by the bromodomain-containing proteins Brd2, Brd3 and Brd4, and by the chromodomain-containing heterochromatin proteins HP1 beta and HP1 alpha. Histone PTMs were quantified by mass spectrometry (ChIP-qMS), and their associated DNAs were mapped using deep sequencing. Our results reveal that Brd- and HP1-bound nucleosomes are enriched in histone PTMs consistent with actively transcribed euchromatin and silent heterochromatin, respectively. Data collected using RNA-Seq show that Brd-bound sites correlate with highly expressed genes. In particular, Brd3 and Brd4 are most enriched on nucleosomes located within HOX gene clusters, whose expression is reduced upon Brd4 depletion by short hairpin RNA. Conclusions: Proteogenomic mapping of histone PTM readers, alongside the characterization of their local chromatin environments and transcriptional information, should prove useful for determining how histone PTMs are bound by these readers and how they contribute to distinct transcriptional states. C1 [LeRoy, Gary; DiMaggio, Peter A.; Blanco, Mario A.; Zee, Barry M.; Garcia, Benjamin A.] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. [Chepelev, Iouri; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Zee, Barry M.; Garcia, Benjamin A.] Univ Penn, Dept Biochem & Biophys, Perelman Sch Med, Epigenet Program, Philadelphia, PA 19104 USA. [Garcia, Benjamin A.] Princeton Univ, Dept Chem, Princeton, NJ 08544 USA. [Garcia, Benjamin A.] Princeton Univ, Quantitat & Computat Biol Program, Princeton, NJ 08544 USA. RP Garcia, BA (reprint author), Princeton Univ, Dept Mol Biol, 415 Schultz Lab, Princeton, NJ 08544 USA. EM bagarcia@princeton.edu OI DiMaggio, Peter/0000-0003-1996-0813 FU National Science Foundation (NSF) [CBET-0941143]; NIH Innovator award from the Office of the Director, National Institutes of Health [DP2OD007447]; American Society for Mass Spectrometry Research Award; NIH NRSA F32 Postdoctoral Fellowship; NIH/NIGMS [P50GM071508]; Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, USA FX Support from a National Science Foundation (NSF) Early Faculty CAREER award, an NIH Innovator award (DP2OD007447) from the Office of the Director, National Institutes of Health, an NSF grant (CBET-0941143) and the American Society for Mass Spectrometry Research Award to BAG is gratefully acknowledged. PAD is supported by an NIH NRSA F32 Postdoctoral Fellowship. This research was also supported by an NIH/NIGMS P50GM071508 to the Lewis-Sigler Institute at Princeton University (PI D Botstein). BMZ is supported by an NSF graduate fellowship. The work of IC and KZ was supported by the Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, USA. NR 49 TC 36 Z9 36 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-760X J9 GENOME BIOL JI Genome Biol. PY 2012 VL 13 IS 8 AR R68 DI 10.1186/gb-2012-13-8-r68 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 102TR UT WOS:000315867500002 PM 22897906 ER PT J AU Stamatoyannopoulos, JA Snyder, M Hardison, R Ren, B Gingeras, T Gilbert, DM Groudine, M Bender, M Kaul, R Canfield, T Giste, E Johnson, A Zhang, M Balasundaram, G Byron, R Roach, V Sabo, PJ Sandstrom, R Stehling, AS Thurman, RE Weissman, SM Cayting, P Hariharan, M Lian, J Cheng, Y Landt, SG Ma, ZH Wold, BJ Dekker, J Crawford, GE Keller, CA Wu, WS Morrissey, C Kumar, SA Mishra, T Jain, D Byrska-Bishop, M Blankenberg, D Lajoie, BR Jain, G Sanyal, A Chen, KB Denas, O Taylor, J Blobel, GA Weiss, MJ Pimkin, M Deng, WL Marinov, GK Williams, BA Fisher-Aylor, KI Desalvo, G Kiralusha, A Trout, D Amrhein, H Mortazavi, A Edsall, L McCleary, D Kuan, S Shen, Y Yue, F Ye, Z Davis, CA Zaleski, C Jha, S Xue, CH Dobin, A Lin, W Fastuca, M Wang, HI Guigo, R Djebali, S Lagarde, J Ryba, T Sasaki, T Malladi, VS Cline, MS Kirkup, VM Learned, K Rosenbloom, KR Kent, WJ Feingold, EA Good, PJ Pazin, M Lowdon, RF Adams, LB AF Stamatoyannopoulos, John A. Snyder, Michael Hardison, Ross Ren, Bing Gingeras, Thomas Gilbert, David M. Groudine, Mark Bender, Michael Kaul, Rajinder Canfield, Theresa Giste, Erica Johnson, Audra Zhang, Mia Balasundaram, Gayathri Byron, Rachel Roach, Vaughan Sabo, Peter J. Sandstrom, Richard Stehling, A. Sandra Thurman, Robert E. Weissman, Sherman M. Cayting, Philip Hariharan, Manoj Lian, Jin Cheng, Yong Landt, Stephen G. Ma, Zhihai Wold, Barbara J. Dekker, Job Crawford, Gregory E. Keller, Cheryl A. Wu, Weisheng Morrissey, Christopher Kumar, Swathi A. Mishra, Tejaswini Jain, Deepti Byrska-Bishop, Marta Blankenberg, Daniel Lajoie, Bryan R. Jain, Gaurav Sanyal, Amartya Chen, Kaun-Bei Denas, Olgert Taylor, James Blobel, Gerd A. Weiss, Mitchell J. Pimkin, Max Deng, Wulan Marinov, Georgi K. Williams, Brian A. Fisher-Aylor, Katherine I. Desalvo, Gilberto Kiralusha, Anthony Trout, Diane Amrhein, Henry Mortazavi, Ali Edsall, Lee McCleary, David Kuan, Samantha Shen, Yin Yue, Feng Ye, Zhen Davis, Carrie A. Zaleski, Chris Jha, Sonali Xue, Chenghai Dobin, Alex Lin, Wei Fastuca, Meagan Wang, Huaien Guigo, Roderic Djebali, Sarah Lagarde, Julien Ryba, Tyrone Sasaki, Takayo Malladi, Venkat S. Cline, Melissa S. Kirkup, Vanessa M. Learned, Katrina Rosenbloom, Kate R. Kent, W. James Feingold, Elise A. Good, Peter J. Pazin, Michael Lowdon, Rebecca F. Adams, Leslie B. CA Mouse ENCODE Consortium TI An encyclopedia of mouse DNA elements (Mouse ENCODE) SO GENOME BIOLOGY LA English DT Article DE ENCODE Project; mouse genome; DNasel hypersensitive sites; histone modifications; transcriptome; transcription factor binding sites; comparative genomics; ChIP-seq; RNA-seq ID HUMAN-DISEASE; COMPARATIVE GENOMICS; MODELS AB To complement the human Encyclopedia of DNA Elements (ENCODE) project and to enable a broad range of mouse genomics efforts, the Mouse ENCODE Consortium is applying the same experimental pipelines developed for human ENCODE to annotate the mouse genome. C1 [Stamatoyannopoulos, John A.; Kaul, Rajinder; Canfield, Theresa; Giste, Erica; Johnson, Audra; Roach, Vaughan; Sabo, Peter J.; Sandstrom, Richard; Stehling, A. Sandra; Thurman, Robert E.; Lajoie, Bryan R.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. [Snyder, Michael; Hariharan, Manoj; Cheng, Yong; Landt, Stephen G.; Ma, Zhihai; Lajoie, Bryan R.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Hardison, Ross; Keller, Cheryl A.; Wu, Weisheng; Morrissey, Christopher; Kumar, Swathi A.; Mishra, Tejaswini; Jain, Deepti; Byrska-Bishop, Marta; Blankenberg, Daniel] Penn State Univ, Ctr Comparat Genom & Bioinformat, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Ren, Bing; Edsall, Lee; McCleary, David; Kuan, Samantha; Shen, Yin; Yue, Feng; Ye, Zhen] Univ Calif San Diego, Inst Genom Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Gingeras, Thomas; Davis, Carrie A.; Zaleski, Chris; Jha, Sonali; Xue, Chenghai; Dobin, Alex; Lin, Wei; Fastuca, Meagan; Wang, Huaien] Cold Spring Harbor Lab, Dept Funct Genom, Cold Spring Harbor, NY 11724 USA. [Groudine, Mark; Sasaki, Takayo] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Groudine, Mark; Bender, Michael; Zhang, Mia; Balasundaram, Gayathri; Byron, Rachel] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98104 USA. [Weissman, Sherman M.; Cayting, Philip] Yale Univ, Dept Genet, New Haven, CT 06510 USA. [Cayting, Philip; Lian, Jin] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT USA. [Cayting, Philip] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT USA. [Wold, Barbara J.; Marinov, Georgi K.; Fisher-Aylor, Katherine I.; Desalvo, Gilberto; Kiralusha, Anthony; Trout, Diane; Amrhein, Henry] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Dekker, Job; Jain, Gaurav; Sanyal, Amartya] Univ Massachusetts, Sch Med, Dept Mol Pharmacol & Biochem, Worcester, MA USA. [Crawford, Gregory E.; Chen, Kaun-Bei; Denas, Olgert] Duke Univ, Inst Genome Sci & Policy, Durham, NC USA. [Crawford, Gregory E.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Taylor, James] Emory Univ, Dept Math & Comp Sci, Atlanta, GA 30322 USA. [Blobel, Gerd A.; Weiss, Mitchell J.; Pimkin, Max; Deng, Wulan] Childrens Hosp Philadelphia, Div Hematol, Abramson Res Ctr, Philadelphia, PA 19104 USA. [Mortazavi, Ali] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92717 USA. [Guigo, Roderic; Djebali, Sarah; Lagarde, Julien] Ctr Genom Regulat, Div Bioinformat & Genom, Barcelona, Catalunya, Spain. [Malladi, Venkat S.; Cline, Melissa S.; Kirkup, Vanessa M.; Learned, Katrina; Rosenbloom, Kate R.; Kent, W. James] Univ Calif Santa Cruz, Sch Engn, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Feingold, Elise A.; Good, Peter J.; Pazin, Michael; Lowdon, Rebecca F.; Adams, Leslie B.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Stamatoyannopoulos, JA (reprint author), Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. EM jstam@uw.edu RI cheng, yong/I-4270-2012; Byrska-Bishop, Marta/E-7804-2012; Djebali, Sarah/O-9817-2014; SANYAL, AMARTYA/D-7240-2015; Ma, Zhihai/E-7130-2015; Guigo, Roderic/D-1303-2010; Hariharan, Manoj/N-2855-2015; Taylor, James/F-1026-2011; Hardison, Ross/G-1142-2010; OI Djebali, Sarah/0000-0002-0599-1267; SANYAL, AMARTYA/0000-0002-2109-4478; Guigo, Roderic/0000-0002-5738-4477; Hariharan, Manoj/0000-0002-1006-5372; Taylor, James/0000-0001-5079-840X; Gingeras, Thomas/0000-0001-9106-3573; Edsall, Lee Elizabeth/0000-0002-0326-2829; Hardison, Ross/0000-0003-4084-7516; Pazin, Michael/0000-0002-7561-3640 NR 22 TC 119 Z9 120 U1 4 U2 24 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-7596 J9 GENOME BIOL JI Genome Biol. PY 2012 VL 13 IS 8 AR 418 DI 10.1186/gb-2012-13-8-418 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 102TR UT WOS:000315867500017 ER PT J AU Xu, P Yang, JY Kovac, P AF Xu, Peng Yang, Jacqueline Y. Kovac, Pavol TI Observations on the Preparation of beta-Lactose Octaacetate SO JOURNAL OF CARBOHYDRATE CHEMISTRY LA English DT Article DE 1,2,3,6,2 ',3 ',4 ',6 '-Octa-O-acetyl-beta-lactose; 2,3,4,6-Tetra-O-acetyl-beta-D-galactopyranosyl-(1 -> 4)-1; 2,3,6-tetra-O-acetyl-beta-D-glucopyranose; 2,3,4,6-Tetra-O-acetyl-beta-D-galactopyranosyl-(1 -> 4)-1; 2,6-tri-O-acetyl-alpha,beta-D-glucopyranose; 2,3,4,6-Tetra-O-acetyl-beta-D-galactopyranosyl-(1 -> 4)-12,6-tri-O-acetyl-beta-D-glucopyranose; Crystallization ID CHEMISTRY; SUGARS AB Attempts to substantially increase the relative proportion of beta-lactose octaacetate in products of acetylation of alpha-lactose monohydrate using various acetylation protocols failed. Nevertheless, the revised protocol for isolation and crystallization, based on the classical work by Hudson and Johnson, rendered preparation of beta-lactose octaacetate less labor intensive. It is proposed that the melting point and [alpha](D) value are not reliable criteria of purity of beta-lactose octaacetate, which can be confidently determined by 1H NMR spectroscopy. C1 [Xu, Peng; Yang, Jacqueline Y.; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIDDK, LBC, NIH, Bethesda, MD 20892 USA. EM kpn@hlix.nih.gov FU NIH, NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 10 TC 0 Z9 0 U1 2 U2 9 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0732-8303 J9 J CARBOHYD CHEM JI J. Carbohydr. Chem. PY 2012 VL 31 IS 9 BP 711 EP 720 DI 10.1080/07328303.2012.739230 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 104QT UT WOS:000316010400004 ER PT J AU Cravedi, P Sharma, SK Bravo, RF Islam, N Tchokhonelidze, I Ghimire, M Pahari, B Thapa, S Basnet, A Tataradze, A Tinatin, D Beglarishvili, L Fwu, CW Kopp, JB Eggers, P Ene-Iordache, B Carminati, S Perna, A Chianca, A Couser, WG Remuzzi, G Perico, N AF Cravedi, Paolo Sharma, Sanjib Kumar Flores Bravo, Rodolfo Islam, Nazmul Tchokhonelidze, Irma Ghimire, Madhav Pahari, Bishnu Thapa, Sanjeev Basnet, Anil Tataradze, Avtandil Tinatin, Davitaia Beglarishvili, Lela Fwu, Chyng-Wen Kopp, Jeffrey B. Eggers, Paul Ene-Iordache, Bogdan Carminati, Sergio Perna, Annalisa Chianca, Antonietta Couser, William G. Remuzzi, Giuseppe Perico, Norberto TI Preventing renal and cardiovascular risk by renal function assessment: insights from a cross-sectional study in low-income countries and the USA SO BMJ OPEN LA English DT Article ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; GENERAL-POPULATION; ALL-CAUSE; PREVALENCE; MORTALITY; ALBUMINURIA; BURDEN; PROGRAMS AB Objective: To assess the prevalence of microalbuminuria and kidney dysfunction in low-income countries and in the USA. Design: Cross-sectional study of screening programmes in five countries. Setting: Screening programmes in Nepal, Bolivia, the USA (National Health and Nutrition Examination Survey (NHANES) 2005-2008) Bangladesh and Georgia. Participants: General population in Nepal (n=20 811), Bolivia (n=3436) and in the USA (n=4299) and high-risk subjects in Bangladesh (n=1518) and Georgia (n=1549). Primary and secondary outcome measures: Estimated glomerular filtration rate (eGFR)<60ml/min/1.73 m(2) and microalbuminuria (defined as urinary albumin creatinine ratio values of 30-300 mg/g) were the main outcome measures. The cardiovascular (CV) risk was also evaluated on the basis of demographic, clinical and blood data. Results: The prevalence of eGFR<60ml/min/1.73 m(2) was 19%, 3.2% and 7% in Nepal, Bolivia and the USA, respectively. In Nepal, 7% of subjects were microalbuminuric compared to 8.6% in the USA. The prevalence of participants with predicted 10-year CV disease (CVD) risk >= 10% was 16.9%, 9.4% and 17% in Nepal, Bolivia and in the USA, respectively. In Bangladesh and Georgia, subjects with eGFR<60 ml/min/1.73 m(2) were 8.6% and 4.9%, whereas those with microalbuminuria were 45.4% and 56.5%, respectively. Predicted 10-year CVD risk >= 10% was 25.4% and 25% in Bangladesh and Georgia, respectively. Conclusions: Renal abnormalities are common among low-income countries and in the USA. Prevention programmes, particularly focused on those with renal abnormalities, should be established worldwide to prevent CVD and progression to end-stage renal disease. C1 [Cravedi, Paolo; Ene-Iordache, Bogdan; Carminati, Sergio; Perna, Annalisa; Chianca, Antonietta; Remuzzi, Giuseppe; Perico, Norberto] Clin Res Ctr Rare Dis Aldo & Cele Dacco, Ranica, Italy. [Cravedi, Paolo; Ene-Iordache, Bogdan; Carminati, Sergio; Perna, Annalisa; Chianca, Antonietta; Remuzzi, Giuseppe; Perico, Norberto] Mario Negri Inst Pharmacol Res, Ctr Anna Maria Astori Sci & Technol Pk Kilometro, I-24126 Bergamo, Italy. [Sharma, Sanjib Kumar; Ghimire, Madhav; Pahari, Bishnu; Thapa, Sanjeev; Basnet, Anil] BP Koirala Inst Hlth Sci, Dept Med, Dharan, Nepal. [Flores Bravo, Rodolfo] Hosp Joan 23, Dept Med, La Paz, Bolivia. [Islam, Nazmul] N E Med Coll Hosp Sylhet, Dept Nephrol, Sylhet, Bangladesh. [Tchokhonelidze, Irma; Tataradze, Avtandil; Beglarishvili, Lela] Natl Ctr Urol, Tbilisi, Rep of Georgia. [Tinatin, Davitaia] M Iashvili Children Cent Hosp, Dept Pediat, Tbilisi, Rep of Georgia. [Fwu, Chyng-Wen] Social & Sci Syst Inc, Silver Spring, MD USA. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD USA. [Eggers, Paul] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. [Couser, William G.] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. RP Remuzzi, G (reprint author), Clin Res Ctr Rare Dis Aldo & Cele Dacco, Ranica, Italy. EM gremuzzi@marionegri.it OI Ene-Iordache, Bogdan/0000-0002-4011-9343; Kopp, Jeffrey/0000-0001-9052-186X FU International Society of Nephrology (ISN); Intramural Research Program; Division of Kidney, Urology and Hematology, NIDDK, NIH FX This study was funded by a grant from the International Society of Nephrology (ISN). Additional support was provided by the Intramural Research Program and Division of Kidney, Urology and Hematology, NIDDK, NIH. NR 26 TC 2 Z9 2 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-6055 J9 BMJ OPEN JI BMJ Open PY 2012 VL 2 IS 5 AR e001357 DI 10.1136/bmjopen-2012-001357 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA 091MN UT WOS:000315053900058 ER PT J AU Engdahl, B Krog, NH Kvestad, E Hoffman, HJ Tambs, K AF Engdahl, Bo Krog, Norun Hjertager Kvestad, Ellen Hoffman, Howard J. Tambs, Kristian TI Occupation and the risk of bothersome tinnitus: results from a prospective cohort study (HUNT) SO BMJ OPEN LA English DT Article ID TRONDELAG HEARING-LOSS; NORD-TRONDELAG; OLDER-ADULTS; EXPOSURE; NOISE; POPULATION; PREVALENCE AB Objectives: Estimates of occupation-specific tinnitus prevalence may help identify high-risk occupations where interventions are warranted. The authors studied the effect of occupation on prevalence of bothersome tinnitus and estimated the attributable fraction due to occupation. The authors also studied how much of the effect remained after adjusting for noise exposure, education income, hearing thresholds and other risk factors. Design: A prospective cohort study. Setting: A health survey of the Nord-Trondelag county of Norway. Participants: A sample of the general adult population (n = 49 948). Primary outcome measure: The primary outcome measure is bothersome tinnitus. Results: Occupation had a marked effect on tinnitus prevalence. The effect of occupation on tinnitus was reduced in men by controlling for self-reported occupational noise exposure and in women by controlling for education and income. Adding hearing loss as a predictor increased the effect of occupation somewhat. In men, age-adjusted prevalence ratios of tinnitus ranged from 1.5 (workshop mechanics) to 2.1 (crane and hoist operators) in the 10 occupations with highest tinnitus prevalence. In women, the most important contribution to the tinnitus prevalence was from the large group of occupationally inactive persons, with a prevalence ratio of 1.5. Conclusion: This study found a moderate association between occupation and bothersome tinnitus. C1 [Engdahl, Bo; Krog, Norun Hjertager; Kvestad, Ellen; Tambs, Kristian] Norwegian Inst Publ Hlth, Div Mental Hlth, Oslo, Norway. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders NIDCD, Epidemiol & Stat Program, NIH, Bethesda, MD USA. [Tambs, Kristian] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. [Tambs, Kristian] Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. RP Engdahl, B (reprint author), Norwegian Inst Publ Hlth, Div Mental Hlth, Oslo, Norway. EM bo.engdahl@fhi.no FU National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH) [N01-DC-6-2104] FX This work was supported by the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH) via research contract No. N01-DC-6-2104. NR 30 TC 9 Z9 9 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-6055 J9 BMJ OPEN JI BMJ Open PY 2012 VL 2 IS 1 AR e000512 DI 10.1136/bmjopen-2011-000512 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 091GK UT WOS:000315037200043 PM 22267709 ER PT J AU Golding, J Northstone, K Emmett, P Steer, C Hibbeln, JR AF Golding, Jean Northstone, Kate Emmett, Pauline Steer, Colin Hibbeln, Joseph R. TI Do omega-3 or other fatty acids influence the development of 'growing pains'? A prebirth cohort study SO BMJ OPEN LA English DT Article ID CHILDREN; OMEGA-3-FATTY-ACIDS; TRANSESTERIFICATION; ASSOCIATION; PREVALENCE; CHILDHOOD; ALSPAC AB Objectives: To assess whether the prevalence of growing pains varies with indicators of fatty acid exposure. Growing pains (limb pains of no obvious explanation) have been shown to be strongly linked to a family history of arthritis, and are thought to predict an increased risk of the development of arthritis in adulthood. Much has been made of the possibility of fatty acids, particularly the omega-3 fatty acids, playing a preventive role in the development of arthritis, but little research has been undertaken to determine whether such fatty acids might reduce the risk of growing pains. We aimed to assess whether the prevalence of growing pains varies with indicators of fatty acid exposures. Design: Case-control study nested within a prospective longitudinal cohort comparing prenatal and postnatal diet, blood measures and variants in fatty acid desaturase (FADS) genes that influence the metabolism of fatty acids. Statistical analysis took account of factors such as gender, smoke exposure, maternal age and education, social class and parity. Setting: Avon Longitudinal Study of Parents & Children. Participants: All children born between 1 April 1991 and 31 December 1992 (approximately14 000) within the Avon area (only that part of Avon under the South-West Regional Health Authority). This project compared 1676 children who reported 'growing pains' at age 8 with 6155 with no such pain. Primary outcome: Reported limb pains of no apparent origin. Results: There was no indication that the affected children had diets that differed with regard to omega-3, plasma levels of fatty acids, or the FADS genetic variants. We also assessed fetal and infant exposure but neither maternal prenatal blood levels nor maternal dietary intake, or duration of breast feeding showed any significant relationships even after adjustment for confounders. Conclusions: Thus, there is no evidence that omega-3 fatty acid status protects against the development of growing pains in childhood. C1 [Golding, Jean; Northstone, Kate; Emmett, Pauline; Steer, Colin] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Hibbeln, Joseph R.] NIAAA, Sect Nutr Neurosci, LMBB, NIH, Rockville, MD 20852 USA. RP Golding, J (reprint author), Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. EM jean.golding@bristol.ac.uk OI Emmett, Pauline/0000-0003-1076-4779 FU EU [FP7-212652]; Waterloo Foundation; intramural research programme of the National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Oceanic and Atmospheric Administration (NOAA); Arthritic Association FX The UK Medical Research Council, the Wellcome Trust and the University of Bristol currently provide core support for ALSPAC. The assays of the maternal blood samples were carried out by Scotia at the instigation of the late David Horrobin, to whom we are extremely grateful. Funding for the genotyping and analysis of the genetic variants was partly undertaken with funding from the EU grant no.FP7-212652 and partly by the Waterloo Foundation. The assays of the child's blood were conducted and supported by the intramural research programme of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) with funding from the National Oceanic and Atmospheric Administration (NOAA). Statistical analysis of the information was funded by the Arthritic Association. NR 24 TC 2 Z9 2 U1 1 U2 6 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-6055 J9 BMJ OPEN JI BMJ Open PY 2012 VL 2 IS 4 AR e001370 DI 10.1136/bmjopen-2012-001370 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 091KW UT WOS:000315049300090 ER PT J AU Parr, LA Boudreau, M Hecht, E Winslow, JT Nemeroff, CB Sanchez, MM AF Parr, Lisa A. Boudreau, Matthew Hecht, Erin Winslow, James T. Nemeroff, Charles B. Sanchez, Mar M. TI Early life stress affects cerebral glucose metabolism in adult rhesus monkeys (Macaca mulatta) SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Article DE Early life stress; Rearing; HPA axis; Monkey; PET; Social brain ID SUPERIOR TEMPORAL SULCUS; CORTICOTROPIN-RELEASING-FACTOR; NONHUMAN PRIMATE MODELS; HIPPOCAMPAL VOLUME; CORPUS-CALLOSUM; MACAQUE MONKEY; ORBITOFRONTAL CORTEX; ANTERIOR CINGULATE; PREFRONTAL CORTEX; ANXIETY DISORDERS AB Early life stress (ELS) is a risk factor for anxiety, mood disorders and alterations in stress responses. Less is known about the long-term neurobiological impact of ELS. We used [F-18]-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) to assess neural responses to a moderate stress test in adult monkeys that experienced ELS as infants. Both groups of monkeys showed hypothalamic-pituitary-adrenal (HPA) axis stress-induced activations and cardiac arousal in response to the stressor. A whole brain analysis detected significantly greater regional cerebral glucose metabolism (rCGM) in superior temporal sulcus, putamen, thalamus, and inferotemporal cortex of ELS animals compared to controls. Region of interest (ROI) analyses performed in areas identified as vulnerable to ELS showed greater activity in the orbitofrontal cortex of ELS compared to control monkeys, but greater hippocampal activity in the control compared to ELS monkeys. Together, these results suggest hyperactivity in emotional and sensory processing regions of adult monkeys with ELS, and greater activity in stress-regulatory areas in the controls. Despite these neural responses, no group differences were detected in neuroendocrine, autonomic or behavioral responses, except for a trend towards increased stillness in the ELS monkeys. Together, these data suggest hypervigilance in the ELS monkeys in the absence of immediate danger. (c) 2011 Elsevier Ltd. All rights reserved. C1 [Parr, Lisa A.; Boudreau, Matthew; Sanchez, Mar M.] Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. [Parr, Lisa A.; Nemeroff, Charles B.; Sanchez, Mar M.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. [Parr, Lisa A.; Sanchez, Mar M.] Ctr Behav Neurosci, Atlanta, GA USA. [Boudreau, Matthew] Yale Univ, Sch Med, New Haven, CT USA. [Hecht, Erin] Emory Univ, Grad Program Neurosci, Atlanta, GA 30322 USA. [Winslow, James T.] NIMH, IRP Neurobiol Nonhuman Primate Core, NIH, Bethesda, MD 20892 USA. [Nemeroff, Charles B.] Univ Miami, Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. RP Parr, LA (reprint author), Yerkes Natl Primate Res Ctr, 954 Gatewood Rd, Atlanta, GA 30329 USA. EM lparr@emory.edu FU NIMH Conte Center for the Neuroscience of Mental Disorders [P50MH058922]; NIH/NCRR [RR-00165]; NIH; AHRQ; [R01MH-068791] FX This investigation was supported by grants P50MH058922 (NIMH Conte Center for the Neuroscience of Mental Disorders), RR-00165 from the NIH/NCRR to the Yerkes National Primate Research Center, and R01MH-068791 to L.A. Parr. The Yerkes National Primate Research Center is fully accredited by the American Association for Accreditation of Laboratory Animal Care. All procedures described here were approved by the Institutional Animal Care and Use Committee (IACUC) for Emory University and were performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals.; Charles B. Nemeroff is supported by grants from NIH and AHRQ. He is a consultant to Takeda, SK Pharma and Pharmaneuroboost. He serves on the Scientific Advisory Boards of Cenerx, Pharmaneuroboost and Xhale. He serves on the Board of Directors of Novadel Pharma and the American Foundation for Suicide Prevention. He owns equity or stock options in Xhale, Cenerx, Pharmaneuroboost, Reevax and Novadel Pharma. He serves on the Scientific Council of the American Foundation for Suicide Prevention, NARSAD, Skyland Trail and the Anxiety Disorders Association of America. He owns two patents, US 6,375,990B1 and US 7,148,027B2). NR 72 TC 12 Z9 12 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD JAN PY 2012 VL 2 IS 1 BP 181 EP 193 DI 10.1016/j.dcn.2011.09.003 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 095EM UT WOS:000315317500017 PM 22682736 ER PT J AU Monami, M Di Pasquale, G Rowzee, A Rotella, CM Mannucci, E AF Monami, Matteo Di Pasquale, Giovanni Rowzee, Anna Rotella, Carlo Maria Mannucci, Edoardo TI Glucagon-Like Peptide-1 and Diabetes 2012 SO EXPERIMENTAL DIABETES RESEARCH LA English DT Editorial Material C1 [Monami, Matteo] Careggi Teaching Hosp, Sect Geriatr Cardiol & Med, I-50141 Florence, Italy. [Di Pasquale, Giovanni; Rowzee, Anna] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Rotella, Carlo Maria] Careggi Teaching Hosp, Obes Agcy, I-50141 Florence, Italy. [Mannucci, Edoardo] Careggi Teaching Hosp, Diabet Agcy, I-50141 Florence, Italy. RP Monami, M (reprint author), Careggi Teaching Hosp, Sect Geriatr Cardiol & Med, Via Oblate 4, I-50141 Florence, Italy. EM mmonami@libero.it OI Rowzee, Anne/0000-0003-1969-9133 NR 0 TC 1 Z9 2 U1 0 U2 3 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1687-5214 J9 EXP DIABETES RES JI Exp. Diabetes Res. PY 2012 AR 768760 DI 10.1155/2012/768760 PG 1 WC Endocrinology & Metabolism; Medicine, Research & Experimental SC Endocrinology & Metabolism; Research & Experimental Medicine GA 085ER UT WOS:000314597600001 ER PT J AU Conlan, S Mijares, LA Becker, J Blakesley, RW Bouffard, GG Brooks, S Coleman, H Gupta, J Gurson, N Park, M Schmidt, B Thomas, PJ Otto, M Kong, HH Murray, PR Segre, JA AF Conlan, Sean Mijares, Lilia A. Becker, Jesse Blakesley, Robert W. Bouffard, Gerard G. Brooks, Shelise Coleman, Holly Gupta, Jyoti Gurson, Natalie Park, Morgan Schmidt, Brian Thomas, Pamela J. Otto, Michael Kong, Heidi H. Murray, Patrick R. Segre, Julia A. CA NISC Comparative Sequencing TI Staphylococcus epidermidis pan-genome sequence analysis reveals diversity of skin commensal and hospital infection-associated isolates SO GENOME BIOLOGY LA English DT Article ID ANTIBIOTIC-RESISTANCE; BIOFILM FORMATION; TYPING DATA; STRAINS; AUREUS; GENES; VIRULENCE; EVOLUTION; IDENTIFICATION; RECOMBINATION AB Background: While Staphylococcus epidermidis is commonly isolated from healthy human skin, it is also the most frequent cause of nosocomial infections on indwelling medical devices. Despite its importance, few genome sequences existed and the most frequent hospital-associated lineage, ST2, had not been fully sequenced. Results: We cultivated 71 commensal S. epidermidis isolates from 15 skin sites and compared them with 28 nosocomial isolates from venous catheters and blood cultures. We produced 21 commensal and 9 nosocomial draft genomes, and annotated and compared their gene content, phylogenetic relatedness and biochemical functions. The commensal strains had an open pan-genome with 80% core genes and 20% variable genes. The variable genome was characterized by an overabundance of transposable elements, transcription factors and transporters. Biochemical diversity, as assayed by antibiotic resistance and in vitro biofilm formation, demonstrated the varied phenotypic consequences of this genomic diversity. The nosocomial isolates exhibited both large-scale rearrangements and single-nucleotide variation. We showed that S. epidermidis genomes separate into two phylogenetic groups, one consisting only of commensals. The formate dehydrogenase gene, present only in commensals, is a discriminatory marker between the two groups. Conclusions: Commensal skin S. epidermidis have an open pan-genome and show considerable diversity between isolates, even when derived from a single individual or body site. For ST2, the most common nosocomial lineage, we detect variation between three independent isolates sequenced. Finally, phylogenetic analyses revealed a previously unrecognized group of S. epidermidis strains characterized by reduced virulence and formate dehydrogenase, which we propose as a clinical molecular marker. C1 [Conlan, Sean; Mijares, Lilia A.; Segre, Julia A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Mijares, Lilia A.; Murray, Patrick R.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Mijares, Lilia A.] Univ Maryland, Sch Med, Dept Med Res & Technol, Baltimore, MD 21201 USA. [Becker, Jesse; Blakesley, Robert W.; Bouffard, Gerard G.; Brooks, Shelise; Coleman, Holly; Gupta, Jyoti; Gurson, Natalie; Park, Morgan; Schmidt, Brian; Thomas, Pamela J.; NISC Comparative Sequencing] NIH, Intramural Sequencing Ctr, Rockville, MD 20852 USA. [Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM Patrick_Murray@bd.com RI Conlan, Sean/B-4401-2008; OI Conlan, Sean/0000-0001-6848-3465; Otto, Michael/0000-0002-2222-4115; Kong, Heidi/0000-0003-4424-064X FU NHGRI; NIH CC; NCI Intramural Research Programs; NIH Common Fund Human Microbiome Project [1UH2AR057504-01, 4UH3 AR057504-02] FX We thank the volunteers who participated in this study; C Yang for assistance with sample collection and preparation; E Green, L Marraffini, T Scharschmidt, M Fishback, M Feldgarden and members of the Segre laboratory for valuable comments on the manuscript; The Human Microbiome Project Reference Genome catalog for access to draft sequences for BCM-HMP0060, W23144, SK135. This work was supported by the NHGRI, NIH CC and NCI Intramural Research Programs and NIH Common Fund Human Microbiome Project grant 1UH2AR057504-01 and 4UH3 AR057504-02. NR 49 TC 34 Z9 34 U1 2 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1474-7596 J9 GENOME BIOL JI Genome Biol. PY 2012 VL 13 IS 7 AR R64 DI 10.1186/gb-2012-13-7-r64 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 093IY UT WOS:000315186500008 PM 22830599 ER PT B AU Hinnebusch, BJ Sebbane, F Vadyvaloo, V AF Hinnebusch, B. Joseph Sebbane, Florent Vadyvaloo, Viveka BE Carniel, E Hinnebusch, BJ TI Transcriptional Profiling of the Yersinia pestis Life Cycle SO YERSINIA: SYSTEMS BIOLOGY AND CONTROL LA English DT Article; Book Chapter ID STORAGE HMS(+) PHENOTYPE; OUTER-MEMBRANE PROTEIN; BUBONIC PLAGUE; FLEA VECTOR; ASPARTASE DEFICIENCY; BIOFILM FORMATION; PNEUMONIC PLAGUE; INNATE IMMUNITY; VIRULENCE; TRANSMISSION AB DNA microarray technology enables a comprehensive, systems biology approach to investigate the microbial gene expression programme associated with adaptation to different environments. Monitoring the whole-genome transcriptional response of pathogens within infected tissues has rarely been achieved, but has been possible with Yersinia pestis. The transcriptional profiles of Y. pestis in infective fleas and in the lymph node of rats during bubonic plague were compared as a means to identify important adaptational responses associated with successful colonization of the flea, transmission, and the establishment of disease in the mammal. The differential patterns of gene expression indicate metabolic reprogramming, response to different stresses, and specific induction of virulence and transmission factors as Y. pestis alternates between its two hosts. C1 [Hinnebusch, B. Joseph] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Sebbane, Florent] Univ Lille Nord France, INSERM, U801, Lille, France. [Sebbane, Florent] Inst Pasteur, F-59019 Lille, France. [Vadyvaloo, Viveka] Washington State Univ, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. [Vadyvaloo, Viveka] Washington State Univ, Sch Global Anim Hlth, Pullman, WA 99164 USA. RP Hinnebusch, BJ (reprint author), NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM jhinnebusch@niaid.nih.gov; florent.sebbane@inserm.fr; viveka@vetmed.wsu.edu NR 68 TC 5 Z9 5 U1 1 U2 10 PU CAISTER ACADEMIC PRESS PI WYMONDHAM PA 32 HEWITTS LANE, WYMONDHAM NR 18 0JA, ENGLAND BN 978-1-908230-05-8 PY 2012 BP 1 EP 18 PG 18 WC Infectious Diseases SC Infectious Diseases GA BDO15 UT WOS:000314140400002 ER PT B AU Carniel, E Hinnebusch, BJ AF Carniel, Elisabeth Hinnebusch, B. Joseph BE Carniel, E Hinnebusch, BJ TI Yersinia Systems Biology and Control Preface SO YERSINIA: SYSTEMS BIOLOGY AND CONTROL LA English DT Editorial Material; Book Chapter C1 [Carniel, Elisabeth] Inst Pasteur, Natl Reference Lab, Yersinia Res Unit, Paris, France. [Carniel, Elisabeth] Inst Pasteur, WHO Collaborating Ctr Yersinia, Paris, France. [Hinnebusch, B. Joseph] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Carniel, E (reprint author), Inst Pasteur, Natl Reference Lab, Yersinia Res Unit, Paris, France. EM jhinnebusch@niaid.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 3 PU CAISTER ACADEMIC PRESS PI WYMONDHAM PA 32 HEWITTS LANE, WYMONDHAM NR 18 0JA, ENGLAND BN 978-1-908230-05-8 PY 2012 BP IX EP IX PG 1 WC Infectious Diseases SC Infectious Diseases GA BDO15 UT WOS:000314140400001 ER PT J AU Schymick, JC Traynor, BJ AF Schymick, Jennifer C. Traynor, Bryan J. TI Expanding the genetics of amyotrophic lateral sclerosis and frontotemporal dementia SO ALZHEIMERS RESEARCH & THERAPY LA English DT Review ID HEXANUCLEOTIDE REPEAT EXPANSION; GENOME-WIDE ASSOCIATION; MOTOR-NEURON DISEASE; LOBAR DEGENERATION; CHROMOSOME 9P; CLINICAL CHARACTERISTICS; COGNITIVE IMPAIRMENT; SPORADIC ALS; C9ORF72; MUTATIONS AB Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. It is now recognized that ALS and frontotemporal lobar degeneration (FTLD) form a clinical spectrum of disease with overlapping clinical, pathological and genetic features. This past year, the genetic causes of ALS have expanded to include mutations in the genes OPTN, VCP, and UBQLN2, and the hexanucleotide repeat expansion in C9ORF72. The C9ORF72 repeat expansion solidifies the notion that ALS and FTLD are phenotypic variations of a disease spectrum with a common molecular etiology. Furthermore, the C9ORF72 expansion is the genetic cause of a substantial portion of apparently sporadic ALS and FTLD cases, showing that genetics plays a clear role in sporadic disease. Here we describe the progress made in the genetics of ALS and FTLD, including a detailed look at how new insights brought about by C9ORF72 have both broadened and unified current concepts in neurodegeneration. C1 [Schymick, Jennifer C.] Univ Calif Irvine, Sch Med, Irvine, CA 92697 USA. [Schymick, Jennifer C.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Schymick, JC (reprint author), Univ Calif Irvine, Sch Med, Irvine, CA 92697 USA. EM schymicj@hs.uci.edu RI Traynor, Bryan/G-5690-2010 FU Intramural Research Programs of the NIH, National Institute on Aging [Z01-AG000949-02] FX This work was supported by the Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949-02). NR 60 TC 4 Z9 4 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-9193 J9 ALZHEIMERS RES THER JI Alzheimers Res. Ther. PY 2012 VL 4 IS 4 AR 30 DI 10.1186/alzrt133 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 093ME UT WOS:000315195200008 PM 22835154 ER PT J AU Lee, BH Carcamo, WC Chiorini, JA Peck, AB Nguyen, CQ AF Lee, Byung Ha Carcamo, Wendy C. Chiorini, John A. Peck, Ammon B. Nguyen, Cuong Q. TI Gene therapy using IL-27 ameliorates Sjogren's syndrome-like autoimmune exocrinopathy SO ARTHRITIS RESEARCH & THERAPY LA English DT Article ID ADENOASSOCIATED VIRUS VECTOR; SYNDROME-LIKE DISEASE; REGULATORY T-CELLS; CYSTIC-FIBROSIS; SALIVARY-GLANDS; AUTOANTIBODY PRODUCTION; LYMPHOCYTE POPULATIONS; TRANSGENE EXPRESSION; CYTOKINE PRODUCTION; ADENOVIRUS VECTORS AB Introduction: Sjogren's syndrome (SjS) is a systemic autoimmune disease characterized by decreased salivary and lacrimal gland secretions, resulting in severe dry mouth and dry eyes. Recent studies have suggested that T(H)17 cells and its signature cytokine IL-17 are involved in the underlying pathogenic mechanisms leading to destructive inflammation and autoimmunity. In the present study, we examined whether IL-27, a natural inhibitor of T(H)17 activity, could down-regulate or reverse SjS in C57BL/6.NOD-Aec1Aec2 mice, a model of primary-SjS. Methods: Recombinant serotype 2 adeno-associated viral (AAV2) vectors expressing either IL-27 (rAAV2-IL27) or LacZ (rAAV2-LacZ) were injected into 6 or 14 week-old C57BL/6.NOD-Aec1Aec2 mice. Changes in IL-27, IL-17, and IL-10 cytokine levels in peripheral blood were determined by ELISAs, while flow cytometry analyses were used to quantify cytokine-positive splenocytes. Histological assessment of salivary glands, anti-nuclear autoantibody (ANA) staining, and stimulated saliva flow rates were used to profile SjS disease severity. Results: Mice systemically treated with intravenous rAAV2-IL27 injections at either 6 or 14 weeks of age exhibited long-term elevated levels of serum IL-27 with concomitantly reduced levels of IL-17 compared with sera from mice injected with rAAV2-LacZ or saline out to 20 weeks post-inoculation. Most importantly, disease profiles revealed that rAAV2-IL27 treatment had little effect on lymphocytic focus (LF) scores, but resulted in structural changes in LF, lower titers of ANAs with changes in staining patterns, and a less severe clinical disease as determined by saliva flow rates. Conclusions: These data support the concept that IL-27, when provided exogenously, can induce a suppressive effect on SjS development and thus may be an effective therapeutic agent for regulating T(H)17 pro-inflammatory activity in autoimmune diseases where the T(H)17 system has been shown to play an important role in their pathogenesis. C1 [Lee, Byung Ha] Univ Florida, Coll Dent, Dept Oral & Maxillofacial Diagnost Sci, Gainesville, FL 32610 USA. [Lee, Byung Ha; Carcamo, Wendy C.; Peck, Ammon B.] Univ Florida, Coll Dent, Dept Oral Biol, Gainesville, FL 32610 USA. [Chiorini, John A.] Natl Inst Dent & Cranial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Peck, Ammon B.; Nguyen, Cuong Q.] Univ Florida, Coll Dent, Ctr Orphan Autoimmune Disorders, Gainesville, FL 32610 USA. [Peck, Ammon B.] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA. [Nguyen, Cuong Q.] Univ Florida, Coll Vet Med, Dept Infect Dis & Pathol, Gainesville, FL 32608 USA. RP Nguyen, CQ (reprint author), Univ Florida, Coll Dent, Ctr Orphan Autoimmune Disorders, Gainesville, FL 32610 USA. EM nguyenc@ufl.edu FU Sjogren's Syndrome Foundation; Public Health Service (PHS) grant from the National Institute of Dental and Craniofacial Research [K99 DE018958]; PHS grant from National Institute of Allergy and Infectious Diseases [1R21AI081952] FX We thank Sergi Zolotuhkin (Department of Pediatrics, University of Florida College of Medicine) for generously providing the AAV2 vectors (pTR-UF14). We thank Tegan N Lavoie for helping with the flow cytometry analysis used in this study. This work was supported by the Sjogren's Syndrome Foundation (CQN) and Public Health Service (PHS) grant K99 DE018958 (CQN) from the National Institute of Dental and Craniofacial Research. ABP and CQN were supported by PHS grant 1R21AI081952 from National Institute of Allergy and Infectious Diseases. NR 63 TC 14 Z9 17 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2012 VL 14 IS 4 AR R172 DI 10.1186/ar3925 PG 14 WC Rheumatology SC Rheumatology GA 090JF UT WOS:000314974600016 PM 22827855 ER PT J AU Li, Y Zhao, LD Tong, LS Qian, SN Ren, Y Zhang, L Ding, X Chen, Y Wang, YX Zhang, W Zeng, XF Zhang, FC Tang, FL Zhang, X Ba, DN He, W Cao, XT Lipsky, PE AF Li, Yang Zhao, Li-dan Tong, Lu-sha Qian, Su-ning Ren, Yan Zhang, Lei Ding, Xin Chen, Yang Wang, Yan-xia Zhang, Wen Zeng, Xiao-feng Zhang, Feng-chun Tang, Fu-lin Zhang, Xuan Ba, De-nian He, Wei Cao, Xue-tao Lipsky, Peter E. TI Aberrant CD200/CD200R1 expression and function in systemic lupus erythematosus contributes to abnormal T-cell responsiveness and dendritic cell activity SO ARTHRITIS RESEARCH & THERAPY LA English DT Article ID CD200 RECEPTOR; APOPTOTIC CELLS; MONOCLONAL-ANTIBODIES; THERAPEUTIC TARGET; DISEASE-ACTIVITY; DOWN-REGULATION; MRC OX-2; MACROPHAGES; INDUCTION; TOLERANCE AB Introduction: CD200 is a type I transmembrane glycoprotein that can regulate the activation threshold of inflammatory immune responses, polarize cytokine production, and maintain immune homeostasis. We therefore evaluated the functional status of CD200/CD200 receptor 1 (CD200R1) interactions in subjects with systemic lupus erythematosus (SLE). Methods: Serum CD200 level was detected by ELISA. The expression of CD200/CD200R1 by CD4(+) T cells and dendritic cells (DCs) was examined by flow cytometry, and then compared between SLE patients and healthy controls. Peripheral blood mononuclear cells were stained with carboxyfluorescein diacetate succinimidyl ester and annexin V/propidium iodide for evaluation of the effect of CD200 on cell proliferation and apoptosis. In addition, the effect of CD200 on DC function was determined by transwell migration assay as well as by measurement of binding and phagocytosis of apoptotic cells. Results: In SLE patients, the number of CD200(+) cells and the level of soluble CD200 were significantly higher than in healthy controls, whereas the expression of CD200R1 by CD4(+) T cells and DCs was decreased. Furthermore, the increased CD200 expression by early apoptotic cells contributed to their diminished binding and phagocytosis by DCs in SLE. Importantly, the engagement of CD200 receptor on CD4(+) T cells with CD200-Fc fusion protein in vitro reduced the differentiation of T-helper type 17 cells and reversed the defective induction of CD4(+)CD25(high)FoxP3(+) T cells by transforming growth factor beta in SLE patients. Conversely, blockade of CD200-CD200R1 interaction with anti-CD200R1 antibody promoted CD4(+) T-cell proliferation. Conclusion: CD200 and CD200R1 expression and function are abnormal in SLE and may contribute to the immunologic abnormalities in SLE. C1 [Li, Yang; Zhao, Li-dan; Tong, Lu-sha; Qian, Su-ning; Ren, Yan; Zhang, Lei; Ding, Xin; Chen, Yang; Wang, Yan-xia; Zhang, Wen; Zeng, Xiao-feng; Zhang, Feng-chun; Tang, Fu-lin; Zhang, Xuan] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rheumatol & Clin Immunol, Beijing 100032, Peoples R China. [Li, Yang; Zhao, Li-dan; Tong, Lu-sha; Qian, Su-ning; Ren, Yan; Zhang, Lei; Ding, Xin; Chen, Yang; Wang, Yan-xia; Zhang, Wen; Zeng, Xiao-feng; Zhang, Feng-chun; Tang, Fu-lin; Zhang, Xuan] Peking Union Med Coll, Beijing 100032, Peoples R China. [Ba, De-nian; He, Wei; Cao, Xue-tao] Chinese Acad Med Sci, Peking Union Med Coll, Inst Basic Med Sci, Dept Immunol,Sch Basic Med, Beijing 100005, Peoples R China. [Lipsky, Peter E.