FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Molavi, O Xiong, XB Douglas, D Kneteman, N Nagata, S Pastan, I Chu, Q Lavasanifar, A Lai, R AF Molavi, Ommoleila Xiong, Xiao-Bing Douglas, Donna Kneteman, Norm Nagata, Satoshi Pastan, Ira Chu, Quincy Lavasanifar, Afsaneh Lai, Raymond TI Anti-CD30 antibody conjugated liposomal doxorubicin with significantly improved therapeutic efficacy against anaplastic large cell lymphoma SO BIOMATERIALS LA English DT Article DE Doxorubicin; Liposome; CD30; Anaplastic large cell lymphoma; Targeted therapy ID ANTI-HER2 IMMUNOLIPOSOMES; TUMOR-LOCALIZATION; POLYMERIC MICELLES; ENHANCED EFFICACY; TARGETED DELIVERY; HODGKINS-DISEASE; LINE KARPAS-299; DRUG-DELIVERY; BREAST-CANCER; PHASE-II AB The use of nano-carriers has been shown to improve the delivery and efficacy of chemotherapeutic agents in cancer patients. Recent studies suggest that decoration of the surface of nano-carriers with various targeting moieties may further improve the overall therapeutic efficacy. In this study, we compared the therapeutic efficacy of Doxil (R) (commercial doxorubicin-loaded liposomes) and that of Doxil (R) conjugated with anti-CD30 antibodies (CD30-targeted Doxil (R)) in treating anaplastic large cell lymphoma (ALCL), a type of T-cell lymphoma characterized by a high CD30 expression. Compared to Doxil (R), the CD30-targeted Doxil (R) showed a significantly higher binding affinity to ALCL cells (5.3% versus 27%, p = 0.005) and a lower inhibitory concentration at 50% (IC50) in-vitro (32.6 mu g/mL versus 12.6 mu g/ml, p = 0.006). In a SCID mouse xenograft model, CD30-targeted Doxil (R) inhibited tumor growth more significantly than the unconjugated formulation; specifically, tumors in mice treated with CD30-targeted Doxil (R) were significantly smaller than those in mice treated with Doxil (R) (average, 117 mm(3) versus 270 mm(3), p = 0.001) at 18 days after the tumors were inoculated. Our findings have provided the proof-of-principle of using CD30-targeted nano-carriers to treat cancers that are characterized by a high level of CD30 expression, such as ALCL. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Molavi, Ommoleila; Lai, Raymond] Univ Alberta, Fac Med & Dent, Dept Lab Med & Pathol, Edmonton, AB T6G 2E1, Canada. [Molavi, Ommoleila] Tabriz Univ Med Sci, Sch Pharm, Res Ctr Pharmaceut Nanotechnol, Tabriz, Iran. [Xiong, Xiao-Bing; Lavasanifar, Afsaneh] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2E1, Canada. [Douglas, Donna; Kneteman, Norm] Univ Alberta, Fac Med & Dent, Dept Surg, Edmonton, AB T6G 2E1, Canada. [Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Chu, Quincy; Lai, Raymond] Univ Alberta, Fac Med & Dent, Dept Oncol, Edmonton, AB T6G 2E1, Canada. RP Lavasanifar, A (reprint author), Univ Alberta, Katz Ctr Pharm & Hlth Res, 2-142F, Edmonton, AB T6G 2E1, Canada. EM alavasanifar@pharmacy.ualberta.ca; rlai@ualberta.ca FU Alberta Cancer Foundation; Canadian Institute of Health Research; NIH COBRE grant [1P20RR024219-01A2]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by a research operating grant from the Alberta Cancer Foundation awarded to RL and AL. OM was supported by a fellowship grant from the Canadian Institute of Health Research. SN was supported by a NIH COBRE grant (1P20RR024219-01A2). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 44 TC 14 Z9 14 U1 1 U2 69 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD NOV PY 2013 VL 34 IS 34 BP 8718 EP 8725 DI 10.1016/j.biomaterials.2013.07.068 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 218RR UT WOS:000324450600017 PM 23942212 ER PT J AU Ivey, SL Laditka, SB Price, AE Tseng, W Beard, RL Liu, R Fetterman, D Wu, B Logsdon, RG AF Ivey, Susan L. Laditka, Sarah B. Price, Anna E. Tseng, Winston Beard, Renee L. Liu, Rui Fetterman, David Wu, Bei Logsdon, Rebecca G. TI Experiences and concerns of family caregivers providing support to people with dementia: A cross-cultural perspective SO DEMENTIA-INTERNATIONAL JOURNAL OF SOCIAL RESEARCH AND PRACTICE LA English DT Article DE aging; Alzheimer's disease; Filipinos; focus groups; qualitative research ID HEALTHY BRAIN; PERCEPTIONS; PROJECT; BURDEN; CARE AB We examined experiences and concerns among caregivers of community-dwelling people with dementia from two ethnic groups. We conducted a thematic analysis of responses to the question, 'What is your life like as a caregiver?' in nine focus groups (n = 75) with Filipino and non-Hispanic White caregivers. Constant comparison methods identified themes by ethnicity. Experiences and concerns expressed across groups were related to care recipient symptoms commonly associated with dementia, including severe memory loss and behavioral changes. Participants in both ethnic groups described strategies that help them cope, such as receiving help from family and friends, receiving respite support, and participating in support groups. Filipino caregivers more often emphasized positive aspects of caregiving, whereas Whites often expressed that others do not understand the daily experiences of caregiving. Filipinos more commonly described caregivers as a 'good person' or 'saint' and emphasized that caregiving made them stronger. C1 [Ivey, Susan L.