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Zhang, X (reprint author), Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rheumatol & Clin Immunol, 41 Da Mu Cang Hu Tong St, Beijing 100032, Peoples R China. EM zxpumch2003@yahoo.com.cn; peterlipsky@comcast.net OI zhang, xuan/0000-0001-8775-1699 NR 45 TC 11 Z9 13 U1 0 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2012 VL 14 IS 3 AR R123 DI 10.1186/ar3853 PG 17 WC Rheumatology SC Rheumatology GA 090IL UT WOS:000314972600025 PM 22621248 ER PT J AU Liu, R Wu, Q Su, DL Che, N Chen, HF Geng, LY Chen, JY Chen, WJ Li, X Sun, LY AF Liu, Rui Wu, Qian Su, Dinglei Che, Nan Chen, Haifeng Geng, Linyu Chen, Jinyun Chen, Wanjun Li, Xia Sun, Lingyun TI A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis SO ARTHRITIS RESEARCH & THERAPY LA English DT Article ID DISEASE-ACTIVITY; IMMUNE-RESPONSES; CUTTING EDGE; INTERLEUKIN-21; RECEPTOR; GENERATION; DIFFERENTIATION; CYTOKINE; ANTIBODY; MICE AB Introduction: Interleukin (IL)-21 is a member of type I cytokine family. Recent studies indicate that IL-21 can promote T follicular helper (Tfh) cell differentiation and survival, a specialized T cell subset which provides help for B cell. It can also regulate the activation, proliferation and differentiation of human B cell and immunoglobulin (Ig) production as well as isotype switching of plasma cell. Rheumatoid arthritis (RA) is characterized by auto-antibodies overproduction such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody, suggesting a pivotal role of Tfh cell and B cell in the pathogenesis of RA. This study aimed to investigate whether IL-21 had a regulatory effect on Tfh cell and B cell in RA. Methods: Serum IL-21 concentrations were measured by ELISA. The correlations between serum IL-21 levels and clinical features of RA patients were analyzed by Spearman's rank test. The percentages of Tfh-like cells, IL-21 receptor (R) expression on Tfh-like cells and B cells in peripheral blood (PB) were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) were stimulated by rIL-21 (100 ng/ml) in the presence or absence of anti-CD40 and/or anti-IgM, and changes of IL-21R, activation-associated surface markers (CD25, CD69 and CD40), the proliferation, apoptosis and differentiation of B cells were analyzed by flow cytometry. Production of IgG and IgM in the culture supernatants was determined by ELISA. Results: The results showed that the serum IL-21 levels in RA patients were significantly higher than that of healthy controls (HC). IL-21 concentrations were positively correlated with 28-joint count disease activity score (DAS28) and anti-CCP antibody in RA patients with high IL-21 levels. Furthermore, the frequencies of peripheral CXCR5(+)PD-1(+)CD4(+) Tfh-like cells markedly increased in RA patients and the percentages of Tfh-like cells were positively correlated with DAS28 and anti-CCP antibody levels. Moreover, elevated IL-21 levels were also correlated with the frequencies of Tfh-like cells. IL-21R expression on both Tfh-like cells and B cells were significantly enhanced in RA patients. In cultures vitro, exogenous IL-21 upregulated IL-21R expression and activation-associated surface markers on B cells and promoted more B cell proliferation in RA than in HC. This IL-21-mediated effect could be reversed by IL-21R-specific neutralizing antibody. Importantly, IL-21 promoted more differentiation of B cell into plasmablast and higher levels of IgG and IgM production in RA than in HC. Conclusions: Increased serum IL-21 levels in RA patients correlate with DAS28, anti-CCP antibody and frequencies of Tfh-like cells. IL-21 supports B cell activation, proliferation and antibody secretion via IL-21R pathway. Thus, IL-21 may be involved in the pathogenesis of RA and antagonizing IL-21 could be a novel strategy for the therapy of RA. C1 [Liu, Rui; Su, Dinglei; Che, Nan; Li, Xia; Sun, Lingyun] Nanjing Med Univ, Drum Tower Clin Med Coll, Dept Immunol & Rheumatol, Nanjing 210008, Jiangsu, Peoples R China. [Wu, Qian; Chen, Haifeng; Geng, Linyu; Chen, Jinyun] Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Dept Immunol & Rheumatol, Nanjing 210008, Jiangsu, Peoples R China. [Chen, Wanjun] Natl Inst Dent & Craniofacial Res, Mucosal Immun Sect, NIH, Bethesda, MD USA. [Li, Xia] Dalian Med Univ, Dept Biochem, Dalian 116044, Liaoning, Peoples R China. RP Li, X (reprint author), Nanjing Med Univ, Drum Tower Clin Med Coll, Dept Immunol & Rheumatol, Nanjing 210008, Jiangsu, Peoples R China. EM lixia416@yahoo.com.cn; Lingyunsun2001@yahoo.com.cn FU National Natural Science Foundation of China [81172847, 30972736]; Jiangsu Province Natural Science Foundation [BK2009034]; Major International (Regional) Joint Research Project, Jiangsu Province Kejiao Xingwei Program [81120108021]; National Basic Research Program of China [2010 CB 529100]; Nanjing Young Medical Talent Project; China Postdoctoral Science Foundation the First Class [2012M510073]; Intramural Research Program of the National Institutes of Health, NIDCR FX This work was funded by the National Natural Science Foundation of China (No. 81172847, 30972736); Jiangsu Province Natural Science Foundation (BK2009034); Major International (Regional) Joint Research Project (81120108021), Jiangsu Province Kejiao Xingwei Program and National Basic Research Program of China (Grant No. 2010 CB 529100); Nanjing Young Medical Talent Project; China Postdoctoral Science Foundation the First Class (2012M510073), and the Intramural Research Program of the National Institutes of Health, NIDCR. NR 47 TC 44 Z9 47 U1 2 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2012 VL 14 IS 6 AR R255 DI 10.1186/ar4100 PG 12 WC Rheumatology SC Rheumatology GA 093LB UT WOS:000315192300031 PM 23176102 ER PT J AU Yong, PFK Freeman, AF Engelhardt, KR Holland, S Puck, JM Grimbacher, B AF Yong, Patrick F. K. Freeman, Alexandra F. Engelhardt, Karin R. Holland, Steven Puck, Jennifer M. Grimbacher, Bodo TI An update on the hyper-IgE syndromes SO ARTHRITIS RESEARCH & THERAPY LA English DT Review ID HYPERIMMUNOGLOBULIN-E SYNDROME; CHRONIC MUCOCUTANEOUS CANDIDIASIS; STEM-CELL TRANSPLANTATION; INFECTION JOBS SYNDROME; COLD STAPHYLOCOCCAL ABSCESSES; SYSTEMIC-LUPUS-ERYTHEMATOSUS; BONE-MARROW-TRANSPLANTATION; CORONARY-ARTERY ANEURYSMS; RECURRENT-INFECTION; DOCK8 DEFICIENCY AB The hyper-IgE syndromes (HIES; originally named Job's syndrome) are a collection of primary immunodeficiency syndromes resulting in elevated serum IgE levels and typified by recurrent staphylococcal skin abscesses, eczema and pulmonary infections. The disorder has autosomal dominant and recessive forms. Autosomal dominant HIES has been shown to be mainly due to STAT3 mutations and additionally results in connective tissue, skeletal, vascular and dental abnormalities. Autosomal recessive HIES has been shown to be mainly due to mutations in DOCK8; these patients are more prone to viral skin infections instead. This review article discusses the common clinical features of the syndrome, the genetic mutations responsible and the pathogenesis of the disease, as well as treatments currently used. C1 [Yong, Patrick F. K.] Barts Hlth NHS Trust, Dept Immunol, London E1 2ES, England. [Freeman, Alexandra F.; Holland, Steven] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Engelhardt, Karin R.; Grimbacher, Bodo] Royal Free Hosp, Dept Immunol & Mol Pathol, London NW3 2QG, England. [Engelhardt, Karin R.; Grimbacher, Bodo] UCL, London NW3 2QG, England. [Engelhardt, Karin R.; Grimbacher, Bodo] Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, D-79108 Freiburg, Germany. [Engelhardt, Karin R.; Grimbacher, Bodo] Univ Freiburg, D-79108 Freiburg, Germany. [Puck, Jennifer M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Grimbacher, B (reprint author), Royal Free Hosp, Dept Immunol & Mol Pathol, Pond St, London NW3 2QG, England. EM b.grimbacher@ucl.ac.uk OI Yong, Patrick/0000-0003-1736-2756 NR 91 TC 35 Z9 36 U1 2 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2012 VL 14 IS 6 AR 228 DI 10.1186/ar4069 PG 10 WC Rheumatology SC Rheumatology GA 093LB UT WOS:000315192300007 PM 23210525 ER PT J AU Zonios, D Sheikh, V Sereti, I AF Zonios, Dimitrios Sheikh, Virginia Sereti, Irini TI Idiopathic CD4 lymphocytopenia: a case of missing, wandering or ineffective T cells SO ARTHRITIS RESEARCH & THERAPY LA English DT Review ID PRIMARY SJOGRENS-SYNDROME; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; CRYPTOCOCCAL MENINGITIS; HIV-INFECTION; INTERFERON-GAMMA; IL-2 THERAPY; LYMPHOPENIA; PATIENT; AUTOIMMUNITY; SARCOIDOSIS AB Idiopathic CD4 lymphocytopenia (ICL) is a presumed heterogenous syndrome with key element low CD4 T-cell counts (below 300/mm(3)) without evidence of HIV infection or other known immunodeficiency. The etiology, pathogenesis, and management of ICL remain poorly understood and inadequately defined. The clinical presentation can range from serious opportunistic infections to incidentally diagnosed asymptomatic individuals. Cryptococcal and non-tuberculous mycobacterial infections and progressive multifocal leukoencephalopathy are the most significant presenting infections, although the spectrum of opportunistic diseases can be similar to that in patients with lymphopenia and HIV infection. Malignancy is common and related to opportunistic pathogens with an oncogenic potential. Autoimmune diseases are also seen in ICL with an increased incidence. The etiology of ICL is unknown. Mechanisms implicated in CD4 reduction may include decreased production, increased destruction, and tissue sequestration. New distinct genetic defects have been identified in certain patients with ICL, supporting the hypothesis of the lack of a common etiology in this syndrome. The management of ICL is focused on the treatment of opportunistic infections, appropriate prophylactic antibiotics, and close monitoring. In selected patients with life-threatening infections or profound immunodeficiency, strategies to increase T-cell counts or enhance immune function could be considered and have included interleukin-2, interferon-gamma, interleukin-7, and hematopoietic stem cell transplantation. The prognosis is influenced by the accompanying opportunistic infections and may be affected by publication bias of severe cases with unfavorable outcomes. As newer laboratory investigation techniques are being developed and targeted experimental treatments become available, our comprehension and prognosis of this rare syndrome could be significantly improved. C1 [Sheikh, Virginia; Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Sereti, I (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases/National Institutes of Health FX The work of VS and IS was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases/National Institutes of Health. NR 49 TC 15 Z9 15 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2012 VL 14 IS 4 AR 222 DI 10.1186/ar4027 PG 7 WC Rheumatology SC Rheumatology GA 090JF UT WOS:000314974600048 PM 22971990 ER PT S AU Memarzadeh, F AF Memarzadeh, Farhad GP ASHRAE TI Literature Review of the Effect of Temperature and Humidity on Viruses SO ASHRAE TRANSACTIONS 2012, VOL 118, PT 1 SE ASHRAE Transactions LA English DT Proceedings Paper CT ASHRAE Winter Conference CY 2012 CL Chicago, IL SP ASHRAE ID INFLUENZA-A VIRUS; RESPIRATORY SYNCYTIAL VIRUS; RELATIVE-HUMIDITY; AIRBORNE TRANSMISSION; SERRATIA-MARCESCENS; ANIMAL-MODEL; HONG-KONG; INFECTION; SURVIVAL; AEROSOLS AB An extensive literature review of more than 120 papers was conducted on the effect of humidity and temperature on the transmission of infectious viruses. This review targets infectious viruses known to be transmitted through the air as well as direct and indirect contact. Evidence is cited from both direct and indirect study results examining environmental conditions that affect infectious disease aerosol transmission in enclosed environments. These results will have a major influence on the choice of infection control measures in indoor environments as well as an associated cost for equipment and renovations to the ventilation system or room design. C1 NIH, Div Tech Resources, Bethesda, MD 20892 USA. RP Memarzadeh, F (reprint author), NIH, Div Tech Resources, Bldg 10, Bethesda, MD 20892 USA. NR 107 TC 4 Z9 4 U1 1 U2 10 PU AMER SOC HEATING, REFRIGERATING AND AIR-CONDITIONING ENGS PI ATLANTA PA 1791 TULLIE CIRCLE NE, ATLANTA, GA 30329 USA SN 0001-2505 J9 ASHRAE TRAN PY 2012 VL 118 BP 1049 EP 1060 PN 1 PG 12 WC Thermodynamics; Construction & Building Technology SC Thermodynamics; Construction & Building Technology GA BDC57 UT WOS:000312640000110 ER PT J AU Patton, JT AF Patton, John T. TI Rotavirus Diversity and Evolution in the Post-Vaccine World SO DISCOVERY MEDICINE LA English DT Article ID POLYMERASE-CHAIN-REACTION; UNITED-STATES; GLOBAL DISTRIBUTION; VP7 GENES; STRAINS; CHILDREN; G9; INFECTION; BOVINE; GASTROENTERITIS AB Rotaviruses (RVs) are a large genetically diverse population of segmented double-stranded (ds) RNA viruses that are important causes of gastroenteritis in many animal species. The human RVs are responsible for the deaths of nearly 450,000 infants and young children each year, most occurring in developing countries. Recent large-scale sequencing efforts have revealed that the genomes of human RVs typically consist of phylogenetically linked constellations of eleven dsRNA segments. The presence of such preferred constellations indicate that the human RV genes have co-evolved to produce protein sets that work optimally together to support virus replication. Two of the viral genes encode virion outer capsid proteins (VP7 and VP4) whose antigenic properties define the G/P type of the virus. From year-to-year and place-to-place, the G/P type of human RVs associated with disease can fluctuate dramatically, phenomena that can be associated with the presence and behavior of genetically distinct RV clades. The recent introduction of two live attenuated RV vaccines (RotaTeq (TM) and Rotarix (TM)) into the childhood vaccination programs of various countries has been highly effective in reducing the incidence of RV diarrheal disease. Whether the widespread use of these vaccines will introduce selective pressures on human RVs, triggering genetic and antigenic changes that undermine the effectiveness of vaccinations programs, is uncertain and will require continued surveillance of human RVs. [Discovery Medicine 13(68):85-97, January 2012] C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 50 Ctr Dr, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health (USA) FX I am indebted to Natalie Leach, Kristen Ogden, and Shane Trask for their help in preparing and editing the manuscript. My appreciation also goes to Jelle Matthijnssens and Sarah McDonald for their reviews and to Miren Iturriza-Gomara (EuroRotaNet) and Annemarie Wasley (WHO) for providing surveillance information. J.T.P. was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (USA). NR 96 TC 21 Z9 23 U1 1 U2 1 PU DISCOVERY MEDICINE PI TIMONIUM PA 10 GERARD AVE, STE 201, TIMONIUM, MD 21093 USA SN 1539-6509 EI 1944-7930 J9 DISCOV MED JI Discov. Med. PD JAN PY 2012 VL 13 IS 68 BP 85 EP 97 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 091LG UT WOS:000315050300008 ER PT J AU Ostrander, EA Ruvinsky, A AF Ostrander, Elaine A. Ruvinsky, Anatoly BE Ostrander, EA Ruvinsky, A TI The Genetics of the Dog, 2nd Edition Preface SO GENETICS OF THE DOG, 2ND EDITION LA English DT Editorial Material; Book Chapter C1 [Ostrander, Elaine A.] NHGRI, Canc Genet Sect, NIH, Bethesda, MD 20892 USA. [Ruvinsky, Anatoly] Univ New England, Armidale, NSW 2351, Australia. RP Ostrander, EA (reprint author), NHGRI, Canc Genet Sect, NIH, 50 South Dr,Bldg 50,Room 5351, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CABI PUBLISHING-C A B INT PI WALLINGFORD PA CABI PUBLISHING, WALLINGFORD 0X10 8DE, OXON, ENGLAND BN 978-1-84593-940-3 PY 2012 BP XI EP XII D2 10.1079/9781845939403.0000 PG 2 WC Genetics & Heredity; Veterinary Sciences SC Genetics & Heredity; Veterinary Sciences GA BDK96 UT WOS:000313626100001 ER PT J AU Parker, HG AF Parker, Heidi G. BE Ostrander, EA Ruvinsky, A TI The History and Relationships of Dog Breeds SO GENETICS OF THE DOG, 2ND EDITION LA English DT Article; Book Chapter ID GENOME-WIDE ASSOCIATION; ROD-CONE DEGENERATION; DOMESTIC DOG; LINKAGE DISEQUILIBRIUM; PRIMARY CATARACTS; POPULATION-STRUCTURE; GENETIC-STRUCTURE; MUTATION; IDENTIFICATION; CANDIDATE C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Parker, HG (reprint author), NHGRI, NIH, 50 South Dr,Bldg 50,Room 5351, Bethesda, MD 20892 USA. NR 57 TC 2 Z9 2 U1 1 U2 5 PU CABI PUBLISHING-C A B INT PI WALLINGFORD PA CABI PUBLISHING, WALLINGFORD 0X10 8DE, OXON, ENGLAND BN 978-1-84593-940-3 PY 2012 BP 38 EP 56 D2 10.1079/9781845939403.0000 PG 19 WC Genetics & Heredity; Veterinary Sciences SC Genetics & Heredity; Veterinary Sciences GA BDK96 UT WOS:000313626100004 ER PT J AU Ostrander, EA Bustamante, CD AF Ostrander, Elaine A. Bustamante, Carlos D. BE Ostrander, EA Ruvinsky, A TI Genetics of Morphological Traits in the Domestic Dog SO GENETICS OF THE DOG, 2ND EDITION LA English DT Article; Book Chapter ID CANINE GENOME; COAT COLOR; MAJOR DETERMINANT; ASSOCIATION; MUTATIONS; GENES; HAPLOTYPE; SEQUENCE; CATENIN; ALLELE C1 [Ostrander, Elaine A.] NHGRI, Canc Genet Sect, NIH, Bethesda, MD 20892 USA. [Bustamante, Carlos D.] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. RP Ostrander, EA (reprint author), NHGRI, Canc Genet Sect, NIH, 50 South Dr,Bldg 50,Room 5351, Bethesda, MD 20892 USA. OI Ostrander, Elaine/0000-0001-6075-9738 NR 55 TC 0 Z9 0 U1 16 U2 23 PU CABI PUBLISHING-C A B INT PI WALLINGFORD PA CABI PUBLISHING, WALLINGFORD 0X10 8DE, OXON, ENGLAND BN 978-1-84593-940-3 PY 2012 BP 359 EP 374 D2 10.1079/9781845939403.0000 PG 16 WC Genetics & Heredity; Veterinary Sciences SC Genetics & Heredity; Veterinary Sciences GA BDK96 UT WOS:000313626100017 ER PT J AU Huson, HJ AF Huson, Heather J. BE Ostrander, EA Ruvinsky, A TI Genetic Aspects of Performance in Working Dogs SO GENETICS OF THE DOG, 2ND EDITION LA English DT Article; Book Chapter ID ALASKAN SLED DOGS; WORLD-TRADE-CENTER; STRENUOUS EXERCISE; GLYCOGEN CONCENTRATIONS; PROLONGED EXERCISE; HUMAN REMAINS; SURVEILLANCE; ASSOCIATION; RECOVERY; PENTAGON C1 [Huson, Heather J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Huson, Heather J.] Univ Alaska, Inst Arctic Biol, Fairbanks, AK 99775 USA. RP Huson, HJ (reprint author), NHGRI, NIH, 50 South Dr,Bldg 50,Room 5351, Bethesda, MD 20892 USA. NR 64 TC 0 Z9 0 U1 2 U2 13 PU CABI PUBLISHING-C A B INT PI WALLINGFORD PA CABI PUBLISHING, WALLINGFORD 0X10 8DE, OXON, ENGLAND BN 978-1-84593-940-3 PY 2012 BP 477 EP 495 D2 10.1079/9781845939403.0000 PG 19 WC Genetics & Heredity; Veterinary Sciences SC Genetics & Heredity; Veterinary Sciences GA BDK96 UT WOS:000313626100023 ER PT S AU May-Simera, H Kelley, MW AF May-Simera, Helen Kelley, Matthew W. BE Yang, Y TI Planar Cell Polarity in the Inner Ear SO PLANAR CELL POLARITY DURING DEVELOPMENT SE Current Topics in Developmental Biology LA English DT Review; Book Chapter ID NEURAL-TUBE DEFECTS; WINGLESS MORPHOGEN GRADIENT; HAIR-CELLS; ASYMMETRIC LOCALIZATION; CONVERGENT EXTENSION; MAMMALIAN COCHLEA; STEREOCILIARY BUNDLES; SIGNALING PATHWAY; KIDNEY-DISEASE; DROSOPHILA EYE AB The inner ears of vertebrates represent one of the most striking examples of planar cell polarity (PCP). Populations of directionally sensitive mechanosensory hair cells develop actin-based stereociliary bundles that are uniformly oriented. Analysis of perturbations in bundle polarity in mice with mutations in Vangl2 formed the basis for the initial demonstration of conservation of the PCP signaling pathway in vertebrates. Subsequent studies have demonstrated roles for other "core" PCP genes, such as Frizzled, Disheveled, and Celsr, and for identifying novel PCP molecules such as Scribble and Ptk7. In addition, the demonstration of hearing deficits in humans with mutations in cilia genes combined with analysis of PCP defects in mice with ciliary deletion has implicated the cilia as an important modulator of hair cell polarization. Finally, the presence of shortened cochleae in many PCP mouse mutants has revealed an additional role for the PCP pathway in the development of the auditory system. C1 [May-Simera, Helen; Kelley, Matthew W.] NIDCD, Lab Cochlear Dev, NIH, Bethesda, MD 20892 USA. RP Kelley, MW (reprint author), NIDCD, Lab Cochlear Dev, NIH, Bethesda, MD 20892 USA. EM kelleymt@nidcd.nih.gov NR 109 TC 16 Z9 16 U1 1 U2 8 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0070-2153 BN 978-0-12-394592-1 J9 CURR TOP DEV BIOL JI Curr. Top. Dev. Biol. PY 2012 VL 101 BP 111 EP 140 DI 10.1016/B978-0-12-394592-1.00006-5 PG 30 WC Developmental Biology SC Developmental Biology GA BDO14 UT WOS:000314133400006 PM 23140627 ER PT S AU Gao, B AF Gao, Bo BE Yang, Y TI Wnt Regulation of Planar Cell Polarity (PCP) SO PLANAR CELL POLARITY DURING DEVELOPMENT SE Current Topics in Developmental Biology LA English DT Review; Book Chapter ID NEURAL-TUBE DEFECTS; CONVERGENT EXTENSION MOVEMENTS; RECESSIVE ROBINOW-SYNDROME; BRACHYDACTYLY TYPE-B; LEFT-RIGHT ASYMMETRY; SIGNAL-TRANSDUCTION PATHWAY; DROSOPHILA WING EPITHELIUM; RECEPTOR TYROSINE KINASES; APICAL ECTODERMAL RIDGE; LEFT-RIGHT AXIS AB Planar cell polarity (PCP), a process controlling coordinated, uniformly polarized cellular behaviors in a field of cells, has been identified to be critically required for many fundamental developmental processes. However, a global directional cue that establishes PCP in a three-dimensional tissue or organ with respect to the body axes remains elusive. In vertebrate, while Wnt-secreted signaling molecules have been implicated in regulating PCP in a beta-catenin-independent manner, whether they function permissively or act as a global cue to convey directional information is not clearly defined. In addition, the underlying molecular mechanism by which Wnt signal is transduced to core PCP proteins is largely unknown. In this chapter, I review the roles of Wnt signaling in regulating PCP during vertebrate development and update our knowledge of its regulatory mechanism. C1 NHGRI, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NHGRI, Bethesda, MD 20892 USA. EM gaob@mail.nih.gov RI Gao, Bo/F-4688-2013 FU Intramural NIH HHS NR 203 TC 36 Z9 36 U1 2 U2 18 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0070-2153 BN 978-0-12-394592-1 J9 CURR TOP DEV BIOL JI Curr. Top. Dev. Biol. PY 2012 VL 101 BP 263 EP 295 DI 10.1016/B978-0-12-394592-1.00008-9 PG 33 WC Developmental Biology SC Developmental Biology GA BDO14 UT WOS:000314133400012 PM 23140633 ER PT J AU Wang, SJ McKenna, M Petrick, N Sahiner, B Linguraru, MG Wei, ZS Yao, JH Summers, RM AF Wang, Shijun McKenna, Matthew Petrick, Nicholas Sahiner, Berkman Linguraru, Marius G. Wei, Zhuoshi Yao, Jianhua Summers, Ronald M. GP IEEE TI ROC-LIKE OPTIMIZATION BY SAMPLE RANKING: APPLICATION TO CT COLONOGRAPHY SO 2012 9TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING (ISBI) LA English DT Proceedings Paper CT 9th IEEE International Symposium on Biomedical Imaging (ISBI) - From Nano to Macro CY MAY 02-05, 2012 CL Barcelona, SPAIN SP IEEE, IEEE Engn Med & Biol Soc (EMBS), IEEE Signal Proc Soc DE ROC analysis; AUC optimization; semi-definite programming; computed tomographic colonography; computer-aided diagnosis AB In this study, we propose a new binary classification algorithm which optimizes the area under the receiver operating characteristic curve (AUC) based on a ranking of training samples. We first solved the traditional AUC maximization problem using semi-definite programming. We then introduced auxiliary variables to rank training samples. In this way, we can select the most representative samples to avoid over-training to noisy data. We applied our proposed classifier to a CT colonography dataset containing 50 patients. Preliminary experimental results indicate that our proposed method can achieve higher classification performance than support vector machines. C1 [Wang, Shijun; McKenna, Matthew; Wei, Zhuoshi; Yao, Jianhua; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM rms@nih.gov FU Intramural Research Programs of the NIH Clinical Center; Food and Drug Administration FX This work was supported by the Intramural Research Programs of the NIH Clinical Center and the Food and Drug Administration. We thank Drs. Perry Pickhardt, J. Richard Choi, and William Schindler for providing CTC data. No official endorsement by the National Institutes of Health or the Food and Drug Administration of any equipment or product of any company mentioned in the publication should be inferred. NR 9 TC 1 Z9 1 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1858-8 PY 2012 BP 478 EP 481 PG 4 WC Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BDA85 UT WOS:000312384100120 ER PT J AU Wei, ZS Wang, SJ Petrick, N Yao, JH Periaswamy, S Summers, RM AF Wei, Zhuoshi Wang, Shijun Petrick, Nicholas Yao, Jianhua Periaswamy, Senthil Summers, Ronald M. GP IEEE TI SUPINE AND PRONE CT COLONOGRAPHY REGISTRATION BY MATCHING GRAPHS OF TENIAE COLI SO 2012 9TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING (ISBI) LA English DT Proceedings Paper CT 9th IEEE International Symposium on Biomedical Imaging (ISBI) - From Nano to Macro CY MAY 02-05, 2012 CL Barcelona, SPAIN SP IEEE, IEEE Engn Med & Biol Soc (EMBS), IEEE Signal Proc Soc DE CTC; registration; graph; teniae coli ID COLONOSCOPY; TRIAL AB This paper proposes a registration method for supine and prone CTC scans. The method matches graphs built using the teniae coli, three muscles that run the length of the colon. The teniae are visible on CTC and were detected using fully-automatically software. Then key points of the teniae were obtained by non-uniformed sampling of the teniae. Graphs were built using these key points. The colon registration was formulated as a graph matching problem. Mean field theory was applied to match the graphs. The proposed method was tested on 10 pairs of supine and prone CTC scans. The average registration error was 2.5cm (+/- 0.7 cm, 95% C.I. [2.1 2.9]), significantly improving the baseline graph matching method for CTC registration. C1 [Wei, Zhuoshi; Wang, Shijun; Yao, Jianhua; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab Radiol &, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Petrick, Nicholas] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Periaswamy, Senthil] ICAD Inc, Nashua, NH 03062 USA. RP Wei, ZS (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab Radiol &, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. FU Intramural Research Programs of the NIH Clinical Center; Food and Drug Administration; CRADA with iCAD FX This research was supported by the Intramural Research Programs of the NIH Clinical Center and the Food and Drug Administration. We thank Drs. Perry Pickhardt, J. Richard Choi and William Schindler for providing CTC data and Viatronix Inc. for providing V3D Colon software. Support also provided in part by a CRADA with iCAD. NR 12 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1858-8 PY 2012 BP 712 EP 715 PG 4 WC Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BDA85 UT WOS:000312384100179 ER PT J AU Jajamovich, GH Pamulapati, V Alam, S Mehari, A Kato, GJ Wood, BJ Linguraru, MG AF Jajamovich, Guido H. Pamulapati, Vivek Alam, Shoaib Mehari, Alem Kato, Gregory J. Wood, Bradford J. Linguraru, Marius George GP IEEE TI NON-INVASIVE INDICATORS OF PULMONARY HYPERTENSION FROM PULMONARY VEINS QUANTIFICATION IN SICKLE CELL DISEASE SO 2012 9TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING (ISBI) LA English DT Proceedings Paper CT 9th IEEE International Symposium on Biomedical Imaging (ISBI) - From Nano to Macro CY MAY 02-05, 2012 CL Barcelona, SPAIN SP IEEE, IEEE Engn Med & Biol Soc (EMBS), IEEE Signal Proc Soc DE Pulmonary hypertension; pulmonary veins; segmentation; quantification; sickle cell disease ID MULTIDETECTOR CT; SEGMENTATION; DRAINAGE; SURFACE AB Pulmonary hypertension is a common cause of death among patients with sickle cell disease. This retrospective study investigates the use of pulmonary vein analysis to diagnose pulmonary hypertension non-invasively with CT-Angiography images. Ten images from patients with pulmonary hypertension were matched with controls. An adaptive fast marching approach is applied in order to segment the left atrium and pulmonary veins, followed by a geodesic active contour to isolate the atrium. The ostia of the pulmonary veins are determined by computing the skeleton and finding the intersections with the contour of the atrium. 96.3% of the ostia are identified correctly by the technique. The diameters of the veins are then measured and their sum is computed at fixed distances from the ostium. These quantitative indicators are significantly larger in patients as compared to controls (p-values < 0.01). Furthermore, the non-invasive estimations of the method present a high and significant correlation with the clinical hemodynamics measurements obtained from right heart catheterization. C1 [Jajamovich, Guido H.] Columbia Univ, Dept Elect Engn, New York, NY 10027 USA. [Pamulapati, Vivek; Wood, Bradford J.; Linguraru, Marius George] Natl Inst Hlth, Ctr Clin, Radiol & Imaging Sci, Bethesda, MD USA. [Alam, Shoaib; Mehari, Alem; Kato, Gregory J.] Natl Inst Hlth, Sickle Cell Vasc Dis Sect Hematol Branch, Bethesda, MD USA. [Alam, Shoaib; Mehari, Alem; Kato, Gregory J.] Natl Heart Lung & Blood Inst, Sickle Cell Vasc Dis Sect Hematol Branch, Bethesda, MD USA. [Mehari, Alem] Howard Univ, Coll Med, Washington, DC USA. [Linguraru, Marius George] Childrens Natl Med Ctr, Sheikh Zayed Inst Pediat Surg Innovat, Washington, DC USA. RP Jajamovich, GH (reprint author), Columbia Univ, Dept Elect Engn, New York, NY 10027 USA. OI Kato, Gregory/0000-0003-4465-3217 FU National Institutes of Health Clinical Center; National Heart, Lung, and Blood Institute [1 ZIA HL006014- 03] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health Clinical Center and National Heart, Lung, and Blood Institute ( 1 ZIA HL006014- 03). NR 15 TC 1 Z9 1 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1858-8 PY 2012 BP 840 EP 843 PG 4 WC Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BDA85 UT WOS:000312384100211 ER PT J AU Kadoury, S Zagorchev, L Wood, BJ Venkatesan, A Weese, J Jago, J Kruecker, J AF Kadoury, S. Zagorchev, L. Wood, B. J. Venkatesan, A. Weese, J. Jago, J. Kruecker, J. GP IEEE TI A MODEL-BASED REGISTRATION APPROACH OF PREOPERATIVE MRI WITH 3D ULTRASOUND OF THE LIVER FOR INTERVENTIONAL GUIDANCE PROCEDURES SO 2012 9TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING (ISBI) LA English DT Proceedings Paper CT 9th IEEE International Symposium on Biomedical Imaging (ISBI) - From Nano to Macro CY MAY 02-05, 2012 CL Barcelona, SPAIN SP IEEE, IEEE Engn Med & Biol Soc (EMBS), IEEE Signal Proc Soc DE MRI; ultrasound; surface-based registration; deformable shape models; image-guided liver interventions ID 3-D ULTRASOUND; IMAGES; SEGMENTATION AB In this paper, we present a novel approach to rigidly register intraoperative electromagnetically tracked ultrasound (US) with preoperative contrast-enhanced magnetic resonance (MR) images. The clinical rationale for this work is to allow accurate needle placement during thermal ablations of liver metastases using multimodal imaging. We adopt a model-based approach that rigidly matches segmented liver surface shapes obtained from the multimodal image volumes. Towards this end, a shape-constrained deformable surface model combining the strengths of both deformable and active shape models is used to segment the liver surface from the MR scan. It incorporates a priori shape information while external forces guide the deformation and adapts the model to a target structure. The liver boundary is extracted from US by merging a dynamic region-growing method with a graph-based segmentation framework anchored on adaptive priors of neighboring surface points. Registration is performed with a weighted ICP algorithm with a physiological penalizing term. The MR segmentation model was trained with 30 datasets and validated on a separate cohort of 10 patients with corresponding ground truth. The accuracy and robustness of the method were assessed by registering four US/MR datasets, yielding accurate landmark registration errors (3.7 +/- 0.69mm) and high robustness, and is thus acceptable for radiofrequency clinical applications. C1 [Kadoury, S.; Zagorchev, L.; Weese, J.; Kruecker, J.] Philips Res N Amer, Briarcliff Manor, NY USA. [Wood, B. J.; Venkatesan, A.] Natl Inst Hlth, Ctr Intervent Oncol, Bethesda, MD USA. Philips Res Europe, Hamburg, Germany. [Jago, J.] Philips Healthcare, Bothell, WA USA. RP Kadoury, S (reprint author), Philips Res N Amer, Briarcliff Manor, NY USA. FU National Institutes of Health Clinical Center; National Institutes of Health; Philips Healthcare FX This work was supported in part by the Intramural Research Program of the National Institutes of Health Clinical Center and by a Collaborative Research and Development Agreement between the National Institutes of Health and Philips Healthcare. NR 10 TC 1 Z9 1 U1 0 U2 4 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1858-8 PY 2012 BP 952 EP 955 PG 4 WC Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BDA85 UT WOS:000312384100246 ER PT J AU Zhang, WD Liu, JM Yao, JH Nguyen, TB Louie, A Wank, S Nowinski, WL Summers, RM AF Zhang, Weidong Liu, Jiamin Yao, Jianhua Nguyen, Tan B. Louie, Adeline Wank, Stephen Nowinski, Wieslaw L. Summers, Ronald M. GP IEEE TI MESENTERIC VASCULATURE-GUIDED SMALL BOWEL SEGMENTATION ON HIGH-RESOLUTION 3D CT ANGIOGRAPHY SCANS SO 2012 9TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING (ISBI) LA English DT Proceedings Paper CT 9th IEEE International Symposium on Biomedical Imaging (ISBI) - From Nano to Macro CY MAY 02-05, 2012 CL Barcelona, SPAIN SP IEEE, IEEE Engn Med & Biol Soc (EMBS), IEEE Signal Proc Soc DE vessel segmentation; small bowel segmentation; maximum intensity projection AB Due to the low image contrast and high tortuosity of the small bowel on CT scans, it is difficult for even experienced radiologists to localize small bowel. To facilitate this, we propose a novel mesenteric vasculature-guided method for small bowel region segmentation on high-resolution contrast-enhanced CT angiography (CTA) scans. It is essential and useful for further localizing small bowel tumors. The mesenteric vasculature is first segmented using multi-view multi-scale vesselness enhancement filters on maximum intensity projection images. Second, the small bowel region is automatically segmented based on the map of mesenteric vasculature and its relationship to the small bowel. The method is applied to high-resolution contrast-enhanced abdominal CTA scans of patients suspected of having carcinoid tumors. The result, 79.3% volume overlap accuracy compared with the reference standard, shows it is feasible to segment the small bowel using the mesenteric vasculature as a roadmap on CTA scans. C1 [Zhang, Weidong; Liu, Jiamin; Yao, Jianhua; Nguyen, Tan B.; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. [Louie, Adeline; Wank, Stephen] Natl Inst Hlth, Natl Inst Diabetes, Digest & Kidney Dis, Los Angeles, CA USA. [Nowinski, Wieslaw L.] ASTAR, Biomed Imaging Lab, Singapore, Singapore. RP Zhang, WD (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. FU National Institute of Health, Clinical Center; NIDDK FX This research was supported by the intramural research programs of the National Institute of Health, Clinical Center and NIDDK. NR 12 TC 5 Z9 5 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1858-8 PY 2012 BP 1280 EP 1283 PG 4 WC Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BDA85 UT WOS:000312384100328 ER PT J AU Liu, JM Feng, CH Hua, J Yao, JH White, JM Summers, RM AF Liu, Jiamin Feng, Chin-Hsiang Hua, Jeremy Yao, Jianhua White, Jacob M. Summers, Ronald M. GP IEEE TI AUTOMATIC DETECTION AND SEGMENTATION OF ABDOMINOPELVIC LYMPH NODES ON COMPUTED TOMOGRAPHY SCANS SO 2012 9TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING (ISBI) LA English DT Proceedings Paper CT 9th IEEE International Symposium on Biomedical Imaging (ISBI) - From Nano to Macro CY MAY 02-05, 2012 CL Barcelona, SPAIN SP IEEE, IEEE Engn Med & Biol Soc (EMBS), IEEE Signal Proc Soc DE lymph node detection; Hessian matrix; object scale AB We proposed a local scale-based Hessian analysis method for automated lymph node detection in contrast-enhanced abdominopelvic CT scans. First, spine and pelvic girdle were automatically segmented to locate the abdominopelvic region. Blood vessels were then segmented to narrow the search region to the perivascular space where lymph nodes are located. Lymph node candidates were generated by scale-based Hessian analysis. The detected candidates were segmented by curve evolution. Characteristic features were calculated on the segmented nodes. Support vector machine was utilized for classification and false positive reduction. We applied our method to 22 patients with 37 enlarged lymph nodes. The system achieved 83% sensitivity at 5 false positives per patient. Our results indicated that computer-aided abdominopelvic lymph node detection is feasible with a high sensitivity and a relatively low FP rate. C1 [Liu, Jiamin; Feng, Chin-Hsiang; Hua, Jeremy; Yao, Jianhua; White, Jacob M.; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. RP Liu, JM (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bldg 10,Room 1C224 MSC 1182, Bethesda, MD 20892 USA. NR 17 TC 2 Z9 2 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1858-8 PY 2012 BP 1455 EP 1458 PG 4 WC Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BDA85 UT WOS:000312384100377 ER PT J AU Bagci, U Miller-Jaster, K Yao, JH Wu, A Caban, J Olivier, KN Aras, O Mollura, DJ AF Bagci, Ulas Miller-Jaster, Kirsten Yao, Jianhua Wu, Albert Caban, Jesus Olivier, Kenneth. N. Aras, Omer Mollura, Daniel J. GP IEEE TI AUTOMATIC QUANTIFICATION OF TREE-IN-BUD PATTERNS FROM CT SCANS SO 2012 9TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING (ISBI) LA English DT Proceedings Paper CT 9th IEEE International Symposium on Biomedical Imaging (ISBI) - From Nano to Macro CY MAY 02-05, 2012 CL Barcelona, SPAIN SP IEEE, IEEE Engn Med & Biol Soc (EMBS), IEEE Signal Proc Soc DE Quantification; CAD; Tree-in-Bud; Lung; CT ID COMPUTER-AIDED DIAGNOSIS; IMAGE FEATURE ANALYSIS; DIGITAL RADIOGRAPHY; CLASSIFICATION; DISEASE AB In this paper, we present a fully automatic method to quantify Tree-in- Bud (TIB) patterns for respiratory tract infections. The proposed quantification method is based on our previous effort to detect and track TIB patterns with a computer assisted detection (CAD) system [9]. In addition to accurately identifying TIB on CT, quantifying TIB is important for measuring the volume of affected lung as a potantial marker of disease severity. This quantification can be challenging due to the complex shape of TIB and high intensity variation contributing mixed features. Our proposed quantification method is based on a local scale concept such that TIB regions detected via the CAD system are quantified adaptively, and volume percentages of the quantified regions are compared to visual scoring of participating radiologists. We conducted the experiments with a data set of 94 chest CTs (laboratory confirmed 39 viral bronchiolitis caused by human parainfluenza (HPIV), 34 nontuberculous mycobacterial (NTM), and 21 normal control). Experimental results show that the proposed quantification system is well suited to the CAD system for detecting TIB patterns. Correlations of observer- CAD agreements are reported as (R-2 = 0.824, p < 0.01) and (R-2 = 0.801, p < 0.01) for HPIV and NTM cases, respectively. C1 [Bagci, Ulas; Miller-Jaster, Kirsten; Wu, Albert; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging, Bethesda, MD 20892 USA. [Bagci, Ulas; Miller-Jaster, Kirsten; Yao, Jianhua; Wu, Albert; Aras, Omer; Mollura, Daniel J.] Dept Radiol & Imaging Sci NIH, Bethesda, MD 20892 USA. [Caban, Jesus] Naval Med Ctr NICoE, Bethesda, MD 20892 USA. [Olivier, Kenneth. N.] Lab Clin Infect Dis NIH, Bethesda, MD 20892 USA. [Aras, Omer] Natl Canc Inst NIH, Bethesda, MD 20892 USA. RP Bagci, U (reprint author), NIH, Ctr Infect Dis Imaging, Bethesda, MD 20892 USA. OI Bagci, Ulas/0000-0001-7379-6829 NR 12 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1858-8 PY 2012 BP 1459 EP 1462 PG 4 WC Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BDA85 UT WOS:000312384100378 ER PT J AU Chowdhury, AS Burns, JE Mukherjee, A Sen, B Yao, JH Summers, RM AF Chowdhury, Ananda S. Burns, Joseph E. Mukherjee, Arka Sen, Bhaskar Yao, Jianhua Summers, Ronald M. GP IEEE TI AUTOMATED DETECTION OF PELVIC FRACTURES FROM VOLUMETRIC CT IMAGES SO 2012 9TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING (ISBI) LA English DT Proceedings Paper CT 9th IEEE International Symposium on Biomedical Imaging (ISBI) - From Nano to Macro CY MAY 02-05, 2012 CL Barcelona, SPAIN SP IEEE, IEEE Engn Med & Biol Soc (EMBS), IEEE Signal Proc Soc DE Pelvic fracture; Graph Cut; Mean and Gaussian curvatures ID SEGMENTATION; EPIDEMIOLOGY AB Pelvic fractures are a major cause of trauma patient mortality. Detection and management of pelvic injuries is challenging due to myriad injury patterns and associated complications such as hemorrhage and infection. In this paper, we propose an automated method of pelvic fracture detection from volumetric CT images. A coarse-to-fine strategy is adopted where a potential region containing the fracture is identified first using intensity and curvature information. The above region is modeled as a weighted graph and a fracture is modeled as a minimum cut in this graph. A second localizing algorithm models the same fracture as a valley, based on the signs of the mean and Gaussian curvature. The minimum cuts as well as the spatial consistent valleys, in isolation, generate a small number of false positives in addition to the true fracture. A joint decision process based on the volumetric graph cuts and the spatially consistent valleys eliminates the false positives. Experimental results indicate the effectiveness of the proposed scheme. C1 [Chowdhury, Ananda S.; Mukherjee, Arka; Sen, Bhaskar] Jadavpur Univ, Dept Elect & Telecom Engn, Kolkata 700032, India. [Burns, Joseph E.; Yao, Jianhua; Summers, Ronald M.] NIH, Ctr Clin, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Burns, Joseph E.] Univ Calif Irvine, Dept Radiol Sci, Irvine, CA 92697 USA. RP Chowdhury, AS (reprint author), Jadavpur Univ, Dept Elect & Telecom Engn, Kolkata 700032, India. EM aschowdhury@etce.jdvu.ac.in; jburns@uci.edu; arkamukherjee49@gmail.com; bhaskarsen.ju@gmail.com; jyao@cc.nih.gov; rms@nih.gov FU Radiology and Imaging Sciences Department; National Institute of Biomedical Imaging and Bioengineering; National Institutes of Health; National Institutes of Health Clinical Center FX This research was supported in part by the Imaging Sciences Training Program sponsored by the Radiology and Imaging Sciences Department and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health. This research was also supported in part by the National Institutes of Health Clinical Center. NR 14 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1858-8 PY 2012 BP 1687 EP 1690 PG 4 WC Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BDA85 UT WOS:000312384100435 ER PT J AU Lim, PH Bagci, U Aras, O Wang, Y Bai, L AF Lim, Poay Hoon Bagci, Ulas Aras, Omer Wang, Yan Bai, Li GP IEEE TI A NOVEL SPINAL VERTEBRAE SEGMENTATION FRAMEWORK COMBINING GEOMETRIC FLOW AND SHAPE PRIOR WITH LEVEL SET METHOD SO 2012 9TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING (ISBI) LA English DT Proceedings Paper CT 9th IEEE International Symposium on Biomedical Imaging (ISBI) - From Nano to Macro CY MAY 02-05, 2012 CL Barcelona, SPAIN SP IEEE, IEEE Engn Med & Biol Soc (EMBS), IEEE Signal Proc Soc DE Vertebrae segmentation; level set method; Willmore flow; kernel density estimation; computed tomography ID ACTIVE CONTOURS AB Segmentation of spinal vertebrae is extremely important in the study of spinal related disease or disorders. However, limited work has been done on precise segmentation of spinal vertebrae. The complexity of vertebrae shapes, with gaps in the cortical bone, internal boundaries, as well as the noisy, incomplete or missing information from the images have undoubtedly increased the challenge for image analysis. In this paper, we introduce a novel level set segmentation framework that integrates shape prior and the Willmore flow to drive the level set evolution. While the shape energy draws the level set function towards a range of possible prior shapes, the edge-mounted Willmore energy captures the localized geometry information and smooths the surface during the level set evolution. Experimental results on segmentation of spinal vertebrae from CT images demonstrate the powerful combination of prior knowledge and geometrical flow. C1 [Lim, Poay Hoon; Bai, Li] Univ Nottingham, Sch Comp Sci, Nottingham NG8 1BB, England. [Bagci, Ulas; Aras, Omer] Natl Inst Hlth, Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Aras, Omer] Natl Canc Inst, Mol Imaging Program, Bethesda, MD 20892 USA. [Wang, Yan] Univ Bradford, Sch Comp Informat & Media, Bradford BD7 1DP, W Yorkshire, England. RP Lim, PH (reprint author), Univ Nottingham, Sch Comp Sci, Nottingham NG8 1BB, England. OI Bagci, Ulas/0000-0001-7379-6829 NR 11 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1858-8 PY 2012 BP 1703 EP 1706 PG 4 WC Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BDA85 UT WOS:000312384100439 ER PT J AU Yao, JH Burns, JE Summers, RM AF Yao, Jianhua Burns, Joseph E. Summers, Ronald M. GP IEEE TI SCLEROTIC RIB METASTASES DETECTION ON ROUTINE CT IMAGES SO 2012 9TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING (ISBI) LA English DT Proceedings Paper CT 9th IEEE International Symposium on Biomedical Imaging (ISBI) - From Nano to Macro CY MAY 02-05, 2012 CL Barcelona, SPAIN SP IEEE, IEEE Engn Med & Biol Soc (EMBS), IEEE Signal Proc Soc DE computer aided detection; bone metastasis; sclerotic lesion; ribs AB This work presents a computer-aided detection (CAD) system to aid radiologists in finding sclerotic bone metastases in the ribs on routine body imaging CT protocols with 5mm chest/abdomen CT images. First, the spine is segmented to locate the ribs using thresholding, region growing and a vertebra template. The centerlines of ribs are then traced by a progressive algorithm based on maximizing the cross-section overlap. The profile of the ribs along the centerline is analyzed to generate the initial detections. A set of quantitative features is then extracted and sent to a support vector machine for classification. Novel visualization techniques are also developed to display all ribs and the distribution of bone lesions in one single view. The system was tested on 10 data sets with 185 sclerotic lesions identified by an expert. A leave-one-out cross-validation results in 75.4% sensitivity at an average of 5.6 false positives per case. C1 [Yao, Jianhua; Summers, Ronald M.] NIH, Imaging Biomarkers & Comp Aided Diag Lab Radiol &, Ctr Clin, Bethesda, MD 20892 USA. [Burns, Joseph E.] Univ Calif Irvine, Sch Med, Dept Radiol Sci, Irvine, CA USA. RP Yao, JH (reprint author), NIH, Imaging Biomarkers & Comp Aided Diag Lab Radiol &, Ctr Clin, Bethesda, MD 20892 USA. FU Intramural Research Program of NIH, Clinical Center FX This research was supported in part by the Intramural Research Program of NIH, Clinical Center. NR 9 TC 2 Z9 2 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1858-8 PY 2012 BP 1767 EP 1770 PG 4 WC Engineering, Electrical & Electronic; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA BDA85 UT WOS:000312384100455 ER PT S AU Battle, KE Gething, PW Elyazar, IRF Moyes, CL Sinka, ME Howes, RE Guerra, CA Price, RN Baird, JK Hay, SI AF Battle, Katherine E. Gething, Peter W. Elyazar, Iqbal R. F. Moyes, Catherine L. Sinka, Marianne E. Howes, Rosalind E. Guerra, Carlos A. Price, Ric N. Baird, J. Kevin Hay, Simon I. BE Hay, SI Price, R Baird, JK TI The Global Public Health Significance of Plasmodium vivax SO ADVANCES IN PARASITOLOGY, VOL 80: EPIDEMIOLOGY OF PLASMODIUM VIVAX: HISTORY, HIATUS AND HUBRIS, PT A SE Advances in Parasitology LA English DT Review; Book Chapter ID DUFFY-BLOOD-GROUP; DOMINANT ANOPHELES VECTORS; PAPUA-NEW-GUINEA; ARTEMISININ COMBINATION THERAPY; LINKED-IMMUNOSORBENT-ASSAY; FALCIPARUM PARASITE RATE; MALARIA ATLAS PROJECT; SAN-DIEGO COUNTY; COMPARATIVE SUSCEPTIBILITY; DISTRIBUTION MAPS AB Plasmodium vivax occurs globally and thrives in both temperate and tropical climates. Here, we review the evidence of the biological limits of its contemporary distribution and the global population at risk (PAR) of the disease within endemic countries, We also review the most recent evidence for the endemic level of transmission within its range and discuss the implications for burden of disease assessments. Finally, the evidence-base for defining the contemporary distribution and PAR of P. vivax are discussed alongside a description of the vectors of human malaria within the limits of risk. This information along with recent data documenting the severe morbid and fatal consequences of P. vivax infection indicates that the public health significance of P vivax is likely to have been seriously underestimated. C1 [Battle, Katherine E.; Gething, Peter W.; Moyes, Catherine L.; Sinka, Marianne E.; Howes, Rosalind E.; Hay, Simon I.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Elyazar, Iqbal R. F.; Baird, J. Kevin] Eijkman Oxford Clin Res Unit, Jakarta, Indonesia. [Guerra, Carlos A.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Baird, J. Kevin] Univ Oxford, Ctr Trop Med, Nuffield Dept Med, Oxford, England. [Price, Ric N.] Charles Darwin Univ, Global & Trop Hlth Div, Menzies Sch Hlth Res, Darwin, NT 0909, Australia. RP Battle, KE (reprint author), Univ Oxford, Dept Zool, S Parks Rd, Oxford OX1 3PS, England. RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Price, Richard/0000-0003-2000-2874; Gething, Peter/0000-0001-6759-5449; Battle, Katherine/0000-0003-2401-2615; Moyes, Catherine/0000-0002-8028-4079 FU Wellcome Trust [089276, #083534, #091625, 091625, 091835, 095066] NR 315 TC 45 Z9 45 U1 2 U2 17 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-308X BN 978-0-12-397900-1 J9 ADV PARASIT JI Adv.Parasitol. PY 2012 VL 80 BP 1 EP 111 DI 10.1016/B978-0-12-397900-1.00001-3 PG 111 WC Public, Environmental & Occupational Health; Infectious Diseases; Parasitology SC Public, Environmental & Occupational Health; Infectious Diseases; Parasitology GA BDO74 UT WOS:000314253200001 PM 23199486 ER PT J AU Kamran, F Rother, KI Cochran, E Zadeh, ES Gorden, P Brown, RJ AF Kamran, F. Rother, K. I. Cochran, E. Zadeh, E. Safar Gorden, P. Brown, R. J. TI Consequences of Stopping and Restarting Leptin in an Adolescent with Lipodystrophy SO HORMONE RESEARCH IN PAEDIATRICS LA English DT Article DE Lipodystrophy; Leptin; Nonalcoholic steatohepatitis; Diabetes; Adipose tissue; Adolescent ID GENERALIZED LIPODYSTROPHY; REPLACEMENT THERAPY; INSULIN-RESISTANCE; OBESITY; HUMANS; GENE AB Background/Aims: Lipodystrophy encompasses a group of rare disorders characterized by deficiency of adipose tissue resulting in hypoleptinemia, and metabolic abnormalities including insulin resistance, diabetes, dyslipidemia, and nonalcoholic steatohepatitis. Leptin replacement effectively ameliorates these metabolic derangements. We report effects of leptin discontinuation and resumption in a child with acquired generalized lipodystrophy. Methods: Intermittent treatment with leptin with follow-up over 5 years. Results: Pretreatment metabolic abnormalities included insulin resistance, hypertriglyceridemia and steatohepatitis. Leptin was started at the age of 10 years. After 2 years, the family requested discontinuation of leptin due to lack of visible physical changes. Nine months later, worsened metabolic abnormalities and arrest of pubertal development were observed. Leptin was restarted, followed by improvements in metabolic parameters. Laboratory changes (before vs. 6 months after restarting leptin) were: fasting glucose from 232 to 85 mg/dl, insulin from 232 to 38.9 mu U/ml, HbA(1c) from 7.5 to 4.8%, triglycerides from 622 to 96 mg/dl, ALT from 229 to 61 U/l, AST from 91 to 18 U/l, and urine protein:creatinine ratio from 5.4 to 0.3. Progression of puberty was observed 1 year after restarting leptin. Conclusion: Initial leptin therapy likely prevented progression of metabolic abnormalities. Treatment discontinuation led to rapid metabolic decomposition and pubertal arrest. Reintroduction of leptin reversed metabolic abnormalities and allowed normal pubertal progression. Copyright (C) 2012 S. Karger AG, Basel C1 [Kamran, F.] NICHHD, NIH, Bethesda, MD 20892 USA. [Rother, K. I.; Cochran, E.; Zadeh, E. Safar; Gorden, P.; Brown, R. J.