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94704 USA. [Laditka, Sarah B.] Univ N Carolina, Charlotte, NC 28223 USA. [Price, Anna E.] Sacred Heart Univ, Dept Phys Therapy & Human Movement Sci, Coll Hlth Profess, Fairfield, CT USA. [Beard, Renee L.] Coll Holy Cross, Worcester, MA 01610 USA. [Liu, Rui] NIEHS, Epidemiol Branch, Res Triangle Pk, NC USA. [Fetterman, David] Westminster Presbyterian Church, Pittsburgh, PA USA. [Wu, Bei] Duke Univ, Sch Nursing, Durham, NC 27706 USA. [Wu, Bei] Duke Univ, Global Hlth Inst, Durham, NC 27706 USA. [Wu, Bei] Duke Univ, Ctr Study Aging & Human Dev, Durham, NC 27706 USA. [Logsdon, Rebecca G.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. RP Ivey, SL (reprint author), Univ Calif Berkeley, Sch Publ Hlth, 2140 Shattuck Ave,10th Floor, Berkeley, CA 94704 USA. EM sivey@berkeley.edu FU NCCDPHP CDC HHS [U48-DP-001908, U48-DP-001911, U48-DP-001921, U48-DP-001924, U48-DP-001936, U48-DP-001938, U48-DP-001944] NR 30 TC 5 Z9 5 U1 4 U2 13 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1471-3012 EI 1741-2684 J9 DEMENTIA-LONDON JI Dement.-Int. J. soc. Res. Pract. PD NOV PY 2013 VL 12 IS 6 BP 806 EP 820 DI 10.1177/1471301212446872 PG 15 WC Gerontology SC Geriatrics & Gerontology GA AR7MA UT WOS:000343762600009 PM 24337641 ER PT J AU Agrawal, L Moore, H Vaught, J AF Agrawal, L. Moore, H. Vaught, J. TI Serum and tissue biomarkers for cancer biospecimen integrity SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Agrawal, L.; Moore, H.; Vaught, J.] NCI, BBRB Canc Diag Program, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2013 VL 49 SU 4 MA MC13-0047 BP S25 EP S25 PG 1 WC Oncology SC Oncology GA V40HW UT WOS:000209470700079 ER PT J AU Conley, B Conley, BA Lively, TG Rohan, J Bharti, S Cavenagh, MM Lih, C Williams, PM AF Conley, B. Conley, B. A. Lively, T. G. Rohan, J. Bharti, S. Cavenagh, M. M. Lih, C. Williams, P. M. TI National Cancer Institute (US) clinical assay development program SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Conley, B.; Conley, B. A.; Lively, T. G.; Bharti, S.; Cavenagh, M. M.] NCI, DCDT CDP, Bethesda, MD 20892 USA. [Rohan, J.; Lih, C.; Williams, P. M.] NCI, DCTD FNLCR, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2013 VL 49 SU 4 MA MC13-0068 BP S31 EP S31 PG 1 WC Oncology SC Oncology GA V40HW UT WOS:000209470700096 ER PT J AU Demchok, J Taube, S Fombonne, B Lubensky, I AF Demchok, J. Taube, S. Fombonne, B. Lubensky, I. TI The National Cancer Institute (NCI) specimen resource locator SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Demchok, J.; Taube, S.; Fombonne, B.; Lubensky, I.] Nat Canc Inst, Natl Inst Hlth, Canc Diagnosis Program, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2013 VL 49 SU 4 MA MC13-0092 BP S37 EP S38 PG 3 WC Oncology SC Oncology GA V40HW UT WOS:000209470700116 ER PT J AU Kummar, S Chen, A Lih, J Williams, M Rubinstein, L Conley, B Doroshow, JH AF Kummar, S. Chen, A. Lih, J. Williams, M. Rubinstein, L. Conley, B. Doroshow, J. H. TI Molecular profiling based assignment of cancer therapy (MPACT) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Kummar, S.; Chen, A.; Rubinstein, L.; Conley, B.; Doroshow, J. H.] Natl Canc Inst, Bethesda, MD USA. [Lih, J.; Williams, M.] SAIC NCI Frederick Natl Lab Canc Res, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2013 VL 49 SU 4 MA SP007 BP S3 EP S3 PG 1 WC Oncology SC Oncology GA V40HW UT WOS:000209470700009 ER PT J AU Lih, C Sims, D Polley, E Zhao, Y Mehaffey, M Forbes, T Harrington, R Walsh, W McGregor, P Simon, R Conley, B Kummar, S Doroshow, J Williams, PM AF Lih, C. Sims, D. Polley, E. Zhao, Y. Mehaffey, M. Forbes, T. Harrington, R. Walsh, W. McGregor, P. Simon, R. Conley, B. Kummar, S. Doroshow, J. Williams, P. M. TI Analytical validation of the MPACT assay, a targeted next generation sequencing clinical assay for cancer patient treatment selection SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Lih, C.; Sims, D.; Mehaffey, M.; Forbes, T.; Harrington, R.; Walsh, W.; McGregor, P.; Williams, P. M.] Frederick Natl Lab Canc Res, Mol Characterizat Lab, Frederick, MD USA. [Polley, E.; Zhao, Y.; Simon, R.] NCI, Biometr Res Branch, Shady Grove, MD USA. [Conley, B.] NCI, Canc Diagnosis Program, Shady Grove, MD USA. [Kummar, S.; Doroshow, J.] NCI, Div Canc Treatment & Diagnosis, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2013 VL 49 SU 4 MA MC13-0060 BP S11 EP S11 PG 1 WC Oncology SC Oncology GA V40HW UT WOS:000209470700037 ER PT J AU Moore, H Engel, KB AF Moore, H. Engel, K. B. TI NCI biospecimen evidence-based practices SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Moore, H.; Engel, K. B.] Natl Canc Inst, Biorepositories & Biospecimen Res Branch, Canc Diag Program, Div Canc Treatment & Diag, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2013 VL 49 SU 4 MA SP035 BP S9 EP S9 PG 1 WC Oncology SC Oncology GA V40HW UT WOS:000209470700033 ER PT J AU Polley, M Polley, E Huang, E Freidlin, B Simon, R AF Polley, M. Polley, E. Huang, E. Freidlin, B. Simon, R. TI Two-stage adaptive cutoff design for building and validating a prognostic biomarker signature SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Polley, M.; Polley, E.; Huang, E.; Freidlin, B.; Simon, R.] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2013 VL 49 SU 4 MA MC13-0049 BP S11 EP S11 PG 1 WC Oncology SC Oncology GA V40HW UT WOS:000209470700036 ER PT J AU Shive, C Qi, L Tabor, D Hariharan, P Wu, S Um, KS McLean, J Lockhart, N Guan, P AF Shive, C. Qi, L. Tabor, D. Hariharan, P. Wu, S. Um, K. S. McLean, J. Lockhart, N. Guan, P. TI A comprehensive IT platform to support GTEx operation SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Shive, C.; Qi, L.; Tabor, D.; Hariharan, P.; Wu, S.; Um, K. S.; McLean, J.] SAIC F, BBRB Support Program, Bethesda, MD USA. [Lockhart, N.] Natl Human Genom Res Inst, Div Genom & Soc, Bethesda, MD USA. [Guan, P.] NCI, BBRB CDP DCTD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD NOV PY 2013 VL 49 SU 4 MA MC13-0057 BP S28 EP S28 PG 1 WC Oncology SC Oncology GA V40HW UT WOS:000209470700087 ER PT J AU Diers, AR Chang, CF Keszler, A Terunuma, A Ambs, S Bennett, B Hogg, N AF Diers, Anne R. Chang, Ching-Fang Keszler, Agnes Terunuma, Atsushi Ambs, Stefan Bennett, Brian Hogg, Neil TI NOS2-Derived Nitric Oxide Controls the Metabolic Phenotype of Breast Cancer Cells through Regulation of Aconitase Activity SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Diers, Anne R.; Chang, Ching-Fang; Keszler, Agnes; Hogg, Neil] Med Coll Wisconsin, Redox Biol Program, Milwaukee, WI USA. [Diers, Anne R.; Chang, Ching-Fang; Keszler, Agnes; Bennett, Brian; Hogg, Neil] Med Coll Wisconsin, Dept Biophys, Milwaukee, WI USA. [Terunuma, Atsushi; Ambs, Stefan] NCI, Lab Human Carcinogenesis, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2013 VL 65 SU 2 MA 210 BP S97 EP S97 DI 10.1016/j.freeradbiomed.2013.10.631 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40JU UT WOS:000209475700228 ER PT J AU Esworthy, S Kim, BW Wang, J Chow, J Doroshow, JH Chu, FF AF Esworthy, Steve Kim, Byung-Wook Wang, Joanna Chow, Joni Doroshow, James H. Chu, Fong-Fong TI NOX1 Causes Ileitis in Mice Deficient in Glutathione Peroxidase-1 and-2 SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Esworthy, Steve; Kim, Byung-Wook; Wang, Joanna; Chow, Joni; Chu, Fong-Fong] City Hope Natl Med Ctr, City Hope, PA USA. [Doroshow, James H.] 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 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2013 VL 65 SU 2 MA 52 BP S35 EP S35 DI 10.1016/j.freeradbiomed.2013.10.467 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40JU UT WOS:000209475700071 ER PT J AU Juhasz, A Antony, S Wu, YZ Lu, JM Jiang, GJ Liu, H Roy, K Doroshow, J AF Juhasz, Agnes Antony, Smitha Wu, Yongzhong Lu, Jiamo Jiang, Guojian Liu, Han Roy, Krishnendu Doroshow, James TI Effect of Stable Knockdown of Nox1 Gene Expression with siRNA in Human Colon Cancer Cells SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Juhasz, Agnes; Antony, Smitha; Wu, Yongzhong; Lu, Jiamo; Jiang, Guojian; Liu, Han; Roy, Krishnendu; Doroshow, James] NCI, 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 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2013 VL 65 SU 2 MA 8 BP S17 EP S18 DI 10.1016/j.freeradbiomed.2013.10.421 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40JU UT WOS:000209475700027 ER PT J AU Mukhopadhyay, P Hao, EK Cao, ZX Holovac, E Erdelyi, K Pacher, P AF Mukhopadhyay, Partha Hao, Enkui Cao, Zongxian Holovac, Eileen Erdelyi, Katalin Pacher, Pal TI Cannabidiol Attenuates Cardiac Dysfunction, Oxidative Stress, and Cell Death in Doxorubicin Induced Cardiomyopathy SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Mukhopadhyay, Partha; Hao, Enkui; Cao, Zongxian; Holovac, Eileen; Erdelyi, Katalin; Pacher, Pal] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2013 VL 65 SU 2 MA 163 BP S79 EP S79 DI 10.1016/j.freeradbiomed.2013.10.582 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40JU UT WOS:000209475700181 ER PT J AU Mukhopadhyay, P Mohanraj, R Cao, ZX Horvath, B Park, O Erdelyi, K Holovac, E Gao, B Pacher, P AF Mukhopadhyay, Partha Mohanraj, Rajesh Cao, Zongxian Horvath, Bela Park, Ogyi Erdelyi, Katalin Holovac, Eileen Gao, Bin Pacher, Pal TI Poly (ADP-ribose) Polymerase-1 is a Key Mediator of Liver Inflammation and Fibrosis SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Mukhopadhyay, Partha; Mohanraj, Rajesh; Cao, Zongxian; Horvath, Bela; Park, Ogyi; Erdelyi, Katalin; Holovac, Eileen; Gao, Bin; Pacher, Pal] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2013 VL 65 SU 2 MA 63 BP S38 EP S39 DI 10.1016/j.freeradbiomed.2013.10.478 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40JU UT WOS:000209475700082 ER PT J AU Pickrell, A Wang, X Pinto, M Moraes, C AF Pickrell, Alicia Wang, Xiao Pinto, Milena Moraes, Carlos TI MECHANISMS LINKING mtDNA DAMAGE AND AGING SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Pickrell, Alicia] NINDS, NIH, Bethesda, MD 20892 USA. [Wang, Xiao] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Pinto, Milena; Moraes, Carlos] Univ Miami, Coral Gables, FL 33124 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 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2013 VL 65 SU 2 MA P12 BP S9 EP S9 DI 10.1016/j.freeradbiomed.2013.10.406 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40JU UT WOS:000209475700013 ER PT J AU Yasui, H Saito, K Nishida, N Matsumoto, S Yamamori, T Krishna, MC Inanami, O AF Yasui, Hironobu Saito, Keita Nishida, Naoya Matsumoto, Shingo Yamamori, Tohru Krishna, Murali Cherukuri Inanami, Osamu TI Metabolic-targeted Treatment with Dichloroacetate Transiently Induces Tumor Hypoxia in Murine Squamous Cell Carcinoma Model SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Yasui, Hironobu; Nishida, Naoya; Yamamori, Tohru; Inanami, Osamu] Hokkaido Univ, Sapporo, Hokkaido 060, Japan. [Saito, Keita; Matsumoto, Shingo; Krishna, Murali Cherukuri] NCI, 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 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD NOV 1 PY 2013 VL 65 SU 2 MA 34 BP S26 EP S26 DI 10.1016/j.freeradbiomed.2013.10.447 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40JU UT WOS:000209475700053 ER PT J AU Orr, SK Palumbo, S Bosetti, F Mount, HT Kang, JX Greenwood, CE Ma, DWL Serhan, CN Bazinet, RP AF Orr, Sarah K. Palumbo, Sara Bosetti, Francesca Mount, Howard T. Kang, Jing X. Greenwood, Carol E. Ma, David W. L. Serhan, Charles N. Bazinet, Richard P. TI Unesterified docosahexaenoic acid is protective in neuroinflammation SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE neuroinflammation; unesterified docosahexaenoic acid AB Docosahexaenoic acid (22: 6n-3) is the major brain n-3 polyunsaturated fatty acid and it is possible that docosahexaenoic acid is anti-inflammatory in the brain as it is known to be in other tissues. Using a combination of models including the fat-1 transgenic mouse, chronic dietary n-3 polyunsaturated fatty acid modulation in transgenic and wild-type mice, and acute direct brain infusion, we demonstrated that unesterified docosahexaenoic acid attenuates neuroinflammation initiated by intracerebroventricular lipopolysaccharide. Hippocampal neuroinflammation was assessed by gene expression and immunohistochemistry. Furthermore, docosahexaenoic acid protected against lipopolysaccharide-induced neuronal loss. Acute intracerebroventricular infusion of unesterified docosahexaenoic acid or its 12/15-lipoxygenase product and precursor to protectins and resolvins, 17S-hydroperoxy-docosahexaenoic acid, mimics anti-neuroinflammatory aspects of chronically increased unesterified docosahexaenoic acid. LC-MS/MS revealed that neuroprotectin D1 and several other docosahexaenoic acid-derived specialized pro-resolving mediators are present in the hippocampus. Acute intracerebroventricular infusion of 17S-hydroperoxy-docosahexaenoic acid increases hippocampal neuroprotectin D1 levels concomitant to attenuating neuroinflammation. These results show that unesterified docosahexaenoic acid is protective in a lipopolysaccharide-initiated mouse model of acute neuroinflammation, at least in part, via its conversion to specialized pro-resolving mediators; these docosahexaenoic acid stores may provide novel targets for the prevention and treatment(s) of neurological disorders with a neuroinflammatory component. C1 [Orr, Sarah K.; Greenwood, Carol E.; Bazinet, Richard P.] Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada. [Palumbo, Sara; Bosetti, Francesca] NIA, Brain Physiol & Metab Sect, Mol Neurosci Unit, Bethesda, MD 20892 USA. [Mount, Howard T.] Univ Toronto, Dept Med Neurol, Toronto, ON, Canada. [Kang, Jing X.] Massachusetts Gen Hosp, Lab Lipid Med & Technol, Boston, MA 02114 USA. [Kang, Jing X.; Serhan, Charles N.] Harvard Med Sch, Boston, MA USA. [Ma, David W. L.] Univ Guelph, Dept Human Hlth & Nutr Sci, Guelph, ON, Canada. [Serhan, Charles N.] Brigham & Womens Hosp, Dept Anesthesiol, Ctr Expt Therapeut & Reperfus Injury, 75 Francis St, Boston, MA 02115 USA. RP Bazinet, RP (reprint author), Univ Toronto, Fac Med, Dept Nutr Sci, FitzGerald Bldg,150 Coll St,Room 306, Toronto, ON M5S 3E2, Canada. EM richard.bazinet@utoronto.ca