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Brown, RJ (reprint author), Bldg 10 CRC,Rm 6-5942,10 Ctr Dr, Bethesda, MD 20892 USA. EM brownrebecca@mail.nih.gov FU Intramural NIH HHS [Z99 DK999999] NR 21 TC 6 Z9 6 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1663-2818 J9 HORM RES PAEDIAT JI Horm. Res. Paediatr. PY 2012 VL 78 IS 5-6 BP 320 EP 325 DI 10.1159/000341398 PG 6 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 087SZ UT WOS:000314784500007 PM 22965160 ER PT J AU Michaelides, M Thanos, PK Volkow, ND Wang, GJ AF Michaelides, Michael Thanos, Panayotis K. Volkow, Nora D. Wang, Gene-Jack TI Translational Neuroimaging in Drug Addiction and Obesity SO ILAR JOURNAL LA English DT Article DE addiction; dopamine; functional magnetic resonance imaging (fMRI); leptin; neuroimaging; obesity; positron emission tomography (PET); rodent model ID POSITRON-EMISSION-TOMOGRAPHY; BRAIN GLUCOSE-METABOLISM; COCAINE ADDICTION; IN-VIVO; FUNCTIONAL MRI; RAT-BRAIN; CORTICAL ACTIVATION; ANTERIOR CINGULATE; FOOD RESTRICTION; OPIATE ADDICTS AB The use of translational noninvasive neuroimaging has revealed that drug addiction and obesity share striking similarities in functional impairment in discrete brain regions and neurotransmitter circuits. Imaging experiments in both humans and rodents (using complementary experimental designs) show similar abnormalities in brain glucose metabolism in the prefrontal cortex (involved in inhibitory control) and hippocampus (memory) as well as impairments in dopamine signaling in the striatum (involved in food and drug reward, goal orientation, motivation, and habit formation). In both species, many of these observations have been obtained through concurrent and parallel monitoring of both brain activity and behavioral manifestations during drug administration, food sensory (visual, olfactory) stimulation, and craving. This review aims to show that noninvasive brain imaging strategies such as small animal positron emission tomography offer significant potential and promise for modeling motivational disorders such as drug addiction and obesity in humans. Rodent addiction models will prove valuable for understanding brain responses to drug cues and will help guide treatment, especially in relapse situations triggered by exposure to conditioned drug cues. C1 [Michaelides, Michael; Thanos, Panayotis K.; Wang, Gene-Jack] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Michaelides, Michael] Mt Sinai Sch Med, Pharmacol & Syst Therapeut Dept, New York, NY USA. [Volkow, Nora D.] NIDA, NIH, Bethesda, MD 20892 USA. RP Wang, GJ (reprint author), Brookhaven Natl Lab, Dept Med, 30 Bell Ave, Upton, NY 11973 USA. EM gjwang@bnl.gov RI Michaelides, Michael/K-4736-2013 OI Michaelides, Michael/0000-0003-0398-4917 FU National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [AA11034, AA07574, AA07611]; National Institute on Drug Abuse (NIDA) [DA006278]; NIDA Postdoctoral Training Program at Mount Sinai School of Medicine [DA007135] FX This work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism (AA11034, AA07574, AA07611) and the National Institute on Drug Abuse (NIDA; DA006278). The NIDA Postdoctoral Training Program at Mount Sinai School of Medicine also provided support (DA007135, Michaelides). NR 57 TC 9 Z9 9 U1 1 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1084-2020 J9 ILAR J JI ILAR J. PY 2012 VL 53 IS 1 BP 59 EP 68 DI 10.1093/ilar.53.1.59 PG 10 WC Veterinary Sciences SC Veterinary Sciences GA 084NP UT WOS:000314546600015 PM 23520600 ER PT J AU Wu, A Zheng, HY Kraenzle, J Biller, A Vanover, CD Proctor, M Sherwood, L Steffen, M Ng, C Mollura, DJ Jonsson, CB AF Wu, Albert Zheng, Huaiyu Kraenzle, Jennifer Biller, Ashley Vanover, Carol D. Proctor, Mary Sherwood, Leslie Steffen, Marlene Ng, Chin Mollura, Daniel J. Jonsson, Colleen B. TI Ferret Thoracic Anatomy by 2-Deoxy-2-(18F)Fluoro-D-Glucose (18F-FDG) Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) Imaging SO ILAR JOURNAL LA English DT Article DE animal model; FDG-PET/CT; ferret; imaging; molecular imaging; pulmonary imaging; radiology; thoracic anatomy ID H1N1 INFLUENZA-VIRUS; SMALL ANIMAL-MODELS; FDG-PET; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; NUCLEAR-MEDICINE; INFECTION; MICE; VACCINES; METAANALYSIS AB The domestic ferret (Mustela putorius furo) has been a long-standing animal model used in the evaluation and treatment of human diseases. Molecular imaging techniques such as 2-deoxy-2-(F-18)fluoro-D-glucose (F-18-FDG) positron emission tomography (PET) would be an invaluable method of tracking disease in vivo, but this technique has not been reported in the literature. Thus, the aim of this study was to establish baseline imaging characteristics of PET/computed tomography (CT) with F-18-FDG in the ferret model. Twelve healthy female ferrets were anesthetized and underwent combined PET/CT scanning. After the images were fused, volumes of interest (VOIs) were generated in the liver, heart, thymus, and bilateral lung fields. For each VOI, standardized uptake values (SUVs) were calculated. Additional comparisons were made between radiotracer uptake periods (60, 90, and >90 minutes), intravenous and intraperitoneal injections of F-18-FDG, and respiratory gated and ungated acquisitions. Pulmonary structures and the surrounding thoracic and upper abdominal anatomy were readily identified on the CT scans of all ferrets and were successfully fused with PET. VOIs were created in various tissues with the following SUV calculations: heart (maximum standardized uptake value [SUVMax] 8.60, mean standardized uptake value [SUVMean] 5.42), thymus (SUVMax 3.86, SUVMean 2.59), liver (SUVMax 1.37, SUVMean 0.99), right lung (SUVMax 0.92, SUVMean 0.56), and left lung (SUVMax 0.88, SUVMean 0.51). Sixty- to 90-minute uptake periods were sufficient to separate tissues based on background SUV activity. No gross differences in image quality were seen between intraperitoneal and intravenous injections of F-18-FDG. Respiratory gating also did not have a significant impact on image quality of lung parenchyma. The authors concluded that F-18-FDG PET and CT imaging can be performed successfully in normal healthy ferrets with the parameters identified in this study. They obtained similar imaging features and uptake measurements with and without respiratory gating as well as with intraperitoneal and intravenous F-18-FDG injections. F-18-FDG PET and CT can be a valuable resource for the in vivo tracking of disease progression in future studies that employ the ferret model. C1 [Wu, Albert; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Zheng, Huaiyu; Kraenzle, Jennifer; Biller, Ashley; Vanover, Carol D.; Proctor, Mary; Sherwood, Leslie; Steffen, Marlene; Ng, Chin] Univ Louisville, Ctr Predict Med, Louisville, KY 40292 USA. RP Mollura, DJ (reprint author), NIH, Ctr Infect Dis Imaging, Dept Radiol & Imaging Sci, 10 Ctr Dr,Bldg 10,1C349,Mailstop 1182, Bethesda, MD 20892 USA. EM molluradj@cc.nih.gov; cbjons01@louisville.edu FU Commonwealth of Kentucky; Clinical Research Training Program; National Institutes of Health (NIH); Pfizer Inc.; Center for Infectious Disease Imaging in the Intramural Research Program of NIH FX This study was supported in part by the Commonwealth of Kentucky-funded Clinical and Translational Science Pilot Project Program at the University of Louisville, the Clinical Research Training Program (a public-private partnership supported jointly by the National Institutes of Health (NIH) and Pfizer Inc. via a grant to the Foundation for NIH from Pfizer Inc.), and the Center for Infectious Disease Imaging in the Intramural Research Program of NIH. NR 52 TC 1 Z9 1 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1084-2020 J9 ILAR J JI ILAR J. PY 2012 VL 53 IS 1 BP E9 EP + DI 10.1093/ilar.53.1.9 PG 14 WC Veterinary Sciences SC Veterinary Sciences GA 084NP UT WOS:000314546600002 PM 23382267 ER PT J AU Kirkpatrick, SI Midthune, D Dodd, KW Potischman, N Subar, AF Thompson, FE AF Kirkpatrick, Sharon I. Midthune, Douglas Dodd, Kevin W. Potischman, Nancy Subar, Amy F. Thompson, Frances E. TI Reactivity and Its Association with Body Mass Index across Days on Food Checklists SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article ID 24-HOUR DIETARY RECALLS; ENERGY-INTAKE; FREQUENCY QUESTIONNAIRE; WEIGHT STATUS; LIFE-STYLE; VALIDATION; VALIDITY; OBESITY; RELIABILITY; ADULTS AB Characterizing relationships between diet, body weight, and health is complicated by reporting errors in dietary intake data that are associated with body weight. The objectives of this study were to assess changes in reporting across days (reactivity) on food checklists and associations between reactivity and body mass index (BMI) using data from two cross-sectional studies: (a) the Recontacting Participants in the Observing Protein and Energy Nutrition study (n=297), which was conducted in 2003-2004 and included a 7-day checklist and a 4-day food record, and (b) the America's Menu Daily Food Report Study (n=530), which was conducted in 1996 and included a 30-day checklist. Zero-inflated Poisson regression was used to assess effects of reporting day on frequency of consumption for the checklists and number of items reported for the food record. Interactions between day and BMI were tested using contrast statements. Frequency of reported consumption decreased across days among males and females for total items and many of the eight food groups on the 7-day checklist; among females, the effect of reporting day differed by BMI category for the meat, fish, and poultry group. Smaller declines across days were observed for some of the 22 food groups, on the 30-day checklist; no interactions with BMI were apparent. No reporting day effects were observed in the food record data. The results suggest inconsistent reactivity across days, possibly reflecting changes in reporting or consumption behavior. However, the effects are generally small and independent of body weight, suggesting that checklists are potentially useful for the study of. body weight and diet. J Acad Nutr Diet. 2012;112:110-118. C1 [Kirkpatrick, Sharon I.; Subar, Amy F.; Thompson, Frances E.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Midthune, Douglas; Dodd, Kevin W.] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Potischman, Nancy] NCI, Off Associate Director, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Kirkpatrick, SI (reprint author), NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4005, Bethesda, MD 20892 USA. EM kirkpatricksi@mail.nih.gov OI Kirkpatrick, Sharon/0000-0001-9896-5975 FU Intramural NIH HHS [Z99 CA999999] NR 35 TC 5 Z9 5 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD JAN PY 2012 VL 112 IS 1 BP 110 EP 118 DI 10.1016/j.jada.2011.10.004 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 083CH UT WOS:000314439800014 PM 22308230 ER PT J AU Hennessy, E Hughes, SO Goldberg, JP Hyatt, RR Economos, CD AF Hennessy, Erin Hughes, Sheryl O. Goldberg, Jeanne P. Hyatt, Raymond R. Economos, Christina D. TI Permissive Parental Feeding Behavior Is Associated with an Increase in Intake of Low-Nutrient-Dense Foods among American Children Living in Rural Communities SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article ID CONFIRMATORY FACTOR-ANALYSIS; PSYCHOMETRIC PROPERTIES; DIETARY-INTAKE; WEIGHT STATUS; US CHILDREN; ADOLESCENTS; QUESTIONNAIRE; CONSUMPTION; OBESITY; STYLE AB Parents play an important role in shaping children's eating habits. Few studies have evaluated the influence of both parenting style and parenting practices on child outcomes such as dietary intake. During spring 2007, 99 parent-child dyads from four rural US areas participated in this cross-sectional study. Child food intake was reported during two interviewer-administered, parent-assisted 24-hour recalls. Diet quality was defined as the average number of low-nutrient-dense (LND) foods consumed. Validated questionnaires were used to assess parental feeding practices and feeding style. Pearson correlations identified relationships among child food intake, parental feeding style typologies, and covariates. Regression analyses were used to predict child diet quality. Sixty percent of children and 76% of parents were overweight or obese. A permissive feeding style, which is highly responsive to a child's requests and sets few demands on him or her, was the most common (n=37) parental feeding style. This feeding style was associated with child intake of LND foods (r=0.3; P<0.001) and moderated the relationship between parental feeding practices and child intake of LND foods. In the presence of a permissive feeding style, higher levels of monitoring were associated with child intake of LND foods (beta=.69; P<0.05). Parental feeding style may alter the effectiveness of parental feeding practices on children's food intake. More research is needed to understand the parent child feeding relationship in the context of parental feeding styles and practices. J Acad Nutr Diet. 2012;112:142-148. C1 [Hennessy, Erin] NCI, NIH, Bethesda, MD 20892 USA. [Hennessy, Erin; Goldberg, Jeanne P.; Economos, Christina D.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Hughes, Sheryl O.] Baylor Univ, USDA ARS, Childrens Nutr Res Ctr, Dept Pediat,Baylor Coll Med, Houston, TX 77030 USA. [Hyatt, Raymond R.] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Economos, Christina D.] Tufts Univ, John Hancock Res Ctr Phys Act Nutr & Obes Prevent, Boston, MA 02111 USA. RP Hennessy, E (reprint author), NCI, NIH, 6130 Execut Blvd,EPN 4087C, Bethesda, MD 20892 USA. EM hennessye@mail.nih.gov FU Centers for Disease Control and Prevention (Public Health Dissertation Research Award) [1R36DP001325-01]; New Balance Foundation; Save the Children, US Programs; Robert Wood Johnson Foundation [59458] FX This research was supported by awards from the Centers for Disease Control and Prevention (Public Health Dissertation Research Award, grant no. 1R36DP001325-01) and New Balance Foundation, with additional funding provided by Save the Children, US Programs, and the Robert Wood Johnson Foundation (grant no. 59458). NR 52 TC 28 Z9 28 U1 4 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD JAN PY 2012 VL 112 IS 1 BP 142 EP 148 DI 10.1016/j.jada.2011.08.030 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 083CH UT WOS:000314439800019 PM 22709645 ER PT S AU Scott, I AF Scott, Iain BE Scott, I TI Regulation of cellular homoeostasis by reversible lysine acetylation SO LYSINE-BASED POST-TRANSLATIONAL MODIFICATION OF PROTEINS SE Essays in Biochemistry LA English DT Review; Book Chapter ID SACCHAROMYCES-CEREVISIAE; GLUCOSE-HOMEOSTASIS; HISTONE ACETYLATION; ENERGY-EXPENDITURE; GENE ACTIVATION; LIFE-SPAN; SIRT1; PGC-1-ALPHA; METABOLISM; AMPK AB Acetylation, through the post-transcriptional modification of histones, is a well-established regulator of gene transcription. More recent research has also identified an important role for acetylation in the regulation of non-histone proteins, both inside and outside the nucleus. As a fast (and reversible) post-translational process, acetylation allows cells to rapidly alter the function of existing proteins, making it ideally suited to biological programmes that require an immediate response to changing conditions. Using metabolic programmes as an example, the present chapter looks at how reversible acetylation can be used to regulate important enzymes in an ever-changing cellular environment. C1 NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Scott, I (reprint author), NHLBI, Ctr Mol Med, NIH, Room 5-3216,Bldg 10 CRC,9000 Rockville Pike, Bethesda, MD 20892 USA. EM scotti@mail.nih.gov FU Intramural NIH HHS NR 27 TC 10 Z9 11 U1 0 U2 7 PU PORTLAND PRESS LTD PI LONDON PA 59 PORTLAND PL, LONDON W1N 3AJ, ENGLAND SN 0071-1365 BN 978-1-85578-185-6 J9 ESSAYS BIOCHEM JI Essays Biochem. PY 2012 VL 52 BP 13 EP 22 DI 10.1042/BSE0520013 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BDT10 UT WOS:000314729500003 PM 22708560 ER PT J AU Divekar, G Pradhan, AK Pollatsek, A Fisher, DL AF Divekar, Gautam Pradhan, Anuj Kumar Pollatsek, Alexander Fisher, Donald L. TI Effect of External Distractions Behavior and Vehicle Control of Novice and Experienced Drivers Evaluated SO TRANSPORTATION RESEARCH RECORD LA English DT Article ID PERCEPTION; RISK AB Distractions are a major contributor to automobile crashes, almost one-third of which are thought to be caused by distractions external to the vehicle. Increasingly, external distractions include video billboards, marquees, and variable message signs placed above and beside the highway. It is known that distractions outside the vehicle, especially video billboards, have effects on various vehicle control measures, such as the minimum headway distance to a braking lead vehicle, and that novice drivers and experienced drivers spend equally long times looking at distractions outside the vehicle. In contrast, experienced drivers are much less likely than novice drivers to take long glances at distractions inside the vehicle. This finding raises two questions. First, why are experienced drivers taking such long glances at an external distraction when they are not willing do so when a secondary task arises inside the vehicle? Second, if experienced drivers are sacrificing some of their ability to monitor visible hazards in the roadway ahead, are they sacrificing even more of their ability to anticipate unseen hazards? An experiment to evaluate these two questions had novice and experienced drivers perform an external search task (similar to reading a digital billboard) while driving in a simulator. Monitored throughout were eye movements of the participants and measures of the vehicle, such as lane position and speed. The major finding was that the long glances of both experienced and novice drivers came at the cost of identifying potential hidden hazards and seeing exposed moving threats. C1 [Divekar, Gautam] Univ Massachusetts, Dept Mech & Ind Engn, Amherst, MA 01033 USA. [Pollatsek, Alexander] Univ Massachusetts, Dept Psychol, Amherst, MA 01033 USA. [Fisher, Donald L.] Univ Massachusetts, Dept Mech & Ind Engn, Human Performance Lab, Amherst, MA 01033 USA. [Pradhan, Anuj Kumar] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Divekar, G (reprint author), Univ Massachusetts, Dept Mech & Ind Engn, Amherst, MA 01033 USA. EM gautamdivekar2000@gmail.com FU National Institutes of Health; National Science Foundation; Arbella Insurance Group Charitable Foundation FX Portions of this research were funded by grants from the National Institutes of Health, the National Science Foundation, and the Arbella Insurance Group Charitable Foundation. NR 16 TC 9 Z9 9 U1 4 U2 33 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0361-1981 J9 TRANSPORT RES REC JI Transp. Res. Record PY 2012 IS 2321 BP 15 EP 22 DI 10.3141/2321-03 PG 8 WC Engineering, Civil; Transportation; Transportation Science & Technology SC Engineering; Transportation GA 088TL UT WOS:000314859900004 ER PT J AU Glatz, M Degen, D French, LE Aberer, W Mullegger, RR AF Glatz, Martin Degen, Daniela French, Lars E. Aberer, Werner Muellegger, Robert R. TI Erysipelas of the Thigh and the Gluteal Region: Retrospective Multicenter Analysis of a Very Rare Entity in 39 Patients SO DERMATOLOGY LA English DT Article DE Erysipelas; Gluteal region; Thigh; Metabolic syndrome ID TOTAL HIP-REPLACEMENT; RISK-FACTORS; INCISIONAL CELLULITIS; RECURRENT ERYSIPELAS; BACTERIAL CELLULITIS; LEG; SKIN; MANAGEMENT; CARE AB Background: Erysipelas of the thigh and the gluteal region are rarely described and not well characterized. Therefore we aim to describe the prevalence, clinical characteristics, and risk factors of these erysipelas types. Methods:The files of 1,423 patients with erysipelas were analyzed. Data from patients with erysipelas of the thigh or the gluteal region were compared between the two groups and with a control group with erysipelas of the lower leg. Results: The thigh was exclusively affected in 2.1%, and the gluteal region in 0.6% of erysipelas patients. Gluteal erysipelas had conspicuous irregular borders and sometimes appeared bilaterally. Major risk factors for erysipelas of both sites were previous surgical interventions. Gluteal erysipelas was common in patients with the metabolic syndrome and required a more intense antibiotic therapy. Conclusion: Erysipelas of the thigh and the gluteal region are rare and significantly associated with prior surgical disruption of lymphatic vessels. copyright (C) 2012 S. Karger AG, Basel C1 [Glatz, Martin; French, Lars E.] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. [Degen, Daniela; Muellegger, Robert R.] State Hosp Wiener Neustadt, Dept Dermatol, Wiener Neustadt, Austria. [Aberer, Werner] Med Univ Graz, Dept Dermatol, Graz, Austria. RP Glatz, M (reprint author), NCI, Dermatol Branch, NIH, Bldg 10-12N260,10 Ctr Dr, Bethesda, MD 20892 USA. EM martin.glatz@nih.gov NR 38 TC 0 Z9 0 U1 1 U2 4 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1018-8665 J9 DERMATOLOGY JI Dermatology PY 2012 VL 225 IS 3 BP 277 EP 283 DI 10.1159/000345619 PG 7 WC Dermatology SC Dermatology GA 079SL UT WOS:000314192400014 PM 23257902 ER PT S AU Huang, JX Bluemke, DA Zhang, X Summers, RM Folio, LR Yao, JH AF Huang, Jiaxin Bluemke, David A. Zhang, Xiao Summers, Ronald M. Folio, Les R. Yao, Jianhua GP IEEE TI A Cross-Platform and Distributive Database System for Cumulative Tumor Measurement SO 2012 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 34th Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBS) CY AUG 28-SEP 01, 2012 CL San Diego, CA SP IEEE, Engn Med & Biol Soc (EMBS), CAS, SMC, PubMed, MEDLINE AB This paper discusses the development of a cross-platform, web accessible, vendor-independent database system capable of storing and comparing longitudinal tumor measurements for multiple tumors. This innovative system can create a comprehensive cumulative report that summarizes clinical findings and links to the original image studies, which will clinically enhance the workflow of oncologists. A case study on a pancreatic tumor data set with 524 tumor measurements and 134 patients is demonstrated. C1 [Huang, Jiaxin; Bluemke, David A.; Zhang, Xiao; Summers, Ronald M.; Folio, Les R.; Yao, Jianhua] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Yao, JH (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM jessica.huang@nih.gov; bluemked@nih.gov; zhangxn@cc.nih.gov; RSummers@cc.nih.gov; les.folio@nih.gov; jyao@cc.nih.gov OI Bluemke, David/0000-0002-8323-8086 NR 12 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4577-1787-1 J9 IEEE ENG MED BIO PY 2012 BP 1266 EP 1269 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BDH78 UT WOS:000313296501132 ER PT S AU Tan, S Yao, JH Yao, L Ward, MM AF Tan, Sovira Yao, Jianhua Yao, Lawrence Ward, Michael M. GP IEEE TI High Precision Semi-Automated Vertebral Height Measurement Using Computed Tomography: a Phantom Study SO 2012 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 34th Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBS) CY AUG 28-SEP 01, 2012 CL San Diego, CA SP IEEE, Engn Med & Biol Soc (EMBS), CAS, SMC, PubMed, MEDLINE ID MORPHOMETRY; IMAGES; CT AB The measurement of vertebral heights is necessary for the evaluation of many disorders affecting the spine. High precision is particularly important for longitudinal studies where subtle changes are to be detected. Computed tomography (CT) is the modality of choice for high precision studies. Radiography and dual emission X-ray absorptiometry (DXA) use 2D images to assess 3D structures, which can result in poor visualization due to the superimposition of extraneous anatomical objects on the same 2D space. We present a semi-automated computer algorithm to measure vertebral heights in the 3D space of a CT scan. The algorithm segments the vertebral bodies, extracts their end plates and computes vertebral heights as the mean distance between end plates. We evaluated the precision of our algorithm using repeat scans of an anthropomorphic vertebral phantom. Our method has high precision, with a coefficient of variation of only 0.197% and Bland-Altmann 95% limits of agreement of [-0.11, 0.13] mm. For local heights (anterior, middle, posterior) the algorithm was up to 4.2 times more precise than a manual mid-sagittal plane method. C1 [Tan, Sovira; Ward, Michael M.] NIAMSD, NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Tan, S (reprint author), NIAMSD, NIH, Ctr Clin, 10 Ctr Dr MSC 1182, Bethesda, MD 20892 USA. EM tanso@mail.nih.gov NR 11 TC 1 Z9 1 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4577-1787-1 J9 IEEE ENG MED BIO PY 2012 BP 1554 EP 1557 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BDH78 UT WOS:000313296501201 ER PT S AU Kim, J Stanley, CJ Curatalo, LA Park, HS AF Kim, Jonghyun Stanley, Christopher J. Curatalo, Lindsey A. Park, Hyung-Soon GP IEEE TI A User-driven Treadmill Control Scheme for Simulating Overground Locomotion SO 2012 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 34th Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBS) CY AUG 28-SEP 01, 2012 CL San Diego, CA SP IEEE, Engn Med & Biol Soc (EMBS), CAS, SMC, PubMed, MEDLINE ID WALKING; REHABILITATION; GAIT; FEEDBACK; INJURY; SPEED AB Treadmill-based locomotor training should simulate overground walking as closely as possible for optimal skill transfer. The constant speed of a standard treadmill encourages automaticity rather than engagement and fails to simulate the variable speeds encountered during real-world walking. To address this limitation, this paper proposes a user-driven treadmill velocity control scheme that allows the user to experience natural fluctuations in walking velocity with minimal unwanted inertial force due to acceleration/deceleration of the treadmill belt. A smart estimation limiter in the scheme effectively attenuates the inertial force during velocity changes. The proposed scheme requires measurement of pelvic and swing foot motions, and is developed for a treadmill of typical belt length (1.5m). The proposed scheme is quantitatively evaluated here with four healthy subjects by comparing it with the most advanced control scheme identified in the literature. C1 [Kim, Jonghyun; Stanley, Christopher J.; Curatalo, Lindsey A.; Park, Hyung-Soon] NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Park, HS (reprint author), NIH, Funct & Appl Biomech Sect, Dept Rehabil Med, Ctr Clin, 10 Ctr Dr,Room 1-1469, Bethesda, MD 20892 USA. EM jonghyun.kim@nih.gov; stanleycj@cc.nih.gov; lindsey.curatalo@nih.gov; parkhs@cc.nih.gov NR 14 TC 5 Z9 5 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4577-1787-1 J9 IEEE ENG MED BIO PY 2012 BP 3061 EP 3064 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BDH78 UT WOS:000313296503071 ER PT S AU Jaeger, S Karargyris, A Antani, S Thoma, G AF Jaeger, Stefan Karargyris, Alexandros Antani, Sameer Thoma, George GP IEEE TI Detecting Tuberculosis in Radiographs Using Combined Lung Masks SO 2012 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 34th Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBS) CY AUG 28-SEP 01, 2012 CL San Diego, CA SP IEEE, Engn Med & Biol Soc (EMBS), CAS, SMC, PubMed, MEDLINE ID CHEST RADIOGRAPHS; SEGMENTATION; CLASSIFICATION; DATABASE; NODULES; IMAGES AB Tuberculosis (TB) is a major health threat in many regions of the world, while diagnosing tuberculosis still remains a challenge. Mortality rates of patients with undiagnosed TB are high. Modern diagnostic techniques are often too slow or too expensive for highly-populated developing countries that bear the brunt of the disease. In an effort to reduce the burden of the disease, this paper presents an automated approach for detecting TB on conventional posteroanterior chest radiographs. The idea is to provide developing countries, which have limited access to radiological services and radiological expertise, with an inexpensive detection system that allows screening of large parts of the population in rural areas. In this paper, we present results produced by our TB screening system. We combine a lung shape model, a segmentation mask, and a simple intensity model to achieve a better segmentation mask for the lung. With the improved masks, we achieve an area under the ROC curve of more than 83%, measured on data compiled within a tuberculosis control program. C1 [Jaeger, Stefan; Karargyris, Alexandros; Antani, Sameer; Thoma, George] NIH, Natl Lib Med, Bethesda, MD 20894 USA. RP Jaeger, S (reprint author), NIH, Natl Lib Med, Bethesda, MD 20894 USA. EM stefan.jaeger@nih.gov; alexandros.karargyris@nih.gov; sameer.antani@nih.gov; george.thoma@nih.gov OI Antani, Sameer/0000-0002-0040-1387 NR 24 TC 8 Z9 8 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4577-1787-1 J9 IEEE ENG MED BIO PY 2012 BP 4978 EP 4981 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BDH78 UT WOS:000313296505048 ER PT S AU Liu, YX Nacif, MS Liu, ST Sibley, CT Bluemke, DA Summers, RM Yao, JH AF Liu, Yixun Nacif, Marcelo Souto Liu, Songtao Sibley, Christopher T. Bluemke, David A. Summers, Ronald M. Yao, Jianhua GP IEEE TI Point-Guided Modeling and Segmentation of Myocardium for Low Dose Cardiac CT Images SO 2012 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) SE IEEE Engineering in Medicine and Biology Society Conference Proceedings LA English DT Proceedings Paper CT 34th Annual International Conference of the IEEE Engineering-in-Medicine-and-Biology-Society (EMBS) CY AUG 28-SEP 01, 2012 CL San Diego, CA SP IEEE, Engn Med & Biol Soc (EMBS), CAS, SMC, PubMed, MEDLINE ID HEART; MR AB Cardiac CT is emerging as a preferable modality to detect myocardial stress/rest perfusion; however the insufficient contrast of myocardium on CT image makes its segmentation difficult. In this paper, we present a point-guided modeling and deformable model-based segmentation method. This method first builds a triangular surface model of myocardium through Bezier contour fitting based on a few points selected by clinicians. Then, a deformable model-based segmentation method is developed to refine the segmentation result. The experiments on 8 cases show the accuracy of the segmentation in terms of true positive volume fraction, false positive volume fractions, and average surface distance can reach 91.0%, 0.3%, and 0.6mm, respectively. The comparison between the proposed method and a graph cut-based method is performed. The results demonstrate that this method is effective in improving the accuracy further. C1 [Liu, Yixun; Nacif, Marcelo Souto; Liu, Songtao; Sibley, Christopher T.; Bluemke, David A.; Summers, Ronald M.; Yao, Jianhua] NIH, Bethesda, MD 20892 USA. RP Liu, YX (reprint author), NIH, Bethesda, MD 20892 USA. EM yixun.liu@nih.gov; JYao@cc.nih.gov OI Bluemke, David/0000-0002-8323-8086 NR 9 TC 2 Z9 2 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1557-170X BN 978-1-4577-1787-1 J9 IEEE ENG MED BIO PY 2012 BP 5327 EP 5330 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BDH78 UT WOS:000313296505134 ER PT J AU Anthenelli, R Grandison, L AF Anthenelli, Robert Grandison, Lindsey TI Effects of Stress on Alcohol Consumption SO ALCOHOL RESEARCH-CURRENT REVIEWS LA English DT Editorial Material C1 [Anthenelli, Robert] San Diego Healthcare Syst, Mental Hlth, Vet Affairs, San Diego, CA USA. [Anthenelli, Robert] Univ Calif San Diego, Sch Med, Dept Psychiat, Pacific Treatment & Res Ctr, San Diego, CA 92103 USA. [Grandison, Lindsey] NIAAA, Div Neurosci & Behav, Bethesda, MD USA. RP Anthenelli, R (reprint author), San Diego Healthcare Syst, Mental Hlth, Vet Affairs, San Diego, CA USA. NR 1 TC 4 Z9 4 U1 1 U2 7 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 1535-7414 J9 ALCOHOL RES-CURR REV JI Alcohol Res.-Curr. Rev. PY 2012 VL 34 IS 4 BP 381 EP 382 PG 2 WC Substance Abuse SC Substance Abuse GA 066QB UT WOS:000313234200001 PM 23729049 ER PT J AU Keyes, KM Hatzenbuehler, ML Grant, BF Hasin, DS AF Keyes, K. M. Hatzenbuehler, M. L. Grant, Bridget F. Hasin, Deborah S. TI Stress and Alcohol Epidemiologic Evidence SO ALCOHOL RESEARCH-CURRENT REVIEWS LA English DT Article DE Alcohol use and abuse; alcohol use disorders; stress; stress as a cause of alcohol and other drug use; risk factors; psychological stress; stress response; coping; stressors; general life stress; catastrophe; child abuse; minority group; epidemiological indicators ID NATIONAL-COMORBIDITY-SURVEY; CHILDHOOD SEXUAL-ABUSE; POSTDISASTER PSYCHIATRIC-DISORDERS; SUBSTANCE USE DISORDERS; MENTAL-HEALTH PROBLEMS; UNITED-STATES; DRUG-USE; DRINKING BEHAVIOR; TERRORIST ATTACKS; OKLAHOMA-CITY AB Exposure to stress often is psychologically distressing. The impact of stress on alcohol use and the risk of alcohol use disorders (AUDs) depends on the type, timing during the life course, duration, and severity of the stress experienced. Four important categories of stressors that can influence alcohol consumption are general life stress, catastrophic/fateful stress, childhood maltreatment, and minority stress. General life stressors, including divorce and job loss, increase the risk for AUDs. Exposure to terrorism or other disasters causes population-level increases in overall alcohol consumption but little increase in the incidence of AUDs. However, individuals with a history of AUDs are more likely to drink to cope with the traumatic event. Early onset of drinking in adolescence, as well as adult AUDs, are more common among people who experience childhood maltreatment. Finally, both perceptions and objective indicators of discrimination are associated with alcohol use and AUDs among racial/ethnic and sexual minorities. These observations demonstrate that exposure to stress in many forms is related to subsequent alcohol consumption and AUDs. However, many areas of this research remain to be studied, including greater attention to the role of various stressors in the course of AUDs and potential risk moderators when individuals are exposed to stressors. C1 [Keyes, K. M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10027 USA. [Keyes, K. M.; Hasin, Deborah S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Hatzenbuehler, M. L.] Columbia Univ, Mailman Sch Publ Hlth, Ctr Study Social Inequal Hlth, New York, NY USA. [Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Bethesda, MD USA. [Hasin, Deborah S.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. RP Keyes, KM (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10027 USA. FU NIAAA NIH HHS [K05 AA014223, K05-AA-014223, U01 AA018111, U01-AA-018111]; NIDA NIH HHS [F31 DA026689, F31-DA-026689] NR 123 TC 33 Z9 34 U1 9 U2 31 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 1535-7414 J9 ALCOHOL RES-CURR REV JI Alcohol Res.-Curr. Rev. PY 2012 VL 34 IS 4 BP 391 EP 400 PG 10 WC Substance Abuse SC Substance Abuse GA 066QB UT WOS:000313234200003 PM 23584105 ER PT J AU Klatt, NR Silvestri, G Hirsch, V AF Klatt, Nichole R. Silvestri, Guido Hirsch, Vanessa TI Nonpathogenic Simian Immunodeficiency Virus Infections SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID AFRICAN-GREEN MONKEYS; T-CELL DEPLETION; NONHUMAN PRIMATE HOSTS; CROSS-SPECIES TRANSMISSION; NATURAL SIV HOSTS; SOOTY MANGABEYS; HIV-INFECTION; MANDRILLUS-SPHINX; AIDS PATHOGENESIS; NONPANDEMIC HIV-1 AB The simian immunodeficiency viruses (SIVs) are a diverse group of viruses that naturally infect a wide range of African primates, including African green monkeys (AGMs) and sooty mangabey monkeys (SMs). Although natural infection is widespread in feral populations of AGMs and SMs, this infection generally does not result in immunodeficiency. However, experimental inoculation of Asian macaques results in an immunodeficiency syndrome remarkably similar to human AIDS. Thus, natural nonprogressive SIV infections appear to represent an evolutionary adaptation between these animals and their primate lentiviruses. Curiously, these animals maintain robust virus replication but have evolved strategies to avoid disease progression. Adaptations observed in these primates include phenotypic changes to CD4(+) T cells, limited chronic immune activation, and altered mucosal immunity. It is probable that these animals have achieved a unique balance between T-cell renewal and proliferation and loss through activation-induced apoptosis, and virus-induced cell death. A clearer understanding of the mechanisms underlying the lack of disease progression in natural hosts for SIV infection should therefore yield insights into the pathogenesis of AIDS and may inform vaccine design. C1 [Klatt, Nichole R.; Hirsch, Vanessa] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Silvestri, Guido] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Silvestri, Guido] Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. RP Hirsch, V (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM vhirsch@niaid.nih.gov NR 104 TC 24 Z9 25 U1 2 U2 7 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD JAN PY 2012 VL 2 IS 1 AR a007153 DI 10.1101/cshperspect.a007153 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 080JX UT WOS:000314239200008 PM 22315718 ER PT J AU Rasku, J Pyykko, I Juhola, M Garcia, M Harris, T Launer, L Eiriksdottir, G Siggeirsdottir, K Jonsson, P Hoffman, HJ Petersen, H Rasmussen, C Caserotti, P Toppila, E Pajala, S Gudnason, V AF Rasku, Jyrki Pyykko, Ilmari Juhola, Martti Garcia, Melissa Harris, Tamara Launer, Lenore Eiriksdottir, Gudny Siggeirsdottir, Kristin Jonsson, Palmi Hoffman, Howard J. Petersen, Hannes Rasmussen, Cuno Caserotti, Paolo Toppila, Esko Pajala, Satu Gudnason, Vilmundur TI Evaluation of the postural stability of elderly persons using time domain signal analysis SO JOURNAL OF VESTIBULAR RESEARCH-EQUILIBRIUM & ORIENTATION LA English DT Article DE Force platform; postural control; variable; correlation; factor analysis ID BODY-SWAY; COMPUTERIZED POSTUROGRAPHY; BALANCE; STIMULATION; STIFFNESS; RISK; AGE AB A force platform is widely used in the evaluation of postural stability in man. Although an abundance of parameters are typically retrieved from force platform data, no uniform analysis of the data has been carried out. In general, the signal analysis does not analyze the underlying postural event, i.e., whether the signal consists of several small corrections or large excursions. In the present work, we studied the postural stability of 4589 elderly persons from Iceland on a force platform under visual and non-visual conditions during stance on a solid surface. We analyzed the internal relationship between frequently used time domain variables. In addition, we conducted a factor analysis using a subset of selected variables. Factor analysis yielded three components that can be considered different strategies for maintaining posture. In one control strategy, long swaying amplitues were pronounced, allowing the person to react when postural confidence limits are reached. In a second strategy, a high oscillation rate about the stationary point was the dominant characteristic of maintaining postural control. The third strategy appears to involve a short critical time period during which an open loop control changes into a closed loop that very rapidly controls excessive postural oscillations. The findings suggest that conventional parameters such as swaying velocity and amplitude alone do not provide sufficient information regarding a person's ability to maintain an upright stance. C1 [Rasku, Jyrki; Pyykko, Ilmari] Tampere Univ Hosp, Dept Otorhinolaryngol, Tampere, Finland. [Juhola, Martti] Univ Tampere, Dept Comp Sci, FIN-33101 Tampere, Finland. [Garcia, Melissa; Harris, Tamara; Launer, Lenore; Caserotti, Paolo] Natl Inst Ageing, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. [Eiriksdottir, Gudny; Siggeirsdottir, Kristin; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Jonsson, Palmi] Landspitali Univ Hosp, Dept Geriatr, Reykjavik, Iceland. [Jonsson, Palmi] Univ Iceland, Fac Med, Reykjavik, Iceland. [Hoffman, Howard J.] Nat Inst Deafness & Other Commun Disorders, Bethesda, MD USA. [Petersen, Hannes] Landspitali Univ Hosp, Dept Anat & Otorhinolaryngol, Reykjavik, Iceland. [Rasmussen, Cuno] Univ Aarhus, Dept Sport Sci, Aarhus, Denmark. [Toppila, Esko] Inst Occupat Hlth, Helsinki, Finland. [Pajala, Satu] Fac Sport & Hlth Sci, Jyvaskyla, Finland. RP Rasku, J (reprint author), Tampere Univ Hosp, Dept Otorhinolaryngol, Tampere, Finland. EM jyrki.rasku@uta.fi RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 FU PSHP [9L080, 9M083] FX This work is funded by PSHP projects 9L080 and 9M083. NR 24 TC 2 Z9 2 U1 0 U2 2 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0957-4271 J9 J VESTIBUL RES-EQUIL JI J. Vestib. Res.-Equilib. Orientat. PY 2012 VL 22 IS 5-6 BP 243 EP 252 DI 10.3233/VES-120465 PG 10 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 071AQ UT WOS:000313558000003 PM 23302705 ER PT J AU Bennett, CN Tomlinson, CC Michalowski, AM Chu, IM Luger, D Mittereder, LR Aprelikova, O Shou, J Piwinica-Worms, H Caplen, NJ Hollingshead, MG Green, JE AF Bennett, Christina N. Tomlinson, Christine C. Michalowski, Aleksandra M. Chu, Isabel M. Luger, Dror Mittereder, Lara R. Aprelikova, Olga Shou, James Piwinica-Worms, Helen Caplen, Natasha J. Hollingshead, Melinda G. Green, Jeffrey E. TI Cross-species genomic and functional analyses identify a combination therapy using a CHK1 inhibitor and a ribonucleotide reductase inhibitor to treat triple-negative breast cancer SO BREAST CANCER RESEARCH LA English DT Article ID TRANSGENIC MOUSE MODEL; DNA-DAMAGE RESPONSE; TUMOR-SUPPRESSOR; PROTEIN-KINASE; CELL-LINES; BASAL-LIKE; CARCINOMAS; SURVIVAL; SUBTYPES; UCN-01 AB Introduction: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is diagnosed in approximately 15% of all human breast cancer (BrCa) patients. Currently, no targeted therapies exist for this subtype of BrCa and prognosis remains poor. Our laboratory has previously identified a proliferation/DNA repair/cell cycle gene signature (Tag signature) that is characteristic of human TNBC. We hypothesize that targeting the dysregulated biological networks in the Tag gene signature will lead to the identification of improved combination therapies for TNBC. Methods: Cross-species genomic analysis was used to identify human breast cancer cell lines that express the Tag signature. Knock-down of the up-regulated genes in the Tag signature by siRNA identified several genes that are critical for TNBC cell growth. Small molecule inhibitors to two of these genes were analyzed, alone and in combination, for their effects on cell proliferation, cell cycle, and apoptosis in vitro and tumor growth in vivo. Synergy between the two drugs was analyzed by the Chou-Talalay method. Results: A custom siRNA screen was used to identify targets within the Tag signature that are critical for growth of TNBC cells. Ribonucleotide reductase 1 and 2 (RRM1 and 2) and checkpoint kinase 1 (CHK1) were found to be critical targets for TNBC cell survival. Combination therapy, to simultaneously attenuate cell cycle checkpoint control through inhibition of CHK1 while inducing DNA damage with gemcitabine, improved therapeutic efficacy in vitro and in xenograft models of TNBC. Conclusions: This combination therapy may have translational value for patients with TNBC and improve therapeutic response for this aggressive form of breast cancer. C1 [Bennett, Christina N.; Tomlinson, Christine C.; Michalowski, Aleksandra M.; Chu, Isabel M.; Luger, Dror; Mittereder, Lara R.; Aprelikova, Olga; Shou, James; Green, Jeffrey E.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Piwinica-Worms, Helen] Washington Univ, BRIGHT Inst, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. [Piwinica-Worms, Helen] Washington Univ, BRIGHT Inst, Dept Internal Med, St Louis, MO 63110 USA. [Caplen, Natasha J.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Hollingshead, Melinda G.] NCI, Biol Testing Branch, NIH, Frederick, MD 21702 USA. RP Green, JE (reprint author), NCI, Lab Canc Biol & Genet, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM jegreen@mail.nih.gov RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 FU Intramural Research Program of the NIH, CCR, NCI; Komen Foundation [KG081551] FX We would like to thank Peter Blumberg for useful discussions and critical reading of the manuscript, Chang Hee Kim for generating the microarray data, and Kelly Dougherty and John Carter for technical assistance with the animal studies. We also thank Barbara J. Taylor for assistance in performing FACS analyses. This research was supported in part by the Intramural Research Program of the NIH, CCR, NCI and by a grant from the Komen Foundation (KG081551) to H.P.W. NR 32 TC 13 Z9 14 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X J9 BREAST CANCER RES JI Breast Cancer Res. PY 2012 VL 14 IS 4 AR R109 DI 10.1186/bcr3230 PG 16 WC Oncology SC Oncology GA 065ZP UT WOS:000313189600012 PM 22812567 ER PT J AU Lazzeroni, M Serrano, D Dunn, BK Heckman-Stoddard, BM Lee, O Khan, S Decensi, A AF Lazzeroni, Matteo Serrano, Davide Dunn, Barbara K. Heckman-Stoddard, Brandy M. Lee, Oukseub Khan, Seema Decensi, Andrea TI Oral low dose and topical tamoxifen for breast cancer prevention: modern approaches for an old drug SO BREAST CANCER RESEARCH LA English DT Review ID SURGICAL ADJUVANT BREAST; GROWTH-FACTOR-I; C-REACTIVE PROTEIN; BOWEL PROJECT P-1; POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; ESTROGEN-RECEPTOR; ENDOCRINE THERAPY; RANDOMIZED-TRIAL; HEALTHY WOMEN AB Tamoxifen is a drug that has been in worldwide use for the treatment of estrogen receptor (ER)-positive breast cancer for over 30 years; it has been used in both the metastatic and adjuvant settings. Tamoxifen's approval for breast cancer risk reduction dates back to 1998, after results from the Breast Cancer Prevention Trial, co-sponsored by the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project, showed a 49% reduction in the incidence of invasive, ER-positive breast cancer in high-risk women. Despite these positive findings, however, the public's attitude toward breast cancer chemoprevention remains ambivalent, and the toxicities associated with tamoxifen, particularly endometrial cancer and thromboembolic events, have hampered the drug's uptake by high-risk women who should benefit from its preventive effects. Among the strategies to overcome such obstacles to preventive tamoxifen, two novel and potentially safer modes of delivery of this agent are discussed in this paper. Low-dose tamoxifen, expected to confer fewer adverse events, is being investigated in both clinical biomarker-based trials and observational studies. A series of systemic biomarkers (including lipid and insulin-like growth factor levels) and tissue biomarkers (including Ki-67) are known to be favorably affected by conventional tamoxifen dosing and have been shown to be modulated in a direction consistent with a putative anti-cancer effect. These findings suggest possible beneficial clinical preventive effects by low-dose tamoxifen regimens and they are supported by observational studies. An alternative approach is topical administration of active tamoxifen metabolites directly onto the breast, the site where the cancer is to be prevented. Avoidance of systemic administration is expected to reduce the distribution of drug to tissues susceptible to tamoxifen-induced toxicity. Clinical trials of topical tamoxifen with biological endpoints are still ongoing whereas pharmacokinetic studies have already shown that appropriate formulations of drug successfully penetrate the skin to reach breast tissue, where a preventive effect is sought. C1 [Lazzeroni, Matteo; Serrano, Davide; Decensi, Andrea] European Inst Oncol, Canc Prevent Div, I-20141 Milan, Italy. [Lazzeroni, Matteo; Serrano, Davide; Decensi, Andrea] European Inst Oncol, Div Genet, I-20141 Milan, Italy. [Dunn, Barbara K.; Heckman-Stoddard, Brandy M.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Lee, Oukseub; Khan, Seema] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Dept Surg, Chicago, IL 60611 USA. [Decensi, Andrea] EO Osped Galliera, Div Med Oncol, I-16128 Genoa, Italy. RP Lazzeroni, M (reprint author), European Inst Oncol, Canc Prevent Div, I-20141 Milan, Italy. EM matteo.lazzeroni@ieo.it OI Lazzeroni, Matteo/0000-0002-2162-4002 NR 77 TC 18 Z9 19 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X J9 BREAST CANCER RES JI Breast Cancer Res. PY 2012 VL 14 IS 5 AR 214 DI 10.1186/bcr3233 PG 11 WC Oncology SC Oncology GA 066AQ UT WOS:000313192400004 PM 23106852 ER PT J AU Stolzenberg-Solomon, RZ Falk, RT Stanczyk, F Hoover, RN Appel, LJ Ard, JD Batch, BC Coughlin, J Han, X Lien, LF Pinkston, CM Svetkey, LP Katki, HA AF Stolzenberg-Solomon, Rachael Z. Falk, Roni T. Stanczyk, Frank Hoover, Robert N. Appel, Lawrence J. Ard, Jamy D. Batch, Bryan C. Coughlin, Janelle Han, Xu Lien, Lillian F. Pinkston, Christina M. Svetkey, Laura P. Katki, Hormuzd A. TI Sex hormone changes during weight loss and maintenance in overweight and obese postmenopausal African-American and non-African-American women SO BREAST CANCER RESEARCH LA English DT Article ID BREAST-CANCER RISK; RANDOMIZED CONTROLLED-TRIAL; BINDING GLOBULIN; SERUM ANDROGENS; CLINICAL-TRIAL; ENDOGENOUS HORMONES; MULTIETHNIC COHORT; PHYSICAL-EXERCISE; BODY-FAT; ESTROGEN AB Introduction: Changes in sex hormones with weight loss might have implications for breast cancer prevention but have not been examined extensively, particularly in African-American (AA) women. Methods: We conducted a prospective study of 278 overweight/obese postmenopausal women (38% AA) not taking hormone therapy within the Weight Loss Maintenance Trial. All participants lost at least 4 kg after a 6-month weight-loss phase and attempted to maintain weight loss during the subsequent 12 months. We evaluated the percentage changes in estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate and sex hormone-binding globulin (SHBG) using generalized estimating equations. Results: In all study phases, AA women had higher levels of estrogen and testosterone concentrations, independent of adiposity. On average, participants lost 7.7 kg during the weight-loss phase, and concentrations of estrone (-5.7%, P = 0.006), estradiol (-9.9%, P < 0.001), free estradiol (-13.4%, P < 0.0001), and free testosterone (-9.9%, P < 0.0001) decreased, while the SHBG concentration (16.2%, P < 0.001) increased. Weight change did not significantly affect total testosterone or other androgen concentrations. Compared with non-AA women, AA women experienced less change in estrogens per kilogram of weight change (that is, per 1 kg weight loss: estrone, -0.6% vs. -1.2%, P-interaction = 0.10; estradiol, -1.1% vs. -1.9%, P-interaction = 0.04; SHBG, 0.9% vs. 1.6%, P-interaction = 0.006; free estradiol, -1.4% vs. -2.1%, P-interaction = 0.01). Conclusion: To the best of our knowledge this is the first study to examine and compare the effects of intentional weight loss and maintenance on a panel of sex hormones in AA women and non-AA women. Although speculative, these data suggest hormonal differences may contribute to different racial patterns of breast cancer incidence and mortality and encourage further investigations to understand the long-term effects of weight loss on sex hormones in obese postmenopausal women. C1 [Stolzenberg-Solomon, Rachael Z.; Falk, Roni T.; Hoover, Robert N.; Han, Xu; Pinkston, Christina M.; Katki, Hormuzd A.] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD 20854 USA. [Stanczyk, Frank] Reprod Endocrine Res Lab, Los Angeles, CA 90033 USA. [Appel, Lawrence J.] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21287 USA. [Ard, Jamy D.] Wake Forest Univ, Baptist Med Ctr, Maya Angelou Ctr Hlth Equ, Winston Salem, NC 27157 USA. [Batch, Bryan C.] Duke Univ, Med Ctr, Div Endocrinol Metab & Nutr, Durham, NC 27710 USA. [Coughlin, Janelle] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Lien, Lillian F.] Duke Univ, Med Ctr, Sarah Stedman Nutr & Metab Ctr, Div Metab Endocrinol & Nutr, Durham, NC 27710 USA. [Svetkey, Laura P.] Duke Hypertens Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27705 USA. RP Stolzenberg-Solomon, RZ (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, 6120 Execut Blvd, Rockville, MD 20854 USA. EM rs221z@nih.gov RI Katki, Hormuzd/B-4003-2015 FU National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services FX The authors acknowledge the contributions of all WLM investigators and staff in conducting the parent WLM and thereby making this ancillary study possible. They also acknowledge Dr Thomas Erlinger for his assistance with the study concept and collecting the data, and Dr Sihui Zhao for his assistance with the statistical analysis. This research was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services NR 56 TC 3 Z9 3 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X J9 BREAST CANCER RES JI Breast Cancer Res. PY 2012 VL 14 IS 5 AR R141 DI 10.1186/bcr3346 PG 11 WC Oncology SC Oncology GA 066AQ UT WOS:000313192400029 PM 23113944 ER PT J AU Switzer, CH Cheng, RYS Ridnour, LA Glynn, SA Ambs, S Wink, DA AF Switzer, Christopher H. Cheng, Robert Y-S Ridnour, Lisa A. Glynn, Sharon A. Ambs, Stefan Wink, David A. TI Ets-1 is a transcriptional mediator of oncogenic nitric oxide signaling in estrogen receptor-negative breast cancer SO BREAST CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION; BASAL-LIKE; CELL PROLIFERATION; POOR SURVIVAL; LUNG-CANCER; KINASE; RAS; PATHWAY; GROWTH; INVASION AB Introduction: The Ets-1 transcription factor is a candidate breast cancer oncogene that regulates the expression of genes involved in tumor progression and metastasis. Ets-1 signaling has also been linked to the development of a basal-like breast cancer phenotype. We recently described a nitric oxide (NO)-induced gene signature that is associated with poor disease outcome in estrogen receptor-negative (ER-) breast cancer and contains both stem cell-like and basal-like components. Thus, we examined the role of Ets-1 in NO signaling and NO-induced phenotypes in ER- human breast cancer cells. Methods: Promoter region analyses were performed on genes upregulated in inducible nitric oxide synthase (NOS2) high expressing tumors for Ets-binding sites. In vitro mechanisms were examined in human basal-like breast cancer cells lines. NO signaling effects were studied using either forced NOS2 expression or the use of a chemical NO-donor, diethlylenetriamine NONOate (DETANO). Results: Promoter region analysis of genes that are up-regulated in human ER-negative breast tumors with high NOS2 expression revealed that the Ets-binding sequence is the only common promoter element present in all of these genes, indicating that Ets-1 is the key transcriptional factor down-stream of oncogenic NOS2-signaling. Accordingly, both forced NOS2 over-expression and exposure to NO-donors resulted in significant Ets-1 transcriptional activation in ER- breast cancer cells. Functional studies showed that NO activated Ets-1 transcriptional activity via a Ras/MEK/ERK signaling pathway by a mechanism that involved Ras S-nitrosylation. RNA knock-down of Ets-1 suppressed NO-induced expression of selected basal-like breast cancer markers such as P-cadherin, S100A8, IL-8 and alpha beta-crystallin. Additionally, Ets-1 knock-down reduced NO-mediated cellular proliferation, matrix metalloproteinase and cathepsin B activities, as well as matrigel invasion. Conclusions: These data show that Ets-1 is a key transcriptional mediator of oncogenic NO signaling that promotes the development of an aggressive disease phenotype in ER- breast cancer in an Ets-1 and Ras-dependent manner, providing novel clues of how NOS2 expression in human breast tumors is functionally linked to poor patient survival. C1 [Switzer, Christopher H.; Cheng, Robert Y-S; Ridnour, Lisa A.; Glynn, Sharon A.; Wink, David A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Glynn, Sharon A.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Glynn, Sharon A.] Natl Univ Ireland Galway, Prostate Canc Inst, Galway, Ireland. RP Switzer, CH (reprint author), NCI, Radiat Biol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM switzerc@mail.nih.gov RI Glynn, Sharon/D-7136-2013; Switzer, Christopher/D-9203-2013; OI Glynn, Sharon/0000-0003-1459-2580; Cheng, Robert/0000-0003-0287-6439 FU NIH, National Cancer Institute FX The authors thank Dr. Atsushi Terunuma (NCI, NIH) for assistance with genetic analyses. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 60 TC 27 Z9 29 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X J9 BREAST CANCER RES JI Breast Cancer Res. PY 2012 VL 14 IS 5 AR R125 DI 10.1186/bcr3319 PG 13 WC Oncology SC Oncology GA 066AQ UT WOS:000313192400013 PM 22971289 ER PT J AU Albright, KC Savitz, SI Raman, R Martin-Schild, S Broderick, J Ernstrom, K Ford, A Khatri, R Kleindorfer, D Liebeskind, D Marshall, R Merino, JG Meyer, DM Rost, N Meyer, BC AF Albright, Karen C. Savitz, Sean I. Raman, Rema Martin-Schild, Sheryl Broderick, Joseph Ernstrom, Karin Ford, Andria Khatri, Rakesh Kleindorfer, Dawn Liebeskind, David Marshall, Randolph Merino, Jose G. Meyer, Dawn M. Rost, Natalia Meyer, Brett C. CA SPOTRIAS Investigators TI Comprehensive Stroke Centers and the 'Weekend Effect': The SPOTRIAS Experience SO CEREBROVASCULAR DISEASES LA English DT Article DE The 'weekend effect'; Acute stroke; Organized stroke care ID CASE-FATALITY; WEEKDAY ADMISSION; MORTALITY; LENGTH; IMPACT; UNITS; STAY; TIME AB Background and Purpose: Previous studies have found mortality among ischemic stroke patients to be higher on weekends. We sought to evaluate whether weekend admission was associated with worse outcomes in a large comprehensive stroke center (CSC) cohort. Methods: Consecutive ischemic stroke patients presenting within 6 h of symptom onset were identified using the 8 CSC SPOTRIAS (Specialized Programs of Translational Research in Acute Stroke) database. Patients who received intra-arterial therapy or who were enrolled in a nonobservational clinical trial were excluded. All patients meeting the inclusion criteria were then divided into two groups: weekday admissions or weekend admissions. Weekend admission was defined as Friday 17: 01 to Monday 08:59. The remainder were classified as weekday admissions. Multivariate logistic regression was used, adjusting for age, stroke severity on admission [according to the National Institutes of Health Stroke Scale (NIHSS)] and admission glucose, in order to compare the outcomes of the weekend versus the weekday groups. Results: Eight thousand five hundred and eighty-one subjects from the combined SPOTRIAS database were screened from 2002 to 2009; 2,090 (24.4%) of these met the inclusion criteria. There was no significant difference in tissue plasminogen activator treatment rates between the weekday and weekend groups (58.5 vs. 60.4%, p = 0.397). Weekend admission was not a significant independent predictor of inhospital mortality (8.4 vs. 9.9%, p = 0.056), length of stay (4 vs. 5 days, p = 0.442), favorable discharge disposition (38.0 vs. 42.2%, p = 0.122), favorable functional outcome at discharge (41.6 vs. 43.4%, p = 0.805), favorable 90-day functional outcome (54.2 vs. 46.9%, p = 0.301), or 90-day mortality (18.2 vs. 19.8%, p = 0.680) when adjusting for age, NIHSS and admission glucose. Conclusions: In this large cohort of ischemic stroke patients treated at CSCs, we did not observe the 'weekend effect.' This may be due to access to stroke specialists 24 h a day on 365 days a year, nurses with stroke experience and the organized system for delivering care that is available at CSCs. These results suggest that EMS protocol should be reexamined regarding the preferential delivery of weekend stroke victims to hospitals that provide all levels of reperfusion therapy. This further highlights the importance of organized stroke care. Copyright (C) 2012 S. Karger AG, Basel C1 [Albright, Karen C.] Univ Alabama Birmingham, Hlth Serv, Birmingham, AL USA. [Albright, Karen C.] Univ Alabama Birmingham, Ctr Outcome & Effectiveness Res & Educ, Birmingham, AL USA. [Albright, Karen C.] Univ Alabama Birmingham, Ctr Excellence Comparat Effectiveness Res Elimina, Minor Hlth & Hlth Dispar Res Ctr, Birmingham, AL USA. [Albright, Karen C.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Albright, Karen C.] Univ Alabama Birmingham, Dept Neurol, Sch Med, Birmingham, AL 35294 USA. [Savitz, Sean I.] Univ Texas Houston, Dept Neurol, Houston, TX USA. [Raman, Rema; Ernstrom, Karin] Univ Calif San Diego, Div Biostat & Bioinformat, Dept Family & Prevent Med, San Diego, CA USA. [Meyer, Dawn M.; Meyer, Brett C.] Univ Calif San Diego, Dept Neurosci, San Diego, CA USA. [Martin-Schild, Sheryl] Tulane Univ, Sch Med, Dept Neurol, New Orleans, LA 70112 USA. [Broderick, Joseph; Khatri, Rakesh; Kleindorfer, Dawn] Univ Cincinnati, Dept Neurol, Cincinnati, OH USA. [Ford, Andria] Washington Univ, Sch Med, Dept Neurol, Cerebrovasc Dis Sect, St Louis, MO 63110 USA. [Liebeskind, David] Univ Calif Los Angeles, Stroke Ctr, Los Angeles, CA USA. [Marshall, Randolph] Columbia Univ, Med Ctr, New York, NY USA. [Merino, Jose G.] Natl Inst Neurol Disorders & Stroke, Sect Stroke Diag & Therapeut, NIH, Bethesda, MD USA. [Rost, Natalia] Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Boston, MA 02114 USA. RP Albright, KC (reprint author), RWUH M226,619 19th St S, Birmingham, AL 35249 USA. EM kca@uab.edu FU Intramural Research Program of the NINDS, NIH; Agency for Healthcare Research and Quality (AHRQ) [5 T32 HS013852-10]; National Institute on Minority Health and Health Disparities, NIH [3 P60 MD000502-08S1]; [P50 NS044227] FX The authors would like to thank Patrick D. Lyden, MD, for his invaluable assistance with study design, interpretation of data and critical revision of the manuscript and Sharyl Martini, MD, PhD for her support and assistance. The study was supported by P50 NS044227. The research was supported, in part, by the Intramural Research Program of the NINDS, NIH as well as by Award Nos. 5 T32 HS013852-10 from The Agency for Healthcare Research and Quality (AHRQ) and 3 P60 MD000502-08S1 from The National Institute on Minority Health and Health Disparities, NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the AHRQ or the NIH. NR 21 TC 24 Z9 24 U1 0 U2 4 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1015-9770 J9 CEREBROVASC DIS JI Cerebrovasc. Dis. PY 2012 VL 34 IS 5-6 BP 424 EP 429 DI 10.1159/000345077 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 072GA UT WOS:000313656300014 PM 23207423 ER PT J AU Nandurdikar, RS Kaliappan, KP AF Nandurdikar, Rahul S. Kaliappan, Krishna P. TI Recent Developments on Domino Metathesis Reactions in India SO CHIMIA LA English DT Article DE Domino reactions; Enyne metathesis; IMDA; Metathesis reactions; RCM ID RING-CLOSING METATHESIS; MEDIUM-SIZED RINGS; OLEFIN-METATHESIS; ORGANIC-SYNTHESIS; ENYNE METATHESIS; ROM-RCM; NORBORNENE DERIVATIVES; CARBOHYDRATE-CHEMISTRY; ILLICIUM-MERRILLIANUM; ANISLACTONE-B AB This review summarizes research work carried out in India on domino metathesis reactions using ruthenium-carbene complexes. This reaction has been widely used by synthetic chemists in India for the synthesis of polycyclic systems and complex molecular architectures. C1 [Nandurdikar, Rahul S.] ETH, Zurich, Switzerland. [Nandurdikar, Rahul S.] NCI Frederick, NIH, Frederick, MD USA. [Kaliappan, Krishna P.] Indian Inst Technol, Dept Chem, Bombay 400076, Maharashtra, India. [Kaliappan, Krishna P.] Univ Geneva, CH-1211 Geneva 4, Switzerland. [Kaliappan, Krishna P.] Duke Univ, Durham, NC 27706 USA. RP Kaliappan, KP (reprint author), Indian Inst Technol, Dept Chem, Bombay 400076, Maharashtra, India. EM kpk@chem.iitb.ac.in NR 78 TC 1 Z9 1 U1 0 U2 7 PU SWISS CHEMICAL SOC PI BERN PA SCHWARZTORSTRASSE 9, CH-3007 BERN, SWITZERLAND SN 0009-4293 J9 CHIMIA JI Chimia PY 2012 VL 66 IS 12 BP 899 EP 904 DI 10.2533/chimia.2012.899 PN 1 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 066QM UT WOS:000313235300003 PM 23394273 ER PT J AU Ettner, SL Schoenbaum, M Williams, JA AF Ettner, Susan L. Schoenbaum, Michael Williams, Jessica A. BE Jones, AM TI The role of economic incentives in improving the quality of mental health care SO ELGAR COMPANION TO HEALTH ECONOMICS, 2ND EDITION LA English DT Article; Book Chapter ID PAY-FOR-PERFORMANCE; FINANCIAL INCENTIVES; DEPRESSION CARE; BEHAVIORAL HEALTH; OF-CARE; MANAGEMENT; IMPROVEMENT; PROVIDERS; SERVICES; MEDICARE C1 [Ettner, Susan L.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. [Ettner, Susan L.; Williams, Jessica A.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Schoenbaum, Michael] NIMH, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Ettner, SL (reprint author), Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. NR 46 TC 0 Z9 0 U1 0 U2 2 PU EDWARD ELGAR PUBLISHING LTD PI CHELTENHAM PA GLENSANDA HOUSE, MONTPELLIER PARADE, CHELTENHAM GL50 1UA, GLOS, ENGLAND BN 978-1-84980-267-3 PY 2012 BP 297 EP 306 PG 10 WC Economics; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA BBC33 UT WOS:000306426400029 ER PT J AU Uhlemann, AC Kennedy, AD Martens, C Porcella, SF DeLeo, FR Lowy, FD AF Uhlemann, Anne-Catrin Kennedy, Adam D. Martens, Craig Porcella, Stephen F. DeLeo, Frank R. Lowy, Franklin D. TI Toward an Understanding of the Evolution of Staphylococcus aureus Strain USA300 during Colonization in Community Households SO GENOME BIOLOGY AND EVOLUTION LA English DT Article DE evolution; genome rearrangement; repeat deletions ID PANTON-VALENTINE LEUKOCIDIN; FIELD GEL-ELECTROPHORESIS; METHICILLIN-RESISTANT; EMERGENCY-DEPARTMENT; VIRULENCE; GENE; TRANSMISSION; INFECTIONS; CLONE; MRSA AB Staphylococcus aureus is a frequent cause of serious infections and also a human commensal. The emergence of community-associated methicillin-resistant S. aureus led to a dramatic increase in skin and soft tissue infections worldwide. This epidemic has been driven by a limited number of clones, such as USA300 in the United States. To better understand the extent of USA300 evolution and diversification within communities, we performed comparative whole-genome sequencing of three clinical and five colonizing USA300 isolates collected longitudinally from three unrelated households over a 15-month period. Phylogenetic analysis that incorporated additional geographically diverse USA300 isolates indicated that all but one likely arose from a common recent ancestor. Although limited genetic adaptation occurred over the study period, the greatest genetic heterogeneity occurred between isolates from different households and within one heavily colonized household. This diversity allowed for a more accurate tracking of interpersonal USA300 transmission. Sequencing of persisting USA300 isolates revealed mutations in genes involved in major aspects of S. aureus function: adhesion, cell wall biosynthesis, virulence, and carbohydrate metabolism. Genetic variations also included accumulation of multiple polymorphisms within select genes of two multigene operons, suggestive of small genome rearrangements rather than de novo single point mutations. Such rearrangements have been underappreciated in S. aureus and may represent novel means of strain variation. Subtle genetic changes may contribute to USA300 fitness and persistence. Elucidation of small genome rearrangements reveals a potentially new and intriguing mechanism of directed S. aureus genome diversification in environmental niches and during pathogen-host interactions. C1 [Uhlemann, Anne-Catrin; Lowy, Franklin D.] Columbia Univ, Coll Phys & Surg, Div Infect Dis, Dept Med, New York, NY 10027 USA. [Kennedy, Adam D.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. [Martens, Craig; Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Branch, Rocky Mt Labs,NIH, Hamilton, MT USA. [Lowy, Franklin D.] Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA. RP Uhlemann, AC (reprint author), Columbia Univ, Coll Phys & Surg, Div Infect Dis, Dept Med, New York, NY 10027 USA. EM au2110@columbia.edu OI DeLeo, Frank/0000-0003-3150-2516 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health [K08 AI090013, R01 AI077690, R01 AI077690-S1]; Centers for Diseases Control; Paul A. Marks scholarship FX This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health and by National Institutes of Health grants (K08 AI090013 to A.-C. U. and R01 AI077690 and R01 AI077690-S1 to F. D. L.); the Centers for Diseases Control (to F. L.); and the Paul A. Marks scholarship (to A.-C.U.). NR 55 TC 16 Z9 16 U1 3 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1759-6653 J9 GENOME BIOL EVOL JI Genome Biol. Evol. PY 2012 VL 4 IS 12 BP 1275 EP 1285 DI 10.1093/gbe/evs094 PG 11 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 066JE UT WOS:000313215900007 PM 23104992 ER PT J AU Wolf, YI Koonin, EV AF Wolf, Yuri I. Koonin, Eugene V. TI A Tight Link between Orthologs and Bidirectional Best Hits in Bacterial and Archaeal Genomes SO GENOME BIOLOGY AND EVOLUTION LA English DT Article DE orthology; bidirectional best hit; genome comparison; synteny ID CONSERVATION; ARCHITECTURE; EVOLUTION; PARALOGS; BLAST AB Orthologous relationships between genes are routinely inferred from bidirectional best hits (BBH) in pairwise genome comparisons. However, to our knowledge, it has never been quantitatively demonstrated that orthologs form BBH. To test this "BBH-orthology conjecture," we take advantage of the operon organization of bacterial and archaeal genomes and assume that, when two genes in compared genomes are flanked by two BBH show statistically significant sequence similarity to one another, these genes are bona fide orthologs. Under this assumption, we tested whether middle genes in "syntenic orthologous gene triplets" form BBH. We found that this was the case in more than 95% of the syntenic gene triplets in all genome comparisons. A detailed examination of the exceptions to this pattern, including maximum likelihood phylogenetic tree analysis, showed that some of these deviations involved artifacts of genome annotation, whereas very small fractions represented random assignment of the best hit to one of closely related in-paralogs, paralogous displacement in situ, or even less frequent genuine violations of the BBH-orthology conjecture caused by acceleration of evolution in one of the orthologs. We conclude that, at least in prokaryotes, genes for which independent evidence of orthology is available typically form BBH and, conversely, BBH can serve as a strong indication of gene orthology. C1 [Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov FU U.S. Department of Health and Human Services FX This research was supported by intramural funds of the U.S. Department of Health and Human Services to the National Library of Medicine. NR 25 TC 36 Z9 36 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1759-6653 J9 GENOME BIOL EVOL JI Genome Biol. Evol. PY 2012 VL 4 IS 12 BP 1286 EP 1294 DI 10.1093/gbe/evs100 PG 9 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 066JE UT WOS:000313215900009 PM 23160176 ER PT J AU Yoosuf, N Yutin, N Colson, P Shabalina, SA Pagnier, I Robert, C Azza, S Klose, T Wong, J Rossmann, MG La Scola, B Raoult, D Koonin, EV AF Yoosuf, Niyaz Yutin, Natalya Colson, Philippe Shabalina, Svetlana A. Pagnier, Isabelle Robert, Catherine Azza, Said Klose, Thomas Wong, Jimson Rossmann, Michael G. La Scola, Bernard Raoult, Didier Koonin, Eugene V. TI Related Giant Viruses in Distant Locations and Different Habitats: Acanthamoeba polyphaga moumouvirus Represents a Third Lineage of the Mimiviridae That Is Close to the Megavirus Lineage SO GENOME BIOLOGY AND EVOLUTION LA English DT Article DE moumouvirus; mimivirus; giant virus; megavirus; Mimiviridae; Megavirales; horizontal gene transfer; viral genome; nucleo-cytoplasmic large DNA viruses ID NUCLEOCYTOPLASMIC DNA VIRUSES; GENOME; GENES; EVOLUTION; AMEBAS; EUKARYOTES; HIGHLIGHTS; SEARCH; ORIGIN AB The 1,021,348 base pair genome sequence of the Acanthamoeba polyphaga moumouvirus, a new member of the Mimiviridae family infecting Acanthamoeba polyphaga, is reported. The moumouvirus represents a third lineage beside mimivirus and megavirus. Thereby, it is a new member of the recently proposed Megavirales order. This giant virus was isolated from a cooling tower water in southeastern France but is most closely related to Megavirus chiliensis, which was isolated from ocean water off the coast of Chile. The moumouvirus is predicted to encode 930 proteins, of which 879 have detectable homologs. Among these predicted proteins, for 702 the closest homolog was detected in Megavirus chiliensis, with the median amino acid sequence identity of 62%. The evolutionary affinity of moumouvirus and megavirus was further supported by phylogenetic tree analysis of conserved genes. The moumouvirus and megavirus genomes share near perfect orthologous gene collinearity in the central part of the genome, with the variations concentrated in the terminal regions. In addition, genomic comparisons of the Mimiviridae reveal substantial gene loss in the moumouvirus lineage. The majority of the remaining moumouvirus proteins are most similar to homologs from other Mimiviridae members, and for 27 genes the closest homolog was found in bacteria. Phylogenetic analysis of these genes supported gene acquisition from diverse bacteria after the separation of the moumouvirus and megavirus lineages. Comparative genome analysis of the three lineages of the Mimiviridae revealed significant mobility of Group I self-splicing introns, with the highest intron content observed in the moumouvirus genome. C1 [Yoosuf, Niyaz; Colson, Philippe; Pagnier, Isabelle; Robert, Catherine; Azza, Said; La Scola, Bernard; Raoult, Didier] Aix Marseille Univ, URMITE, Fac Med & Pharm, Marseille, France. [Yutin, Natalya; Shabalina, Svetlana A.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Colson, Philippe; La Scola, Bernard; Raoult, Didier] Ctr Hosp Univ Timone, IHU Mediterranee Infect, Assistance Publ Hop Marseille, Marseille, France. [Klose, Thomas; Wong, Jimson; Rossmann, Michael G.] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov RI Shabalina, Svetlana/N-8939-2013; Colson, Philippe/P-6355-2014; LA SCOLA, Bernard/P-6477-2016; OI Shabalina, Svetlana/0000-0003-2272-7473; Colson, Philippe/0000-0001-6285-0308; LA SCOLA, Bernard/0000-0001-8006-7704; Pagnier, Isabelle/0000-0002-1724-3450 FU US Department of Health and Human Services (National Library of Medicine) FX The authors thank Gregory Gimenez and Ghislain Fournous for help with bioinformatic analyses and Lina Barrassi for technical assistance in the isolation of the moumouvirus. This work was supported by intramural funds of the US Department of Health and Human Services (National Library of Medicine) to N.Y., S.A.S., and E.V.K. NR 37 TC 53 Z9 55 U1 0 U2 21 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1759-6653 J9 GENOME BIOL EVOL JI Genome Biol. Evol. PY 2012 VL 4 IS 12 BP 1324 EP 1330 DI 10.1093/gbe/evs109 PG 7 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 066JE UT WOS:000313215900012 PM 23221609 ER PT J AU Marques, PI Bernardino, R Fernandes, T Green, ED Hurle, B Quesada, V Seixas, S AF Marques, Patricia Isabel Bernardino, Rui Fernandes, Teresa Green, Eric D. Hurle, Belen Quesada, Victor Seixas, Susana CA NISC Comparative Sequencing TI Birth-and-Death of KLK3 and KLK2 in Primates: Evolution Driven by Reproductive Biology SO GENOME BIOLOGY AND EVOLUTION LA English DT Article DE serine proteases; adaptive evolution; mating system; semen coagulation; semenogelins ID AMINO-ACID SITES; DETECTING POSITIVE SELECTION; CODON-SUBSTITUTION MODELS; MOLECULAR EVOLUTION; GENE; LIKELIHOOD; PROMISCUITY; SPECIFICITY; SEMENOGELIN; INHIBITORS AB The kallikrein (KLK) gene family comprises the largest uninterrupted locus of serine proteases in the human genome and represents a notable case for studying the evolutionary fate of duplicated genes. In primates, a recent duplication event gave rise to KLK2 and KLK3, both encoding essential proteins for the cascade of seminal plasma liquefaction. We reconstructed the evolutionary history of KLK2 and KLK3 by comparative analysis of the orthologous sequences from 22 primate species, calculated d(N)/d(S) ratios, and addressed the hypothesis of coevolution with their substrates, the semenogelins (SEMG1 and SEMG2). Our findings support the placement of the KLK2-KLK3 duplication in the Catarrhini ancestor and unveil the frequent loss of KLK2 throughout primate evolution by different genomic mechanisms, including unequal crossing-over, deletions, and pseudogenization. We provide evidences for an adaptive evolution of KLK3 toward an expanded enzymatic spectrum, with an effect on the hydrolysis of semen coagulum. Furthermore, we found associations between mating system, the number of SEMG repeat units, and the number of functional KLK2 and KLK3, suggesting complex evolutionary dynamics shaped by reproductive biology. C1 [Marques, Patricia Isabel; Seixas, Susana] Univ Porto IPATIMUP, Inst Mol Pathol & Immunol, Oporto, Portugal. [Marques, Patricia Isabel; Quesada, Victor] Univ Oviedo, Dept Biochem & Mol Biol IUOPA, Oviedo, Spain. [Marques, Patricia Isabel] Univ Porto, Inst Biomed Sci Abel Salazar ICBAS, P-4100 Oporto, Portugal. [Bernardino, Rui; Fernandes, Teresa] Lisbon Zoo Vet Hosp, Lisbon, Portugal. [NISC Comparative Sequencing] NHGRI, NIH Intramural Sequencing Ctr NISC, NIH, Bethesda, MD 20892 USA. RP Seixas, S (reprint author), Univ Porto IPATIMUP, Inst Mol Pathol & Immunol, Oporto, Portugal. EM quesadavictor@uniovi.es; sseixas@ipatimup.pt RI Quesada, Victor/B-6557-2014; Seixas, Susana /I-5084-2013; OI Quesada, Victor/0000-0002-8398-3457; Seixas, Susana /0000-0002-7035-7422; Marques, Patricia Isabel/0000-0001-6050-628X FU Portuguese Foundation for Science and Technology (FCT) [SFRH/BD/68940/2010]; POPH-QREN-Promotion of Scientific Employment; European Social Fund; Ministry of Education and Science; National Human Genome Research Institute; FCT FX The authors thank the Lisbon Zoo for their collaboration in providing the primate samples. This work was supported by a fellowship SFRH/BD/68940/2010 from the Portuguese Foundation for Science and Technology (FCT) to P. I. M., by POPH-QREN-Promotion of Scientific Employment, by the European Social Fund, and by national funds of the Ministry of Education and Science to P. I. M. and S. S., and in part by the Intramural Research Program of the National Human Genome Research Institute. IPATIMUP (an Associate Laboratory of the Portuguese Ministry of Education and Science) is partially supported by FCT. NR 37 TC 7 Z9 7 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1759-6653 J9 GENOME BIOL EVOL JI Genome Biol. Evol. PY 2012 VL 4 IS 12 BP 1331 EP 1338 DI 10.1093/gbe/evs111 PG 8 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 066JE UT WOS:000313215900013 PM 23204305 ER PT J AU Cai, H Mcneilly, AS Luttrell, LM Martin, B AF Cai, Huan Mcneilly, Alan S. Luttrell, Louis M. Martin, Bronwen TI Endocrine Function in Aging SO INTERNATIONAL JOURNAL OF ENDOCRINOLOGY LA English DT Editorial Material C1 [Cai, Huan; Martin, Bronwen] NIA, Metab Unit, NIH, Baltimore, MD 21224 USA. [Mcneilly, Alan S.] Univ Edinburgh, Queens Med Res Inst, MRC, Ctr Reprod Hlth, Edinburgh EH16 4TJ, Midlothian, Scotland. [Luttrell, Louis M.] Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. RP Martin, B (reprint author), NIA, Metab Unit, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM martinbro@nia.nih.gov RI Cai, Huan/B-6578-2016 OI Cai, Huan/0000-0001-7731-8891 NR 0 TC 3 Z9 3 U1 1 U2 2 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1687-8337 J9 INT J ENDOCRINOL JI Int. J. Endocrinol. PY 2012 AR 872478 DI 10.1155/2012/872478 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 069QZ UT WOS:000313452900001 ER PT S AU Rifkind, JM Salgado, MT Cao, ZL AF Rifkind, Joseph M. Salgado, Maria T. Cao, Zeling BE Wolf, M Bucher, HU Rudin, M VanHuffel, S Wolf, U Bruley, DF Harrison, DK TI Regulation of Oxygen Delivery by the Reaction of Nitrite with RBCs Under Hypoxic Conditions SO OXYGEN TRANSPORT TO TISSUE XXXIII SE Advances in Experimental Medicine and Biology LA English DT Article; Proceedings Paper CT 38th Annual Conference of the International-Society-on-Oxygen-Transport-to-Tissue (ISOTT) CY JUL 18-23, 2010 CL Centro Stefano Franscini, ETH Zurich, Ascona, SWITZERLAND SP Int Soc Oxygen Transport Tissue (ISOTT), Swiss Natl Sci Fdn (FNSNF), Zurich Ctr Imaging Sci & Technol (CIMST), Swiss Acad Med Sci, Hamamatsu Photon, CASMED, Artinis Med Syst HO Centro Stefano Franscini, ETH Zurich ID RED-CELL; OXIDE; DEOXYHEMOGLOBIN; REDUCTION; HEMOGLOBIN; BINDING; ATP C1 [Rifkind, Joseph M.; Salgado, Maria T.; Cao, Zeling] Mol Dynam NIA NIH, Baltimore, MD 21224 USA. RP Rifkind, JM (reprint author), Mol Dynam NIA NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM rifkindj@mail.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 12 TC 2 Z9 3 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0065-2598 BN 978-1-4614-1566-4 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2012 VL 737 BP 183 EP 189 DI 10.1007/978-1-4614-1566-4_27 PG 7 WC Biology; Medicine, Research & Experimental SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine GA BDG75 UT WOS:000313161700028 PM 22259100 ER PT J AU Hart, AF Verma, R Mattmann, CA Crichton, DJ Kelly, S Kincaid, H Hughes, S Ramirez, P Goodale, C Anton, K Colbert, M Downs, RR Patriotis, C Srivastava, S AF Hart, Andrew F. Verma, Rishi Mattmann, Chris A. Crichton, Daniel J. Kelly, Sean Kincaid, Heather Hughes, Steven Ramirez, Paul Goodale, Cameron Anton, Kristen Colbert, Maureen Downs, Robert R. Patriotis, Christos Srivastava, Sudhir BE Zhang, C Joshi, J Bertino, E Thuraisingham, B TI Developing an Open Source, Reusable Platform for Distributed Collaborative Information Management in the Early Detection Research Network SO 2012 IEEE 13TH INTERNATIONAL CONFERENCE ON INFORMATION REUSE AND INTEGRATION (IRI) LA English DT Proceedings Paper CT 13th IEEE International Conference on Information Reuse and Integration (IEEE IRI) / DIM / WICSOC / IEEE EM- RITE / IRI-HI CY AUG 08-10, 2012 CL Las Vegas, NV SP IEEE Syst Man & Cybernet Soc (IEEE SMC), Soc Informat Reuse & Integrat (SIRI), IEEE ID OPEN SOURCE SOFTWARE AB For the past decade, the NASA Jet Propulsion Laboratory, in collaboration with Dartmouth University has served as the center for informatics for the Early Detection Research Network (EDRN). The EDRN is a multi-institution research effort funded by the U. S. National Cancer Institute (NCI) and tasked with identifying and validating biomarkers for the early detection of cancer. As the distributed network has grown, increasingly formal processes have been developed for the acquisition, curation, storage, and dissemination of heterogeneous research information assets, and an informatics infrastructure has emerged. In this paper we discuss the evolution of EDRN informatics, its success as a mechanism for distributed information integration, and the potential sustainability and reuse benefits of emerging efforts to make the platform components themselves open source. We describe our experience transitioning a large closed-source software system to a community-driven, open source project at the Apache Software Foundation, and point to lessons learned that will guide our present efforts to promote the reuse of the EDRN informatics infrastructure by a broader community. C1 [Hart, Andrew F.; Verma, Rishi; Mattmann, Chris A.; Crichton, Daniel J.; Kelly, Sean; Kincaid, Heather; Hughes, Steven; Ramirez, Paul; Goodale, Cameron] CALTECH, Jet Prop Lab, 4800 Oak Grove Dr, Pasadena, CA 91109 USA. [Anton, Kristen; Colbert, Maureen] Dartmouth Med Sch, Lebanon, NH 03766 USA. [Downs, Robert R.] Columbia Univ, Ctr Int Earth Sci Informat Network, Palisades, NY 10964 USA. [Patriotis, Christos; Srivastava, Sudhir] Natl Canc Inst, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Hart, AF (reprint author), CALTECH, Jet Prop Lab, 4800 Oak Grove Dr, Pasadena, CA 91109 USA. EM hart@jpl.nasa.gov; rishi.verma@jpl.nasa.gov; mattmann@jpl.nasa.gov; crichton@jpl.nasa.gov; kristen.anton@dartmouth.edu; maureen.colbert@dartmouth.edu; rdowns@ciesin.columbia.edu; patriotisc@mail.nih.gov; srivasts@mail.nih.gov RI Downs, Robert/B-4153-2013 OI Downs, Robert/0000-0002-8595-5134 FU Jet Propulsion Laboratory; California Institute of Technology under a contract with the National Aeronautics and Space Administration; NCI FX This effort was supported by the Jet Propulsion Laboratory, managed by the California Institute of Technology under a contract with the National Aeronautics and Space Administration. The authors would like to thank Christos Patriotis, and Sudhir Srivastava, and the NCI leadership as a whole for their collaborative guidance and support. NR 18 TC 0 Z9 0 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4673-2284-3 PY 2012 BP 263 EP 270 PG 8 WC Computer Science, Theory & Methods; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BDC08 UT WOS:000312540300041 ER PT J AU Dooley, MA Parks, CG Cooper, GS AF Dooley, M. A. Parks, C. G. Cooper, G. S. TI Differing environmental risk factors for membranous versus proliferative lupus nephritis SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT Meeting of the Lupus - New Targets, New Approaches CY SEP 27-30, 2012 CL Whistler, CANADA C1 [Dooley, M. A.] Univ N Carolina, Chapel Hill, NC USA. [Parks, C. G.; Cooper, G. S.] NIEHS, City Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2012 VL 14 SU 3 MA A23 PG 2 WC Rheumatology SC Rheumatology GA 059OP UT WOS:000312715200024 ER PT J AU Ward, MM Tektonidou, M AF Ward, M. M. Tektonidou, M. TI Contemporary estimates of the risk of end-stage renal disease in the first decade of proliferative lupus nephritis SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT Meeting of the Lupus - New Targets, New Approaches CY SEP 27-30, 2012 CL Whistler, CANADA C1 [Ward, M. M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Tektonidou, M.] Natl Univ Athens, Sch Med, Athens, Greece. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2012 VL 14 SU 3 MA A12 PG 1 WC Rheumatology SC Rheumatology GA 059OP UT WOS:000312715200013 ER PT J AU Yazdany, J Feldman, C Liu, J Ward, MM Fischer, MA Costenbader, KH AF Yazdany, J. Feldman, C. Liu, J. Ward, M. M. Fischer, M. A. Costenbader, K. H. TI Usual source of care and geographic region are largest predictors of healthcare quality for incident lupus nephritis in US Medicaid recipients SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT Meeting of the Lupus - New Targets, New Approaches CY SEP 27-30, 2012 CL Whistler, CANADA C1 [Yazdany, J.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Feldman, C.; Liu, J.; Fischer, M. A.; Costenbader, K. H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ward, M. M.] NIAMSD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2012 VL 14 SU 3 MA A17 PG 2 WC Rheumatology SC Rheumatology GA 059OP UT WOS:000312715200018 ER PT J AU Vij, N AF Vij, Neeraj BE Vij, N TI PULMONARY NANOMEDICINE: DIAGNOSTICS, IMAGING, AND THERAPEUTICS Preface SO PULMONARY NANOMEDICINE: DIAGNOSTICS, IMAGING, AND THERAPEUTICS LA English DT Editorial Material; Book Chapter C1 [Vij, Neeraj] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PAN STANFORD PUBLISHING PTE LTD PI SINGAPORE PA PENTHOUSE LEVEL, SUNTEC TOWER 3, 8 TEMASEK BLVD, SINGAPORE, 038988, SINGAPORE BN 978-981-4364-14-0 PY 2012 BP XXI EP XXI D2 10.1201/b12778 PG 1 WC Biotechnology & Applied Microbiology; Respiratory System SC Biotechnology & Applied Microbiology; Respiratory System GA BDD36 UT WOS:000312773700001 ER PT J AU Bonner, JC Card, JW Garantziotis, S Zeldin, DC AF Bonner, James C. Card, Jeffrey W. Garantziotis, Stavros Zeldin, Darryl C. BE Vij, N TI Potential Respiratory Health Risks of Engineered Carbon Nanotubes SO PULMONARY NANOMEDICINE: DIAGNOSTICS, IMAGING, AND THERAPEUTICS LA English DT Article; Book Chapter ID INTRATRACHEAL INSTILLATION; PULMONARY TOXICITY; DRUG-DELIVERY; LUNG-DISEASE; MICE; NANOPARTICLES; RESPONSES; LIPOPOLYSACCHARIDE; INFLAMMATION; DEPOSITION C1 [Bonner, James C.] N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. [Card, Jeffrey W.] Ashuren Hlth Sci, Mississauga, ON, Canada. [Garantziotis, Stavros; Zeldin, Darryl C.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Bonner, JC (reprint author), N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. EM james_bonner@ncsu.edu RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X NR 34 TC 0 Z9 0 U1 0 U2 1 PU PAN STANFORD PUBLISHING PTE LTD PI SINGAPORE PA PENTHOUSE LEVEL, SUNTEC TOWER 3, 8 TEMASEK BLVD, SINGAPORE, 038988, SINGAPORE BN 978-981-4364-14-0 PY 2012 BP 259 EP 273 D2 10.1201/b12778 PG 15 WC Biotechnology & Applied Microbiology; Respiratory System SC Biotechnology & Applied Microbiology; Respiratory System GA BDD36 UT WOS:000312773700010 ER PT J AU Anafi, R Nikonova, EV Arnardottir, ES Shockley, KR McDonald, TP Podtelezhnikov, AA Winrow, CJ Hogenesch, JB Renger, JJ Pack, A AF Anafi, R. Nikonova, E., V Arnardottir, E. S. Shockley, K. R. McDonald, T. P. Podtelezhnikov, A. A. Winrow, C. J. Hogenesch, J. B. Renger, J. J. Pack, A. TI ASSESSING CIRCADIAN PHASE IN HUMAN SUBJECTS USING LIMITED PERIPHERAL BLOOD MEASUREMENTS SO SLEEP LA English DT Meeting Abstract CT Annual Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 09-13, 2012 CL Boston, MA SP Associated Professi Sleep Soc (APSS) C1 [Anafi, R.; Pack, A.] Univ Penn, Div Sleep Med, Philadelphia, PA 19104 USA. [Arnardottir, E. S.] Landspitali Univ Hosp, Dept Resp Med & Sleep, Reykjavik, Iceland. [Shockley, K. R.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Nikonova, E., V; McDonald, T. P.; Podtelezhnikov, A. A.; Winrow, C. J.; Renger, J. J.] Merck Res Labs, Dept Neurosci, West Point, PA USA. [Hogenesch, J. B.] Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA. [Anafi, R.; Pack, A.] Univ Penn, Ctr Sleep & Circadian Neurobiol, Philadelphia, PA 19104 USA. RI Winrow, Christopher/K-1864-2014 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PY 2012 VL 35 SU S MA 0385 BP A133 EP A134 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 063KH UT WOS:000312996500387 ER PT J AU Miller, CM Rindflesch, TC Strohl, KP Koo, BB AF Miller, C. M. Rindflesch, T. C. Strohl, K. P. Koo, B. B. TI LITERATURE-BASED DISCOVERY SUGGESTS NEUROMELANIN AND IRON METABOLISM IN RESTLESS LEGS SYNDROME SO SLEEP LA English DT Meeting Abstract CT Annual Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 09-13, 2012 CL Boston, MA SP Associated Professi Sleep Soc (APSS) C1 [Miller, C. M.; Rindflesch, T. C.] NIH, Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20892 USA. [Koo, B. B.] Univ Hostipals Case Med Ctr, Dept Neurol, Cleveland, OH USA. [Strohl, K. P.] Louis Strokes Cleveland VA Med Ctr, Dept Pulmonlol Crit Care & Sleep Med, Cleveland, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PY 2012 VL 35 SU S MA 0170 BP A61 EP A62 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 063KH UT WOS:000312996500172 ER PT S AU Ock, MS Song, KS Kleinman, H Cha, HJ AF Ock, Mee Sun Song, Kyoung Seob Kleinman, Hynda Cha, Hee-Jae BE Goldstein, AL Garaci, E TI Thymosin beta 4 stabilizes hypoxia-inducible factor-1 alpha protein in an oxygen-independent manner SO THYMOSINS IN HEALTH AND DISEASE I SE Annals of the New York Academy of Sciences LA English DT Article; Proceedings Paper CT 3rd International Symposium on Thymosins in Health and Disease CY MAR 14-16, 2012 CL Washington, DC SP George Washington Univ, Ist Superiore Sanita (ISS), Univ Rome Tor Vergata DE thymosin beta 4; VEGF; HIF-1 alpha; angiogenesis; normoxia; hypoxia ID ACTIN-BINDING SITE; ENDOTHELIAL-CELLS; PROMOTES ANGIOGENESIS; BETA(4); EXPRESSION; APOPTOSIS; METASTASIS; MIGRATION; GROWTH; VEGF AB The small actin-binding protein thymosin beta 4 (T beta 4) is understood to stimulate angiogenesis. Previously, we reported that T beta 4 induces angiogenesis by increasing vascular endothelial growth factor (VEGF) expression, but the mechanism underlying how T beta 4 upregulates VEGF expression remain unknown. To identify the mechanism of VEGF induction by T beta 4, we measured VEGF promoter activity and analyzed the effect of T beta 4 on VEGF RNA stability. The T beta 4 peptide had no effect on either VEGF promoter activity or VEGF RNA stability. We focused on the possibility that T beta 4 may indirectly induce VEGF expression via hypoxia-inducible factor (HIF)-1 alpha. We determined that T beta 4 increased the stability of HIF-1 alpha protein under normoxic conditions. These data suggest that T beta 4 indirectly induces VEGF expression by increasing the protein stability of HIF-1 alpha in an oxygen-independent manner. C1 [Ock, Mee Sun; Cha, Hee-Jae] Kosin Univ, Coll Med, Dept Parasitol & Genet, Pusan 602703, South Korea. [Song, Kyoung Seob] Kosin Univ, Coll Med, Dept Physiol, Pusan 602703, South Korea. [Cha, Hee-Jae] Kosin Univ, Coll Med, Inst Med Sci, Pusan 602703, South Korea. [Kleinman, Hynda] Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD USA. RP Cha, HJ (reprint author), Kosin Univ, Coll Med, Dept Parasitol & Genet, 34 Amnam Dong, Pusan 602703, South Korea. EM hcha@kosin.ac.kr FU Korea Research Foundation [KRF-20110003918]; Korean Government FX This work was supported by the Korea Research Foundation Grant KRF-20110003918, funded by the Korean Government. NR 25 TC 3 Z9 3 U1 0 U2 2 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 BN 978-1-57331-871-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1269 BP 79 EP 83 DI 10.1111/j.1749-6632.2012.06657.x PG 5 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Research & Experimental Medicine; Science & Technology - Other Topics GA BDB67 UT WOS:000312491500012 PM 23045974 ER PT J AU Chowdhuri, SR Hanson, J Cheng, J Rodriguez-Canales, J Fetsch, P Balis, U Filie, AC Giaccone, G Emmert-Buck, MR Hipp, JD AF Chowdhuri, Sinchita Roy Hanson, Jeffrey Cheng, Jerome Rodriguez-Canales, Jaime Fetsch, Patricia Balis, Ulysses Filie, Armando C. Giaccone, Giuseppe Emmert-Buck, Michael R. Hipp, Jason D. TI Semiautomated Laser Capture Microdissection of Lung Adenocarcinoma Cytology Samples SO ACTA CYTOLOGICA LA English DT Article DE Semiautomated laser capture microdissection; Spatially invariant vector quantization; Lung adenocarcinoma; Cytology ID GROWTH-FACTOR RECEPTOR; MOLECULAR ANALYSIS; KRAS MUTATIONS; EGFR MUTATIONS; CANCER; GEFITINIB; ERLOTINIB; TISSUE; RESISTANCE; PROTEOMICS AB Objective: In the past decade molecular diagnostics has changed the clinical management of lung adenocarcinoma patients. Molecular diagnostics, however, is largely dependent on the quantity and quality of the tumor DNA that is retrieved from the tissue or cytology samples. Frequently, patients are diagnosed on cytology specimens where the tumor cells are scattered within the cell block, making selecting for tumor enrichment difficult. In the past we have used laser capture microdissection (LCM) to select for pure populations of tumor cells to increase the sensitivity of molecular assays. This study explores several methods for semiautomated computer-guided LCM. Study Design: Hematoxylin and eosin- or TTF-1-immunostained slides from a pleural effusion cell block with metastatic lung adenocarcinoma were used for LCM with either AutoScan or a recently described pattern-matching algorithm, spatially invariant vector quantization (SIVQ), to define morphologic predicates (vectors) to select cells of interest. Results: We retrieved pure populations of tumor cells using both algorithm-guided LCM approaches with slight variations in cellular retrievals. Both methods were semiautomated, requiring minimum technical supervision. Conclusion: In this study we demonstrate the first semiautomated, computer-guided LCM of a cytology specimen using SIVQ and AutoScan, a first step towards the long-term goal of integrating LCM into the clinical cytology-molecular workflow. Copyright (C) 2012 S. Karger AG, Basel C1 [Chowdhuri, Sinchita Roy; Hanson, Jeffrey; Rodriguez-Canales, Jaime; Fetsch, Patricia; Filie, Armando C.; Emmert-Buck, Michael R.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Giaccone, Giuseppe] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Cheng, Jerome; Balis, Ulysses; Hipp, Jason D.