OI Palumbo, Sara/0000-0002-3809-6058 FU Canadian Institutes of Health Research; International Life Sciences Institute; James H Cummings Foundation; Scottish Rite Charitable Foundation; National Institutes of Health [1P01GM095467]; Natural Sciences and Engineering Research Council of Canada FX This study was supported by the Canadian Institutes of Health Research [RPB]; the International Life Sciences Institute [RPB]; the James H Cummings Foundation [RPB]; and the Scottish Rite Charitable Foundation [RPB]. This study was also supported by the National Institutes of Health [grant number 1P01GM095467 to CNS]. SKO received financial support from the Natural Sciences and Engineering Research Council of Canada. NR 56 TC 35 Z9 35 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2013 VL 127 IS 3 BP 378 EP 393 DI 10.1111/jnc.12392 PG 16 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA V45HG UT WOS:000209807100003 PM 23919613 ER PT J AU Cai, Y Kimura, S AF Cai, Yan Kimura, Shioko TI Noninvasive Intratracheal Intubation to Study the Pathology and Physiology of Mouse Lung SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Medicine; Issue 81; mouse; rodents; intratracheal intubation; delivery of exogenous substances; lung; study of airway pathology and physiology; pulmonary fibrosis AB The use of a model that mimics the condition of lung diseases in humans is critical for studying the pathophysiology and/or etiology of a particular disease and for developing therapeutic intervention. With the increasing availability of knockout and transgenic derivatives, together with a vast amount of genetic information, mice provide one of the best models to study the molecular mechanisms underlying the pathology and physiology of lung diseases. Inhalation, intranasal instillation, intratracheal instillation, and intratracheal intubation are the most widely used techniques by a number of investigators to administer materials of interest to mouse lungs. There are pros and cons for each technique depending on the goals of a study. Here a noninvasive intratracheal intubation method that can directly deliver exogenous materials to mouse lungs is presented. This technique was applied to administer bleomycin to mouse lungs as a model to study pulmonary fibrosis. C1 [Cai, Yan; Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Kimura, S (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM kimuras@mail.nih.gov RI Cai, Yan/P-4383-2015 FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research. NR 11 TC 4 Z9 4 U1 0 U2 3 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD NOV PY 2013 IS 81 AR UNSP e50601 DI 10.3791/50601 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RQ UT WOS:000209228900012 PM 24300823 ER PT J AU Pivovarova, NB Andrews, SB AF Pivovarova, Natalia B. Andrews, S. Brian TI Measurement of Total Calcium in Neurons by Electron Probe X-ray Microanalysis SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Neuroscience; Issue 81; Cryoelectron Microscopy; Spectrum Analysis; Calcium Signaling; Cell Physiological Processes; analytical electron microscopy; cryosectioning; mitochondria; excitotoxicity; ischemia AB In this article the tools, techniques, and instruments appropriate for quantitative measurements of intracellular elemental content using the technique known as electron probe microanalysis (EPMA) are described. Intramitochondrial calcium is a particular focus because of the critical role that mitochondrial calcium overload plays in neurodegenerative diseases. The method is based on the analysis of X-rays generated in an electron microscope (EM) by interaction of an electron beam with the specimen. In order to maintain the native distribution of diffusible elements in electron microscopy specimens, EPMA requires "cryofixation" of tissue followed by the preparation of ultrathin cryosections. Rapid freezing of cultured cells or organotypic slice cultures is carried out by plunge freezing in liquid ethane or by slam freezing against a cold metal block, respectively. Cryosections nominally 80 nm thick are cut dry with a diamond knife at ca. -160 degrees C, mounted on carbon/pioloform-coated copper grids, and cryotransferred into a cryo-EM using a specialized cryospecimen holder. After visual survey and location mapping at <=-160 degrees C and low electron dose, frozen-hydrated cryosections are freeze-dried at -100 degrees C for similar to 30 min. Organelle-level images of dried cryosections are recorded, also at low dose, by means of a slow-scan CCD camera and subcellular regions of interest selected for analysis. X-rays emitted from ROIs by a stationary, focused, high-intensity electron probe are collected by an energy-dispersive X-ray (EDX) spectrometer, processed by associated electronics, and presented as an X-ray spectrum, that is, a plot of X-ray intensity