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. RP Hipp, JD (reprint author), Univ Michigan Hlth Syst, Dept Pathol, M4233A Med Sci 1,1301 Catherine, Ann Arbor, MI 48109 USA. EM Jason.hipp@gmail.com RI Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Rodriguez-Canales, Jaime/0000-0002-0885-2377 FU NCI's Center for Cancer Research in the Intramural Program at NIH; NIH FX This work was supported in part by the NCI's Center for Cancer Research in the Intramural Program at NIH.; Michael Emmert-Buck is an inventor on all NIH-held patents covering LCM technology and receives royalty-based payments through the NIH Technology Transfer Program. NR 38 TC 3 Z9 3 U1 0 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0001-5547 EI 1938-2650 J9 ACTA CYTOL JI Acta Cytol. PY 2012 VL 56 IS 6 BP 622 EP 631 DI 10.1159/000342984 PG 10 WC Pathology SC Pathology GA 057OI UT WOS:000312572500006 ER PT J AU Hull, SC Chan, B Biesecker, LG Berkman, BE AF Hull, Sara Chandros Chan, Ben Biesecker, Leslie G. Berkman, Benjamin E. TI Response to Open Peer Commentaries on "Genomic Inheritances: Disclosing Individual Research Results From Whole-Exome Sequencing to Deceased Participants' Relatives" SO AMERICAN JOURNAL OF BIOETHICS LA English DT Letter ID GENETIC RESEARCH C1 [Chan, Ben] Lawrence Univ, Appleton, WI 54911 USA. [Hull, Sara Chandros; Biesecker, Leslie G.; Berkman, Benjamin E.] NHGRI, Bethesda, MD USA. RP Chan, B (reprint author), Lawrence Univ, Main Hall, Appleton, WI 54911 USA. EM benchan@alum.swarthmore.edu FU Intramural NIH HHS [Z99 HG999999] NR 9 TC 1 Z9 1 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2012 VL 12 IS 12 BP W9 EP W10 DI 10.1080/15265161.2012.739836 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 054IX UT WOS:000312338300003 PM 23215942 ER PT J AU Grabar, N Hamon, T Bodenreider, O AF Grabar, Natalia Hamon, Thierry Bodenreider, Olivier TI Ontologies and terminologies: Continuum or dichotomy? SO APPLIED ONTOLOGY LA English DT Editorial Material DE Terminology; ontology; distinction; entities; relations; knowledge; continuum ID MEDICAL LANGUAGE SYSTEM; NCI THESAURUS; INFORMATION-RETRIEVAL; BIOMEDICAL ONTOLOGY; CLINICAL GUIDELINES; SNOMED CT; WORDNET; MESH; INTEGRATION; SCIENCE AB Since there is a great confusion between the ontologies and other semantic resources, the purpose of this special issue is to address the question on "Ontologies and terminologies: Continuum or dichotomy". We have selected five articles which study the differences and similarities between these semantic resources. More particularly, the articles are dedicated to the differences existing at the level of terms and of relations, the use of the ontologies on corpora and the dynamic and static representation of the knowledge. C1 [Grabar, Natalia] Univ Lille 1, CNRS UMR, Lille, France. [Grabar, Natalia] Univ Lille 3, CNRS UMR, Lille, France. [Hamon, Thierry] Univ Paris 13, LIM&BIO UFR SMBH, Paris, France. [Bodenreider, Olivier] Natl Lib Med, Bethesda, MD USA. RP Grabar, N (reprint author), Univ Lille 1, CNRS UMR STL 8163, BP60149, F-59653 Villeneuve Dascq, France. EM natalia.grabar@univ-lille3.fr; thierry.hamon@univ-paris13.fr; obodenreider@nlm.nih.gov NR 137 TC 3 Z9 3 U1 0 U2 11 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1570-5838 EI 1875-8533 J9 APPL ONTOL JI Appl. Ontol. PY 2012 VL 7 IS 4 BP 375 EP 386 DI 10.3233/AO-2012-0119 PG 12 WC Computer Science, Artificial Intelligence; Computer Science, Information Systems; Computer Science, Theory & Methods SC Computer Science GA 054YQ UT WOS:000312382000001 ER PT S AU Van Itallie, CM Anderson, JM AF Van Itallie, Christina M. Anderson, James M. BE Fromm, M Schulzke, JD TI Caveolin binds independently to claudin-2 and occludin SO BARRIERS AND CHANNELS FORMED BY TIGHT JUNCTION PROTEINS I SE Annals of the New York Academy of Sciences LA English DT Article; Book Chapter DE caveolin; claudin; occluding; tight junction; ZO-1 ID TIGHT-JUNCTION PROTEINS; BARRIER FUNCTION; PHOSPHORYLATION; CHOLESTEROL; ENDOCYTOSIS; SOLUBILITY; SCAFFOLDS; DEPLETION; MEMBRANE; DOMAIN AB Treatment of epithelial and endothelial cells with proinflammatory cytokines can stimulate tight junction protein endocytosis, with associated loss of physiologic barrier function. In some instances, the endocytic scaffolding protein, caveolin-1, has been implicated in the cytokine-dependent retrieval of the tight junction proteins occludin and claudins. How caveolin-1 interacts with these proteins, however, remains undefined. Using co-immunoprecipitation assays, we found that caveolin-1 separately interacts with claudin-2 and occludin, but not with ZO-1, ZO-2, or claudin-4. Further, we found that the interactions of caveolin-1 with claudin-2 and occludin were not disrupted by cholesterol removal, suggesting that they were not dependent on co-localization to cholesterol-rich lipid rafts. Co-immunoprecipitation of caveolin-1 with chimeras between claudin-2 and -4 indicated that the C-terminal cytoplasmic domain of claudin-2 is required for association with caveolin-1; similar analysis showed that the ZO-1 binding region of occludin is not required for its interaction with caveolin-1. The finding that caveolin-1 interacts with claudin-2 and occludin, but not with claudin-4 or ZO-1, suggests a potential mechanism for selective retrieval of tight junction components. C1 [Van Itallie, Christina M.; Anderson, James M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Van Itallie, CM (reprint author), NHLBI, NIH, Bldg 50,Room 4525,50 South Dr, Bethesda, MD 20892 USA. EM Christina.VanItallie@nih.gov NR 20 TC 2 Z9 2 U1 0 U2 3 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 BN 978-1-57331-873-0 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1257 BP 103 EP 107 DI 10.1111/j.1749-6632.2012.06535.x PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Cell Biology; Science & Technology - Other Topics GA BDB53 UT WOS:000312485200012 ER PT S AU Van Itallie, CM Mitic, LL Anderson, JM AF Van Itallie, Christina M. Mitic, Laura L. Anderson, James M. BE Fromm, M Schulzke, JD TI SUMOylation of claudin-2 SO BARRIERS AND CHANNELS FORMED BY TIGHT JUNCTION PROTEINS II SE Annals of the New York Academy of Sciences LA English DT Article; Book Chapter DE claudin; claudin-2; MDCK; SUMO-1; tight junction; yeast two-hybrid ID EPITHELIAL-CELLS; TIGHT JUNCTIONS; SUMO; UBIQUITIN; ZO-1; LOCALIZATION; TRANSPORT; MEMBRANE; PROMOTES; BINDING AB The C-terminal cytoplasmic tails of claudins are likely sites for interaction with proteins that regulate their function. We performed a yeast two-hybrid screen with the tail of human claudin-2 against a human kidney cDNA library and identified interactions with the PDZ3 domain of ZO-2 as well as ubiquitin-conjugating enzyme E2I (SUMO ligase-1) and E3 SUMO-protein ligase PIAS; the first is a predicted interaction, while the latter two are novel and suggest that claudin-2 is a substrate for SUMOylation. Using an in vitro SUMOylation assay, we identified K218 as a conjugation site on claudin-2; mutation of that lysine to arginine blocked SUMOylation. Stable expression of inducible GFP-SUMO- 1 in MDCK cells resulted in decreased levels of claudin-2 protein by immunoblot and decreased claudin-2 membrane expression by immunofluorescence microscopy. We conclude that the cellular levels of claudin-2 may be modulated by SUMOylation, warranting further investigation of cellular pathways that regulate this modification in vivo. C1 [Van Itallie, Christina M.; Anderson, James M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Anderson, James M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Van Itallie, CM (reprint author), NHLBI, NIH, Bldg 50,Rm 4525, Bethesda, MD 20892 USA. EM Christina.VanItallie@nih.gov NR 24 TC 9 Z9 10 U1 0 U2 3 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 BN 978-1-57331-892-1 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1258 BP 60 EP 64 DI 10.1111/j.1749-6632.2012.06541.x PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA BDB54 UT WOS:000312485500008 PM 22731716 ER PT S AU Cizza, G Rother, KI AF Cizza, Giovanni Rother, Kristina I. BE Cizza, G Rother, KI TI The Brain and Obesity Lectures Series - the beginning of a new field? SO BRAIN AND OBESITY SE Annals of the New York Academy of Sciences LA English DT Editorial Material; Book Chapter C1 [Cizza, Giovanni] NIDDK, Sect Neuroendocrinol Obes, Natl Inst Hlth Bethesda, Bethesda, MD 20892 USA. [Rother, Kristina I.] NIDDK, Sect Pediat Diabet & Metab, Natl Inst Hlth Bethesda, Bethesda, MD 20892 USA. RP Cizza, G (reprint author), NIDDK, Sect Neuroendocrinol Obes, Natl Inst Hlth Bethesda, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 BN 978-1-57331-860-0 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1264 BP VII EP XIV DI 10.1111/j.1749-6632.2012.06721.x PG 8 WC Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BDB65 UT WOS:000312490600001 PM 22882313 ER PT S AU Rothman, SM Griffioen, KJ Wan, RQ Mattson, MP AF Rothman, Sarah M. Griffioen, Kathleen J. Wan, Ruiqian Mattson, Mark P. BE Cizza, G Rother, KI TI Brain-derived neurotrophic factor as a regulator of systemic and brain energy metabolism and cardiovascular health SO BRAIN AND OBESITY SE Annals of the New York Academy of Sciences LA English DT Article; Book Chapter DE autonomic nervous system; brain-derived neurotrophic factor; cognition; diabetes; exercise; neurogenesis; synaptic plasticity ID FACTOR MESSENGER-RNA; NUCLEUS-TRACTUS-SOLITARIUS; CALORIC RESTRICTION; DIETARY RESTRICTION; SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE; RAT HIPPOCAMPUS; DIABETIC MICE; DENTATE GYRUS; VOLUNTARY EXERCISE AB Overweight sedentary individuals are at increased risk for cardiovascular disease, diabetes, and some neurological disorders. Beneficial effects of dietary energy restriction (DER) and exercise on brain structural plasticity and behaviors have been demonstrated in animal models of aging and acute (stroke and trauma) and chronic (Alzheimer's and Parkinson's diseases) neurological disorders. The findings described later, and evolutionary considerations, suggest brain-derived neurotrophic factor (BDNF) plays a critical role in the integration and optimization of behavioral and metabolic responses to environments with limited energy resources and intense competition. In particular, BDNF signaling mediates adaptive responses of the central, autonomic, and peripheral nervous systems from exercise and DER. In the hypothalamus, BDNF inhibits food intake and increases energy expenditure. By promoting synaptic plasticity and neurogenesis in the hippocampus, BDNF mediates exercise-and DER-induced improvements in cognitive function and neuroprotection. DER improves cardiovascular stress adaptation by a mechanism involving enhancement of brainstem cholinergic activity. Collectively, findings reviewed in this paper provide a rationale for targeting BDNF signaling for novel therapeutic interventions in a range of metabolic and neurological disorders. C1 [Rothman, Sarah M.; Griffioen, Kathleen J.; Wan, Ruiqian; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Rothman, SM (reprint author), NIA, Neurosci Lab, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM rothmansm@mail.nih.gov FU Intramural NIH HHS [Z99 AG999999] NR 133 TC 43 Z9 48 U1 2 U2 25 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 BN 978-1-57331-860-0 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1264 BP 49 EP 63 DI 10.1111/j.1749-6632.2012.06525.x PG 15 WC Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BDB65 UT WOS:000312490600006 PM 22548651 ER PT S AU Lucassen, EA Rother, KI Cizza, G AF Lucassen, Eliane A. Rother, Kristina I. Cizza, Giovanni BE Cizza, G Rother, KI TI Interacting epidemics? Sleep curtailment, insulin resistance, and obesity SO BRAIN AND OBESITY SE Annals of the New York Academy of Sciences LA English DT Article; Book Chapter DE sleep; obesity; insulin resistance; diabetes; appetite ID BODY-MASS INDEX; MAJOR DEPRESSIVE DISORDER; TYPE-2 DIABETES-MELLITUS; NECROSIS-FACTOR-ALPHA; SLOW-WAVE SLEEP; GROWTH-HORMONE; HEALTHY-MEN; LEPTIN LEVELS; WEIGHT-GAIN; RISK-FACTOR AB In the last 50 years, the average self-reported sleep duration in the United States has decreased by 1.5-2 hours in parallel with an increasing prevalence of obesity and diabetes. Epidemiological studies and meta-analyses report a strong relationship between short or disturbed sleep, obesity, and abnormalities in glucose metabolism. This relationship is likely to be bidirectional and causal in nature, but many aspects remain to be elucidated. Sleep and the internal circadian clock influence a host of endocrine parameters. Sleep curtailment in humans alters multiple metabolic pathways, leading to more insulin resistance, possibly decreased energy expenditure, increased appetite, and immunological changes. On the other hand, psychological, endocrine, and anatomical abnormalities in individuals with obesity and/or diabetes can interfere with sleep duration and quality, thus creating a vicious cycle. In this review, we address mechanisms linking sleep with metabolism, highlight the need for studies conducted in real-life settings, and explore therapeutic interventions to improve sleep, with a potential beneficial effect on obesity and its comorbidities. C1 [Lucassen, Eliane A.] NIH, Immunogenet Sect, Ctr Clin, Bethesda, MD 20892 USA. [Lucassen, Eliane A.] Leiden Univ, Neurophysiol Lab, Dept Mol Cell Biol, Med Ctr, Leiden, Netherlands. [Rother, Kristina I.] NIDDKD, Sect Pediat Diabet & Metab, NIH, Bethesda, MD 20892 USA. [Cizza, Giovanni] NIDDKD, Sect Neuroendocrinol Obes, NIH, Bethesda, MD 20892 USA. RP Lucassen, EA (reprint author), 10 Ctr Dr, Bethesda, MD 20892 USA. EM eliane.lucassen@nih.gov FU Intramural NIH HHS [ZIA DK047054-04] NR 178 TC 52 Z9 54 U1 1 U2 16 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 BN 978-1-57331-860-0 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1264 BP 110 EP 134 DI 10.1111/j.1749-6632.2012.06655.x PG 25 WC Endocrinology & Metabolism; Multidisciplinary Sciences; Neurosciences SC Endocrinology & Metabolism; Science & Technology - Other Topics; Neurosciences & Neurology GA BDB65 UT WOS:000312490600011 PM 22827862 ER PT J AU Galway, K Black, A Cantwell, M Cardwell, CR Mills, M Donnelly, M AF Galway, Karen Black, Amanda Cantwell, Marie Cardwell, Chris R. Mills, Moyra Donnelly, Michael TI Psychosocial interventions to improve quality of life and emotional wellbeing for recently diagnosed cancer patients SO COCHRANE DATABASE OF SYSTEMATIC REVIEWS LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; BREAST-CANCER; SUPPORT GROUPS; PSYCHOEDUCATIONAL INTERVENTION; PSYCHOLOGICAL INTERVENTION; TELEPHONE THERAPY; PROSTATE-CANCER; DISTRESS; DEPRESSION; SURVIVORS AB Background A cancer diagnosis may lead to significant psychological distress in up to 75% of cases. There is a lack of clarity about the most effective ways to address this psychological distress. Objectives To assess the effects of psychosocial interventions to improve quality of life (QoL) and general psychological distress in the 12-month phase following an initial cancer diagnosis. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 4), MEDLINE, EMBASE, and PsycINFO up to January 2011. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. Electronic searches were carried out across all primary sources of peer-reviewed publications using detailed criteria. No language restrictions were imposed. Selection criteria Randomised controlled trials of psychosocial interventions involving interpersonal dialogue between a 'trained helper' and individual newly diagnosed cancer patients were selected. Only trials measuring QoL and general psychological distress were included. Trials involving a combination of pharmacological therapy and interpersonal dialogue were excluded, as were trials involving couples, family members or group formats. Data collection and analysis Trial data were examined and selected by two authors in pairs with mediation from a third author where required. Where possible, outcome data were extracted for combining in a meta-analyses. Continuous outcomes were compared using standardised mean differences and 95% confidence intervals, using a random-effects model. The primary outcome, QoL, was examined in subgroups by outcome measurement, cancer site, theoretical basis for intervention, mode of delivery and discipline of trained helper. The secondary outcome, general psychological distress (including anxiety and depression), was examined according to specified outcome measures. Main results A total of 3309 records were identified, examined and the trials subjected to selection criteria; 30 trials were included in the review. No significant effects were observed for QoL at 6-month follow up (in 9 studies, SMD 0.11; 95% CI-0.00 to 0.22); however, a small improvement in QoL was observed when QoL was measured using cancer-specific measures (in 6 studies, SMD 0.16; 95% CI 0.02 to 0.30). General psychological distress as assessed by 'mood measures' improved also (in 8 studies, SMD -0.81; 95% CI - 1.44 to -0.18), but no significant effect was observed when measures of depression or anxiety were used to assess distress (in 6 studies, depression SMD 0.12; 95% CI -0.07 to 0.31; in 4 studies, anxiety SMD 0.05; 95% CI -0.13 to 0.22). Psychoeducational and nurse-delivered interventions that were administered face to face and by telephone with breast cancer patients produced small positive significant effects on QoL (in 2 studies, SMD 0.23; 95% CI 0.04 to 0.43). Authors' conclusions The significant variation that was observed across participants, mode of delivery, discipline of 'trained helper' and intervention content makes it difficult to arrive at a firm conclusion regarding the effectiveness of psychosocial interventions for cancer patients. It can be tentatively concluded that nurse-delivered interventions comprising information combined with supportive attention may have a beneficial impact on mood in an undifferentiated population of newly diagnosed cancer patients. C1 [Galway, Karen] Queens Univ Belfast, Sch Nursing & Midwifery, Ctr Med Biol, Belfast BT9 7BL, Antrim, North Ireland. [Black, Amanda] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Cantwell, Marie] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Ctr Publ Hlth, Canc Epidemiol & Hlth Serv Res Grp, Belfast BT9 7BL, Antrim, North Ireland. [Mills, Moyra] No Hlth & Social Care Trust, Belfast, Antrim, North Ireland. RP Galway, K (reprint author), Queens Univ Belfast, Sch Nursing & Midwifery, Ctr Med Biol, 97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland. EM k.galway@qub.ac.uk OI Cardwell, Chris/0000-0002-2689-4335 FU Research and Development Office, Northern Ireland, UK FX External sources; Research and Development Office, Northern Ireland, UK. NR 60 TC 20 Z9 20 U1 5 U2 47 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-493X EI 1361-6137 J9 COCHRANE DB SYST REV JI Cochrane Database Syst Rev. PY 2012 IS 11 AR CD007064 DI 10.1002/14651858.CD007064.pub2 PG 66 WC Medicine, General & Internal SC General & Internal Medicine GA 052LC UT WOS:000312198100012 ER PT S AU Silverman, MN Sternberg, EM AF Silverman, Marni N. Sternberg, Esther M. BE DelRey, A Welsh, CJ Schwarz, MJ Besedovsky, HO TI Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction SO NEUROIMMUNOMODULATION IN HEALTH AND DISEASE I SE Annals of the New York Academy of Sciences LA English DT Article DE stress; cortisol; cytokines; autoimmune; depression; psychoneuroimmunology ID PITUITARY-ADRENAL AXIS; CORTICOTROPIN-RELEASING HORMONE; CHRONIC-FATIGUE-SYNDROME; SUSCEPTIBLE LEWIS RATS; CENTRAL-NERVOUS-SYSTEM; PSYCHOLOGICAL STRESS; IMMUNE-SYSTEM; DNA-BINDING; RHEUMATOID-ARTHRITIS; METABOLIC SYNDROME AB Enhanced susceptibility to inflammatory and autoimmune disease can be related to impairments in HPA axis activity and associated hypocortisolism, or to glucocorticoid resistance resulting from impairments in local factors affecting glucocorticoid availability and function, including the glucocorticoid receptor (GR). The enhanced inflammation and hypercortisolism that typically characterize stress-related illnesses, such as depression, metabolic syndrome, cardiovascular disease, or osteoporosis, may also be related to increased glucocorticoid resistance. This review focuses on impaired GR function as a molecular mechanism of glucocorticoid resistance. Both genetic and environmental factors can contribute to impaired GR function. The evidence that glucocorticoid resistance can be environmentally induced has important implications for management of stress-related inflammatory illnesses and underscores the importance of prevention and management of chronic stress. The simultaneous assessment of neural, endocrine, and immune biomarkers through various noninvasive methods will also be discussed. C1 [Silverman, Marni N.; Sternberg, Esther M.] NIMH, Sect Neuroendocrine Immunol & Behav, NIH, Bethesda, MD 20892 USA. RP Sternberg, EM (reprint author), NIMH, Sect Neuroendocrine Immunol & Behav, NIH, 10 Ctr Dr,Rm 2D-39,MSC 1350, Bethesda, MD 20892 USA. EM sternbee@mail.nih.gov FU NIH, NIMH Division of Intramural Research FX This work was supported by the NIH, NIMH Division of Intramural Research. NR 98 TC 130 Z9 137 U1 1 U2 57 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 BN 978-1-57331-868-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1261 BP 55 EP 63 DI 10.1111/j.1749-6632.2012.06633.x PG 9 WC Immunology; Multidisciplinary Sciences; Neurosciences SC Immunology; Science & Technology - Other Topics; Neurosciences & Neurology GA BDC07 UT WOS:000312537900009 PM 22823394 ER PT J AU Liu, WM Maivelett, J Kato, GJ Taylor, JG Yang, WC Liu, YC Yang, YG Gorbach, AM AF Liu, Wei-Min Maivelett, Jordan Kato, Gregory J. Taylor, James G. Yang, Wen-Chin Liu, Yun-Chung Yang, You-Gang Gorbach, Alexander M. TI Reconstruction of thermographic signals to map perforator vessels in humans SO QIRT JOURNAL LA English DT Article DE thermographic signal reconstruction; infrared imaging; reactive hyperemia; perforator vessels; blood flow regulation; skin microcirculation ID ENHANCEMENT; BRAIN AB Thermal representations of underlying perforator vessels on the surface of a human forearm have previously been mapped via recovery-enhanced infrared imaging, which is performed as skin blood flow recovers to baseline levels following cooling of the forearm. We noted that the same vessels could also be observed during reactive hyperaemia tests after the complete 5-min occlusion of the forearm by an inflatable cuff. However, not all the subjects showed vessels with acceptable contrast. Therefore, we applied a thermographic signal reconstruction algorithm to reactive hyperaemia testing, which substantially enhanced signal-to-noise ratios between perforator vessels and their surroundings, thereby enabling their mapping with higher accuracy and a shorter occlusion period. C1 [Maivelett, Jordan; Gorbach, Alexander M.] Natl Inst Biomed Imaging & Bioengn, Infrared Imaging & Thermometry Unit, Bethesda, MD USA. [Liu, Wei-Min; Yang, Wen-Chin; Liu, Yun-Chung; Yang, You-Gang] Natl Chung Cheng Univ, Dept Comp Sci & Informat Engn, Minxiong, Taiwan. [Kato, Gregory J.; Taylor, James G.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Gorbach, AM (reprint author), Natl Inst Biomed Imaging & Bioengn, Infrared Imaging & Thermometry Unit, Bethesda, MD USA. EM gorbacha@mail.nih.gov RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Taylor, James/0000-0002-4421-1809 FU Division of Intramural Research, National Heart, Lung and Blood Institute; National Institute of Biomedical Imaging and Bioengineering [EB000060-05]; National Science Council of Taiwan, Republic of China [NSC 101-2221-E-194-018] FX This study was funded by the Division of Intramural Research, National Heart, Lung and Blood Institute, the National Institute of Biomedical Imaging and Bioengineering (EB000060-05) and National Science Council of Taiwan, Republic of China (NSC 101-2221-E-194-018). NR 10 TC 7 Z9 7 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1768-6733 J9 QIRT J JI QIRT J. PY 2012 VL 9 IS 2 BP 123 EP 133 DI 10.1080/17686733.2012.737157 PG 11 WC Instruments & Instrumentation; Materials Science, Characterization & Testing; Physics, Applied SC Instruments & Instrumentation; Materials Science; Physics GA 059IL UT WOS:000312697600003 PM 23667389 ER PT J AU Rao, MS Collins, FS AF Rao, Mahendra S. Collins, Francis S. TI Steering a New Course for Stem Cell Research: NIH's Intramural Center for Regenerative Medicine SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article AB The phenomenal progress made in stem cell biology in the past few years has infused the field of regenerative medicine with a great deal of scientific enthusiasm. However, along with the excitement of discovery comes a new sense of translational urgency. The prospect of using embryonic and induced pluripotent stem cell tools and technologies to produce cell-based therapies and other treatments is no longer a distant dream; it is a very real opportunity that demands our attention today. As with most new fields, regenerative medicine has experienced some significant growing pains, and we have identified a number of key obstacles to progress. Given our role as the lead U.S. biomedical research agency and the world's largest supporter of medical research, the National Institutes of Health (NIH) has a responsibility to find ways to reduce or remove many of these obstacles and, consequently, has and continues to respond to these challenges in a variety of ways. In this brief essay, we will review our progress and highlight a new development: the founding of a Center for Regenerative Medicine on the NIH campus. C1 [Rao, Mahendra S.; Collins, Francis S.] NIH, Bethesda, MD 20892 USA. RP Rao, MS (reprint author), NIH CRM, 50 South Dr, Bethesda, MD 20892 USA. EM mahendra.rao@nih.gov NR 13 TC 8 Z9 8 U1 1 U2 1 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD JAN PY 2012 VL 1 IS 1 BP 15 EP 17 DI 10.5966/sctm.2011-0032 PG 3 WC Cell & Tissue Engineering SC Cell Biology GA 057NW UT WOS:000312571300016 PM 23197635 ER PT J AU Jackson, WM Nesti, LJ Tuan, RS AF Jackson, Wesley M. Nesti, Leon J. Tuan, Rocky S. TI Concise Review: Clinical Translation of Wound Healing Therapies Based on Mesenchymal Stem Cells SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Review DE Regenerative medicine; Dermal regeneration; Clinical translation; Diabetic ulcer; Tissue engineering; Preclinical research; Immunomodulation; Angiogenesis ID HEPATOCYTE GROWTH-FACTOR; HUMAN SKIN SUBSTITUTE; MARROW STROMAL CELLS; PROGENITOR CELLS; ENDOTHELIAL-CELLS; RENAL FIBROBLASTS; NITRIC-OXIDE; DIFFERENTIATION; REPAIR; TISSUE AB There is enormous worldwide demand for therapies to promote the efficient resolution of hard-to-heal wounds with minimal appearance of scarring. Recent in vitro studies with mesenchymal stem cells (MSCs) have identified numerous mechanisms by which these cells can promote the process of wound healing, and there is significant interest in the clinical translation of an MSC-based therapy to promote dermal regeneration. This review provides a systematic analysis of recent preclinical and clinical research to evaluate the use of MSCs in wound healing applications. These in vivo studies provide overwhelming evidence that MSCs can accelerate wound closure by modulating the inflammatory environment, promoting the formation of a well-vascularized granulation matrix, encouraging the migration of keratinocytes, and inhibiting apoptosis of wound healing cells. The trophic effects of MSC therapy also appear to augment wound healing in diabetic tissues, thereby preventing the formation of nonhealing ulcers. Finally, a number of delivery systems have been evaluated and indicate that MSCs could be the basis of a versatile therapy to fulfill the clinical needs for dermal regeneration. However, despite the apparent advantages of MSC-based therapies, there have been only limited clinical investigations of this type of therapy in humans. Thus, our review concludes with a discussion of the translational barriers that are limiting the widespread clinical use of MSCs to enhance wound healing. STEM CELLS TRANSLATIONAL MEDICINE 2012;1:44-50 C1 [Tuan, Rocky S.] Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, Pittsburgh, PA 15219 USA. [Jackson, Wesley M.; Nesti, Leon J.] Uniformed Serv Univ Hlth Sci, Dept Surg, Clin & Expt Orthopaed Lab, Bethesda, MD 20814 USA. [Nesti, Leon J.] NIAMSD, Orthopaed Res Grp, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, 450 Technol Dr,Room 221, Pittsburgh, PA 15219 USA. EM rst13@pitt.edu FU NIH Intramural Research Program [1ZIAAR041191]; Department of Defense Military Amputee Research Program at Walter Reed Army Medical Center [PO5-A011]; Defense Medical Research and Development Program [D10_I_AR_J8_981]; Peer-Reviewed Orthopaedic Research Program [W81XWH-10-2-0084] FX This work was supported in part by the NIH Intramural Research Program (1ZIAAR041191), and by grants from the Department of Defense Military Amputee Research Program at Walter Reed Army Medical Center (PO5-A011), Defense Medical Research and Development Program (D10_I_AR_J8_981), and Peer-Reviewed Orthopaedic Research Program (W81XWH-10-2-0084) NR 86 TC 72 Z9 79 U1 5 U2 28 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD JAN PY 2012 VL 1 IS 1 BP 44 EP 50 DI 10.5966/sctm.2011-0024 PG 7 WC Cell & Tissue Engineering SC Cell Biology GA 057NW UT WOS:000312571300020 PM 23197639 ER PT S AU Marler, JR AF Marler, John R. BE DelZoppo, GJ Alexandrov, AV TI A strategic plan to accelerate development of acute stroke treatments SO THROMBOLYSIS AND ACUTE STROKE TREATMENT: PREPARING FOR THE NEXT DECADE SE Annals of the New York Academy of Sciences LA English DT Article; Proceedings Paper CT 11th Symposium on Thrombolysis and Acute Stroke Treatment (TAST) - Preparing for the Next Decade CY DEC 01-03, 2011 CL New York Acad Sci, Manhattan, NY SP Natl Inst Neurol Disorders & Stroke (NINDS) HO New York Acad Sci DE acute stroke; clinical trial; network; teletrial ID TISSUE-PLASMINOGEN-ACTIVATOR; ACUTE ISCHEMIC-STROKE; STREPTOKINASE; TRIAL AB In order to reenergize acute stroke research and accelerate the development of new treatments, we need to transform the usual design and conduct of clinical trials to test for small but significant improvements in effectiveness, and treat patients as soon as possible after stroke onset when treatment effects are most detectable. This requires trials that include thousands of acute stroke patients. A plan to make these trials possible is proposed. There are four components: (1) free access to the electronic medical record; (2) a large stroke emergency network and clinical trial coordinating center connected in real time to hundreds of emergency departments; (3) a clinical trial technology development center; and (4) strategic leadership to raise funds, motivate clinicians to participate, and interact with politicians, insurers, legislators, and other national and international organizations working to advance the quality of stroke care. C1 [Marler, John R.] Natl Inst Neurol Disorders & Stroke, Acute Stroke Study Grp, NIH, Rockville, MD USA. RP Marler, JR (reprint author), 637 Blossom Dr, Rockville, MD 20850 USA. EM johnmarler@verizon.net NR 19 TC 0 Z9 0 U1 2 U2 4 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1268 BP 152 EP 156 DI 10.1111/j.1749-6632.2012.06714.x PG 5 WC Multidisciplinary Sciences; Clinical Neurology; Peripheral Vascular Disease SC Science & Technology - Other Topics; Neurosciences & Neurology; Cardiovascular System & Cardiology GA BDC41 UT WOS:000312593800023 PM 22994235 ER PT S AU Treadwell, T Kleinman, HK Crockford, D Hardy, MA Guarnera, GT Goldstein, AL AF Treadwell, Terry Kleinman, Hynda K. Crockford, David Hardy, Mark A. Guarnera, Giorgio T. Goldstein, Allan L. BE Goldstein, AL Garaci, E TI The regenerative peptide thymosin beta 4 accelerates the rate of dermal healing in preclinical animal models and in patients SO THYMOSINS IN HEALTH AND DISEASE II SE Annals of the New York Academy of Sciences LA English DT Article; Proceedings Paper CT 3rd International Symposium on Thymosins in Health and Disease CY MAR 14-16, 2012 CL Washington, DC SP George Washington Univ, Ist Superiore Sanita (ISS), Univ Rome Tor Vergata DE dermal wounds; stasis ulcers; pressure ulcers; clinical trial; thymosin beta 4 ID REPAIR; FLUID; QUANTIFICATION; PROTEIN; BETA(4); FUTURE AB Chronic nonhealing cutaneous wounds are a worldwide problem with no agent able to promote healing. A naturally occurring, endogenous repair molecule, thymosin beta 4 (T beta 4), has many biological activities that promote dermal repair. It is released by platelets at the site of injury and initiates the repair cascade. T beta 4 accelerated dermal healing of full-thickness punch wounds in various animal models, including normal rats and mice, steroid-treated rats, diabetic mice, and aged mice. Furthermore, in two phase 2 clinical trials of stasis and pressure ulcers, it was found to accelerate healing by almost a month in those patients that did heal. T beta 4 likely acts to repair and regenerate wounds by promoting cell migration and stem cell mobilization and differentiation, and by inhibiting inflammation, apoptosis, and infection. We conclude that T beta 4 is a multifunctional regenerative peptide important in dermal repair. C1 [Treadwell, Terry] Inst Adv Wound Care, Montgomery, AL USA. [Kleinman, Hynda K.; Goldstein, Allan L.] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Washington, DC 20037 USA. [Crockford, David] RegeneRx Biopharmaceut Inc, Rockville, MD USA. [Hardy, Mark A.] Columbia Univ, Coll Phys & Surg, Dept Surg, New York, NY USA. [Guarnera, Giorgio T.] Ist Dermatopad Immacolata, Rome, Italy. RP Kleinman, HK (reprint author), NIDCR, NIH, Bldg 30,Room 402,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM hkleinman@dir.nidcr.nih.gov NR 29 TC 11 Z9 13 U1 1 U2 5 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND SN 0077-8923 BN 978-1-57331-910-2 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2012 VL 1270 BP 37 EP 44 DI 10.1111/j.1749-6632.2012.06717.x PG 8 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental; Multidisciplinary Sciences SC Biochemistry & Molecular Biology; Research & Experimental Medicine; Science & Technology - Other Topics GA BDB63 UT WOS:000312489700007 PM 23050815 ER PT J AU Yoshimi, R Ueda, A Ozato, K Ishigatsubo, Y AF Yoshimi, Ryusuke Ueda, Atsuhisa Ozato, Keiko Ishigatsubo, Yoshiaki TI Clinical and Pathological Roles of Ro/SSA Autoantibody System SO CLINICAL & DEVELOPMENTAL IMMUNOLOGY LA English DT Review ID RO SS-A; CONGENITAL HEART-BLOCK; NEONATAL LUPUS-ERYTHEMATOSUS; PRIMARY SJOGRENS-SYNDROME; EXTRACTABLE NUCLEAR ANTIGENS; CONNECTIVE-TISSUE DISEASES; INTERSTITIAL LUNG-DISEASE; SMALL CYTOPLASMIC RIBONUCLEOPROTEINS; IDIOPATHIC INFLAMMATORY MYOPATHY; CULTURED HUMAN KERATINOCYTES AB Anti-Ro/SSA antibodies are among the most frequently detected autoantibodies against extractable nuclear antigens and have been associated with systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). Although the presence of these autoantibodies is one of the criteria for the diagnosis and classification of SS, they are also sometimes seen in other systemic autoimmune diseases. In the last few decades, the knowledge of the prevalence of anti-Ro/SSA antibodies in various autoimmune diseases and symptoms has been expanded, and the clinical importance of these antibodies is increasing. Nonetheless, the pathological role of the antibodies is still poorly understood. In this paper, we summarize the milestones of the anti-Ro/SSA autoantibody system and provide new insights into the association between the autoantibodies and the pathogenesis of autoimmune diseases. C1 [Yoshimi, Ryusuke; Ueda, Atsuhisa; Ishigatsubo, Yoshiaki] Yokohama City Univ, Grad Sch Med, Dept Internal Med & Clin Immunol, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan. [Ozato, Keiko] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Yoshimi, R (reprint author), Yokohama City Univ, Grad Sch Med, Dept Internal Med & Clin Immunol, Kanazawa Ku, 3-9 Fukuura, Yokohama, Kanagawa 2360004, Japan. EM yoshiryu@med.yokohama-cu.ac.jp OI Yoshimi, Ryusuke/0000-0002-3945-307X FU Japan Society for the Promotion of Science KAKENHI [23791118]; Kanagawa Nanbyo Study Foundation; Intramural Program of NICHD, National Institutes of Health, USA FX The authors thank Mr. Tom Kiper for his review of the paper. This work was supported by research Grants from Japan Society for the Promotion of Science KAKENHI (no. 23791118) (R. Yoshimi) and Kanagawa Nanbyo Study Foundation (R. Yoshimi). This work was also supported partly by the Intramural Program of NICHD, National Institutes of Health, USA. NR 162 TC 12 Z9 14 U1 0 U2 4 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1740-2522 J9 CLIN DEV IMMUNOL JI Clin. Dev. Immunol. PY 2012 AR 606195 DI 10.1155/2012/606195 PG 12 WC Immunology SC Immunology GA 054AK UT WOS:000312316200001 ER PT J AU Rezlescu, C Pitcher, D Duchaine, B AF Rezlescu, Constantin Pitcher, David Duchaine, Brad TI Acquired prosopagnosia with spared within-class object recognition but impaired recognition of degraded basic-level objects SO COGNITIVE NEUROPSYCHOLOGY LA English DT Article DE Acquired prosopagnosia; Case study; Face perception; Domain specificity; Object recognition ID FUSIFORM FACE AREA; DEVELOPMENTAL PROSOPAGNOSIA; EXTRASTRIATE CORTEX; TEMPORAL CORTEX; LIVING THINGS; MEMORY TEST; PERCEPTION; AGNOSIA; IMPAIRMENTS; MECHANISMS AB We present a new case of acquired prosopagnosia resulting from extensive lesions predominantly in the right occipitotemporal cortex. Functional brain imaging revealed atypical activation of all core face areas in the right hemisphere, with reduced signal difference between faces and objects compared to controls. In contrast, Herschel's lateral occipital complex showed normal activation to objects. Behaviourally, Herschel is severely impaired with the recognition of familiar faces, discrimination between unfamiliar identities, and the perception of facial expression and gender. Notably, his visual recognition deficits are largely restricted to faces, suggesting that the damaged mechanisms are face-specific. He showed normal recognition memory for a wide variety of object classes in several paradigms, normal ability to discriminate between highly similar items within a novel object category, and intact ability to name basic objects (except four-legged animals). Furthermore, Herschel displayed a normal face composite effect and typical global advantage and global interference effects in the Navon task, suggesting spared integration of both face and nonface information. Nevertheless, he failed visual closure tests requiring recognition of basic objects from degraded images. This abnormality in basic object recognition is at odds with his spared within-class recognition and presents a challenge to hierarchical models of object perception. C1 [Rezlescu, Constantin] UCL, Dept Cognit Perceptual & Brain Sci, London WC1H 0AP, England. [Pitcher, David] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Duchaine, Brad] Dartmouth Coll, Dept Psychol & Brain Sci, Hanover, NH 03755 USA. RP Rezlescu, C (reprint author), UCL, Dept Cognit Perceptual & Brain Sci, 26 Bedford Way, London WC1H 0AP, England. EM c.rezlescu@ucl.ac.uk RI Rezlescu, Constantin/C-3314-2012 OI Rezlescu, Constantin/0000-0001-8960-6305 FU AXA Research Fund FX This research was partly supported by a PhD fellowship from the AXA Research Fund to C. R. We thank Herschel for his participation and enthusiasm and Lucia Garrido and Nicole Whitty for help with running some of the tests. NR 80 TC 16 Z9 16 U1 5 U2 26 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0264-3294 J9 COGN NEUROPSYCHOL JI Cogn. Neuropsychol. PY 2012 VL 29 IS 4 BP 325 EP 347 DI 10.1080/02643294.2012.749223 PG 23 WC Psychology; Psychology, Experimental SC Psychology GA 055VN UT WOS:000312446000002 PM 23216309 ER PT J AU Lewis, JD Wassermann, EM Chao, WD Ramage, AE Robin, DA Clauw, DJ AF Lewis, Jeffrey D. Wassermann, Eric M. Chao, Wendy Ramage, Amy E. Robin, Donald A. Clauw, Daniel J. TI Central sensitization as a component of post-deployment syndrome SO NEUROREHABILITATION LA English DT Article DE Chronic widespread pain; post-deployment; mild traumatic brain injury ID CHRONIC-FATIGUE-SYNDROME; IRRITABLE-BOWEL-SYNDROME; PERSIAN-GULF-WAR; POSTINJURY PAIN HYPERSENSITIVITY; POSTTRAUMATIC-STRESS-DISORDER; CHRONIC WIDESPREAD PAIN; POSTCONCUSSIVE SYMPTOMS; FIBROMYALGIA SYNDROME; MUSCULOSKELETAL PAIN; SOMATIC SYMPTOMS AB Many service members and veterans report chronic unexplained symptoms such as pain, fatigue and memory complaints, which have most recently been characterized as post-deployment syndrome (PDS). Chronic widespread pain is a component of this syndrome, producing significant disability and considerable health care costs. The similarity between the nature of these complaints and other medically unexplained illnesses such as fibromyalgia, irritable bowel syndrome, and chronic fatigue syndrome suggest that they may share a common mechanism. Here, we provide support for PDS as a consequence of pain and sensory amplification secondary to neuroplastic changes within the central nervous system, a phenomenon often termed central sensitization. We also discuss how factors such as stress and genetics may promote chronic widespread pain in veterans and service members who develop PDS. C1 [Lewis, Jeffrey D.; Wassermann, Eric M.] NINDS, Behav Neurol Unit, Bethesda, MD 20892 USA. [Lewis, Jeffrey D.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Chao, Wendy] Brooke Army Med Ctr, Dept Neurol, Ft Sam Houston, TX 78234 USA. [Ramage, Amy E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Robin, Donald A.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Clauw, Daniel J.] Univ Michigan, Chron Pain & Fatigue Ctr, Ann Arbor, MI 48109 USA. RP Wassermann, EM (reprint author), Behav Neurol Univ, NINDS, 10 Ctr Dr,MSC 1440,Bldg 10,Room 7D43, Bethesda, MD 20892 USA. EM Wassermanne@ninds.nih.gov RI Schueter, nicos/A-3625-2014 FU Intramural NIH HHS [Z99 NS999999] NR 76 TC 8 Z9 8 U1 1 U2 9 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 1053-8135 J9 NEUROREHABILITATION JI Neurorehabilitation PY 2012 VL 31 IS 4 BP 367 EP 372 DI 10.3233/NRE-2012-00805 PG 6 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 052GV UT WOS:000312186600004 PM 23232159 ER PT J AU Kim, S Sundaram, R Louis, GMB Pyper, C AF Kim, Sungduk Sundaram, Rajeshwari Louis, Germaine M. Buck Pyper, Cecilia TI Flexible Bayesian Human Fecundity Models SO BAYESIAN ANALYSIS LA English DT Article DE Conception; Fecundity; Generalized t-distribution; Generalized nonlinear model; Markov chain Monte Carlo; Menstrual Cycle; Posterior distribution ID BINARY REGRESSION; MENSTRUAL-CYCLE; HUMAN-FERTILITY; RESPONSE DATA; CONCEPTION; FECUNDABILITY; INTERCOURSE; PREGNANCY; OVULATION; PROBABILITIES AB Human fecundity is an issue of considerable interest for both epidemiological and clinical audiences, and is dependent upon a couple's biologic capacity for reproduction coupled with behaviors that place a couple at risk for pregnancy. Bayesian hierarchical models have been proposed to better model the conception probabilities by accounting for the acts of intercourse around the day of ovulation, i.e., during the fertile window. These models can be viewed in the framework of a generalized nonlinear model with an exponential link. However, a fixed choice of link function may not always provide the best fit, leading to potentially biased estimates for probability of conception. Motivated by this, we propose a general class of models for fecundity by relaxing the choice of the link function under the generalized nonlinear model framework. We use a sample from the Oxford Conception Study (OCS) to illustrate the utility and fit of this general class of models for estimating human conception. Our findings reinforce the need for attention to be paid to the choice of link function in modeling conception, as it may bias the estimation of conception probabilities. Various properties of the proposed models are examined and a Markov chain Monte Carlo sampling algorithm was developed for implementing the Bayesian computations. The deviance information criterion measure and logarithm of pseudo marginal likelihood are used for guiding the choice of links. The supplemental material section contains technical details of the proof of the theorem stated in the paper, and contains further simulation results and analysis. C1 [Kim, Sungduk; Sundaram, Rajeshwari; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Pyper, Cecilia] Univ Oxford, Natl Perinatal Epidemiol Unit, Oxford, England. RP Kim, S (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. EM kims2@mail.nih.gov; sundaramr2@mail.nih.gov; louisg@mail.nih.gov; cilia.pyper@npeu.ox.ac.uk OI Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development; U.K. National Health Service Executive Primary Care Career Scientist and Service Research and Development Awards FX The research work of the three authors, Drs. Kim, Sundaram, and Louis, is supported by the Intramural Research Program of National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. This work was done when Dr. Kim was a research fellow with Dr. Sundaram. The research work of Dr Pyper was supported in part by the U.K. National Health Service Executive Primary Care Career Scientist and Service Research and Development Awards. NR 40 TC 1 Z9 1 U1 0 U2 4 PU INT SOC BAYESIAN ANALYSIS PI PITTSBURGH PA CARNEGIE MELLON UNIV, DEPT STTISTICS, PITTSBURGH, PA 15213 USA SN 1931-6690 J9 BAYESIAN ANAL JI Bayesian Anal. PY 2012 VL 7 IS 4 BP 771 EP 799 DI 10.1214/12-BA726 PG 29 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA 049ID UT WOS:000311975100001 PM 27375829 ER PT J AU Kim, S Sundaram, R Louis, GMB Pyper, C AF Kim, Sungduk Sundaram, Rajeshwari Louis, Germaine M. Buck Pyper, Cecilia TI Rejoinder SO BAYESIAN ANALYSIS LA English DT Editorial Material ID SELECTION; MODELS C1 [Kim, Sungduk; Sundaram, Rajeshwari; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Pyper, Cecilia] Univ Oxford, Natl Perinatal Epidemiol Unit, Oxford, England. RP Kim, S (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. EM kims2@mail.nih.gov; sundaramr2@mail.nih.gov; louisg@mail.nih.gov; cilia.pyper@npeu.ox.ac.uk OI Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural NIH HHS [Z99 HD999999] NR 6 TC 1 Z9 1 U1 0 U2 0 PU INT SOC BAYESIAN ANALYSIS PI PITTSBURGH PA CARNEGIE MELLON UNIV, DEPT STTISTICS, PITTSBURGH, PA 15213 USA SN 1931-6690 J9 BAYESIAN ANAL JI Bayesian Anal. PY 2012 VL 7 IS 4 BP 809 EP 812 DI 10.1214/12-BA726REJ PG 4 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA 049ID UT WOS:000311975100004 PM 26949437 ER PT J AU Resnik, DB AF Resnik, David B. BE Garrett, JR TI Ethical Issues Concerning Transgenic Animals in Biomedical Research SO ETHICS OF ANIMAL RESEARCH: EXPLORING THE CONTROVERSY SE Basic Bioethics LA English DT Article; Book Chapter ID 3 RS C1 NIEHS, Inst Review Board, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, Inst Review Board, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 24 TC 0 Z9 0 U1 1 U2 2 PU MIT PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA BN 978-0-262-30239-5 J9 BASIC BIOETH PY 2012 BP 169 EP 179 PG 11 WC Ethics; Medical Ethics SC Social Sciences - Other Topics; Medical Ethics GA BCH55 UT WOS:000310209200011 ER PT J AU Wust, S van den Brandt, J Reichardt, HM Luhder, F AF Wuest, Simone van den Brandt, Jens Reichardt, Holger M. Luehder, Fred TI Preventive Treatment with Methylprednisolone Paradoxically Exacerbates Experimental Autoimmune Encephalomyelitis SO INTERNATIONAL JOURNAL OF ENDOCRINOLOGY LA English DT Article ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; HIGH-DOSE METHYLPREDNISOLONE; REGULATORY T-CELLS; MULTIPLE-SCLEROSIS; LIPOSOMAL GLUCOCORTICOSTEROIDS; ANIMAL-MODELS; THERAPY; EFFICACY; CORTICOSTEROIDS; STEROIDS AB Glucocorticoids (GCs) represent the standard treatment for acute disease bouts in multiple sclerosis (MS) patients, for which methylprednisolone (MP) pulse therapy is the most frequently used protocol. Here, we compared the efficacy of therapeutic and preventive MP application in MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE) in C57Bl/6 mice. When administered briefly after the onset of the disease, MP efficiently ameliorated EAE in a dose-dependent manner. Surprisingly, MP administration around the time of immunization was contraindicated as it even increased leukocyte infiltration into the CNS and worsened the disease symptoms. Our analyses suggest that in the latter case an incomplete depletion of peripheral T cells by MP triggers homeostatic proliferation, which presumably results in an enhanced priming of autoreactive T cells and causes an aggravated disease course. Thus, the timing and selection of a particular GC derivative require careful consideration in MS therapy. C1 [van den Brandt, Jens; Reichardt, Holger M.] Univ Gottingen, Sch Med, Inst Cellular & Mol Immunol, D-37073 Gottingen, Germany. [Wuest, Simone; Luehder, Fred] Univ Gottingen, Inst Multiple Sclerosis Res, D-37073 Gottingen, Germany. [Wuest, Simone; Luehder, Fred] Gemeinnutzige Hertie Stiftung, D-37073 Gottingen, Germany. [Wuest, Simone] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [van den Brandt, Jens] Ernst Moritz Arndt Univ Greifswald, Sch Med, Dept Lab Anim Sci, D-17489 Greifswald, Germany. RP Reichardt, HM (reprint author), Univ Gottingen, Sch Med, Inst Cellular & Mol Immunol, Humboldtallee 34, D-37073 Gottingen, Germany. EM hreichardt@med.uni-goettingen.de; fred.luehder@med.uni-goettingen.de FU Gemeinnutzige Hertie-Stiftung [1.01.1/06/010]; DFG [LU 634/8-1, SFB-TRR 43, TP B11, B13] FX The authors would like to thank Alexandra Bohl, Martina Weig, and Regine Kruse for technical assistance. They are grateful to H. Luche and H. J. Fehling, University Clinics Ulm, Germany, for the generous gift of RFP-expressing mice. This work was supported by Grants from the Gemeinnutzige Hertie-Stiftung (1.01.1/06/010) and the DFG (LU 634/8-1; SFB-TRR 43; TP B11 and B13). NR 29 TC 2 Z9 2 U1 0 U2 2 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1687-8337 J9 INT J ENDOCRINOL JI Int. J. Endocrinol. PY 2012 AR 417017 DI 10.1155/2012/417017 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 050DC UT WOS:000312031800001 ER PT J AU Ardeshirpour, Y Gandjbakhche, AH Najafizadeh, L AF Ardeshirpour, Yasaman Gandjbakhche, Amir H. Najafizadeh, Laleh TI Biophotonics techniques for structural and functional imaging, in vivo SO ANALYTICAL CELLULAR PATHOLOGY LA English DT Review DE Diffuse optical imaging; near infrared spectroscopy; functional brain imaging; fluorescence imaging; targeted fluorescent probe; Affibody; cancer treatment; cancer diagnostics; human epidermal growth factor receptor 2 ID NEAR-INFRARED SPECTROSCOPY; DIFFUSE OPTICAL TOMOGRAPHY; FLUORESCENCE MOLECULAR TOMOGRAPHY; INDEPENDENT COMPONENT ANALYSIS; MEASUREMENT DENSITY-FUNCTIONS; CEREBRAL OXYGENATION CHANGES; BENIGN BREAST-LESIONS; HUMAN BRAIN-FUNCTION; VISUAL-CORTEX; MOTOR-CORTEX AB In vivo optical imaging is being conducted in a variety of medical applications, including optical breast cancer imaging, functional brain imaging, endoscopy, exercise medicine, and monitoring the photodynamic therapy and progress of neoadjuvant chemotherapy. In the past three decades, in vivo diffuse optical breast cancer imaging has shown promising results in cancer detection, and monitoring the progress of neoadjuvant chemotherapy. The use of near infrared spectroscopy for functional brain imaging has been growing rapidly. In fluorescence imaging, the difference between autofluorescence of cancer lesions compared to normal tissues were used in endoscopy to distinguish malignant lesions from normal tissue or inflammation and in determining the boarders of cancer lesions in surgery. Recent advances in drugs targeting specific tumor receptors, such as AntiBodies (MAB), has created a new demand for developing non-invasive in vivo imaging techniques for detection of cancer biomarkers, and for monitoring their down regulations during therapy. Targeted treatments, combined with new imaging techniques, are expected to potentially result in new imaging and treatment paradigms in cancer therapy. Similar approaches can potentially be applied for the characterization of other disease-related biomarkers. In this chapter, we provide a review of diffuse optical and fluorescence imaging techniques with their application in functional brain imaging and cancer diagnosis. C1 [Ardeshirpour, Yasaman; Gandjbakhche, Amir H.; Najafizadeh, Laleh] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Funct & Analyt Biophoton, NIH, Bethesda, MD USA. [Najafizadeh, Laleh] Henry M Jackson Fdn, Ctr Neurosci & Regenerat Med, Rockville, MD USA. RP Gandjbakhche, AH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Funct & Analyt Biophoton, NIH, Bethesda, MD USA. EM gandjbaa@mail.nih.gov FU intramural program of the Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health; Centre for Neuroscience and Regenerative Medicine, Henry Jackson Foundation FX The authors acknowledge the intramural program of the Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health, and the Centre for Neuroscience and Regenerative Medicine, Henry Jackson Foundation for support of their research. NR 166 TC 1 Z9 1 U1 1 U2 25 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 2210-7177 J9 ANAL CELL PATHOL JI Anal. Cell. Pathol. PY 2012 VL 35 IS 5-6 BP 317 EP 337 DI 10.3233/ACP-2012-0058 PG 21 WC Oncology; Cell Biology; Pathology SC Oncology; Cell Biology; Pathology GA 045DS UT WOS:000311675800001 PM 22433452 ER PT J AU Gonzalez, FJ AF Gonzalez, Frank J. TI ADDRESSING THE MECHANISM OF CLINICAL DRUG TOXICITY USING ANIMAL MODELS AND METABOLOMICS SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 18th North American Regional International-Society-for-the-Study-of-Xenobiotics (ISSX) Meeting CY OCT 14-18, 2012 CL Dallas, TX SP Int Soc Study Xenobiot (ISSX) C1 [Gonzalez, Frank J.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2012 VL 44 SU 1 BP 17 EP 18 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 045EC UT WOS:000311676800032 ER PT J AU Gottesman, M Fung, A Gillet, JP AF Gottesman, Michael Fung, Andy Gillet, Jean-Pierre TI RELEVANCE OF MULTIDRUG TRANSPORTERS TO MULTIDRUG RESISTANCE IN CLINICAL CANCER SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 18th North American Regional International-Society-for-the-Study-of-Xenobiotics (ISSX) Meeting CY OCT 14-18, 2012 CL Dallas, TX SP Int Soc Study Xenobiot (ISSX) C1 [Gottesman, Michael; Fung, Andy; Gillet, Jean-Pierre] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2012 VL 44 SU 1 BP 17 EP 17 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 045EC UT WOS:000311676800031 ER PT J AU Gotoh, S Negishi, M Kodama, S AF Gotoh, Saki Negishi, Masahiko Kodama, Susumu TI LIGANDED PXR FACILITATES BINDING OF SERUM/GLUCOCORTICOID REGULATED KINASE 2 ISOFORM ALPHA TO THE G6PASE PROMOTER TO ACTIVATE IT SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 18th North American Regional International-Society-for-the-Study-of-Xenobiotics (ISSX) Meeting CY OCT 14-18, 2012 CL Dallas, TX SP Int Soc Study Xenobiot (ISSX) C1 [Gotoh, Saki; Negishi, Masahiko] NIEHS, NIH, Bethesda, MD 20892 USA. [Kodama, Susumu] Tohoku Univ, Sendai, Miyagi 980, Japan. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2012 VL 44 SU 1 BP 33 EP 33 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 045EC UT WOS:000311676800065 ER PT J AU Zou, P Stern, ST Helson, L Maitra, A McNeil, SE AF Zou, Peng Stern, Stephan T. Helson, Lawrence Maitra, Anirban McNeil, Scott E. TI EVALUATION OF DMPK AND IN VIVO RELEASE OF A CURCUMIN NANOFORMULATION IN BILE DUCT CANNULATED RATS SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 18th North American Regional International-Society-for-the-Study-of-Xenobiotics (ISSX) Meeting CY OCT 14-18, 2012 CL Dallas, TX SP Int Soc Study Xenobiot (ISSX) C1 [Zou, Peng] NCI Frederick, Frederick, MD USA. [Stern, Stephan T.; McNeil, Scott E.] SAIC Frederick, Nanotechnol Characterizat Lab, Frederick, MD USA. [Maitra, Anirban] Johns Hopkins Univ, Baltimore, MD 21218 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2012 VL 44 SU 1 BP 51 EP 51 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 045EC UT WOS:000311676800099 ER PT J AU Sueyoshi, T Li, LH Wang, HB Moore, R Kodavanti, PRS Lehmler, HJ Negishi, M Birnbaum, L AF Sueyoshi, Tatsuya Li, Linhao Wang, Hongbing Moore, Rick Kodavanti, Prasada Rao S. Lehmler, Hans-Joachim Negishi, Masahiko Birnbaum, Linda TI FLAME RETARDANT BDE-47 EFFECTIVELY ACTIVATES THE NUCLEAR RECEPTOR CAR IN HUMAN PRIMARY HEPATOCYTES SO DRUG METABOLISM REVIEWS LA English DT Meeting Abstract CT 18th North American Regional International-Society-for-the-Study-of-Xenobiotics (ISSX) Meeting CY OCT 14-18, 2012 CL Dallas, TX SP Int Soc Study Xenobiot (ISSX) C1 [Sueyoshi, Tatsuya; Moore, Rick; Negishi, Masahiko; Birnbaum, Linda] NIEHS, NIH, Res Triangle Pk, NC USA. [Li, Linhao; Wang, Hongbing] Univ Maryland, Baltimore, MD 21201 USA. [Kodavanti, Prasada Rao S.] US EPA, Washington, DC USA. [Lehmler, Hans-Joachim] Univ Iowa, Iowa City, IA 52242 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PY 2012 VL 44 SU 1 BP 111 EP 112 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 045EC UT WOS:000311676800221 ER PT J AU Tremblay, CA Uribe, MR Peaceman, D Salit, RB Pavletic, S Adams, SD Flegel, WA AF Tremblay, Christine A. Uribe, Marcela R. Peaceman, Daniel Salit, Rachel B. Pavletic, Steven Adams, Sharon D. Flegel, Willy A. TI RELATIONSHIP BETWEEN HLA RESTRICTED MINOR HISTOCOMPATIBILITY ANTIGENS AND GRAFT VERSUS HOST DISEASE IN PATIENTS FOLLOWING MATCHED UNRELATED PERIPHERAL BLOOD STEM CELL ALLOGRAFTS SO HUMAN IMMUNOLOGY LA English DT Meeting Abstract CT 38th Annual Meeting of the American-Society-for-Histocompatibility-and-Immunogenetics CY OCT 08-12, 2012 CL San Juan, PR SP Amer Soc Histocompatibil & Immunogenet C1 [Tremblay, Christine A.; Uribe, Marcela R.; Adams, Sharon D.; Flegel, Willy A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Peaceman, Daniel; Salit, Rachel B.; Pavletic, Steven] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PY 2012 VL 73 SU 1 BP 41 EP 41 PG 1 WC Immunology SC Immunology GA 038QO UT WOS:000311189400052 ER PT J AU Conradt, E Manian, N Bornstein, MH AF Conradt, Elisabeth Manian, Nanmathi Bornstein, Marc H. TI Screening for depression in the postpartum using the Beck Depression Inventory II: What logistic regression reveals SO JOURNAL OF REPRODUCTIVE AND INFANT PSYCHOLOGY LA English DT Article DE Postpartum depression; Beck Depression Inventory-II; screening ID PERINATAL DEPRESSION; POSTNATAL DEPRESSION; WOMEN; RISK; PSYCHOPATHOLOGY; MOTHERS; SCALE AB Objective: To identify items on the Beck Depression Inventory-II (BDI-II) that best discriminate between clinically depressed and nondepressed postpartum women. Background: Postpartum depression is a serious and widespread health burden, and the BDI-II is commonly used to detect depression in the postpartum. Yet certain depressive symptoms are 'normative' sequelae of childbirth, calling into question the discriminative utility of the BDI-II. Methods: We examined the prospective contribution of BDI-II items to identify items that have the strongest relation with clinical postpartum depression. Women with BDI-II scores >12 were invited to participate in a structured clinical interview. A logistic regression was conducted to determine which BDI-II items discriminated between women who were later diagnosed as Depressed (n = 75) and Nondepressed (n = 78). Results: Of the 11 BDI-II items that differed between the two groups, eight represented cognitive/affective symptoms. Results from the logistic regression indicated that four BDI-II symptoms were significant predictors of Depression status: sadness, pessimism, loss of interest, and changes in appetite. Conclusion: The BDI-II should be used in the postpartum with caution. Professionals who screen for postpartum depression should pay particular attention to cognitive/affective symptoms, as they appear more robust to normative physical and emotional changes that occur in the postpartum. C1 [Conradt, Elisabeth] Women & Infants Hosp Rhode Isl, Dept Pediat, Brown Ctr Study Children Risk, Providence, RI 02908 USA. [Conradt, Elisabeth] Brown Univ, Dept Psychiat, Warren Alpert Med Sch, Providence, RI 02912 USA. [Manian, Nanmathi; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MA USA. RP Conradt, E (reprint author), Women & Infants Hosp Rhode Isl, Dept Pediat, Brown Ctr Study Children Risk, Providence, RI 02908 USA. EM econradt@wihri.org FU Intramural NIH HHS [ZIA HD001119-25]; NIDA NIH HHS [F32 DA032175] NR 31 TC 2 Z9 2 U1 0 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0264-6838 J9 J REPROD INFANT PSYC JI J. Reprod. Infant Psychol. PY 2012 VL 30 IS 5 BP 427 EP 435 DI 10.1080/02646838.2012.743001 PG 9 WC Psychology, Multidisciplinary SC Psychology GA 046SL UT WOS:000311784600002 PM 23569330 ER PT J AU Wade, CH Shiloh, S Roberts, JS Alford, SH Marteau, TM Biesecker, B AF Wade, C. H. Shiloh, S. Roberts, J. S. Alford, S. Hensley Marteau, T. M. Biesecker, B. TI Preferences among Diseases on a Genetic Susceptibility Test for Common Health Conditions: An Ancillary Study of the Multiplex Initiative SO PUBLIC HEALTH GENOMICS LA English DT Article ID CONSENT C1 [Wade, C. H.] Univ Washington, Dept Nursing & Hlth Studies, Bothell, WA 98011 USA. [Shiloh, S.] Tel Aviv Univ, Dept Psychol, IL-69978 Tel Aviv, Israel. [Roberts, J. S.] Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. [Alford, S. Hensley] Henry Ford Hlth Syst, Dept Biostat & Res Epidemiol, Detroit, MI USA. [Marteau, T. M.] Kings Coll London, Dept Psychol, London WC2R 2LS, England. [Biesecker, B.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP Wade, CH (reprint author), Univ Washington, Dept Nursing & Hlth Studies, Box 358532,18115 Campus Way NE, Bothell, WA 98011 USA. EM cwade@uwb.edu OI Marteau, Theresa/0000-0003-3025-1129 FU National Human Genome Research Institute, National Institutes of Health; National Cancer Institute [U19CA 079689]; National Institutes of Health [HHSN268200782096C] FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The proposed research was made possible through a collaboration with the Cancer Research Network funded by the National Cancer Institute (U19CA 079689). Group Health Research Institute and Henry Ford Hospital provided additional resources. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (HHSN268200782096C). Additionally, this research was supported in part by an appointment to the Senior Fellowship Program at the National Institutes of Health. This program is administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the National Institutes of Health. NR 20 TC 6 Z9 6 U1 2 U2 8 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1662-4246 J9 PUBLIC HEALTH GENOM JI Pub. Health Genomics PY 2012 VL 15 IS 6 BP 322 EP 326 DI 10.1159/000338114 PG 5 WC Genetics & Heredity; Public, Environmental & Occupational Health SC Genetics & Heredity; Public, Environmental & Occupational Health GA 046PZ UT WOS:000311778200002 PM 22688356 ER PT J AU Li, X Wu, W Chung, Y Shih, WY Shih, WH Zhou, QF Shung, KK AF Li, Xiang Wu, Wei Chung, Youngsoo Shih, Wan Y. Shih, Wei-Heng Zhou, Qifa Shung, K. Kirk GP IEEE TI 80 MHz Intravascular Ultrasound (IVUS) Transducer SO 2011 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) LA English DT Proceedings Paper CT IEEE International Ultrasonics Symposium (IUS) CY OCT 18-21, 2011 CL Orlando, FL SP IEEE, PZFlex, Avago Technologies DE IVUS; PMN-PT; Thin Film; High Frequency ID FILMS AB [Pb(Mg1/3Nb2/3)O-3]0.63[PbTiO3]0.37 (PMN-PT) free-standing film of comparable piezoelectric properties to bulk material with thickness of 30 mu m has been fabricated using a modified precursor coating approach. At 1 kHz, the dielectric permittivity and loss were 4,364 and 0.033, respectively. The remnant polarization and coercive field were 28 mu C/cm(2) and 18.43 kV/cm. The electromechanical coupling coefficient k(t) was measured to be 0.55, which was close to that of bulk PMN-PT single crystal material. Based on this film, high frequency (82 MHz) miniature ultrasonic transducers were fabricated with 65% bandwidth and 23 dB insertion loss. Axial and lateral resolutions were determined to be as high as 35 mu m and 176 mu m. In vitro intravascular imaging on healthy rabbit aorta and human coronary artery was performed from the thin film transducers. In comparison with a 35 MHz IVUS transducer, the 80 MHz one showed superior resolution and contrast with satisfactory penetration depth. The imaging results suggest that PMN-PT free-standing thin film technology is a feasible and efficient way in fabricating very high frequency ultrasonic transducers. C1 [Li, Xiang; Zhou, Qifa; Shung, K. Kirk] Univ Southern Calif, NIH, Ultrason Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Wu, Wei; Chung, Youngsoo; Shih, Wei-Heng] Drexel Univ, Dept Mat Sci & Engn, Philadelphia, PA 19104 USA. [Shih, Wan Y.] Drexel Univ, Sch Biomed Engn, Philadelphia, PA 19010 USA. [Shih, Wan Y.] Drexel Univ, Hlth Syst, Philadelphia, PA 19010 USA. RP Li, X (reprint author), Univ Southern Calif, NIH, Ultrason Transducer Resource Ctr, Los Angeles, CA 90089 USA. FU NIH [P41-EB2182]; Nanotechnology Institute; Commonwealth of Pennsylvania's Ben Franklin Technology Development Authority through Ben Franklin Technology; USC Provost Fellowship FX We would like to thank Mr. Jay Williams for transducer fabrication; Ms. Jiechen Yin, Mr. Wei Wei and Dr. Zhongping Chen for providing the tissue samples. This project is supported in part by the NIH grant #P41-EB2182 and by the Nanotechnology Institute, a University Grant program of the Commonwealth of Pennsylvania's Ben Franklin Technology Development Authority through Ben Franklin Technology Partners of Southeast Pennsylvania. Mr. Xiang Li is supported in part by USC Provost Fellowship. NR 10 TC 0 Z9 0 U1 0 U2 4 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1252-4 PY 2012 BP 222 EP 225 DI 10.1109/ULTSYM.2011.0054 PG 4 WC Engineering, Electrical & Electronic SC Engineering GA BCD91 UT WOS:000309918400053 ER PT J AU Ballyns, JJ Otto, P Shah, JP Hammond, J Heimur, J Gebreab, T Gerber, LH Sikdar, S AF Ballyns, J. J. Otto, P. Shah, J. P. Hammond, J. Heimur, J. Gebreab, T. Gerber, L. H. Sikdar, S. GP IEEE TI Evaluation of Shear Properties in Muscle Tissue Via Novel Superficial Elastography Technique SO 2011 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) LA English DT Proceedings Paper CT IEEE International Ultrasonics Symposium (IUS) CY OCT 18-21, 2011 CL Orlando, FL SP IEEE, PZFlex, Avago Technologies DE Myofascial Trigger Points; Neck Pain; Shear Wave Elastography; Biomechanics ID MAGNETIC-RESONANCE-ELASTOGRAPHY; MYOFASCIAL TRIGGER POINTS; IN-VIVO; MECHANICAL-PROPERTIES; SKELETAL-MUSCLE; TAUT BANDS; QUANTIFICATION; BREAST; ANISOTROPY; PAIN AB Noninvasive measurement of the mechanical properties of soft tissue is of significant clinical interest. Recent work has demonstrated the ability of ultrasound (US) elastography techniques to measure shear modulus and shear viscosity of bicep muscle and liver tissue in vivo using specialized equipment. The objective of this study was to evaluate a new elastography technique in the upper trapezius muscles in patients with acute neck pain. Ultrasound RF data were acquired from both symptomatic and asymptomatic (pain free) subjects. The upper trapezius muscle was externally vibrated at frequencies in the range of 60 - 200 Hz. The phase of the received RF signals were used to compute the shear wave images that represent the phase of the externally-induced vibration as it travels through the tissue. The spatial gradient of the vibration phase yielded the shear wave velocity, which was used to estimate shear modulus and shear viscosity based on the shear Voigt model for viscoelastic materials. Myofascial Trigger Points (MTrPs) in the upper trapezius had significantly higher shear modulus (12.5 +/- 4.1 kPa) than normal tissue sites (6.4 +/- 2.4 kPa) (P<0.05). The approach presented here provides a quick and effective method for quantitatively measuring region specific shear properties in both normal and symptomatic muscle tissue, and can be easily translated to a clinical setting using commercially-available equipment. C1 [Ballyns, J. J.; Otto, P.; Gerber, L. H.; Sikdar, S.] George Mason Univ, Dept Elect & Comp Engn, Fairfax, VA 22030 USA. [Shah, J. P.; Hammond, J.; Heimur, J.; Gebreab, T.] Natl Inst Hlth, Bethesda, MD USA. RP Sikdar, S (reprint author), George Mason Univ, Dept Elect & Comp Engn, Fairfax, VA 22030 USA. EM ssikdar@gmu.edu FU Intramural Research Program; National Institutes of Health (NIH); Clinical Center and Office of the Director; NIH; National Institutes of Arthritis and Musculoskeletal and Skin Diseases at the NIH [1R01-AR057348] FX This research was supported in part by the Intramural Research Program, National Institutes of Health (NIH), and the Clinical Center and Office of the Director, NIH, and by a grant 1R01-AR057348 from National Institutes of Arthritis and Musculoskeletal and Skin Diseases at the NIH. NR 29 TC 0 Z9 0 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1252-4 PY 2012 BP 668 EP 671 DI 10.1109/ULTSYM.2011.0162 PG 4 WC Engineering, Electrical & Electronic SC Engineering GA BCD91 UT WOS:000309918400160 ER PT J AU Eranki, A Otto, P Curatalo, L Prosser, L Alter, K Damiano, D Sikdar, S AF Eranki, Avinash Otto, Paul Curatalo, Lindsey Prosser, Laura Alter, Katharine Damiano, Diane Sikdar, Siddhartha GP IEEE TI Measurement of Tendon Velocities using Vector Tissue Doppler Imaging and Curved M-Mode in Patients with Cerebral Palsy SO 2011 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) LA English DT Proceedings Paper CT IEEE International Ultrasonics Symposium (IUS) CY OCT 18-21, 2011 CL Orlando, FL SP IEEE, PZFlex, Avago Technologies DE Ultrasonography; vector Doppler; curved m-mode; tissue motion; cerebral palsy; tendon motion; musculoskeletal imaging; signal processing ID MUSCLE; ULTRASOUND AB We have developed two ultrasound-based methods, vector tissue Doppler imaging (vTDI) and curved M-mode (cMM), to directly quantify the magnitude of muscle and tendon velocities. The goal of this study was to investigate the repeatability of the vTDI and cMM system in measuring tendon velocities in vivo and cross validate between these two independent methods. We performed a preliminary study on children with cerebral palsy (CP) who have foot drop (inadequate dorsiflexion during swing phase of gait), and were undergoing treatment using a functional electrical stimulation device. While vTDI estimated peak instantaneous velocity during dorsiflexion, cMM estimated displacement, from which a mean dorsiflexion velocity could be derived. The peak velocities from vTDI and mean velocity from cMM showed strong correlations with peak and mean joint angle velocities from 3D motion capture (R-2 = 0.81 and 0.78, respectively) for all four cases over multiple trials, and the vTDI estimates were consistent with the cMM estimates. These preliminary results demonstrate that direct ultrasonic measurements of muscle and tendon velocities may be used as clinical outcome measures and for studying patients with gait related disorders like CP. C1 [Eranki, Avinash; Otto, Paul; Sikdar, Siddhartha] George Mason Univ, Dept Elect & Comp Engn, Fairfax, VA 22030 USA. [Curatalo, Lindsey; Prosser, Laura; Alter, Katharine; Damiano, Diane] Natl Inst Hlth, Rehabilitat Med Dept, Funct &Appl Biomech Sect, Bethesda, MD 20892 USA. RP Sikdar, S (reprint author), George Mason Univ, Dept Elect & Comp Engn, Fairfax, VA 22030 USA. EM ssikdar@gmu.edu RI Prosser, Laura/C-1242-2009; Damiano, Diane/B-3338-2010; OI Damiano, Diane/0000-0002-2770-5356; Sikdar, Siddhartha/0000-0002-6426-2320 FU National Science Foundation [0953652]; intramural research program at the National Institutes of Health Clinical Center FX This work was supported in part by Grant Number 0953652 from the National Science Foundation and the intramural research program at the National Institutes of Health Clinical Center. NR 14 TC 0 Z9 0 U1 0 U2 3 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1252-4 PY 2012 BP 676 EP 679 DI 10.1109/ULTSYM.2011.0164 PG 4 WC Engineering, Electrical & Electronic SC Engineering GA BCD91 UT WOS:000309918400162 ER PT J AU Yang, HC Cannata, J Williams, J Shung, KK AF Yang, Hao-Chung Cannata, Jonathan Williams, Jay Shung, K. Kirk GP IEEE TI A Study of 1-3 Pseudo-Random Pillar Piezocomposites for Ultrasound Transducers SO 2011 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) LA English DT Proceedings Paper CT IEEE International Ultrasonics Symposium (IUS) CY OCT 18-21, 2011 CL Orlando, FL SP IEEE, PZFlex, Avago Technologies DE Pseudo-Random; Triangle; Square; Pillar; Lateral Interference; Cross-Talk; Piezocomposite ID COMPOSITE TRANSDUCERS; PERFORMANCE; GEOMETRY AB The goal of our research is to develop a new diced 1-3 piezocomposite geometry to reduce pulse-echo ring down and acoustic cross-talk between high frequency ultrasonic array elements. Two PZT-5H based 1-3 composites (10 and 15 MHz) with different pillar geometries (square (SQ), 45 degrees triangle (TR), and pseudo-random (PR)) were fabricated and then made into single element ultrasound transducers. The measured pulse-echo waveforms and their envelopes indicate that the PR composites had the shortest -20 dB pulse length and strongest sensitivity among all the composites. Using these composites, 15 MHz array sub-apertures with a 0.95 lambda pitch were fabricated to measure the acoustic cross-talk between array elements. The combined electrical and acoustical crosstalk between the nearest array elements of the PR array sub-apertures (-32 dB @ 15 MHz) was 6 dB and 2 dB lower than that of the SQ and the TR array sub-apertures, respectively. These results demonstrate that the 1-3 piezocomposite with the pseudo-random pillars may be a good choice for fabricating enhanced high frequency linear array ultrasound transducers; especially when mechanical dicing is used. C1 [Yang, Hao-Chung; Cannata, Jonathan; Williams, Jay; Shung, K. Kirk] Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP Yang, HC (reprint author), Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM yangh@usc.edu NR 11 TC 0 Z9 0 U1 0 U2 3 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4577-1252-4 PY 2012 BP 1743 EP 1746 DI 10.1109/ULTSYM.2011.0435 PG 4 WC Engineering, Electrical & Electronic SC Engineering GA BCD91 UT WOS:000309918400415 ER PT J AU Duarte, H Matta, JR Muldoon, N Masur, H Hadigan, C Gharib, AM AF Duarte, Horacio Matta, Jatin R. Muldoon, Nancy Masur, Henry Hadigan, Colleen Gharib, Ahmed M. TI Non-calcified coronary plaque volume inversely related to CD4(+) T-cell count in HIV infection SO ANTIVIRAL THERAPY LA English DT Article ID MYOCARDIAL-INFARCTION; COMPUTED-TOMOGRAPHY; ATHEROSCLEROSIS; RISK; INHIBITORS; THICKNESS; MEN AB Background: Non-calcified coronary artery plaque (NCAP) might be an important predictor of cardiovascular events; however, few studies have directly measured NCAP in HIV-infected individuals. Methods: We completed a prospective cross-sectional evaluation of NCAP and coronary calcium scores using computed tomography angiography in HIV-infected patients (n=26) without known coronary artery disease (CAD), but who had one or more CAD risk factor(s), and compared them with controls matched on age, race, sex, body mass index and Framingham Risk Score (n=26). Results: There was no difference in coronary calcium scores (114 +/- 218 versus 124 +/- 298; P=0.89) or NCAP volume (65 +/- 86 mm(3) versus 63 +/- 82 mm(3); P=0.38) between HIV-infected patients and controls, respectively. Among HIV-infected patients, lower CD4(+) T-cell count was associated with increased NCAP volume (r=-0.52, P=0.006). The CD4(+) T-cell count remained a significant predictor of NCAP in a multivariate analysis that adjusted for age and duration of antiretroviral therapy. Conclusions: Plaque burden is similar between HIV-infected and uninfected individuals when matched on traditional CAD risk factors; however, immune function might mediate the development of atherosclerosis in HIV infection. C1 [Duarte, Horacio; Hadigan, Colleen] NIAID, NIH, Bethesda, MD 20892 USA. [Matta, Jatin R.; Gharib, Ahmed M.] NIDDKD, Biomed & Metab Imaging Branch, NIH, Bethesda, MD 20892 USA. [Muldoon, Nancy; Masur, Henry] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Hadigan, C (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hadiganc@niaid.nih.gov RI Gharib, Ahmed/O-2629-2016 OI Gharib, Ahmed/0000-0002-2476-481X FU National Institutes of Health FX This research was supported by funds from the intramural programmes of the National Institutes of Health. NR 14 TC 7 Z9 8 U1 0 U2 1 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2012 VL 17 IS 4 BP 763 EP 767 DI 10.3851/IMP1994 PG 5 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 036LK UT WOS:000311027200018 PM 22293714 ER PT J AU Okayama, H Schetter, AJ Harris, CC AF Okayama, Hirokazu Schetter, Aaron J. Harris, Curtis C. TI MicroRNAs and Inflammation in the Pathogenesis and Progression of Colon Cancer SO DIGESTIVE DISEASES LA English DT Article DE MicroRNA; Colorectal cancer; Inflammation; Biomarker; miR-21 ID HUMAN COLORECTAL-CANCER; ULCERATIVE-COLITIS; PROGNOSTIC MARKER; BOWEL-DISEASE; C-MYC; EXPRESSION; CELLS; SENESCENCE; SURVIVAL; MIR-21 AB There is a strong connection between inflammation, altered microRNA (miRNA) expression and colon cancer. Longstanding inflammatory bowel diseases-related colitis leads to increased risk for the development of colorectal cancer (CRC), while sporadic CRC is in part driven by the inflammatory microenvironment. This supports a causative role for inflammation in colon carcinogenesis. miRNAs are a class of small noncoding RNAs that have recently emerged as key players in both inflammation and cancer. Some miRNAs act as inflammatory mediators, others can act as either oncogenes or tumor suppressors depending on the cellular environment in which they are expressed. In particular, miR-21 is an oncogenic miRNA that has been implicated as an inflammatory mediator and may promote inflammation-associated colon carcinogenesis. miRNAs have potential as biomarkers and therapeutic targets in CRC. They are currently being evaluated as early detection biomarkers and prognostic classifiers. Polymorphisms in miRNAs and miRNA-binding sites may alter one's risk of CRC. This review will focus on the role of inflammation and miRNAs in colon carcinogenesis and discuss the potential for miRNAs and inflammatory genes to be used as biomarkers and therapeutic targets of CRC. Copyright (c) 2012 S. Karger AG, Basel C1 [Okayama, Hirokazu; Schetter, Aaron J.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov NR 54 TC 25 Z9 25 U1 0 U2 8 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0257-2753 J9 DIGEST DIS JI Dig. Dis. PY 2012 VL 30 SU 2 BP 9 EP 15 DI 10.1159/000341882 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 042TA UT WOS:000311492700003 PM 23207927 ER PT B AU Faye, ACM Mattison, DR AF Faye, Amy C. Mattison Mattison, Donald R. BE SchenckGustafsson, K DeCola, PR Pfaff, DW Pisetsky, DS TI Drug Disposition and Effect SO HANDBOOK OF CLINICAL GENDER MEDICINE LA English DT Article; Book Chapter ID PHARMACOKINETICS; SEX AB Personalized medicine requires knowledge of factors influencing disease susceptibility and progression as well as effective treatments which minimize adverse drug reactions (ADRs). Surprisingly little attention has focused on the impact of sex on clinical therapeutics. Biological factors governed by sex influence pharmacokinetics and pharmacodynamics. Sex differences in pharmacokinetics and pharmacodynamics should be reflected in drug dose and administration schedules, as well as guidance about desired drug responses and ADRs. Unfortunately, drug labeling seldom includes information concerning sex differences. We review sex differences in pharmacokinetics and pharmacodynamics with special attention to ADRs. C1 [Mattison, Donald R.] Risk Sci Int, Ottawa, ON K1N 7G2, Canada. [Faye, Amy C. Mattison] Univ S Carolina, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Mattison, Donald R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. RP Mattison, DR (reprint author), Risk Sci Int, 325 Dalhousie St,10th Floor, Ottawa, ON K1N 7G2, Canada. EM dmattison@risksciencesint.com NR 21 TC 1 Z9 1 U1 0 U2 0 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND BN 978-3-8055-9929-0 PY 2012 BP 473 EP 479 PG 7 WC Primary Health Care SC General & Internal Medicine GA BCO36 UT WOS:000310829000049 ER PT J AU Laditka, SB Tseng, W Price, AE Ivey, SL Friedman, DB Liu, R Wu, B Logsdon, RG Beard, RL AF Laditka, Sarah B. Tseng, Winston Price, Anna E. Ivey, Susan L. Friedman, Daniela B. Liu, Rui Wu, Bei Logsdon, Rebecca G. Beard, Renee L. TI BELIEFS ABOUT PROMOTING COGNITIVE HEALTH AMONG FILIPINO AMERICANS WHO CARE FOR PERSONS WITH DEMENTIA SO INTERNATIONAL JOURNAL OF AGING & HUMAN DEVELOPMENT LA English DT Article ID PACIFIC ISLANDER AMERICANS; OLDER-ADULTS; PHYSICAL-ACTIVITY; ALZHEIMERS-DISEASE; RISK; BRAIN; PERCEPTIONS; COMMUNICATION; CAREGIVERS; PREVENTION AB We examined beliefs about promoting cognitive health among Filipino Americans who care for persons with dementia, their awareness of media information about cognitive health, and their suggestions for communicating such information to other caregivers. We conducted three focus groups (25 participants). The constant comparison method compared themes across focus groups. Caregivers most frequently described cognitive health benefits of social engagement and leisure; next in emphasis were benefits of healthy diets. There was less emphasis on physical activity. Participants had heard from television that avoiding smoking, alcohol, and drugs might promote cognitive health. Ways to inform others about cognitive health included information in Filipino newspapers, and handouts in Filipino languages, distributed in Filipino stores, workplaces, community organizations, and health care facilities. Findings suggest an opportunity to develop public health messages promoting cognitive health that are in-language, published in ethnic-specific media, and that are culturally appropriate for Filipino and other Asian Americans. C1 [Laditka, Sarah B.] Univ N Carolina, Dept Publ Hlth Sci, Charlotte, NC 28223 USA. [Tseng, Winston; Ivey, Susan L.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Price, Anna E.] Univ Cattolica Sacro Cuore, Fairfield, CT USA. [Friedman, Daniela B.] Univ S Carolina, Columbia, SC 29208 USA. [Liu, Rui] NIEHS, Res Triangle Pk, NC 27709 USA. [Wu, Bei] Duke Univ, Durham, NC USA. [Logsdon, Rebecca G.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Beard, Renee L.] Coll Holy Cross, Worcester, MA 01610 USA. RP Laditka, SB (reprint author), Univ N Carolina, Dept Publ Hlth Sci, 9201 Univ City Blvd, Charlotte, NC 28223 USA. EM sladitka@uncc.edu FU NCCDPHP CDC HHS [1-U48-DP-000045, 1-U48-DP-000025, 1-U48-DP-000033, 1-U48-DP-000048, 1-U48-DP-000050, 1-U48-DP-000051, 1-U48-DP-000052, 1-U48-DP-000054, 1-U48-DP-000059] NR 66 TC 5 Z9 5 U1 4 U2 10 PU BAYWOOD PUBL CO INC PI AMITYVILLE PA 26 AUSTIN AVE, PO BOX 337, AMITYVILLE, NY 11701 USA SN 0091-4150 J9 INT J AGING HUM DEV JI Int. J. Aging Human Dev. PY 2012 VL 75 IS 3 BP 273 EP 296 DI 10.2190/AG.75.3.d PG 24 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 039BU UT WOS:000311218600004 PM 23350346 ER PT J AU Pinsky, PF Berg, CD AF Pinsky, Paul F. Berg, Christine D. TI Applying the National Lung Screening Trial eligibility criteria to the US population: what percent of the population and of incident lung cancers would be covered? SO JOURNAL OF MEDICAL SCREENING LA English DT Article ID MORTALITY; RISK AB The National Lung Screening Trial (NLST) demonstrated a 20% reduction in lung cancer mortality for screening with low-dose computed tomography versus chest radiography. The major NLST eligibility criteria were age 55-74, a 30 + pack year smoking history and current smoking status or having quit in the last 15 years. We utilized data from SEER (Surveillance, Epidemiology and End Results), the United States (US) Census and the National Health Interview Survey, as well as two statistical models of lung cancer risk, to estimate the proportion of the total US population and of those currently diagnosed with lung cancer that would be covered by the NLST and other suggested eligibility criteria. For the NLST criteria, 26.7% of lung cancers and 6.2% of the population (over 40) were covered. A criterion of ever smokers aged 50-79 would cover 68% of the cancers while screening 30% of the (over 40) population. To extend recommended screening beyond the NLST eligibility criteria, two questions are key. First, can the 20% mortality reduction observed in NLST be extrapolated to populations at moderately lower risk? Second, given that such an extrapolation is valid, what background incidence rate is high enough for the balance between the benefits and harms of screening to be favourable? Further research on these questions is needed. C1 [Pinsky, Paul F.; Berg, Christine D.] NCI, Early Detect Branch, Canc Prevent Div, Bethesda, MD 20892 USA. RP Pinsky, PF (reprint author), 6130 Execut Blvd,EPN 3064, Bethesda, MD 20892 USA. EM pinskyp@mail.nih.gov RI Berg , Christine/K-1047-2014 NR 4 TC 36 Z9 36 U1 0 U2 1 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0969-1413 J9 J MED SCREEN JI J. Med. Screen. PY 2012 VL 19 IS 3 BP 154 EP 156 DI 10.1258/jms.2012.012010 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 038KS UT WOS:000311174200008 PM 23060474 ER PT J AU Banks, HT Bocharov, G Grossman, Z Meyerhans, A AF Banks, H. T. Bocharov, G. Grossman, Z. Meyerhans, A. TI Distributed Parameter Systems in Immunology Preface SO MATHEMATICAL MODELLING OF NATURAL PHENOMENA LA English DT Editorial Material DE mathematical model; distributed parameter systems; immunophysiological systems; virus infections C1 [Banks, H. T.] NC State Univ, Ctr Res Sci Computat, Ctr Quantitat Sci Biomed, Raleigh, NC 27695 USA. [Bocharov, G.] Russian Acad Sci, Inst Numer Math, Moscow 119333, Russia. [Grossman, Z.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Grossman, Z.] NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. [Meyerhans, A.] Univ Pompeu Fabra, Dept Expt & Hlth Sci, Barcelona 08003, Spain. [Grossman, Z.] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. RP Banks, HT (reprint author), NC State Univ, Ctr Res Sci Computat, Ctr Quantitat Sci Biomed, Raleigh, NC 27695 USA. EM htbanks@ncsu.edu; bocharov@inm.ras.ru; GROSSMANZ@niaid.nih.gov; andreas.meyerhans@upf.edu RI Meyerhans, Andreas/D-3382-2014 OI Meyerhans, Andreas/0000-0003-0620-5317 NR 9 TC 0 Z9 0 U1 0 U2 4 PU EDP SCIENCES S A PI LES ULIS CEDEX A PA 17, AVE DU HOGGAR, PA COURTABOEUF, BP 112, F-91944 LES ULIS CEDEX A, FRANCE SN 0973-5348 J9 MATH MODEL NAT PHENO JI Math. Model. Nat. Phenom. PY 2012 VL 7 IS 5 BP 1 EP 3 DI 10.1051/mmnp/20127501 PG 3 WC Mathematical & Computational Biology; Mathematics, Interdisciplinary Applications; Multidisciplinary Sciences SC Mathematical & Computational Biology; Mathematics; Science & Technology - Other Topics GA 043EI UT WOS:000311525300001 ER PT J AU Paul, WE AF Paul, W. E. TI The Immune System - Complexity Exemplified SO MATHEMATICAL MODELLING OF NATURAL PHENOMENA LA English DT Editorial Material DE immune system; complexity; diversity; tuning; response to perturbations; specificity; cellular/molecular environment; anatomic constraints C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Paul, WE (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM WPAUL@niaid.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 3 PU EDP SCIENCES S A PI LES ULIS CEDEX A PA 17, AVE DU HOGGAR, PA COURTABOEUF, BP 112, F-91944 LES ULIS CEDEX A, FRANCE SN 0973-5348 J9 MATH MODEL NAT PHENO JI Math. Model. Nat. Phenom. PY 2012 VL 7 IS 5 BP 4 EP 6 DI 10.1051/mmnp/20127502 PG 3 WC Mathematical & Computational Biology; Mathematics, Interdisciplinary Applications; Multidisciplinary Sciences SC Mathematical & Computational Biology; Mathematics; Science & Technology - Other Topics GA 043EI UT WOS:000311525300002 ER PT J AU Anantharaman, V Iyer, LM Aravind, L AF Anantharaman, Vivek Iyer, Lakshminarayan M. Aravind, L. TI Ter-dependent stress response systems: novel pathways related to metal sensing, production of a nucleoside-like metabolite, and DNA-processing SO MOLECULAR BIOSYSTEMS LA English DT Article ID TELLURITE RESISTANCE DETERMINANT; RESTRICTION-ENDONUCLEASE MCRBC; PYR MESSENGER-RNA; ESCHERICHIA-COLI; COMPARATIVE GENOMICS; BACILLUS-SUBTILIS; MYCOBACTERIUM-TUBERCULOSIS; STRUCTURAL BASIS; KLEBSIELLA-PNEUMONIAE; STRUCTURE PREDICTION AB The mode of action of the bacterial ter cluster and TelA genes, implicated in natural resistance to tellurite and other xenobiotic toxic compounds, pore-forming colicins and several bacteriophages, has remained enigmatic for almost two decades. Using comparative genomics, sequence-profile searches and structural analysis we present evidence that the ter gene products and their functional partners constitute previously underappreciated, chemical stress response and anti-viral defense systems of bacteria. Based on contextual information from conserved gene neighborhoods and domain architectures, we show that the ter gene products and TelA lie at the center of membrane-linked metal recognition complexes with regulatory ramifications encompassing phosphorylation-dependent signal transduction, RNA-dependent regulation, biosynthesis of nucleoside-like metabolites and DNA processing. Our analysis suggests that the multiple metal-binding and non-binding TerD paralogs and TerC are likely to constitute a membrane-associated complex, which might also include TerB and TerY, and feature several, distinct metal-binding sites. Versions of the TerB domain might also bind small molecule ligands and link the TerD paralog-TerC complex to biosynthetic modules comprising phosphoribosyltransferases (PRTases), ATP grasp amidoligases, TIM-barrel carbon-carbon lyases, and HAD phosphoesterases, which are predicted to synthesize novel nucleoside-like molecules. One of the PRTases is also likely to interact with RNA by means of its Pelota/Ribosomal protein L7AE-like domain. The von Willebrand factor A domain protein, TerY, is predicted to be part of a distinct phosphorylation switch, coupling a protein kinase and a PP2C phosphatase. We show, based on the evidence from numerous conserved gene neighborhoods and domain architectures, that both the TerB and TelA domains have been linked to diverse lipid-interaction domains, such as two novel PH-like and the Coq4 domains, in different bacteria, and are likely to comprise membrane-associated sensory complexes that might additionally contain periplasmic binding-protein-II and OmpA domains. We also show that the TerD and TerB domains and the TerY-associated phosphorylation system are functionally linked to many distinct DNA-processing complexes, which feature proteins with SWI2/SNF2 and RecQ-like helicases, multiple AAA + ATPases, McrC-N-terminal domain proteins, several restriction endonuclease fold DNases, DNA-binding domains and a type-VII/Esx-like system, which is at the center of a predicted DNA transfer apparatus. These DNA-processing modules and associated genes are predicted to be involved in restriction or suicidal action in response to phages and possibly repairing xenobiotic-induced DNA damage. In some eukaryotes, certain components of the ter system appear to be recruited to function in conjunction with the ubiquitin system and calcium-signaling pathways. C1 [Anantharaman, Vivek; Iyer, Lakshminarayan M.; Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov OI Anantharaman, Vivek/0000-0001-8395-0009 FU National Library of Medicine; National Institutes of Health, USA. FX The authors are supported by the intra-mural funds of the National Library of Medicine, National Institutes of Health, USA. NR 119 TC 31 Z9 32 U1 3 U2 14 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1742-206X EI 1742-2051 J9 MOL BIOSYST JI Mol. Biosyst. PY 2012 VL 8 IS 12 BP 3142 EP 3165 DI 10.1039/c2mb25239b PG 24 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 042LR UT WOS:000311473200005 PM 23044854 ER PT S AU Stokes, WS Kulpa-Eddy, J Brown, K Srinivas, G McFarlands, R AF Stokes, W. S. Kulpa-Eddy, J. Brown, K. Srinivas, G. McFarlands, R. BE Jungback, C TI Recent Progress and Future Directions for Reduction, Refinement, and Replacement of Animal Use in Veterinary Vaccine Potency and Safety Testing: A report from the 2010 NICEATM-ICCVAM International Vaccine Workshop SO POTENCY TESTING OF VETERINARY VACCINES FOR ANIMALS: THE WAY FROM IN VIVO TO IN VITRO SE Developments in Biologicals LA English DT Proceedings Paper CT International Scientific Workshop on Potency Testing of Veterinary Vaccines - Way from in Vivo to in Vitro CY DEC 01-03, 2010 CL Paul Ehrlich Inst, Langen, GERMANY SP Paul Ehrlich Inst, European Directorate Qual Med & Healthcare, Int Alliance Biol Standardizat HO Paul Ehrlich Inst DE Veterinary vaccines; potency; safety; ICCVAM; recommendations; workshop ID HUMANE END-POINTS; RABIES VACCINES AB Veterinary vaccines contribute to improved animal and human health and welfare by preventing infectious diseases. However, testing necessary to ensure vaccine effectiveness and safety can involve large numbers of animals and significant pain and distress. NICEATM and ICCVAM recently convened an international workshop to review the state of the science of human and veterinary vaccine potency and safety testing, and to identify priority activities to advance new and improved methods that can further reduce, refine and replace animal use. Rabies, Clostridium sp., and Leptospira sp. vaccines were identified as the highest priorities, while tests requiring live viruses and bacteria hazardous to laboratory workers, livestock, pets, and wildlife were also considered high priorities. Priority research, development and validation activities to address critical knowledge and data gaps were identified, including opportunities to apply new science and technology. Enhanced international harmonization and cooperation and closer collaborations between human and veterinary researchers were recommended to expedite progress. Implementation of the workshop recommendations is expected to advance new methods for vaccine testing that will benefit animal welfare and ensure continued and improved protection of human and animal health. C1 [Stokes, W. S.] NIEHS, Natl Toxicol Program Interagency Ctr Evaluat Alte, POB 12233,Mail Stop K2-16, Res Triangle Pk, NC 27709 USA. [Kulpa-Eddy, J.; Srinivas, G.] US Dept Agr, Riverdale, MD USA. [Brown, K.] Pair O Docs Enterprises, Parkville, Vic, Australia. [McFarlands, R.] United States Food & Drug Adm, Rockville, MD USA. RP Stokes, WS (reprint author), NIEHS, Natl Toxicol Program Interagency Ctr Evaluat Alte, POB 12233,Mail Stop K2-16, Res Triangle Pk, NC 27709 USA. EM stokes@niehs.nih.gov NR 14 TC 4 Z9 4 U1 0 U2 5 PU KARGER PI BASEL PA POSTFACH, CH-4009 BASEL, SWITZERLAND SN 1424-6074 BN 978-3-8055-9892-7 J9 DEV BIOLOGICALS JI Dev. Biols PY 2012 VL 134 BP 9 EP + PG 3 WC Pharmacology & Pharmacy; Veterinary Sciences SC Pharmacology & Pharmacy; Veterinary Sciences GA BCP26 UT WOS:000310938700002 PM 22888590 ER PT J AU Demir, A Oguariri, RM Magis, A Ostrov, DA Imamichi, T Dunn, BM AF Demir, Ahu Oguariri, Raphael M. Magis, Andrew Ostrov, David A. Imamichi, Tomozumi Dunn, Ben M. TI Kinetic characterization of newly discovered inhibitors of various constructs of human T-cell leukemia virus-1 (HTLV-1) protease and their effect on HTLV-1-infected cells SO ANTIVIRAL THERAPY LA English DT Article ID C-TERMINAL RESIDUES; TYPE-1 PROTEASE; SUBSTRATE-SPECIFICITY; ENZYMATIC-ACTIVITY; I PROTEASE; CLEAVAGE; BINDING; TARGET; AUTOPROTEOLYSIS; REPLICATION AB Background: Human T-cell leukemia virus-1 (HTLV-1) was the first identified human retrovirus and was shown to be associated with diseases such as adult T-cell leukemia lymphoma and tropical spastic paraparesis/HTLV-1 associated myelopathy. Retroviral proteases (PRs) are essential for viral replication by processing viral Gag and Gag-(Pro)-Pol polyproteins during maturation. Full-length HTLV-1 PR is 125 residues long; whether the C-terminal region is required for catalytic activity is still controversial. In this study, we characterized the effect of C-terminal amino acids of HTLV-1 PR for PR activity and examined the binding of compounds identified by in silico screening. One compound showed inhibition against the virus in infected cells. Methods: Truncated (116-, 121- and 122-residue) forms of HTLV-1 PR were prepared and proteins from expression of the genes were purified. In silico screening was performed by docking small molecules into the active site of HTLV-1 PR. The kinetic constants k(cat), K-m, k(cat)/K-m and inhibition constants K-i for inhibitors identified by the computational screening were determined. Western blot and ELISA analyses were used to determine the effect of the most potent PR inhibitors on HTLV-1 protein processing in infected cells. Results: The constructs showed similar catalytic efficiency constants (k(cat)/K-m); thus HTLV-1 PR C-terminal amino acids are not essential for full activity. Computational screening revealed new PR inhibitors and some were shown to be inhibitory in enzyme assays. In HTLV-1-infected cells, one of the small molecules inhibited HTLV-1 gag cleavage and decreased the amount of HTLV-1 p19 produced in the cells. Conclusions: We have identified an HTLV-1 PR inhibitor that is biologically functional. Inhibitor screening will continue to develop possible drugs for therapy of HTLV-1 infection. C1 [Demir, Ahu; Dunn, Ben M.] Univ Florida, Coll Med Biochem & Mol Biol, Gainesville, FL 32611 USA. [Oguariri, Raphael M.; Imamichi, Tomozumi] NCI, Sci Applicat Int Corp Frederick Inc, Lab Human Retrovirol, Frederick, MD 21701 USA. [Magis, Andrew] Univ Illinois, Dept Ctr Biophys & Computat Biol, Urbana, IL 61801 USA. [Ostrov, David A.] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL USA. RP Dunn, BM (reprint author), Univ Florida, Coll Med Biochem & Mol Biol, Gainesville, FL 32611 USA. EM bdunn@ufl.edu RI DEMIR, AHU/A-5650-2015 OI DEMIR, AHU/0000-0001-9276-6318 NR 23 TC 3 Z9 3 U1 0 U2 5 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PY 2012 VL 17 IS 5 BP 883 EP 892 DI 10.3851/IMP2090 PG 10 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 037CV UT WOS:000311080200013 PM 22436331 ER PT J AU Fleming, JM Miller, TC Kidacki, M Ginsburg, E Stuelten, CH Stewart, DA Troester, MA Vonderhaar, BK AF Fleming, Jodie M. Miller, Tyler C. Kidacki, Michal Ginsburg, Erika Stuelten, Christina H. Stewart, Delisha A. Troester, Melissa A. Vonderhaar, Barbara K. TI Paracrine interactions between primary human macrophages and human fibroblasts enhance murine mammary gland humanization in vivo SO BREAST CANCER RESEARCH LA English DT Article ID STIMULATING FACTOR-I; TUMOR-ASSOCIATED MACROPHAGES; NECROSIS-FACTOR-ALPHA; CANCER CELL-LINES; BREAST-CANCER; EPITHELIAL-CELLS; MATRIX METALLOPROTEINASES; GAMMA-INTERFERON; TNF-ALPHA; PROLIFERATION AB Introduction: Macrophages comprise an essential component of the mammary microenvironment necessary for normal gland development. However, there is no viable in vivo model to study their role in normal human breast function. We hypothesized that adding primary human macrophages to the murine mammary gland would enhance and provide a novel approach to examine immune-stromal cell interactions during the humanization process. Methods: Primary human macrophages, in the presence or absence of ectopic estrogen stimulation, were used to humanize mouse mammary glands. Mechanisms of enhanced humanization were identified by cytokine/chemokine ELISAs, zymography, western analysis, invasion and proliferation assays; results were confirmed with immunohistological analysis. Results: The combined treatment of macrophages and estrogen stimulation significantly enhanced the percentage of the total gland humanized and the engraftment/outgrowth success rate. Timecourse analysis revealed the disappearance of the human macrophages by two weeks post-injection, suggesting that the improved overall growth and invasiveness of the fibroblasts provided a larger stromal bed for epithelial cell proliferation and structure formation. Confirming their promotion of fibroblasts humanization, estrogen-stimulated macrophages significantly enhanced fibroblast proliferation and invasion in vitro, as well as significantly increased proliferating cell nuclear antigen (PCNA) positive cells in humanized glands. Cytokine/chemokine ELISAs, zymography and western analyses identified TNF alpha and MMP9 as potential mechanisms by which estrogen-stimulated macrophages enhanced humanization. Specific inhibitors to TNFa and MMP9 validated the effects of these molecules on fibroblast behavior in vitro, as well as by immunohistochemical analysis of humanized glands for human-specific MMP9 expression. Lastly, glands humanized with macrophages had enhanced engraftment and tumor growth compared to glands humanized with fibroblasts alone. Conclusions: Herein, we demonstrate intricate immune and stromal cell paracrine interactions in a humanized in vivo model system. We confirmed our in vivo results with in vitro analyses, highlighting the value of this model to interchangeably substantiate in vitro and in vivo results. It is critical to understand the signaling networks that drive paracrine cell interactions, for tumor cells exploit these signaling mechanisms to support their growth and invasive properties. This report presents a dynamic in vivo model to study primary human immune/fibroblast/epithelial interactions and to advance our knowledge of the stromal-derived signals that promote tumorigenesis. C1 [Fleming, Jodie M.; Kidacki, Michal; Ginsburg, Erika; Vonderhaar, Barbara K.] NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Fleming, Jodie M.; Stuelten, Christina H.] N Carolina Cent Univ, Dept Biol, Durham, NC 27707 USA. [Fleming, Jodie M.] NCI, Lab Cell & Mol Biol, Ctr Canc Res, Bethesda, MD 20892 USA. [Stewart, Delisha A.; Troester, Melissa A.] Univ N Carolina, Dept Epidemiol, Gillings Sch Publ Health, Chapel Hill, NC 27599 USA. RP Fleming, JM (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM jodie.fleming@nccu.edu FU Center for Cancer Research, an Intramural Research Program of the National Cancer Institute; Breast Cancer Research Stamp proceeds awarded through competitive peer review; NCI [R01 CA138255]; NIEHS/NCI [U01 ES019472]; UNC Breast SPORE [P50 CA58233-18] FX This research was supported by the Center for Cancer Research, an Intramural Research Program of the National Cancer Institute, and by Breast Cancer Research Stamp proceeds awarded through competitive peer review. DAS and MAT were supported by NCI (R01 CA138255), NIEHS/NCI U01 ES019472, and UNC Breast SPORE P50 CA58233-18. NR 69 TC 12 Z9 13 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X J9 BREAST CANCER RES JI Breast Cancer Res. PY 2012 VL 14 IS 3 AR R97 DI 10.1186/bcr3215 PG 18 WC Oncology SC Oncology GA 036AI UT WOS:000310998000028 PM 22731827 ER PT J AU Tressler, R Godfrey, C AF Tressler, Randall Godfrey, Catherine TI NRTI Backbone in HIV Treatment Will it Remain Relevant? SO DRUGS LA English DT Article ID REVERSE-TRANSCRIPTASE INHIBITOR; TENOFOVIR DISOPROXIL FUMARATE; BONE-MINERAL DENSITY; ANTIRETROVIRAL THERAPY INITIATION; DRUG-RESISTANCE; INFECTED PATIENTS; ABACAVIR-LAMIVUDINE; RENAL-FUNCTION; MITOCHONDRIAL TOXICITY; CONTAINING REGIMENS AB Nucleoside reverse transcriptase inhibitors (NRTIs) remain a critical component of therapy for HIV-infected patients. The drugs are effective, relatively inexpensive and an important component of antiretroviral therapy (ART), particularly in areas where the introduction of effective therapy has been delayed. They are an essential part of initial therapy for HIV and for prevention of mother-to-child transmission; however, toxicities and resistance may limit their use. The role for pre-exposure prophylaxis (PrEP) to reduce sexual transmission of HIV is still undefined, but this use may have a significant impact on NRTI resistance worldwide, most particularly in areas where subtype C predominates. With increasing prevalence of resistant HIV, the approval of new agents that are effective against resistant virus, and those that use novel cellular targets, are essential. Large studies are now in progress examining the safety and efficacy of NRTI-sparing regimens, but results are not currently available. NRTIs may lose relevance in the not distant future unless steps are put in place to reduce the development and spread of NRTI-resistant viruses, and new NRTIs with minimal toxicity are developed that have a novel resistance profile. This article describes the principal NRTIs, their mechanism of action, and resistance and selected toxicities of the class and of the individual drugs. C1 [Tressler, Randall] NIAID, Div Aids, HJF, NIH, Bethesda, MD 20892 USA. RP Godfrey, C (reprint author), 6700 B Rockledge Dr, Bethesda, MD 20892 USA. EM cgodfrey@niaid.nih.gov FU National Institute of Allergy and Infectious Disease, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C] FX This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Disease, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800014C. NR 94 TC 7 Z9 8 U1 0 U2 7 PU ADIS INT LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND SN 0012-6667 J9 DRUGS JI Drugs PY 2012 VL 72 IS 16 BP 2051 EP 2062 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 035EW UT WOS:000310927000002 PM 23083109 ER PT B AU Maehr, ML AF Maehr, Martin L. BA Maehr, ML BF Maehr, ML TI Encouraging a Continuing Personal Investment in Learning Introduction and Overview SO ENCOURAGING A CONTINUING PERSONAL INVESTMENT IN LEARNING: MOTIVATION AS AN INSTRUCTIONAL OUTCOME LA English DT Editorial Material; Book Chapter C1 [Maehr, Martin L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maehr, Martin L.] Concordia Senior Coll, Ft Wayne, IN USA. [Maehr, Martin L.] NIMH, Bethesda, MD USA. RP Maehr, ML (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMATION AGE PUBLISHING-IAP PI CHARLOTTE PA PO BOX 79049, CHARLOTTE, NC 28271-7047 USA BN 978-1-61735-713-8 PY 2012 BP 1 EP + PG 10 WC Education & Educational Research SC Education & Educational Research GA BCL21 UT WOS:000310546000001 ER PT B AU Maehr, ML AF Maehr, Martin L. BA Maehr, ML BF Maehr, ML TI The Role of Motivation in Prompting and Shaping Action and Self-Actualization SO ENCOURAGING A CONTINUING PERSONAL INVESTMENT IN LEARNING: MOTIVATION AS AN INSTRUCTIONAL OUTCOME LA English DT Article; Book Chapter C1 [Maehr, Martin L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maehr, Martin L.] Concordia Senior Coll, Ft Wayne, IN USA. [Maehr, Martin L.] NIMH, Bethesda, MD USA. RP Maehr, ML (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMATION AGE PUBLISHING-IAP PI CHARLOTTE PA PO BOX 79049, CHARLOTTE, NC 28271-7047 USA BN 978-1-61735-713-8 PY 2012 BP 7 EP 8 PG 2 WC Education & Educational Research SC Education & Educational Research GA BCL21 UT WOS:000310546000002 ER PT B AU Maehr, ML AF Maehr, Martin L. BA Maehr, ML BF Maehr, ML TI The Nature, Nurture and Impact of Motivation on Learning, School Achievement, and Personal and Intellectual Growth SO ENCOURAGING A CONTINUING PERSONAL INVESTMENT IN LEARNING: MOTIVATION AS AN INSTRUCTIONAL OUTCOME LA English DT Article; Book Chapter C1 [Maehr, Martin L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maehr, Martin L.] Concordia Senior Coll, Ft Wayne, IN USA. [Maehr, Martin L.] NIMH, Bethesda, MD USA. RP Maehr, ML (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMATION AGE PUBLISHING-IAP PI CHARLOTTE PA PO BOX 79049, CHARLOTTE, NC 28271-7047 USA BN 978-1-61735-713-8 PY 2012 BP 9 EP 10 PG 2 WC Education & Educational Research SC Education & Educational Research GA BCL21 UT WOS:000310546000003 ER PT B AU Maehr, ML AF Maehr, Martin L. BA Maehr, ML BF Maehr, ML TI What Prompts Interest Leading to a Continuing Personal Investment in a Specific Area of Learning SO ENCOURAGING A CONTINUING PERSONAL INVESTMENT IN LEARNING: MOTIVATION AS AN INSTRUCTIONAL OUTCOME LA English DT Article; Book Chapter C1 [Maehr, Martin L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maehr, Martin L.] Concordia Senior Coll, Ft Wayne, IN USA. [Maehr, Martin L.] NIMH, Bethesda, MD USA. RP Maehr, ML (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMATION AGE PUBLISHING-IAP PI CHARLOTTE PA PO BOX 79049, CHARLOTTE, NC 28271-7047 USA BN 978-1-61735-713-8 PY 2012 BP 11 EP 21 PG 11 WC Education & Educational Research SC Education & Educational Research GA BCL21 UT WOS:000310546000004 ER PT B AU Maehr, ML AF Maehr, Martin L. BA Maehr, ML BF Maehr, ML TI Toward Evaluating Schools in Terms of Individual Personal Growth of Students SO ENCOURAGING A CONTINUING PERSONAL INVESTMENT IN LEARNING: MOTIVATION AS AN INSTRUCTIONAL OUTCOME LA English DT Article; Book Chapter C1 [Maehr, Martin L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maehr, Martin L.] Concordia Senior Coll, Ft Wayne, IN USA. [Maehr, Martin L.] NIMH, Bethesda, MD USA. RP Maehr, ML (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMATION AGE PUBLISHING-IAP PI CHARLOTTE PA PO BOX 79049, CHARLOTTE, NC 28271-7047 USA BN 978-1-61735-713-8 PY 2012 BP 23 EP 28 PG 6 WC Education & Educational Research SC Education & Educational Research GA BCL21 UT WOS:000310546000005 ER PT B AU Maehr, ML AF Maehr, Martin L. BA Maehr, ML BF Maehr, ML TI Instructional Environments and Motivational Outcomes SO ENCOURAGING A CONTINUING PERSONAL INVESTMENT IN LEARNING: MOTIVATION AS AN INSTRUCTIONAL OUTCOME LA English DT Article; Book Chapter C1 [Maehr, Martin L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maehr, Martin L.] Concordia Senior Coll, Ft Wayne, IN USA. [Maehr, Martin L.] NIMH, Bethesda, MD USA. RP Maehr, ML (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMATION AGE PUBLISHING-IAP PI CHARLOTTE PA PO BOX 79049, CHARLOTTE, NC 28271-7047 USA BN 978-1-61735-713-8 PY 2012 BP 29 EP 33 PG 5 WC Education & Educational Research SC Education & Educational Research GA BCL21 UT WOS:000310546000006 ER PT B AU Maehr, ML AF Maehr, Martin L. BA Maehr, ML BF Maehr, ML TI One Small Step for Educational Practice, One Giant Leap for Society SO ENCOURAGING A CONTINUING PERSONAL INVESTMENT IN LEARNING: MOTIVATION AS AN INSTRUCTIONAL OUTCOME LA English DT Article; Book Chapter C1 [Maehr, Martin L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maehr, Martin L.] Concordia Senior Coll, Ft Wayne, IN USA. [Maehr, Martin L.] NIMH, Bethesda, MD USA. RP Maehr, ML (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMATION AGE PUBLISHING-IAP PI CHARLOTTE PA PO BOX 79049, CHARLOTTE, NC 28271-7047 USA BN 978-1-61735-713-8 PY 2012 BP 35 EP 39 PG 5 WC Education & Educational Research SC Education & Educational Research GA BCL21 UT WOS:000310546000007 ER PT B AU Maehr, ML AF Maehr, Martin L. BA Maehr, ML BF Maehr, ML TI The Possible Future of Motivation Theory and Research SO ENCOURAGING A CONTINUING PERSONAL INVESTMENT IN LEARNING: MOTIVATION AS AN INSTRUCTIONAL OUTCOME LA English DT Article; Book Chapter C1 [Maehr, Martin L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maehr, Martin L.] Concordia Senior Coll, Ft Wayne, IN USA. [Maehr, Martin L.] NIMH, Bethesda, MD USA. RP Maehr, ML (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU INFORMATION AGE PUBLISHING-IAP PI CHARLOTTE PA PO BOX 79049, CHARLOTTE, NC 28271-7047 USA BN 978-1-61735-713-8 PY 2012 BP 41 EP 43 PG 3 WC Education & Educational Research SC Education & Educational Research GA BCL21 UT WOS:000310546000008 ER PT B AU Maehr, ML AF Maehr, Martin L. BA Maehr, ML BF Maehr, ML TI Bases and Precedents for Considering Motivation as an Instructional Outcome SO ENCOURAGING A CONTINUING PERSONAL INVESTMENT IN LEARNING: MOTIVATION AS AN INSTRUCTIONAL OUTCOME LA English DT Article; Book Chapter C1 [Maehr, Martin L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maehr, Martin L.] Concordia Senior Coll, Ft Wayne, IN USA. [Maehr, Martin L.] NIMH, Bethesda, MD USA. RP Maehr, ML (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMATION AGE PUBLISHING-IAP PI CHARLOTTE PA PO BOX 79049, CHARLOTTE, NC 28271-7047 USA BN 978-1-61735-713-8 PY 2012 BP 45 EP 54 PG 10 WC Education & Educational Research SC Education & Educational Research GA BCL21 UT WOS:000310546000009 ER PT B AU Maehr, ML AF Maehr, Martin L. BA Maehr, ML BF Maehr, ML TI Steps Toward Encouraging a Continuing Personal Investment in Learning SO ENCOURAGING A CONTINUING PERSONAL INVESTMENT IN LEARNING: MOTIVATION AS AN INSTRUCTIONAL OUTCOME LA English DT Article; Book Chapter C1 [Maehr, Martin L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maehr, Martin L.] Concordia Senior Coll, Ft Wayne, IN USA. [Maehr, Martin L.] NIMH, Bethesda, MD USA. RP Maehr, ML (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMATION AGE PUBLISHING-IAP PI CHARLOTTE PA PO BOX 79049, CHARLOTTE, NC 28271-7047 USA BN 978-1-61735-713-8 PY 2012 BP 55 EP 57 PG 3 WC Education & Educational Research SC Education & Educational Research GA BCL21 UT WOS:000310546000010 ER PT B AU Maehr, ML AF Maehr, Martin L. BA Maehr, ML BF Maehr, ML TI Motivation as an Instructional Outcome SO ENCOURAGING A CONTINUING PERSONAL INVESTMENT IN LEARNING: MOTIVATION AS AN INSTRUCTIONAL OUTCOME LA English DT Article; Book Chapter C1 [Maehr, Martin L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maehr, Martin L.] Concordia Senior Coll, Ft Wayne, IN USA. [Maehr, Martin L.] NIMH, Bethesda, MD USA. RP Maehr, ML (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU INFORMATION AGE PUBLISHING-IAP PI CHARLOTTE PA PO BOX 79049, CHARLOTTE, NC 28271-7047 USA BN 978-1-61735-713-8 PY 2012 BP 59 EP 60 PG 2 WC Education & Educational Research SC Education & Educational Research GA BCL21 UT WOS:000310546000011 ER PT B AU Maehr, ML AF Maehr, Martin L. BA Maehr, ML BF Maehr, ML TI Encouraging a Continuing Personal Investment in Learning Motivation as an Instructional Outcome Conclusion SO ENCOURAGING A CONTINUING PERSONAL INVESTMENT IN LEARNING: MOTIVATION AS AN INSTRUCTIONAL OUTCOME LA English DT Editorial Material; Book Chapter C1 [Maehr, Martin L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maehr, Martin L.] Concordia Senior Coll, Ft Wayne, IN USA. [Maehr, Martin L.] NIMH, Bethesda, MD USA. RP Maehr, ML (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU INFORMATION AGE PUBLISHING-IAP PI CHARLOTTE PA PO BOX 79049, CHARLOTTE, NC 28271-7047 USA BN 978-1-61735-713-8 PY 2012 BP 61 EP 62 PG 2 WC Education & Educational Research SC Education & Educational Research GA BCL21 UT WOS:000310546000012 ER PT J AU Maddison, P Damian, MS Sewry, C McGorrian, C Winer, JB Odgerel, Z Shatunov, A Lee, HS Goldfarb, LG AF Maddison, Paul Damian, Maxwell S. Sewry, Caroline McGorrian, Catherine Winer, John B. Odgerel, Zagaa Shatunov, Alexey Lee, Hee Suk Goldfarb, Lev G. TI Clinical and Myopathological Characteristics of Desminopathy Caused by a Mutation in Desmin Tail Domain SO EUROPEAN NEUROLOGY LA English DT Article DE Intermediate filaments; Desminopathy; Myofibrillar myopathy; Cardiomyopathy; Desmin gene mutations ID DUCHENNE MUSCULAR-DYSTROPHY; MYOFIBRILLAR MYOPATHY; SKELETAL MYOPATHY; CARDIOMYOPATHY; FILAMENT; GENE; ACCUMULATION; VIMENTIN; DISEASE AB Background: Most of the previously described pathogenic mutations in desmin are located in highly conserved alpha-helical domains that play an important role in intermediate filament assembly. The role of the C-terminus non-alpha-helical 'tail' domain is much less investigated and until recently mutations in this domain have been implicated in only a few patients. The majority of reported desminopathy cases caused by the tail mutations were sporadic, creating a representation bias regarding the disease frequency and phenotypic characteristics. Methods: We performed detailed genotype-phenotype analysis of autosomal dominant desminopathy associated with tail domain mutations in a four-generation autosomal dominant family with 16 members affected by a progressive cardiac and/or skeletal myopathy caused by a c.1346A>C (p.Lys449Thr) mutation located in the tail domain of desmin. Results: Phenotypic features in patients with tail domain mutations are similar to those in patients with mutations localized in the 1B and 2B alpha-helical domains. Conclusion: We recommend that the tail domain is searched for mutations as intensely as desmin coil domains which until recently were considered to be more 'functional'. Copyright (C) 2012 S. Karger AG, Basel C1 [Maddison, Paul] Univ Nottingham Hosp, Queens Med Ctr, Dept Neurol, Nottingham NG5 1PB, England. [Damian, Maxwell S.] Cambridge Univ Hosp, Dept Neurol, Cambridge, England. [Sewry, Caroline] Richard Jones & Agnes Hunt Orthopaed Hosp, Wolfson Ctr Inherited Neuromuscular Dis, Oswestry, Shrops, England. [Sewry, Caroline] Dubowitz Neuromuscular Ctr, Inst Child Hlth, London, England. [McGorrian, Catherine] Mater Misericordiae Univ Hosp, Dept Cardiol, Dublin, Ireland. [Winer, John B.] Univ Hosp Birmingham, Queen Elizabeth Med Ctr, Dept Neurol, Birmingham, W Midlands, England. [Odgerel, Zagaa; Shatunov, Alexey; Lee, Hee Suk; Goldfarb, Lev G.] NINDS, Clin Genet Unit, NIH, Bethesda, MD 20892 USA. [Sewry, Caroline] Great Ormond St Hosp Sick Children, London, England. RP Maddison, P (reprint author), Univ Nottingham Hosp, Queens Med Ctr, Dept Clin Neurol, Nottingham NG5 1PB, England. EM paul.maddison@nhs.net FU National Institute of Neurological Disorders and Stroke, NIH FX This research was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH. NR 25 TC 2 Z9 2 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0014-3022 J9 EUR NEUROL JI Eur. Neurol. PY 2012 VL 68 IS 5 BP 279 EP 286 DI 10.1159/000341617 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 036PZ UT WOS:000311042800004 PM 23051780 ER PT J AU Suktitipat, B Mathias, RA Vaidya, D Yanek, LR Young, JH Becker, LC Becker, DM Wilson, AF Fallin, MD AF Suktitipat, Bhoom Mathias, Rasika A. Vaidya, Dhananjay Yanek, Lisa R. Young, J. Hunter Becker, Lewis C. Becker, Diane M. Wilson, Alexander F. Fallin, M. Daniele TI The Robustness of Generalized Estimating Equations for Association Tests in Extended Family Data SO HUMAN HEREDITY LA English DT Article DE Generalized estimating equation; Variance components analysis; Family-based association study; Genome-wide scan ID GENOME-WIDE ASSOCIATION; LONGITUDINAL DATA-ANALYSIS; MODEL; PHENOTYPE AB Variance components analysis (VCA), the traditional method for handling correlations within families in genetic association studies, is computationally intensive for genome-wide analyses, and the computational burden of VCA increases with family size and the number of genetic markers. Alternative approaches that do not require the computation of familial correlations are preferable, provided that they do not inflate type I error or decrease power. We performed a simulation study to evaluate practical alternatives to VCA that use regression with generalized estimating equations (GEE) in extended family data. We compared the properties of linear regression with GEE applied to an entire extended family structure (GEE-EXT) and GEE applied to nuclear family structures split from these extended families (GEE-SPL) to variance components likelihood-based methods (FastAssoc). GEE-EXT was evaluated with and without robust variance estimators to estimate the standard errors. We observed similar average type I error rates from GEE-EXT and FastAssoc compared to GEE-SPL. Type I error rates for the GEE-EXT method with a robust variance estimator were marginally higher than the nominal rate when the minor allele frequency (MAF) was <0.1, but were close to the nominal rate when the MAF was >= 0.2. All methods gave consistent effect estimates and had similar power. In summary, the GEE framework with the robust variance estimator, the computationally fastest and least data management-intensive approach, appears to work well in extended families and thus provides a reasonable alternative to full variance components approaches for extended pedigrees in a genome-wide association study setting. Copyright (C) 2012 S. Karger AG, Basel C1 [Suktitipat, Bhoom; Wilson, Alexander F.] NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Mathias, Rasika A.; Vaidya, Dhananjay; Yanek, Lisa R.; Young, J. Hunter; Becker, Lewis C.; Becker, Diane M.; Fallin, M. Daniele] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Suktitipat, Bhoom; Fallin, M. Daniele] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Suktitipat, Bhoom] Mahidol Univ, Fac Med, Siriraj Hosp, Dept Biochem, Bangkok 10700, Thailand. RP Fallin, MD (reprint author), 615 N Wolfe St,Room 6509, Baltimore, MD 21205 USA. EM dfallin@jhsph.edu OI Suktitipat, Bhoom/0000-0001-8034-7757; Vaidya, Dhananjay/0000-0002-7164-1601 FU National Institutes of Health/National Heart, Lung, and Blood Institute [U01 HL72518, R01 HL087698]; Division of the Intramural Research of the National Human Genome Research Institute, NIH; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and Committee on Higher Education; Royal Thai Government scholarship FX This work was supported in part by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute grants U01 HL72518 and R01 HL087698 (R.A.M., L.R.Y., L.C.B., D.M.B.), Division of the Intramural Research of the National Human Genome Research Institute, NIH, the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and Committee on Higher Education, and the Royal Thai Government scholarship (B.S.). NR 20 TC 4 Z9 5 U1 0 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0001-5652 J9 HUM HERED JI Hum. Hered. PY 2012 VL 74 IS 1 BP 17 EP 26 DI 10.1159/000341636 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 036QS UT WOS:000311045000003 PM 23038411 ER PT J AU Miller, NH Justice, CM Marosy, B Swindle, K Kim, Y Roy-Gagnon, MH Sung, H Behneman, D Doheny, KF Pugh, E Wilson, AF AF Miller, Nancy H. Justice, Cristina M. Marosy, Beth Swindle, Kandice Kim, Yoonhee Roy-Gagnon, Marie-Helene Sung, Heejong Behneman, Dana Doheny, Kimberly F. Pugh, Elizabeth Wilson, Alexander F. TI Intra-Familial Tests of Association between Familial Idiopathic Scoliosis and Linked Regions on 9q31.3-q34.3 and 16p12.3-q22.2 SO HUMAN HEREDITY LA English DT Article DE Idiopathic scoliosis; Chromosome 9; Chromosome 16; Genetic heterogeneity; Genetics; Association; Family-based association study; Complex disease ID GENOME-WIDE ASSOCIATION; CANDIDATE REGIONS; TILED REGRESSION; UNIFIED APPROACH; SUSCEPTIBILITY; LINKAGE; IDENTIFICATION; LOCUS; POPULATION; ASSIGNMENT AB Objective: Custom genotyping of markers in families with familial idiopathic scoliosis were used to fine-map candidate regions on chromosomes 9 and 16 in order to identify candidate genes that contribute to this disorder and prioritize them for next-generation sequence analysis. Methods: Candidate regions on 9q and 16p-16q, previously identified as linked to familial idiopathic scoliosis in a study of 202 families, were genotyped with a high-density map of single nucleotide polymorphisms. Tests of linkage for fine-mapping and intra-familial tests of association, including tiled regression, were performed on scoliosis as both a qualitative and quantitative trait. Results and Conclusions: Nominally significant linkage results were found for markers in both candidate regions. Results from intra-familial tests of association and tiled regression corroborated the linkage findings and identified possible candidate genes suitable for follow-up with next-generation sequencing in these same families. Candidate genes that met our prioritization criteria included FAM129B and CERCAM on chromosome 9 and SYT1, GNAO1, and CDH3 on chromosome 16. Copyright (C) 2012 S. Karger AG, Basel C1 [Miller, Nancy H.; Swindle, Kandice] Univ Colorado Anschutz Med Campus, Dept Orthopaed Surg, Aurora, CO 80045 USA. [Justice, Cristina M.; Kim, Yoonhee; Sung, Heejong; Behneman, Dana; Wilson, Alexander F.] NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Marosy, Beth; Doheny, Kimberly F.; Pugh, Elizabeth] Johns Hopkins Univ, Sch Med, Inst Med Genet, Ctr Inherited Dis Res, Baltimore, MD USA. [Roy-Gagnon, Marie-Helene] Univ Montreal, Dept Social & Prevent Med, CHU St Justine Res Ctr, Montreal, PQ, Canada. RP Miller, NH (reprint author), Univ Colorado Anschutz Med Campus, Dept Orthopaed Surg, 12800 E 19th Ave,MS8343, Aurora, CO 80045 USA. EM Nancy.Miller@childrenscolorado.org FU Center for Inherited Disease Research (National Institutes of Health) [N01-HG-65403]; Center for Inherited Disease Research (National Center for Research Resources) [1 P41 RR03655]; LARRK Foundation; Institute de France Foundation Yves Cotrel; National Institutes of Health [R01-AR048862-01A1]; Division of Intramural Research of the National Human Genome Research Institute, National Institutes of Health FX This work was supported by the Center for Inherited Disease Research (federal contract from the National Institutes of Health to Johns Hopkins University, contract No. N01-HG-65403); S.A.G.E. (National Center for Research Resources grant 1 P41 RR03655); LARRK Foundation (private donation); Institute de France Foundation Yves Cotrel; National Institutes of Health (R01-AR048862-01A1), and the Division of Intramural Research of the National Human Genome Research Institute, National Institutes of Health. Additional SNP genotypes were performed at The SNP Center, Genetic Resources Core Facility, McKusick/Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine. NR 42 TC 5 Z9 5 U1 1 U2 4 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0001-5652 J9 HUM HERED JI Hum. Hered. PY 2012 VL 74 IS 1 BP 36 EP 44 DI 10.1159/000343751 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 036QS UT WOS:000311045000005 PM 23154503 ER PT J AU Hosgood, HD Lan, Q Vermeulen, R Wei, H Reiss, B Coble, J Wei, FS Jun, X Wu, GP Rothman, N AF Hosgood, H. Dean Lan, Qing Vermeulen, Roel Wei, Hu Reiss, Boris Coble, Joseph Wei, Fusheng Jun, Xu Wu, Guoping Rothman, Nat TI Combustion-derived nanoparticle exposure and household solid fuel use in Xuanwei and Fuyuan, China SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH LA English DT Article DE coal; biomass; wood; stove; nanoparticle; respiratory ID PARTICULATE MATTER CONCENTRATIONS; WOOD-BURNING STOVES; LUNG-CANCER; OXIDATIVE-STRESS; IN-VITRO; ULTRAFINE PARTICLES; HOSPITAL ADMISSIONS; SIZE DISTRIBUTION; CARBON-MONOXIDE; DIESEL EXHAUST AB Combustion-derived nanoparticles (CDNPs) have not been readably measurable until recently. We conducted a pilot study to determine CDNP levels during solid fuel burning. The aggregate surface area of CDNP (mu m(2)/cm(3)) was monitored continuously in 15 Chinese homes using varying fuel types (i.e. bituminous coal, anthracite coal, wood) and stove types (i.e. portable stoves, stoves with chimneys, firepits). Information on fuel burning activities was collected and PM2.5 levels were measured. Substantial exposure differences were observed during solid fuel burning (mean: 228.1 mu m(2)/cm(3)) compared to times without combustion (mean: 14.0 mu m(2)/cm(3)). The observed levels during burning were reduced by about four-fold in homes with a chimney (mean: 92.1 mu m(2)/cm(3); n = 9), and effects were present for all fuel types. Each home's CDNP measurement was only moderately correlated with the respective PM2.5 measurements (r(2) = 0.43; p = 0.11). Our results indicate that household coal and wood burning contributes to indoor nanoparticle levels, which are not fully reflected in PM2.5 measurements. C1 [Hosgood, H. Dean; Lan, Qing; Wei, Hu; Coble, Joseph; Jun, Xu; Rothman, Nat] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Vermeulen, Roel; Reiss, Boris] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Wei, Fusheng; Wu, Guoping] China Natl Environm Monitoring Ctr, Beijing, Peoples R China. RP Hosgood, HD (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7240,Execut Plaza S, Bethesda, MD 20892 USA. EM hosgoodd@mail.nih.gov RI Hu, Wei/M-3524-2013; Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU Intramural NIH HHS [Z99 CA999999] NR 35 TC 7 Z9 7 U1 1 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0960-3123 J9 INT J ENVIRON HEAL R JI Int. J. Environ. Health Res. PY 2012 VL 22 IS 6 BP 571 EP 581 DI 10.1080/09603123.2012.684147 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 030SJ UT WOS:000310590100007 PM 22639822 ER PT J AU Thaker, AA Razjouyan, F Woods, DL Haemmerich, D Sekhar, K Wood, BJ Dreher, MR AF Thaker, Ashesh A. Razjouyan, Faezeh Woods, David L. Haemmerich, Dieter Sekhar, Kiran Wood, Bradford J. Dreher, Matthew R. TI Combination therapy of radiofrequency ablation and bevacizumab monitored with power Doppler ultrasound in a murine model of hepatocellular carcinoma SO INTERNATIONAL JOURNAL OF HYPERTHERMIA LA English DT Article DE angiogenesis; bevacizumab; hepatocellular carcinoma; microvascular density; power Doppler ultrasound; radiofrequency ablation ID INTRATUMORAL LIPOSOMAL DOXORUBICIN; RENAL-CELL CARCINOMA; TUMOR BLOOD-FLOW; ANTIANGIOGENIC THERAPY; THERMAL ABLATION; VASCULAR NORMALIZATION; ANTIVASCULAR THERAPY; PHASE-I; CANCER; ANGIOGENESIS AB Purpose: The purpose of this study was to monitor tumour blood flow with power Doppler ultrasound following antiangiogenic therapy with bevacizumab in order to optimally time the application of radiofrequency (RF) ablation to increase ablation diameter. Materials and methods: Athymic nude mice bearing human hepatocellular carcinoma xenografts were treated with bevacizumab and imaged daily with power Doppler ultrasound to quantify tumour blood flow. Mice were treated with RF ablation alone or in combination with bevacizumab at the optimal time, as determined by ultrasound. Ablation diameter was measured with histology and tumour microvascular density was calculated with immunohistochemistry. A computational thermal model of RF ablation was used to estimate ablation volume. Results: A maximum reduction of 27.8 +/- 8.6% in tumour blood flow occurred on day 2 following antiangiogenic therapy, while control tumours increased 29.3 +/- 17.1% (p < 0.05). Tumour microvascular density was similarly reduced by 45.1 +/- 5.9% on day 2 following antiangiogenic therapy. Histology demonstrated a 13.6 +/- 5.6% increase in ablation diameter (40 +/- 21% increase in volume) consistent with a computational model. Conclusion: Quantitative power Doppler ultrasound is a useful biomarker to monitor tumour blood flow following a ntiangiogenic treatment and to guide the application of RF ablation as a drug plus device combination therapy. C1 [Thaker, Ashesh A.; Razjouyan, Faezeh; Woods, David L.; Sekhar, Kiran; Wood, Bradford J.; Dreher, Matthew R.] NCI, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Thaker, Ashesh A.] Univ Penn, Perelman Sch Med, Dept Radiol, Philadelphia, PA 19104 USA. [Haemmerich, Dieter] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Sekhar, Kiran] Albany Med Ctr, Dept Radiol, New York, NY USA. RP Dreher, MR (reprint author), NCI, Ctr Intervent Oncol Radiol & Imaging Sci, Ctr Clin, NIH, 9000 Rockville Pike,Bldg 10,Room 2N212,MSC 1182, Bethesda, MD 20892 USA. EM dreherm@cc.nih.gov OI Thaker, Ashesh/0000-0001-5238-0429; Haemmerich, Dieter/0000-0003-1127-7024 FU Center for Interventional Oncology in the Intramural Research Program of the National Institutes of Health (NIH); Howard Hughes Medical Institute NIH Research Scholars Program FX This research was supported in part by the Center for Interventional Oncology in the Intramural Research Program of the National Institutes of Health (NIH) and the Howard Hughes Medical Institute NIH Research Scholars Program (AAT). The authors report no other conflicts of interest. The authors alone are responsible for the content and writing of the paper. NR 65 TC 7 Z9 7 U1 1 U2 7 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0265-6736 J9 INT J HYPERTHER JI Int. J. Hyperthermia PY 2012 VL 28 IS 8 BP 766 EP 775 DI 10.3109/02656736.2012.724517 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 039HU UT WOS:000311236300009 PM 23043501 ER PT J AU Barkan, D El Touny, L Michalowski, AM Smith, JA Chu, I Davis, AS Webster, JD Hoover, S Simpson, MR Gauldie, J Green, JE AF Barkan, Dalit El Touny, Lara Michalowski, Aleksandra M. Smith, Jane Ann Chu, Isabel Davis, Anne Sally Webster, Joshua D. Hoover, Shelley Simpson, Mark R. Gauldie, Jack Green, Jeffrey E. TI The fibrotic microenvironment: The permissive 'soil' switching disseminated dormant tumor cells to metastatic growth SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Meeting Abstract C1 [Barkan, Dalit] Univ Haifa, Fac Nat Sci, Dept Biol, IL-31999 Haifa, Israel. [El Touny, Lara; Michalowski, Aleksandra M.; Chu, Isabel; Webster, Joshua D.; Hoover, Shelley; Simpson, Mark R.; Green, Jeffrey E.] NCI, Lab Cell Biol & Genet, Bethesda, MD 20892 USA. [Davis, Anne Sally] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. [Smith, Jane Ann; Gauldie, Jack] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PY 2012 VL 30 SU 1 MA 239 BP S39 EP S39 PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 031ON UT WOS:000310651600140 ER PT J AU Parry, C Padgett, LS Zebrack, B AF Parry, Carla Padgett, Lynne S. Zebrack, Brad TI Now What? Toward an Integrated Research and Practice Agenda in Distress Screening SO JOURNAL OF PSYCHOSOCIAL ONCOLOGY LA English DT Article DE distress screening; cancer survivorship; measurement; implementation; distress management; psychosocial care ID 6TH VITAL SIGN; CANCER-PATIENTS; PSYCHOLOGICAL DISTRESS; ASSESSMENT INSTRUMENTS; EMOTIONAL DISTRESS; MOOD DISORDERS; DEPRESSION; METAANALYSIS; THERMOMETER; VALIDATION AB Significant gains have been made in the detection and treatment of cancer, contributing to increased survival, but a cancer diagnosis and treatment may be accompanied by physical and psychosocial after-effects. Distress screening has been championed as a mechanism to identify patients with high levels of psychosocial morbidity for subsequent assessment and psychosocial care delivery. However, implementation of distress screening has been variable, in scope and in the consistency and quality of metrics and methods used. This capstone article identifies challenges in the measurement and implementation of distress screening and examines future opportunities for research and implementation. C1 [Parry, Carla] NCI, NIH, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Zebrack, Brad] Univ Michigan, Sch Social Work, Ann Arbor, MI 48109 USA. RP Parry, C (reprint author), NCI, NIH, Off Canc Survivorship, Div Canc Control & Populat Sci, 6116 Execut Blvd,Suite 404, Bethesda, MD 20892 USA. EM Carla.parry@nih.gov NR 50 TC 4 Z9 4 U1 0 U2 4 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0734-7332 J9 J PSYCHOSOC ONCOL JI J. Psychosoc. Oncol. PY 2012 VL 30 IS 6 SI SI BP 715 EP 727 DI 10.1080/07347332.2012.721486 PG 13 WC Psychology, Social SC Psychology GA 030TT UT WOS:000310593700008 PM 23101553 ER PT J AU Ding, XY Lin, SCS Lapsley, MI Li, SX Guo, X Chan, CY Chiang, IK Wang, L McCoy, JP Huang, TJ AF Ding, Xiaoyun Lin, Sz-Chin Steven Lapsley, Michael Ian Li, Sixing Guo, Xiang Chan, Chung Yu Chiang, I-Kao Wang, Lin McCoy, J. Philip Huang, Tony Jun TI Standing surface acoustic wave (SSAW) based multichannel cell sorting SO LAB ON A CHIP LA English DT Article ID MICROFLUIDIC CHANNEL; MICROPARTICLES; PARTICLE; ACOUSTOPHORESIS; MANIPULATION; TRANSDUCER; SEPARATION; SYSTEMS; FORCE AB We introduce a novel microfluidic device for cell sorting in continuous flow using tunable standing surface acoustic waves. This method allows individual cells to be precisely directed into five different outlet channels in a single step. It is versatile, simple, label-free, non-invasive, and highly controllable. C1 [Ding, Xiaoyun; Lin, Sz-Chin Steven; Lapsley, Michael Ian; Li, Sixing; Guo, Xiang; Chan, Chung Yu; Chiang, I-Kao; Huang, Tony Jun] Penn State Univ, Dept Engn Sci & Mech, University Pk, PA 16802 USA. [Li, Sixing; Huang, Tony Jun] Penn State Univ, Cell & Dev Biol Program, University Pk, PA 16802 USA. [Wang, Lin] Ascent Bionano Technol Inc, State Coll, PA 16801 USA. [McCoy, J. Philip] NHLBI, NIH, Bethesda, MD 20892 USA. RP Huang, TJ (reprint author), Penn State Univ, Dept Engn Sci & Mech, 227 Hammond Bldg, University Pk, PA 16802 USA. EM junhuang@psu.edu RI Ding, Xiaoyun/F-3695-2012; Li, Sixing/F-2383-2013; Chan, Chung Yu/D-1003-2015; Huang, Tony/A-1546-2009 OI Ding, Xiaoyun/0000-0003-4252-9335; Chan, Chung Yu/0000-0001-6726-5087; FU National Institutes of Health (NIH) [1DP2OD007209-01]; National Science Foundation (NSF); NSF [DGE-0750756]; Penn State Center for Nanoscale Science (MRSEC); NSF FX This research was supported by National Institutes of Health (NIH) Director's New Innovator Award (1DP2OD007209-01), National Science Foundation (NSF), NSF Graduate Research Fellowship (Grant No. DGE-0750756), and the Penn State Center for Nanoscale Science (MRSEC). Components of this work were conducted at the Penn State node of the NSF-funded National Nanotechnology Infrastructure Network. We thank Dr Bernhard R. Tittmann and Brian Reinhardt for their assistance with equipment. NR 38 TC 74 Z9 74 U1 8 U2 85 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1473-0197 J9 LAB CHIP JI Lab Chip PY 2012 VL 12 IS 21 BP 4228 EP 4231 DI 10.1039/c2lc40751e PG 4 WC Biochemical Research Methods; Chemistry, Multidisciplinary; Nanoscience & Nanotechnology SC Biochemistry & Molecular Biology; Chemistry; Science & Technology - Other Topics GA 035BF UT WOS:000310916100002 PM 22992833 ER PT J AU Kralj, JG Arya, C Tona, A Forbes, TP Munson, MS Sorbara, L Srivastava, S Forry, SP AF Kralj, Jason G. Arya, Chandamany Tona, Alessandro Forbes, Thomas P. Munson, Matthew S. Sorbara, Lynn Srivastava, Sudhir Forry, Samuel P. TI A simple packed bed device for antibody labelled rare cell capture from whole blood SO LAB ON A CHIP LA English DT Article ID CIRCULATING TUMOR-CELLS; MICROFLUIDICS; AMPLIFICATION; ENUMERATION AB We have developed a system to isolate rare cells from whole blood using commercially available components and simple microfluidics. We characterized the capture of MCF-7 cells spiked into whole human blood using this system to demonstrate that enrichment and enumeration studies give results similar to in situ surface-modified devices while reducing fabrication and operation complexity. C1 [Kralj, Jason G.; Tona, Alessandro; Forbes, Thomas P.; Munson, Matthew S.; Forry, Samuel P.] NIST, Div Biochem Sci, Gaithersburg, MD 20899 USA. [Arya, Chandamany] Univ Maryland, Dept Mech Engn, College Pk, MD 20742 USA. [Sorbara, Lynn; Srivastava, Sudhir] NCI, Early Detect Res Network, NIH, Bethesda, MD 20892 USA. RP Forry, SP (reprint author), NIST, Div Biochem Sci, 100 Bur Dr, Gaithersburg, MD 20899 USA. EM samuel.forry@nist.gov RI Forbes, Thomas/M-3091-2014 OI Forbes, Thomas/0000-0002-7594-5514 NR 19 TC 14 Z9 14 U1 1 U2 28 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1473-0197 J9 LAB CHIP JI Lab Chip PY 2012 VL 12 IS 23 BP 4972 EP 4975 DI 10.1039/c2lc41048f PG 4 WC Biochemical Research Methods; Chemistry, Multidisciplinary; Nanoscience & Nanotechnology SC Biochemistry & Molecular Biology; Chemistry; Science & Technology - Other Topics GA 035BJ UT WOS:000310916500006 PM 23079718 ER PT J AU Mitchell, SJ Huizer-Pajkos, A Cogger, VC McLachlan, AJ Le Couteur, DG Jones, B de Cabo, R Hilmer, SN AF Mitchell, Sarah J. Huizer-Pajkos, Aniko Cogger, Victoria C. McLachlan, Andrew J. Le Couteur, David G. Jones, Brett de Cabo, Rafael Hilmer, Sarah N. TI The Influence of Old Age and Poloxamer-407 on the Hepatic Disposition of Diazepam in the Isolated Perfused Rat Liver SO PHARMACOLOGY LA English DT Article DE Diazepam; Fenestrae; Hepatic clearance; Liver sinusoidal endothelial cell; Pseudocapillarization ID MULTIPLE-INDICATOR DILUTION; SINUSOIDAL ENDOTHELIUM; PROPRANOLOL METABOLISM; DRUG CLEARANCE; CIRRHOSIS; PHARMACOKINETICS; PSEUDOCAPILLARIZATION; ATHEROSCLEROSIS; ELIMINATION; DISPERSION AB Background and Purpose: The normal liver sinusoidal endothelium is thin and punctuated with fenestrations 50-200 nm in diameter that filter endobiotics and xenobiotics. Defenestration of the liver sinusoidal endothelium in old age and after pre-treatment with poloxamer-407 (P407) has been shown to prevent the transfer of small chylomicrons across the liver sinusoidal endothelium. The aim of this study was to investigate the impact of liver sinusoidal endothelium fenestrations on the hepatic uptake of the highly protein-bound drug diazepam. We hypothesized that defenestration will reduce the hepatic extraction of drugs which are highly bound to albumin. Methodology: The isolated perfused rat liver (IPRL) model and multiple indicator dilution technique were used to investigate the effect of fenestrations in the liver sinusoidal endothelium on the hepatic disposition of diazepam in old and young rats, and in young rats treated with P407 or vehicle. A bolus dose of C-14-diazpeam and non-extracted tracers (H-3-sucrose and Evans blue) was injected into the portal vein. The single-pass recovery of diazepam and markers and the apparent volume of distribution were determined. Results: Scanning electron microscopy confirmed reduced porosity of the liver sinusoidal endothelial cells in P407-treated rats and old rats compared to young and control rats. The fractional recovery of diazepam was significantly increased in P407-treated rats compared to controls (0.20 +/- 0.16, n = 12, P407; 0.08 +/- 0.05, n = 8, controls; p = 0.0029), and in old rats compared to young rats (0.15 +/- 0.03, n = 11, old; 0.10 +/- 0.02, n = 11, young; p = 0.0004) following a single pass. Conclusion: Defenestration due to age-related pseudocapillarization and treatment with P407 resulted in reduced hepatic extraction of diazepam after a single pass through the IPRL. These results highlight the importance of the liver sinusoidal endothelium in the ultrafiltration of highly protein-bound drugs, and may also provide an additional mechanism for reduced hepatic clearance of diazepam in conditions associated with defenestration. Copyright (C) 2012 S. Karger AG, Basel C1 [Mitchell, Sarah J.] Royal N Shore Hosp, Kolling Inst Med Res, Lab Ageing & Pharmacol, St Leonards, NSW 2065, Australia. [Mitchell, Sarah J.; Huizer-Pajkos, Aniko; Hilmer, Sarah N.] Royal N Shore Hosp, Dept Clin Pharmacol, St Leonards, NSW 2065, Australia. [Jones, Brett] Royal N Shore Hosp, Dept Gastroenterol & Hepatol, St Leonards, NSW 2065, Australia. [Cogger, Victoria C.; McLachlan, Andrew J.; Le Couteur, David G.] Concord RG Hosp, Ctr Educ & Res Ageing, Sydney, NSW, Australia. [Cogger, Victoria C.; McLachlan, Andrew J.; Le Couteur, David G.] Concord RG Hosp, ANZAC Res Inst, Sydney, NSW, Australia. [Mitchell, Sarah J.; Cogger, Victoria C.; Le Couteur, David G.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [McLachlan, Andrew J.] Univ Sydney, Fac Pharm, Sydney, NSW 2006, Australia. [Mitchell, Sarah J.; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RP Mitchell, SJ (reprint author), Royal N Shore Hosp, Kolling Inst Med Res, Lab Ageing & Pharmacol, Pacific Highway, St Leonards, NSW 2065, Australia. EM sarah.mitchell@sydney.edu.au RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Hilmer, Sarah/0000-0002-5970-1501; , rafael/0000-0003-2830-5693; McLachlan, Andrew/0000-0003-4674-0242 FU Intramural Research Program of the National Institute on Aging of the National Institutes of Health, USA; National Health and Medical Research Council of Australia [201001671]; Geoff and Elaine Penney Ageing Research Unit, Royal North Shore Hospital, National Health and Medical Research Council of Australia [570968]; Aging and Alzheimer's Research Foundation FX We gratefully acknowledge Prof. David Richmond Sullivan, Professor of Biochemistry Royal Prince Alfred Hospital, Sydney, N.S.W., Australia, for assessing lipid levels and liver enzymes in blood samples. R.d.C. is supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health, USA. S.J.M. is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (RIMS Project ID 201001671). This study was supported by grants from the Geoff and Elaine Penney Ageing Research Unit, Royal North Shore Hospital, National Health and Medical Research Council of Australia (Grant Number 570968), the Aging and Alzheimer's Research Foundation and in part by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health, USA. NR 53 TC 5 Z9 5 U1 1 U2 7 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0031-7012 EI 1423-0313 J9 PHARMACOLOGY JI Pharmacology PY 2012 VL 90 IS 5-6 BP 233 EP 241 DI 10.1159/000341724 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 036PX UT WOS:000311042400001 PM 23007459 ER PT J AU Suchkov, SV Rose, N Notkins, A Golubnichaya, O Von Herrath, M Legg, M Marshall, T AF Suchkov, S. V. Rose, N. Notkins, A. Golubnichaya, O. Von Herrath, M. Legg, M. Marshall, T. TI Introduction to preventive and predictive medicine: past experience and future reality SO TERAPEVTICHESKII ARKHIV LA Russian DT Article DE genomics; proteomics; bioinformatics; metabolomics; bioprediction; bioprevention AB The active practical introduction of the achievements of genomics, proteomics, metabolomics, and bioinformatics brought about a fundamental change in views on the role and place of medicine in the structure of healthcare at the turn of the 1980s-1990s, by giving impetus to the development of the radically new health care area preventive, predictive, and personalized medicine (PPPM). The main goals of PPM are to recognize disease signs at the stage of subclinical pathology with d the identification of targets suitable for drug-based prevention for drug-based prevention and to make pharmacorrection of the disturbances identified aimed at the drug-based prevention to promote the suppression of pathological process at the subclinical stage. C1 [Suchkov, S. V.] IM Sechenov First Moscow State Med Univ, Dept Pathol, Moscow, Russia. Johns Hopkins Univ, Ctr Autoimmine Dis, Baltimore, MD USA. Natl Inst Hlth, Bethesda, MD USA. RP Suchkov, SV (reprint author), IM Sechenov First Moscow State Med Univ, Dept Pathol, Moscow, Russia. NR 0 TC 0 Z9 0 U1 0 U2 1 PU IZDATELSTVO MEDITSINA PI MOSCOW PA PETROVERIGSKII PER 6-8, K-142 MOSCOW, RUSSIA SN 0040-3660 J9 TERAPEVT ARKH JI Ter. Arkhiv PY 2012 VL 84 IS 8 BP 81 EP 85 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 016ES UT WOS:000309500900017 PM 22994097 ER PT J AU Kiesewetter, DO Guo, N Guo, JX Gao, HK Zhu, L Ma, Y Niu, G Chen, XY AF Kiesewetter, Dale O. Guo, Ning Guo, Jinxia Gao, Haokao Zhu, Lei Ma, Ying Niu, Gang Chen, Xiaoyuan TI Evaluation of an [F-18]AlF-NOTA Analog of Exendin-4 for Imaging of GLP-1 Receptor in Insulinoma SO THERANOSTICS LA English DT Article DE [F-18]fluoride; insulinoma; exendin-4; PET ID GLUCAGON-LIKE PEPTIDE-1; IN-VIVO; PET; RADIOPHARMACEUTICALS; CANCER; F-18; EXPRESSION; MOUSE; CU-64 AB Introduction: The GLP-1 receptor plays an important role in glucose homeostasis and thus is a very important target for diabetes therapy. The receptor is also overexpressed in insulinoma, a tumor of pancreatic beta-cells. We previously evaluated two fluorine-18-labeled analogs of exendin-4 prepared by conjugation with [F-18]FBEM (N-[2-(4-[F-18]fluorobenzamide) ethyl] maleimide). Both compounds demonstrated good tumor uptake, but the synthesis of the radiotracers was time consuming. To overcome this challenge, we developed a NOTA analog and performed radiolabeling using aluminum [F-18]fluoride complexation. Methods: Cys(40)-exendin-4 was conjugated with NOTA mono N- ethylmaleimide. [F-18]AlF conjugation was conducted and the radiolabeled product purified by preparative HPLC. Dynamic and static PET imaging scans were conducted on nude mice with established INS-1 xenografts. Uptake of tumor and other major organs in static images was quantitated (%ID/g) and comparison with blocking studies was made. PET quantification was also compared with ex vivo biodistribution results. Results: The radiosynthesis provided [F-18]AlF-NOTA-MAL-cys(40)-exendin-4 in 23.6 +/- 2.4 % radiochemical yield (uncorrected, n = 3) after HPLC; the process required about 55 min. The specific activity at time of injection ranged from 19.6 to 31.4 GBq (0.53-0.85 Ci)/mu mol. Tumor uptake had reached its maximum (16.09 +/- 1.18% ID/g, n = 4) by 5 min and remained nearly constant for the duration of the study. Kidney uptake continued to increase throughout the entire one hour time course. Pre-injection of exendin-4 caused a marked reduction in tissue uptake with the major exception of liver and kidneys, in which uptake was not affected. HPLC analysis of the radioactive components in extracts of the tumor and plasma showed primarily parent compound at 60 min post-injection, whereas extracts of kidney and urine contained exclusively one polar radioactive component. Conclusion: The radiotracer is prepared in a simple one-step procedure and obtained in high specific activity after HPLC purification. [F-18]AlF-NOTA-MAL-exendin-4 shows high tumor uptake and highly selective GLP-1 tissue uptake (INS-1 tumor, lung, pancreas), but still suffers from high kidney uptake. C1 [Kiesewetter, Dale O.; Guo, Ning; Guo, Jinxia; Gao, Haokao; Zhu, Lei; Ma, Ying; Niu, Gang; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging, NIH, Bethesda, MD 20892 USA. [Guo, Ning; Guo, Jinxia] Huazhong Univ Sci & Technol, Dept Biomed Engn, Wuhan 430074, Hubei, Peoples R China. [Gao, Haokao] Fourth Mil Med Univ, Dept Cardiol, Xijing Hosp, Xian 710032, Peoples R China. [Zhu, Lei] Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361005, Peoples R China. RP Chen, XY (reprint author), Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging, NIH, Bethesda, MD 20892 USA. EM niug@mail.nih.gov; shawn.chen@nih.gov RI Zhu, Lei/P-9786-2016 OI Zhu, Lei/0000-0002-1820-4795 FU National Institute of Biomedical Imaging and Bioengineering, NIH FX This research was supported by the intramural research program of the National Institute of Biomedical Imaging and Bioengineering, NIH. Fluorine-18 was prepared by the cyclotron facility of the Positron Emission Tomography Department, Warren Grant Magnuson Clinical Center, NIH. NR 27 TC 28 Z9 30 U1 2 U2 25 PU IVYSPRING INT PUBL PI LAKE HAVEN PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA SN 1838-7640 J9 THERANOSTICS JI Theranostics PY 2012 VL 2 IS 10 BP 999 EP 1009 DI 10.7150/thno.5276 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 033ON UT WOS:000310807500004 PM 23139727 ER PT S AU Straehle, CN Koethe, U Knott, G Briggman, K Denk, W Hamprecht, FA AF Straehle, Christoph-N. Koethe, Ullrich Knott, Graham Briggman, Kevin Denk, Winfried Hamprecht, Fred A. GP IEEE TI Seeded watershed cut uncertainty estimators for guided interactive segmentation SO 2012 IEEE CONFERENCE ON COMPUTER VISION AND PATTERN RECOGNITION (CVPR) SE IEEE Conference on Computer Vision and Pattern Recognition LA English DT Proceedings Paper CT IEEE Conference on Computer Vision and Pattern Recognition (CVPR) CY JUN 16-21, 2012 CL Providence, RI SP IEEE AB Watershed cuts are among the fastest segmentation algorithms and therefore well suited for interactive segmentation of very large 3D data sets. To minimize the number of user interactions ("seeds") required until the result is correct, we want the computer to actively query the human for input at the most critical locations, in analogy to active learning. These locations are found by means of suitable uncertainty measures. We propose various such measures for watershed cuts along with a theoretical analysis of some of their properties. Extensive evaluation on two types of 3D electron microscopic volumes of neural tissue shows that measures which estimate the non-local consequences of new user inputs achieve performance close to an oracle endowed with complete knowledge of the ground truth. C1 [Straehle, Christoph-N.; Koethe, Ullrich; Hamprecht, Fred A.] HCI Univ Heidelberg, D-69117 Heidelberg, Germany. [Knott, Graham] EPF, EPFL SV GE, CH-1015 Lausanne, Switzerland. [Briggman, Kevin] Natl Inst Hlth, Bethesda, MD 20892 USA. [Denk, Winfried] MPI Med Res, D-69120 Heidelberg, Germany. RP Straehle, CN (reprint author), HCI Univ Heidelberg, D-69117 Heidelberg, Germany. RI denk, winfried/I-6627-2012 NR 27 TC 8 Z9 8 U1 0 U2 3 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1063-6919 BN 978-1-4673-1228-8 J9 PROC CVPR IEEE PY 2012 BP 765 EP 772 PG 8 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BBZ37 UT WOS:000309166200096 ER PT J AU Blanch-Hartigan, D Andrzejewski, SA Hill, KM AF Blanch-Hartigan, Danielle Andrzejewski, Susan A. Hill, Krista M. TI The Effectiveness of Training to Improve Person Perception Accuracy: A Meta-Analysis SO BASIC AND APPLIED SOCIAL PSYCHOLOGY LA English DT Article ID FACIAL EXPRESSIONS; INTERPERSONAL PERCEPTION; DETECT DECEPTION; NONVERBAL CUES; AFFECTIVE SENSITIVITY; EMOTION RECOGNITION; FACE RECOGNITION; POLICE OFFICERS; THIN SLICES; BEHAVIOR AB Making accurate perceptions of others is a valuable skill. This meta-analysis examines whether accurate person perception is a skill amenable to training in nonclinical adult populations and, if training can increase accuracy, what are the most effective training methods. Across person perception domains, training interventions significantly increased accuracy. Training approach mattered more than length of training. Practice and feedback were more effective approaches than instruction alone; however, a combination of training approaches was the most effective intervention. Results of this meta-analysis advance person perception theory and offer practical advice for future development of trainings to increase person perception accuracy. C1 [Blanch-Hartigan, Danielle] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. [Andrzejewski, Susan A.] Franklin & Marshall Coll, Lancaster, PA 17604 USA. [Hill, Krista M.] Northeastern Univ, Boston, MA USA. RP Blanch-Hartigan, D (reprint author), NCI, Off Canc Survivorship, 6116 Execut Blvd,Suite 404,MSC 8336, Bethesda, MD 20892 USA. EM danielleblanch@gmail.com NR 112 TC 17 Z9 17 U1 4 U2 33 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0197-3533 J9 BASIC APPL SOC PSYCH JI Basic Appl Soc. Psychol. PY 2012 VL 34 IS 6 BP 483 EP 498 DI 10.1080/01973533.2012.728122 PG 16 WC Psychology, Social SC Psychology GA 034EI UT WOS:000310852600001 ER PT B AU Hackstadt, T AF Hackstadt, Ted BE Tan, M Bavoil, PM TI INITIAL INTERACTIONS OF CHLAMYDIAE WITH THE HOST CELL SO INTERCELLULAR PATHOGENS I: CHLAMYDIALES LA English DT Article; Book Chapter ID ENDOGENOUSLY SYNTHESIZED SPHINGOMYELIN; OBLIGATE INTRACELLULAR PATHOGEN; TRACHOMATIS INCLUSION MEMBRANE; ENDOMETRIAL EPITHELIAL-CELLS; PROTEIN DISULFIDE-ISOMERASE; EARLY-CYCLE DEVELOPMENT; HISTONE-LIKE PROTEIN; III SECRETION; HELA-CELLS; INFECTED-CELLS C1 NIAID, Host Parasite Interact Sect, Lab Intracellular Parasites, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Host Parasite Interact Sect, Lab Intracellular Parasites, Rocky Mt Labs,NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 144 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N STREET NW, WASHINGTON, DC 20036-2904 USA BN 978-1-55581-674-2 PY 2012 BP 126 EP 148 DI 10.1128/9781555817329.ch6 PG 23 WC Biochemistry & Molecular Biology; Infectious Diseases; Microbiology SC Biochemistry & Molecular Biology; Infectious Diseases; Microbiology GA BCI76 UT WOS:000310252200007 ER PT J AU Liang, S Liang, Y He, JT Ito, Y AF Liang, Si Liang, Yong He, Junting Ito, Yoichiro TI SEPARATION AND PURIFICATION OF THREE FLAVONOIDS FROM DAPHNE GENKWA SIEB. ET ZUCC.: COMPARISON IN PERFORMANCE BETWEEN MEDIUM-PRESSURE LIQUID CHROMATOGRAPHY AND HIGH-SPEED COUNTERCURRENT CHROMATOGRAPHY SO JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES LA English DT Article DE Daphne genkwa Sieb. et Zucc; flavonoids; high-speed countercurrent chromatography; medium-pressure liquid chromatography; purification; separation of natural products ID PREPARATIVE ISOLATION; FLOWER BUDS; DERIVATIVES; GLYCOSIDES; APOPTOSIS; EFFICIENT AB The two methods of medium-pressure liquid chromatography (MPLC) and high-speed countercurrent chromatography (HSCCC) are compared in the separation and purification of crude extract from Daphne genkwa Sieb. et Zucc. The MPLC method was performed with the mobile phase composed of methanol-0.1% aqueous acetic acid in the gradient elution which yielded apigenin, 30-hydroxygenkwanin, and genkwanin at high purities of 95.3%, 94.0%, and 91.5%, respectively, for 230 min. The same three components were isolated by HSCCC also at high purities of 93.4%, 94.3%, and 92.8%, respectively, using a two-phase solvent system composed of n-hexane-ethyl acetate-methanol-water (5: 7: 5: 5, v/v) for 400 min. Although both methods produced effective separations of Daphne genkwa Sieb. et Zucc., MPLC gave much shorter separation time, whereas HSCCC yielded substantially greater amounts of target compounds due to avoiding irreversible sample loss onto the solid support with less consumption of the solvent. The chemical structures of purified three compounds were identified by HPLC, ESI-MS, and H-1 NMR. C1 [Ito, Yoichiro] NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Liang, Si; Liang, Yong; He, Junting] S China Normal Univ, Sch Chem & Environm, Guangzhou, Guangdong, Peoples R China. RP Ito, Y (reprint author), NHLBI, Bioseparat Technol Lab, Biochem & Biophys Ctr, NIH, Bldg 10,Room 8N230,10 Ctr Dr, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov NR 23 TC 2 Z9 2 U1 2 U2 14 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1082-6076 J9 J LIQ CHROMATOGR R T JI J. Liq. Chromatogr. Relat. Technol. PY 2012 VL 35 IS 18 BP 2610 EP 2622 DI 10.1080/10826076.2011.637271 PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 032RY UT WOS:000310738000009 ER PT S AU Moreno, AM Laguna, AR Zamudio, FET AF Moreno, Montoya A. Laguna, Rodriguez A. Zamudio, Trujillo F. E. BE Zamudio, FET Brandan, ME GamboadeBuen, I HerreraCorral, G MedinaVelazquez, LA TI Implementation Of Test For Quality Assurance In Nuclear Medicine Gamma Camera SO MEDICAL PHYSICS SE AIP Conference Proceedings LA English DT Proceedings Paper CT 12th Mexican Symposium on Medical Physics CY MAR 16-19, 2012 CL Hosp Reg Alta Especialidad Oaxaca (HRAEO), Oaxaca, MEXICO SP Soc Mexicana Fisica, Div Fisica Medica, Centro Latinoamericano Fisica (CLAF) HO Hosp Reg Alta Especialidad Oaxaca (HRAEO) DE Nuclear medicine; gamma cameras; quality control; optimize equipment and false diagnoses AB In nuclear medicine (NM) over 90% of procedures are performed for diagnostic purposes. To ensure adequate diagnostic quality of images and the optimization of the doses received by patients originated from the radioactive material is essential for regular monitoring and equipment performance through a quality assurance program (QAP). The QAP consists of 15 proposed performance tomographic and not tomographic gamma camera (GC) tests, and is based on recommendations of international organizations. We describe some results of the performance parameters of QAP applied to a GC model e. cam Siemens, of the Department of NM of the National Cancer Institute of Mexico (INCan). The results were: (1) The average intrinsic spatial resolution (R-in) was 4.67 +/- 0.25 mm at the limit of acceptance criterion of 4.4 mm. (2) The sensitivity extrinsic (S-ext), with maximum variations of 1.8% (less than 2% which is the criterion of acceptance). (3) Rotational Uniformity (U-rot), with values of integral uniformity (IU) in the useful field of view detector (UFOV), with maximum percentage change of 0.97% and monthly variations equal angles, ranging from 0.13 to 0.99% less than 1%. (4) The displacement of the center of rotation (DCOR), indicated a maximum deviation of 0.155 +/- 0.039 mm less than 4.795 mm, an absolute deviation of less than 0.5 where pixel 0.085 pixel is suggested, the criteria are assigned to low-energy collimator high resolution. (5) In tomographic uniformity (U-tomo), UI values (%) and percentage noise level (rms%) were 7.54 +/- 1.53 and 4.18 +/- 1.69 which are consistent with the limits of acceptance of 7.0-12.0% and 3.0-6.0% respectively. The smallest cold sphere has a diameter of 11.4 mm. The implementation of a QAP allows for high quality diagnostic images, optimization of the doses given to patients, a reduction of exposure to occupationally exposed workers (POE, by its Spanish acronym), and generally improves the productivity of the service. This proposal can be used to develop a similar QAP in other facilities and may serve as a precedent for the proposed regulations for quality assurance (QA) teams in MN. C1 [Moreno, Montoya A.; Laguna, Rodriguez A.] Natl Canc Inst, Dept Nucl Med, San Fernando Ave 22,Col Sect 26, Bethesda, MD 20892 USA. [Zamudio, Trujillo F. E.] Manager Med Phys Hosp Reg High Specialty Oaxac, San Bartolo Coyotepec, Mexico. RP Moreno, AM (reprint author), Natl Canc Inst, Dept Nucl Med, San Fernando Ave 22,Col Sect 26, Bethesda, MD 20892 USA. EM arnulfo.montoya@gmail.com; alejandro.rodriguez.laguna@gmail.com; flaviotrujillo@gmail.com NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 978-0-7354-1106-7 J9 AIP CONF PROC PY 2012 VL 1494 BP 88 EP 90 DI 10.1063/1.4764607 PG 3 WC Engineering, Biomedical; Physics, Applied; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BCM03 UT WOS:000310678900024 ER PT J AU Cragg, GM Katz, F David, JNA Rosenthal, J AF Cragg, Gordon M. Katz, Flora Newman, David J. Rosenthal, Joshua TI The impact of the United Nations Convention on Biological Diversity on natural products research SO NATURAL PRODUCT REPORTS LA English DT Review ID ALGA CALLOPHYCUS-SERRATUS; ANCISTROCLADUS-KORUPENSIS; DRUG DISCOVERY; MICHELLAMINES; ALKALOIDS; HIV; CONSERVATION AB The discovery and development of novel, biologically active agents from natural sources, whether they be drugs, agrochemicals or other bioactive entities, involve a high level of interdisciplinary as well as international collaboration. Such collaboration, particularly at the international level, requires the careful negotiation of collaborative agreements protecting the rights of all parties, with special attention being paid to the rights of host (source) country governments, communities and scientific organizations. While many biodiversity-rich source countries currently might not have the necessary resources for in-country drug discovery and advanced development, they provide valuable opportunities for collaboration in this endeavor with research organizations from more high-income nations. This chapter discusses the experiences of the US National Cancer Institute and the US government-sponsored International Cooperative Biodiversity Groups program in the establishment of international agreements in the context of the Convention of Biological Diversity's objectives of promoting fair and equitable collaboration with multiple parties in many countries, and includes some specific lessons of value in developing such collaborations. C1 [Cragg, Gordon M.; Newman, David J.] NCI, Nat Prod Branch, Frederick, MD 21702 USA. [Katz, Flora; Rosenthal, Joshua] NIH, John E Fogarty Int Ctr, Bethesda, MD 20892 USA. RP David, JNA (reprint author), NCI, Nat Prod Branch, POB B, Frederick, MD 21702 USA. EM dn22a@nih.gov NR 44 TC 24 Z9 24 U1 4 U2 35 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0265-0568 EI 1460-4752 J9 NAT PROD REP JI Nat. Prod. Rep. PY 2012 VL 29 IS 12 BP 1407 EP 1423 DI 10.1039/c2np20091k PG 17 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 032SZ UT WOS:000310740700002 PM 23037777 ER PT J AU Pritchard, JE Dillon, PM Conaway, MR Silva, CM Parsons, SJ AF Pritchard, Jessica E. Dillon, Patrick M. Conaway, Mark R. Silva, Corinne M. Parsons, Sarah J. TI A Mechanistic Study of the Effect of Doxorubicin/Adriamycin on the Estrogen Response in a Breast Cancer Model SO ONCOLOGY LA English DT Article DE Doxorubicin; Breast cancer; Estrogen; Estrogen receptor; Epidermal growth factor receptor ID ACTIVATED PROTEIN-KINASE; CLINICAL-TRIALS GROUP; ANDROGEN RECEPTOR; IN-VIVO; CHEMOTHERAPEUTIC DRUG; NEOADJUVANT CHEMOTHERAPY; MOLECULAR PROFILE; RANDOMIZED-TRIALS; INDUCED APOPTOSIS; HORMONE-RECEPTOR AB Objective: Estrogen treatment limits the cytotoxic effects of chemotherapy in estrogen receptor-positive (ER+) breast cancer cell lines, suggesting that estrogen pathway signaling may confer chemotherapeutic resistance. This study investigates the molecular responses of ER+ breast cancer cell lines to the chemotherapeutic agent, doxorubicin, in the presence or absence of estrogen. Methods: ER+ MCF-7 and T47-D cells were cultured in hormone-starved or estrogen-containing media with or without doxorubicin at concentrations mimicking the low concentrations seen in plasma and tumor microenvironments in humans following typical bolus administration. Protein levels, phosphorylations, and interactions of estrogen-signaling molecules were assessed following these treatments, as well the effects of ER signaling inhibitors on cell proliferation. Results: Surprisingly, estrogen and doxorubicin co-treatment markedly induced pro-growth alterations compared to doxorubicin alone and modestly enhanced estrogen alone-induced changes. Several inhibitors suppressed cell proliferation in the presence of doxorubicin and estrogen. Conclusions: These findings demonstrate that molecular changes caused by doxorubicin in ER+ breast cancer cells can be reversed by estrogen, providing molecular evidence for the poorer responses of ER+ tumors to doxorubicin in the presence of physiologic estrogen levels. Our results also suggest that the addition of drugs targeting the ER, EGFR, the SFKs, MEK, PI3K, and/or the MMP proteins to a conventional chemotherapy regimen may improve chemosensitivity. Copyright (c) 2012 S. Karger AG, Basel C1 [Pritchard, Jessica E.; Parsons, Sarah J.] Univ Virginia, Dept Microbiol, Charlottesville, VA 22908 USA. [Pritchard, Jessica E.; Parsons, Sarah J.] Univ Virginia, Ctr Canc, Charlottesville, VA 22908 USA. [Dillon, Patrick M.] Univ Virginia, Dept Med, Div Hematol & Oncol, Charlottesville, VA 22908 USA. [Conaway, Mark R.] Univ Virginia, Dept Publ Hlth Sci Adm, Charlottesville, VA 22908 USA. [Silva, Corinne M.] NIDDKD, NIH, Charlottesville, VA USA. RP Parsons, SJ (reprint author), Univ Virginia, Dept Microbiol, Carter Harrison Bldg,MR-6,Room B711,345 Crispell, Charlottesville, VA 22908 USA. EM sap@virginia.edu OI Dillon, Patrick/0000-0003-0622-725X FU National Cancer Institute [RO1 CA 123037]; National Cancer Institute Institutional Training Grant [T32 CA009109]; Wagner Fellowship FX We would like to thank W. Faust, Jr., for his technical contribution to this work as well as K. Hulse, Parsons-Weber-Parsons Research Group, the Women's Oncology Group, and the past and present members of the S. Parsons lab for their helpful discussions. We are grateful to the M. Weber group for providing the anti-MAPK and anti-AR Western blotting antibodies. This study was generously supported by the National Cancer Institute (RO1 CA 123037) (S.J.P.), National Cancer Institute Institutional Training Grant (T32 CA009109) (J.E.P.), and the Wagner Fellowship (J.E.P.). NR 86 TC 2 Z9 4 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0030-2414 J9 ONCOLOGY-BASEL JI Oncology PY 2012 VL 83 IS 6 BP 305 EP 320 DI 10.1159/000341394 PG 16 WC Oncology SC Oncology GA 032KX UT WOS:000310718500001 PM 22964943 ER PT S AU Donato, M Draghici, S Tomoiaga, A Westfall, P Xu, ZH Romero, R AF Donato, Michele Draghici, Sorin Tomoiaga, Alin Westfall, Peter Xu, Zhonghui Romero, Roberto GP IEEE TI A method for analysis and correction of cross-talk effects in pathway analysis SO 2012 INTERNATIONAL JOINT CONFERENCE ON NEURAL NETWORKS (IJCNN) SE IEEE International Joint Conference on Neural Networks (IJCNN) LA English DT Proceedings Paper CT International Joint Conference on Neural Networks (IJCNN) CY JUN 10-15, 2012 CL Brisbane, AUSTRALIA ID WHITE ADIPOSE-TISSUE; GENE-EXPRESSION; CELLULAR PLASTICITY; BIOLOGY AB Many analysis techniques are currently available to identify the signaling pathways significantly impacted in a given condition. All these approaches calculate a p-value that aims to quantify the significance of the involvement of a given pathway in the condition under study. These p-values were thought to be related to the likelihood of their respective pathways being involved in the given condition, and to be independent. Here we show that this is not true, and that many pathways are not independent and that can considerably affect each other's p-values through a phenomenon we refer to as "cross-talk." Thus, the significance of a given pathway in a given experiment has to be interpreted in the context of the other pathways that appear to be significant. Using real data, we show that in same cases pathways with significant classical p-values are not biologically meaningful, and that some biologically meaningful pathways with insignificant p-values become significant when the crosstalk effects of other pathways are removed. We show that this phenomenon is related to the amount of common genes between different pathways, affecting the most widely used methods for pathway analysis, and we propose an analysis technique that is able to correct the over-enrichment significance of a pathway when the cross-talk effects of other pathways are removed. C1 [Donato, Michele; Draghici, Sorin] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. [Tomoiaga, Alin; Westfall, Peter] Texas Tech Univ, Ctr Adv Analyt & Business Intelligence, Lubbock, TX 79409 USA. [Xu, Zhonghui; Romero, Roberto] NICHHD, Perinatol Res Branch, Detroit, MI 48202 USA. [Xu, Zhonghui; Romero, Roberto] Natl Inst Hlth, Human Dev, Detroit, MI 48202 USA. RP Donato, M (reprint author), Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. EM sorin@wayne.edu FU NIH [RO1 RDK089167-01]; NSF [DBI-0965741] FX This work has been partially supported by the following grants: NIH RO1 RDK089167-01 and NSF DBI-0965741 (to S.D.). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the NSF, NIH, or any other of the funding agencies NR 13 TC 0 Z9 0 U1 0 U2 4 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2161-4393 BN 978-1-4673-1490-9 J9 IEEE IJCNN PY 2012 PG 7 WC Computer Science, Artificial Intelligence SC Computer Science GA BCA06 UT WOS:000309341302013 ER PT S AU Benjamin, DJ Cesarini, D Chabris, CF Glaeser, EL Laibson, DI Gudnason, V Harris, TB Launer, LJ Purcell, S Smith, AV Johannesson, M Magnusson, PKE Beauchamp, JP Christakis, NA Atwood, CS Hebert, B Freese, J Hauser, RM Hauser, TS Grankvist, A Hultman, CM Lichtenstein, P AF Benjamin, Daniel J. Cesarini, David Chabris, Christopher F. Glaeser, Edward L. Laibson, David I. Gudnason, Vilmundur Harris, Tamara B. Launer, Lenore J. Purcell, Shaun Smith, Albert Vernon Johannesson, Magnus Magnusson, Patrik K. E. Beauchamp, Jonathan P. Christakis, Nicholas A. Atwood, Craig S. Hebert, Benjamin Freese, Jeremy Hauser, Robert M. Hauser, Taissa S. Grankvist, Alexander Hultman, Christina M. Lichtenstein, Paul CA Age Gene Environm Swedish Twin Registry Framingham Heart Study Wisconsin Longitudinal Study Swedish Large Schizophrenia Study BE Arrow, KJ Bresnahan, TF TI The Promises and Pitfalls of Genoeconomics SO ANNUAL REVIEW OF ECONOMICS, VOL 4 SE Annual Review of Economics LA English DT Article; Book Chapter DE genetics; heritability; GWAS ID GENOME-WIDE ASSOCIATION; SEMIALDEHYDE DEHYDROGENASE-DEFICIENCY; BY-ENVIRONMENT INTERACTION; COMMON SNPS EXPLAIN; CANDIDATE GENE; COMPLEX TRAITS; FUNCTIONAL POLYMORPHISM; MENDELIAN RANDOMIZATION; PERSONALITY DIMENSIONS; RISK PREFERENCES AB This article reviews existing research at the intersection of genetics and economics, presents some new findings that illustrate the state of genoeconomics research, and surveys the prospects of this emerging field. Twin studies suggest that economic outcomes and preferences, once corrected for measurement error, appear to be about as heritable as many medical conditions and personality traits. Consistent with this pattern, we present new evidence on the heritability of permanent income and wealth. Turning to genetic association studies, we survey the main ways that the direct measurement of genetic variation across individuals is likely to contribute to economics, and we outline the challenges that have slowed progress in making these contributions. The most urgent problem facing researchers in this field is that most existing efforts to find associations between genetic variation and economic behavior are based on samples that are too small to ensure adequate statistical power. This has led to many false positives in the literature. We suggest a number of possible strategies to improve and remedy this problem: (a) pooling data sets, (b) using statistical techniques that exploit the greater information content of many genes considered jointly, and (c) focusing on economically relevant traits that are most proximate to known biological mechanisms. C1 [Benjamin, Daniel J.] Cornell Univ, Dept Econ, Ithaca, NY 14853 USA. [Benjamin, Daniel J.; Glaeser, Edward L.; Laibson, David I.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Cesarini, David] NYU, Ctr Expt Social Sci, New York, NY 10012 USA. [Cesarini, David] NYU, Dept Econ, New York, NY 10012 USA. [Chabris, Christopher F.] Union Coll, Dept Psychol, Schenectady, NY 12308 USA. [Glaeser, Edward L.; Laibson, David I.; Hebert, Benjamin] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Gudnason, Vilmundur; Smith, Albert Vernon] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Purcell, Shaun] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Johannesson, Magnus] Stockholm Sch Econ, Dept Econ, SE-11383 Stockholm, Sweden. [Magnusson, Patrik K. E.; Grankvist, Alexander; Hultman, Christina M.; Lichtenstein, Paul] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Beauchamp, Jonathan P.] McKinsey Consulting, Montreal, PQ H3B 4W8, Canada. [Christakis, Nicholas A.] Harvard Univ, Dept Sociol, Cambridge, MA 02138 USA. [Christakis, Nicholas A.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Atwood, Craig S.] Univ Wisconsin, Dept Med, Madison, WI 53705 USA. [Freese, Jeremy] Northwestern Univ, Dept Sociol, Evanston, IL 60208 USA. [Hauser, Robert M.; Hauser, Taissa S.] Univ Wisconsin, Dept Sociol, Madison, WI 53706 USA. RP Benjamin, DJ (reprint author), Cornell Univ, Dept Econ, Ithaca, NY 14853 USA. EM db468@cornell.edu RI Johannesson, Magnus/E-9680-2011; Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015; Magnusson, Patrik/C-4458-2017; OI Johannesson, Magnus/0000-0001-8759-6393; lichtenstein, paul/0000-0003-3037-5287; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Cesarini, David/0000-0002-0043-009X FU NIA NIH HHS [P01 AG005842, T32 AG000186] NR 117 TC 43 Z9 43 U1 4 U2 40 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 1941-1383 BN 978-0-8243-4604-1 J9 ANNU REV ECON JI Annu. Rev. Econ. PY 2012 VL 4 BP 627 EP + DI 10.1146/annurev-economics-080511-110939 PG 37 WC Economics SC Business & Economics GA BCG24 UT WOS:000310144600023 PM 23482589 ER PT J AU Chun, JH Pike, VW AF Chun, Joong-Hyun Pike, Victor W. TI Selective syntheses of no-carrier-added 2-and 3-[F-18]fluorohalopyridines through the radiofluorination of halopyridinyl(4 '-methoxyphenyl)iodonium tosylates SO CHEMICAL COMMUNICATIONS LA English DT Article ID NUCLEOPHILIC AROMATIC-SUBSTITUTION; DESIGN AB No-carrier-added 2- and 3-[F-18]fluorohalopyridines were readily synthesized as potentially useful labeling synthons for prospective PET radiotracers through the selective radiofluorination of halopyridinyl(4'-methoxyphenyl)iodonium tosylates, themselves conveniently prepared in a single pot from iodohalopyridines. C1 [Chun, Joong-Hyun; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3 C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIMH) FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIMH). The authors are grateful to the NIH Clinical PET Center (Chief, Dr Peter Herscovitch) for the cyclotron production of [18F]fluoride ion. NR 29 TC 12 Z9 12 U1 1 U2 7 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1359-7345 J9 CHEM COMMUN JI Chem. Commun. PY 2012 VL 48 IS 79 BP 9921 EP 9923 DI 10.1039/c2cc35005j PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 002TX UT WOS:000308560000037 PM 22932709 ER PT J AU Riley, AM Wang, HC Weaver, JD Shears, SB Potter, BVL AF Riley, Andrew M. Wang, Huanchen Weaver, Jeremy D. Shears, Stephen B. Potter, Barry V. L. TI First synthetic analogues of diphosphoinositol polyphosphates: interaction with PP-InsP(5) kinase SO CHEMICAL COMMUNICATIONS LA English DT Article ID INOSITOL; PENTAKISPHOSPHATE; PYROPHOSPHATES; DICTYOSTELIUM; MEDIATORS; BINDING; CELLS AB We synthesised analogues of diphosphoinositol polyphosphates (PP-InsPs) in which the diphosphate is replaced by an a-phosphonoacetic acid (PA) ester. Structural analysis revealed that 5-PA-InsP(5) mimics 5-PP-InsP(5) binding to the kinase domain of PPIP5K2; both molecules were phosphorylated by the enzyme. PA-InsPs are promising candidates for further studies into the biology of PP-InsPs. C1 [Riley, Andrew M.; Potter, Barry V. L.] Univ Bath, Dept Pharm & Pharmacol, Wolfson Lab Med Chem, Bath BA2 7AY, Avon, England. [Wang, Huanchen; Weaver, Jeremy D.; Shears, Stephen B.] NIEHS, Inositol Signaling Grp, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Potter, BVL (reprint author), Univ Bath, Dept Pharm & Pharmacol, Wolfson Lab Med Chem, Bath BA2 7AY, Avon, England. EM b.v.l.potter@bath.ac.uk RI Riley, Andrew/F-3526-2013 FU Wellcome Trust [082837]; NIEHS/NIH; U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX We thank the Wellcome Trust (Programme Grant 082837 to AMR and BVLP) and NIEHS/NIH for support. X-ray Data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-beamline at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions may be found at www.ser-cat.org/members.html. Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. NR 23 TC 17 Z9 17 U1 1 U2 7 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1359-7345 J9 CHEM COMMUN JI Chem. Commun. PY 2012 VL 48 IS 92 BP 11292 EP 11294 DI 10.1039/c2cc36044f PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 026ML UT WOS:000310283000003 PM 23032903 ER PT J AU Zhao, F Korangy, F Greten, TF AF Zhao, Fei Korangy, Firouzeh Greten, Tim F. TI Cellular Immune Suppressor Mechanisms in Patients with Hepatocellular Carcinoma SO DIGESTIVE DISEASES LA English DT Article; Proceedings Paper CT Falk Workshop on Inflammation and Cancer CY JAN 26-27, 2012 CL Hamburg, GERMANY DE Immunotherapy; Tolerance; Cancer; Liver ID REGULATORY T-CELLS; ACTIVATED MONOCYTES; PERITUMORAL STROMA; PROMOTE EXPANSION; MYELOID CELLS; RESPONSES; IMMUNOTHERAPY; PROGRESSION; SURVIVAL; TUMORS AB Hepatocellular carcinoma (HCC) has been shown to induce several immune suppressor mechanisms in patients. Our laboratory has been investigating different cellular mechanisms of immune suppression in patients with HCC. These suppressor mechanisms range from CD4(+) regulatory T cells, functionally impaired dendritic cells, neutrophils, and monocytes to myeloid-derived suppressor cells. In vitro as well as in vivo studies have demonstrated that abrogation of the suppressor cells enhances or unmasks tumor-specific antitumor immune responses. We performed a literature search for immune suppressor cells in HCC, and here we provide a comprehensive summary of the latest studies in this field. Copyright (c) 2012 S. Karger AG, Basel C1 [Zhao, Fei; Korangy, Firouzeh; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Greten, TF (reprint author), NCI, Gastrointestinal Malignancy Sect, Med Oncol Branch, Ctr Canc Res, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 50 TC 8 Z9 12 U1 0 U2 14 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0257-2753 EI 1421-9875 J9 DIGEST DIS JI Dig. Dis. PY 2012 VL 30 IS 5 BP 477 EP 482 DI 10.1159/000341695 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 030IE UT WOS:000310563600005 PM 23108303 ER PT J AU Resnik, DB AF Resnik, David B. BA Resnik, DB BF Resnik, DB TI ENVIRONMENTAL HEALTH ETHICS INTRODUCTION SO ENVIRONMENTAL HEALTH ETHICS LA English DT Editorial Material; Book Chapter C1 [Resnik, David B.] Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. [Resnik, David B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Resnik, David B.] NIEHS Inst Review Board, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-10702-395-6 PY 2012 BP 1 EP + D2 10.1017/CBO9781139161848 PG 52 WC Ethics; Public, Environmental & Occupational Health SC Social Sciences - Other Topics; Public, Environmental & Occupational Health GA BBC41 UT WOS:000306428600001 ER PT J AU Resnik, DB AF Resnik, David B. BA Resnik, DB BF Resnik, DB TI AN OVERVIEW OF ENVIRONMENTAL HEALTH SO ENVIRONMENTAL HEALTH ETHICS LA English DT Article; Book Chapter C1 [Resnik, David B.] Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. [Resnik, David B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Resnik, David B.] NIEHS Inst Review Board, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-10702-395-6 PY 2012 BP 9 EP 37 D2 10.1017/CBO9781139161848 PG 29 WC Ethics; Public, Environmental & Occupational Health SC Social Sciences - Other Topics; Public, Environmental & Occupational Health GA BBC41 UT WOS:000306428600002 ER PT J AU Resnik, DB AF Resnik, David B. BA Resnik, DB BF Resnik, DB TI ETHICAL THEORY SO ENVIRONMENTAL HEALTH ETHICS LA English DT Article; Book Chapter C1 [Resnik, David B.] Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. [Resnik, David B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Resnik, David B.] NIEHS Inst Review Board, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-10702-395-6 PY 2012 BP 38 EP 55 D2 10.1017/CBO9781139161848 PG 18 WC Ethics; Public, Environmental & Occupational Health SC Social Sciences - Other Topics; Public, Environmental & Occupational Health GA BBC41 UT WOS:000306428600003 ER PT J AU Resnik, DB AF Resnik, David B. BA Resnik, DB BF Resnik, DB TI TOWARD AN ENVIRONMENTAL HEALTH ETHICS SO ENVIRONMENTAL HEALTH ETHICS LA English DT Article; Book Chapter C1 [Resnik, David B.] Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. [Resnik, David B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Resnik, David B.] NIEHS Inst Review Board, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-10702-395-6 PY 2012 BP 56 EP 79 D2 10.1017/CBO9781139161848 PG 24 WC Ethics; Public, Environmental & Occupational Health SC Social Sciences - Other Topics; Public, Environmental & Occupational Health GA BBC41 UT WOS:000306428600004 ER PT J AU Resnik, DB AF Resnik, David B. BA Resnik, DB BF Resnik, DB TI PEST CONTROL SO ENVIRONMENTAL HEALTH ETHICS LA English DT Article; Book Chapter C1 [Resnik, David B.] Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. [Resnik, David B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Resnik, David B.] NIEHS Inst Review Board, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-10702-395-6 PY 2012 BP 80 EP 102 D2 10.1017/CBO9781139161848 PG 23 WC Ethics; Public, Environmental & Occupational Health SC Social Sciences - Other Topics; Public, Environmental & Occupational Health GA BBC41 UT WOS:000306428600005 ER PT J AU Resnik, DB AF Resnik, David B. BA Resnik, DB BF Resnik, DB TI GENETIC ENGINEERING, FOOD, AND NUTRITION SO ENVIRONMENTAL HEALTH ETHICS LA English DT Article; Book Chapter C1 [Resnik, David B.] Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. [Resnik, David B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Resnik, David B.] NIEHS Inst Review Board, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-10702-395-6 PY 2012 BP 103 EP 132 D2 10.1017/CBO9781139161848 PG 30 WC Ethics; Public, Environmental & Occupational Health SC Social Sciences - Other Topics; Public, Environmental & Occupational Health GA BBC41 UT WOS:000306428600006 ER PT J AU Resnik, DB AF Resnik, David B. BA Resnik, DB BF Resnik, DB TI POLLUTION AND WASTE SO ENVIRONMENTAL HEALTH ETHICS LA English DT Article; Book Chapter C1 [Resnik, David B.] Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. [Resnik, David B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Resnik, David B.] NIEHS Inst Review Board, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-10702-395-6 PY 2012 BP 133 EP 157 D2 10.1017/CBO9781139161848 PG 25 WC Ethics; Public, Environmental & Occupational Health SC Social Sciences - Other Topics; Public, Environmental & Occupational Health GA BBC41 UT WOS:000306428600007 ER PT J AU Resnik, DB AF Resnik, David B. BA Resnik, DB BF Resnik, DB TI THE BUILT ENVIRONMENT SO ENVIRONMENTAL HEALTH ETHICS LA English DT Article; Book Chapter C1 [Resnik, David B.] Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. [Resnik, David B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Resnik, David B.] NIEHS Inst Review Board, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-10702-395-6 PY 2012 BP 158 EP 170 D2 10.1017/CBO9781139161848 PG 13 WC Ethics; Public, Environmental & Occupational Health SC Social Sciences - Other Topics; Public, Environmental & Occupational Health GA BBC41 UT WOS:000306428600008 ER PT J AU Resnik, DB AF Resnik, David B. BA Resnik, DB BF Resnik, DB TI CLIMATE CHANGE, ENERGY, AND POPULATION SO ENVIRONMENTAL HEALTH ETHICS LA English DT Article; Book Chapter C1 [Resnik, David B.] Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. [Resnik, David B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Resnik, David B.] NIEHS Inst Review Board, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-10702-395-6 PY 2012 BP 171 EP 201 D2 10.1017/CBO9781139161848 PG 31 WC Ethics; Public, Environmental & Occupational Health SC Social Sciences - Other Topics; Public, Environmental & Occupational Health GA BBC41 UT WOS:000306428600009 ER PT J AU Resnik, DB AF Resnik, David B. BA Resnik, DB BF Resnik, DB TI JUSTICE AND ENVIRONMENTAL HEALTH SO ENVIRONMENTAL HEALTH ETHICS LA English DT Article; Book Chapter C1 [Resnik, David B.] Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. [Resnik, David B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Resnik, David B.] NIEHS Inst Review Board, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-10702-395-6 PY 2012 BP 202 EP 221 D2 10.1017/CBO9781139161848 PG 20 WC Ethics; Public, Environmental & Occupational Health SC Social Sciences - Other Topics; Public, Environmental & Occupational Health GA BBC41 UT WOS:000306428600010 ER PT J AU Resnik, DB AF Resnik, David B. BA Resnik, DB BF Resnik, DB TI ENVIRONMENTAL HEALTH RESEARCH INVOLVING HUMAN PARTICIPANTS SO ENVIRONMENTAL HEALTH ETHICS LA English DT Article; Book Chapter C1 [Resnik, David B.] Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. [Resnik, David B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Resnik, David B.] NIEHS Inst Review Board, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-10702-395-6 PY 2012 BP 222 EP 241 D2 10.1017/CBO9781139161848 PG 20 WC Ethics; Public, Environmental & Occupational Health SC Social Sciences - Other Topics; Public, Environmental & Occupational Health GA BBC41 UT WOS:000306428600011 ER PT J AU Resnik, DB AF Resnik, David B. BA Resnik, DB BF Resnik, DB TI ENVIRONMENTAL HEALTH ETHICS CONCLUSION SO ENVIRONMENTAL HEALTH ETHICS LA English DT Editorial Material; Book Chapter C1 [Resnik, David B.] Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. [Resnik, David B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Resnik, David B.] NIEHS Inst Review Board, Res Triangle Pk, NC USA. RP Resnik, DB (reprint author), Natl Inst Hlth, Natl Inst Environm Hlth Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA THE PITT BUILDING, TRUMPINGTON ST, CAMBRIDGE CB2 1RP, CAMBS, ENGLAND BN 978-1-10702-395-6 PY 2012 BP 242 EP 248 D2 10.1017/CBO9781139161848 PG 7 WC Ethics; Public, Environmental & Occupational Health SC Social Sciences - Other Topics; Public, Environmental & Occupational Health GA BBC41 UT WOS:000306428600012 ER PT S AU Lahouar, S Barry, CE Paripati, P Somaiya, S Huyen, Y Rosenthal, A Tartakovsky, M AF Lahouar, Saher Barry, Clifton E., III Paripati, Praveen Somaiya, Sandeep Huyen, Yentram Rosenthal, Alexander Tartakovsky, Michael BE Gaol, FL Nguyen, QV TI Automatic Extraction and Categorization of Lung Abnormalities from HRCT Data in MDR/XDR TB Patients SO PROCEEDINGS OF THE 2011 2ND INTERNATIONAL CONGRESS ON COMPUTER APPLICATIONS AND COMPUTATIONAL SCIENCE, VOL 2 SE Advances in Intelligent and Soft Computing LA English DT Proceedings Paper CT 2nd International Congress on Computer Applications and Computational Science (CACS 2011) CY NOV 15-17, 2011 CL Tuban, INDONESIA DE Lung Abnormalities; HRCT; Pulmonary Tuberculosis; MDR/XDR TB; Automatic Extraction; Lung Nodules ID CT AB An ancient disease, tuberculosis (TB) remains one of the major causes of disability and death worldwide. In 2006, 9.2 million new cases of TB emerged and killed 1.7 million people. We report on the development of tools to help in the detection of lesions and nodules from High Resolution Computed Tomography (HRCT) scans and changes in total lesion volumes across a study. These automated tools are designed to assist radiologists, clinicians and scientists assess patients' responses to therapies during clinical studies. The tools are centered upon a rule-based system that initially segments the lung from HRCT scans and then categorizes the different components of the lung as normal or abnormal. A layered segmentation process, utilizing a combination of adaptive thresholding, three-dimensional region growing and component labeling is used to successively peel off outside entities, isolating lung and trachea voxels. Locating the Carina allows logical labeling of the trachea and left/right lungs. Shape and texture analysis are used to validate and label normal vascular tree voxels. Remaining abnormal voxels are clustered on density, gradient and texture-based criteria. Several practical problems that arise due to large changes in lung morphology due to TB and patients inability to hold their breath during scan operations need to be addressed to provide a viable computational solution. Comparisons of total common volumes of lesions by size for a given patient across multiple visits are in concordance with expert radiologist's manual measurements. C1 [Lahouar, Saher; Paripati, Praveen; Somaiya, Sandeep] Net Esolut Corp, Mclean, VA USA. [Huyen, Yentram; Rosenthal, Alexander; Tartakovsky, Michael] NIH, OCICB, NIAID, Bethesda, MD USA. [Barry, Clifton E., III] NIH, NIAID, Lab Clin Infectous Diseases, Div Inst Res,Tuberculosis Res Sect, Bethesda, MD 20892 USA. RP Lahouar, S (reprint author), Net Esolut Corp, Mclean, VA USA. EM saher@nete.com; cbarry@niaid.nih.gov; Praveen@nete.com; sandeep@nete.com; huyeny@niaid.nih.gov; alexr@niaid.nih.gov; mtartakovs@niaid.nih.gov NR 17 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 1867-5662 BN 978-3-642-28307-9; 978-3-642-28308-6 J9 ADV INTEL SOFT COMPU PY 2012 VL 145 BP 351 EP + PG 4 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications SC Computer Science GA BCI36 UT WOS:000310243500048 ER PT J AU Resnik, DB AF Resnik, David B. TI Ethical Virtues in Scientific Research SO ACCOUNTABILITY IN RESEARCH-POLICIES AND QUALITY ASSURANCE LA English DT Article DE decision-making; education; leadership; mentoring; policy; principles; research ethics; virtue ID RESPONSIBLE CONDUCT; MISCONDUCT; PRINCIPLES; EDUCATION AB Most approaches to promoting integrity in research are principle-based in that they portray ethical conduct as consisting of adherence to ethical rules, duties, or responsibilities. Bruce MacFarlane has recently criticized the principle-based approach to promoting integrity in research and offered a virtue-based alternative. MacFarlane argues that principle-based approaches do not provide adequate guidance for ethical decision-making and are not very useful in moral education. In this article, I examine and critique MacFarlane's defense of the virtue-based approach. I argue that virtue-based and principle-based approaches to ethics are complementary and that they both can help promote research integrity. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Box 12233,Mail Drop CU 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-04] NR 47 TC 7 Z9 7 U1 2 U2 11 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0898-9621 EI 1545-5815 J9 ACCOUNT RES JI Account. Res. PY 2012 VL 19 IS 6 BP 329 EP 343 DI 10.1080/08989621.2012.728908 PG 15 WC Medical Ethics SC Medical Ethics GA 024TS UT WOS:000310132200001 PM 23074991 ER PT S AU Grice, EA Segre, JA AF Grice, Elizabeth A. Segre, Julia A. BE Chakravarti, A Green, E TI The Human Microbiome: Our Second Genome SO ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS, VOL 13 SE Annual Review of Genomics and Human Genetics LA English DT Review; Book Chapter DE bacteria; microbiota; metagenomics; 16S rRNA ID 16S RIBOSOMAL-RNA; ACID-MINE DRAINAGE; INTESTINAL MICROBIOTA; GUT MICROBIOME; HUMAN SKIN; MOLECULAR ANALYSIS; ORAL-CAVITY; BACTERIAL DIVERSITY; FUNCTIONAL-ANALYSIS; PSORIATIC LESIONS AB The human genome has been referred to as the blueprint of human biology. In this review we consider an essential but largely ignored overlay to that blueprint, the human microbiome, which is composed of those microbes that live in and on our bodies. The human microbiome is a source of genetic diversity, a modifier of disease, an essential component of immunity, and a functional entity that influences metabolism and modulates drug interactions. Characterization and analysis of the human microbiome have been greatly catalyzed by advances in genomic technologies. We discuss how these technologies have shaped this emerging field of study and advanced our understanding of the human microbiome. We also identify future challenges, many of which are common to human genetic studies, and predict that in the future, analyzing genetic variation and risk of human disease will sometimes necessitate the integration of human and microbial genomic data sets. C1 [Grice, Elizabeth A.; Segre, Julia A.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Grice, EA (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov OI Grice, Elizabeth/0000-0003-3939-2200 FU Intramural NIH HHS [ZIA HG000180-11, ZIA HG000180-12] NR 109 TC 73 Z9 79 U1 8 U2 128 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0897 USA SN 1527-8204 BN 978-0-8243-3713-1 J9 ANNU REV GENOM HUM G JI Annu. Rev. Genomics Hum. Genet. PY 2012 VL 13 BP 151 EP 170 DI 10.1146/annurev-genom-090711-163814 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA BCG20 UT WOS:000310143800007 PM 22703178 ER PT S AU Salvucci, O Tosato, G AF Salvucci, Ombretta Tosato, Giovanna BE Daar, IO TI Essential Roles of EphB Receptors and EphrinB Ligands in Endothelial Cell Function and Angiogenesis SO GUIDANCE MOLECULES IN CANCER AND TUMOR ANGIOGENESIS SE Advances in Cancer Research LA English DT Review; Book Chapter ID VASCULAR SMOOTH-MUSCLE; INHIBITS TUMOR-GROWTH; COLORECTAL-CANCER PROGRESSION; BLOOD-VESSEL FORMATION; TYROSINE KINASE EPHA2; ANTI-VEGF THERAPY; STEM-LIKE CELLS; HUMAN CYTOTROPHOBLASTS; MACULAR DEGENERATION; MELANOMA-CELLS AB Eph receptor tyrosine kinases and their Ephrin ligands represent an important signaling system with widespread roles in cell physiology and disease. Receptors and ligands in this family are anchored to the cell surface; thus Eph/Ephrin interactions mainly occur at sites of cell-to-cell contact. EphB4 and EphrinB2 are the Eph/Ephrin molecules that play essential roles in vascular development and postnatal angiogenesis. Analysis of expression patterns and function has linked EphB4/EphrinB2 to endothelial cell growth, survival, migration, assembly, and angiogenesis. Signaling from these molecules is complex, with the potential for being bidirectional, emanating both from the Eph receptors (forward signaling) and from the Ephrin ligands (reverse signaling). In this review, we describe recent advances on the roles of EphB/EphrinB protein family in endothelial cell function and outline potential approaches to inhibit pathological angiogenesis based on this understanding. (C) 2012 Elsevier Inc. C1 [Salvucci, Ombretta; Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Salvucci, O (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA BC010782-06] NR 177 TC 41 Z9 47 U1 1 U2 20 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-230X BN 978-0-12-386503-8 J9 ADV CANCER RES JI Adv.Cancer Res. PY 2012 VL 114 BP 21 EP 57 DI 10.1016/B978-0-12-386503-8.00002-8 PG 37 WC Oncology SC Oncology GA BBH98 UT WOS:000306934000002 PM 22588055 ER EF