vs. energy. Additional software facilitates: 1) identification of elemental components by their "characteristic" peak energies and fingerprint; and 2) quantitative analysis by extraction of peak areas/background. This paper concludes with two examples that illustrate typical EPMA applications, one in which mitochondrial calcium analysis provided critical insight into mechanisms of excitotoxic injury and another that revealed the basis of ischemia resistance. C1 [Pivovarova, Natalia B.; Andrews, S. Brian] NINDS, Lab Neurobiol, NIH, Bethesda, MD 20892 USA. RP Pivovarova, NB (reprint author), NINDS, Lab Neurobiol, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM pivovarn@ninds.nih.gov FU Basic Neuroscience Program of the NINDS Intramural Research Program, NIH [Z01 NS002610] FX We would like to thank Ms. Christine A. Winters for excellent technical assistance. This work was supported by the Basic Neuroscience Program of the NINDS Intramural Research Program, NIH (Z01 NS002610). NR 14 TC 1 Z9 1 U1 0 U2 4 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD NOV PY 2013 IS 81 AR UNSP e50807 DI 10.3791/50807 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RQ UT WOS:000209228900039 PM 24300079 ER PT J AU Calabro, L Krug, LM DiPietro, A Antonia, S Hassan, R Narwal, R Robbins, P Fu, DY Shalabi, A Abdullah, H Ibrahim, R Kindler, H Maio, M AF Calabro, Luana Krug, Lee M. DiPietro, Alessandra Antonia, Scott Hassan, Raffit Narwal, Rajesh Robbins, Paul Fu, Dongyue Shalabi, Aiman Abdullah, Hesham Ibrahim, Ramy Kindler, Hedy Maio, Michele TI A Phase II randomized, double-blind, placebo-controlled study of tremelimumab for second- and third-line treatment in patients with unresectable pleural or peritoneal mesothelioma. SO MOLECULAR CANCER THERAPEUTICS LA English DT Meeting Abstract C1 [Calabro, Luana; Maio, Michele] Univ Hosp Siena, Siena, Italy. [Krug, Lee M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [DiPietro, Alessandra; Narwal, Rajesh; Robbins, Paul; Fu, Dongyue; Shalabi, Aiman; Abdullah, Hesham; Ibrahim, Ramy] Medimmune Inc, Gaithersburg, MD 20878 USA. [Antonia, Scott] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Hassan, Raffit] NCI, Bethesda, MD 20892 USA. [Kindler, Hedy] Univ Chicago, Chicago, IL 60637 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD NOV PY 2013 VL 12 IS 11 SU S MA B80 DI 10.1158/1535-7163.TARG-13-B80 PG 2 WC Oncology SC Oncology GA V40RX UT WOS:000209496800300 ER PT J AU Lin, NU Schwartzberg, L Kesari, S Elias, A Anders, C Raizer, J Kozloff, M Amiri-Kordestani, L AF Lin, Nancy U. Schwartzberg, Lee Kesari, Santosh Elias, Anthony Anders, Carey Raizer, Jeffrey Kozloff, Mark Amiri-Kordestani, Laleh TI A phase II study of ANG1005, a novel, brain-penetrant taxane derivative, in breast cancer patients with brain metastases. SO MOLECULAR CANCER THERAPEUTICS LA English DT Meeting Abstract C1 [Lin, Nancy U.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Schwartzberg, Lee] West Clin, Memphis, TN USA. [Kesari, Santosh] Univ Calif San Diego, San Diego, CA 92103 USA. [Elias, Anthony] Univ Colorado, Denver, CO 80202 USA. [Anders, Carey] Univ N Carolina, Chapel Hill, NC USA. [Raizer, Jeffrey] Northwestern Univ, Chicago, IL 60611 USA. [Kozloff, Mark] Ingalls Mem, Harvey, IL USA. [Amiri-Kordestani, Laleh] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD NOV PY 2013 VL 12 IS 11 SU S MA B76 DI 10.1158/1535-7163.TARG-13-B76 PG 2 WC Oncology SC Oncology GA V40RX UT WOS:000209496800296 ER PT J AU Mehta, AK Bettermann, K Lederer, EM Ernst, C Kessler, SM Kojima, K Chen, XT Hoshida, Y Fuchs, BC Svendova, V Schimek, MG Mach, M Speicher, MR Stojakovic, T Magin, TM Strnad, P Trauner, M Kiemer, AK Thorgeirsson, SS Karin, M Llovet, JM Zatloukal, K Denk, H Lackner, C Haybaeck, J AF Mehta, Anita Kuldeep Bettermann, Kira Lederer, Eva M. Ernst, Christina Kessler, Sonja M. Kojima, Kensuke Chen, Xintong Hoshida, Yujin Fuchs, Bryan C. Svendova, Vendula Schimek, Michael G. Mach, Monika Speicher, Michael R. Stojakovic, Tatjana Magin, Thomas M. Strnad, Pavel Trauner, Michael Kiemer, Alexandra K. Thorgeirsson, Snorri S. Karin, Michael Llovet, Josep M. Zatloukal, Kurt Denk, Helmut Lackner, Carolin Haybaeck, Johannes TI Steatohepatitis-associated hepatocellular carcinoma: Evidence of a keratin-based disease. SO MOLECULAR CANCER THERAPEUTICS LA English DT Meeting Abstract C1 [Mehta, Anita Kuldeep; Bettermann, Kira; Lederer, Eva M.; Ernst, Christina; Zatloukal, Kurt; Denk, Helmut; Lackner, Carolin; Haybaeck, Johannes] Med Univ Graz, Inst Pathol, Graz, Austria. [Kessler, Sonja M.; Kiemer, Alexandra K.] Univ Saarland, Dept Pharm, D-66123 Saarbrucken, Germany. [Kojima, Kensuke; Chen, Xintong; Hoshida, Yujin] Icahn Sch Med, Tisch Canc Inst, Mt Sinai, NY USA. [Fuchs, Bryan C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res, Boston, MA USA. [Svendova, Vendula; Schimek, Michael G.] Med Univ Graz, Inst Med Informat, Graz, Austria. [Mach, Monika; Speicher, Michael R.] Med Univ Graz, Inst Human Genet, Graz, Austria. [Stojakovic, Tatjana] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Magin, Thomas M.] Univ Leipzig, Translat Ctr Regenerat Med Leipzig, D-04109 Leipzig, Germany. [Strnad, Pavel] Univ Hosp RWTH, Dept Internal Med 3, Aachen, Germany. [Trauner, Michael] Med Univ Vienna, Dept Internal Med 3, Div Gastroenterol & Hepatol, Vienna, Austria. [Thorgeirsson, Snorri S.] NCI, Ctr Canc Res, NIH, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. [Karin, Michael] Univ Calif San Diego, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA. [Llovet, Josep M.] ICREA, Barcelona, Spain. RI Kiemer, Alexandra/I-9300-2012 OI Kiemer, Alexandra/0000-0002-7224-9900 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD NOV PY 2013 VL 12 IS 11 SU S MA A38 DI 10.1158/1535-7163.TARG-13-A38 PG 2 WC Oncology SC Oncology GA V40RX UT WOS:000209496800036 ER PT J AU Murai, J Huang, SYN Renaud, A Zhang, YP Ji, JP Takeda, S Morris, J Teicher, B Doroshow, JH Pommier, Y AF Murai, Junko Huang, Shar-yin N. Renaud, Amelie Zhang, Yiping Ji, Jiuping Takeda, Shunichi Morris, Joel Teicher, Beverly Doroshow, James H. Pommier, Yves TI Stereospecific trapping of PARP-DNA complexes by BMN 673 and comparison with olaparib and rucaparib SO MOLECULAR CANCER THERAPEUTICS LA English DT Meeting Abstract C1 [Murai, Junko; Huang, Shar-yin N.; Renaud, Amelie; Zhang, Yiping; Ji, Jiuping; Morris, Joel; Teicher, Beverly; Doroshow, James H.; Pommier, Yves] NIH, Bethesda, MD 20892 USA. [Takeda, Shunichi] Kyoto Univ, Dept Radiat Genet, Kyoto, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD NOV PY 2013 VL 12 IS 11 SU S MA A257 DI 10.1158/1535-7163.TARG-13-A257 PG 1 WC Oncology SC Oncology GA V40RX UT WOS:000209496800185 ER PT J AU Barral, S Cosentino, S Costa, R Andersen, SL Christensen, K Eckfeldt, JH Newman, AB Perls, TT Province, MA Hadley, EC Rossi, WK Mayeux, R AF Barral, Sandra Cosentino, Stephanie Costa, Rosann Andersen, Stacey L. Christensen, Kaare Eckfeldt, John H. Newman, Anne B. Perls, Thomas T. Province, Michael A. Hadley, Evan C. Rossi, Winifred K. Mayeux, Richard CA Long Life Family Study TI Exceptional memory performance in the Long Life Family Study SO NEUROBIOLOGY OF AGING LA English DT Article DE Long Life Family Study; Exceptional memory; Quantitative trait; Genetic variants ID GENERAL COGNITIVE-ABILITY; ENVIRONMENTAL ETIOLOGY; GENETICS; TWINS; ASSOCIATION; MORTALITY; HEALTH; OLDER AB Research to understand variability at the highest end of the cognitive performance distribution has been scarce. Our aim was to define a cognitive endophenotype based on exceptional episodic memory (EM) performance and to investigate familial aggregation of EM in families from the Long Life Family Study (LLFS). Using a sample of 1911 nondemented offspring of long-lived probands, we created a quantitative phenotype, EM (memory z >= 1.5), and classified LLFS families as EM and non-EM families based on the number of EM offspring. We then assessed differences in memory performance between LLFS relatives in the parental generation of EM families and those in non-EM families using multivariate analysis adjusted for APOE Apolipoprotein E genotype. LLFS relatives in the proband generation from EM families showed better EM performance than those from non-EM families (beta = 0.74, standard error = 0.19, p = 1.4 x 10(-4)). We demonstrated that there is a familial correlation of the EM endophenotype, suggesting that genetic variants might influence memory performance in long-lived families. (C) 2013 Elsevier Inc. All rights reserved. C1 [Barral, Sandra; Cosentino, Stephanie; Costa, Rosann; Mayeux, Richard] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, Dept Neurol, New York, NY 10032 USA. [Andersen, Stacey L.; Perls, Thomas T.] Boston Univ, Sch Med, Dept Med, Sect Geriatr, Boston, MA 02118 USA. [Andersen, Stacey L.; Perls, Thomas T.] Boston Med Ctr, Boston, MA USA. [Christensen, Kaare] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Eckfeldt, John H.] Univ Southern Denmark, Danish Aging Res Ctr, Odense C, Denmark. [Eckfeldt, John H.] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark. [Eckfeldt, John H.] Odense Univ Hosp, Dept Clin Biochem & Pharmacol, DK-5000 Odense C, Denmark. [Newman, Anne B.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Province, Michael A.] Washington Univ, Sch Med, Data Management Coordinating Ctr, Div Stat Genom, St Louis, MI USA. [Hadley, Evan C.; Rossi, Winifred K.] Natl Inst Aging, Bethesda, MD USA. RP Barral, S (reprint author), Columbia Univ, Med Ctr, GH Sergievsky Ctr, 630 W 168th St, New York, NY 10032 USA. EM smb2174@columbia.edu; rpm2@columbia.edu RI Christensen, Kaare/C-2360-2009; Newman, Anne B./C-6408-2013 OI Christensen, Kaare/0000-0002-5429-5292; Andersen, Stacy/0000-0002-2442-6386; Perls, Thomas/0000-0002-2492-4334; Newman, Anne B./0000-0002-0106-1150 FU National Institute on Aging (NIA) [U01-AG023712, U01-AG23744, U01-AG023746, U01-AG023749, U01-AG023755]; National Institutes of Health/NIA [P01 AG08761]; VELUX Foundation FX LLFS is sponsored by the National Institute on Aging (NIA cooperative agreements U01-AG023712, U01-AG23744, U01-AG023746, U01-AG023749, and U01-AG023755). Danish 1905-cohort is funded by National Institutes of Health/NIA, P01 AG08761 and the Danish Aging Research Center is funded by the VELUX Foundation. The authors specially thank Heidi Dubrouillet, Project Manager, at the Division of Statistical Genomics of Washington University School of Medicine. NR 19 TC 4 Z9 4 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD NOV PY 2013 VL 34 IS 11 BP 2445 EP 2448 DI 10.1016/j.neurobiolaging.2013.05.002 PG 4 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 214HW UT WOS:000324124000001 PM 23759147 ER PT J AU Thambisetty, M An, Y Tanaka, T AF Thambisetty, Madhav An, Yang Tanaka, Toshiko TI Alzheimer's disease risk genes and the age-at-onset phenotype SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; Gene; PICALM; APOE; Age at onset; Risk ID GENOME-WIDE ASSOCIATION; FLUID TAU LEVELS; DATA SET UDS; IDENTIFIES VARIANTS; COMMON VARIANTS; PICALM; LOCI; EPHA1; CD33; CLU AB Despite the recent identification of several novel risk genes for Alzheimer's disease (AD), little is known about their influence on the age at onset (AAO) of AD. The AAO is a phenotype with a heritable component distinct from disease risk and may be a useful trait to study in the context of developing interventions for delaying the onset of AD. We studied the influence of 10 recently identified AD risk genes and APOE in relation to AAO in a large cohort of AD patients (N = 2569). We find that the novel AD risk gene, PICALM, exerts a small effect on the AAO of AD with earlier disease onset in risk allele carriers. In addition, we confirmed the previously reported association between the APOE epsilon 4 allele and earlier disease onset. None of the other AD risk genes influenced AAO of AD. Our results suggest that besides APOE, other genes associated with AD risk do not exert large effects on the AAO phenotype of AD. Published by Elsevier Inc. C1 [Thambisetty, Madhav] NIA, Clin & Translat Neurosci Unit, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [An, Yang] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Tanaka, Toshiko] NIA, Translat Gerontol Branch, Longitudinal Studies Sect, NIH, Baltimore, MD 21224 USA. RP Thambisetty, M (reprint author), NIA, Clin & Translat Neurosci Unit, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. EM thambisettym@mail.nih.gov FU NIA [U24 041689]; NIH, NIA FX Biological samples and associated phenotypic data used in primary data analyses were stored at Principal Investigators' institutions and at the National Cell Repository for Alzheimer's Disease (NCRAD) at Indiana University funded by NIA. Associated phenotypic data used in primary and secondary data analyses were provided by Principal Investigators, the NIA-funded ADCs, and the National Alzheimer's Coordinating Center (NACC), stored at Principal Investigators' institutions, NCRAD, and at the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania, funded by NIA under a cooperative agreement U24 041689. Contributors to the Genetic Analysis Data included Principal Investigators on projects that were individually funded by NIA, other NIH institutes, private US organizations, or foreign governmental or nongovernmental organizations. This research was supported in part by the Intramural Research Program of the NIH, NIA. MT is grateful to Dr Marilyn Miller, PhD Program Director, Genetics of Alzheimer's Disease, Tau, and Hormone Research, Division of Neuroscience, NIA/NIH/Department of Health and Human Services, for advice during the early planning stages of this study. NR 40 TC 2 Z9 2 U1 1 U2 44 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD NOV PY 2013 VL 34 IS 11 AR 2696.e1 DI 10.1016/j.neurobiolaging.2013.05.028 PG 5 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 214HW UT WOS:000324124000033 PM 23870418 ER PT J AU Wilson, LE Pawlita, M Castle, PE Waterboer, T Sahasrabuddhe, V Gravitt, PE Schiffman, M Wentzensen, N AF Wilson, Lauren E. Pawlita, Michael Castle, Phillip E. Waterboer, Tim Sahasrabuddhe, Vikrant Gravitt, Patti E. Schiffman, Mark Wentzensen, Nicolas TI Natural immune responses against eight oncogenic human papillomaviruses in the ASCUS-LSIL Triage Study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE human papillomavirus; seroepidemiology; antibodies ID FEMALE UNIVERSITY-STUDENTS; GLUTATHIONE-S-TRANSFERASE; POPULATION-BASED COHORT; VIRUS-LIKE PARTICLES; COSTA-RICA; IMMUNOGLOBULIN LEVELS; YOUNG-WOMEN; HPV TYPE-16; INFECTION; SMOKING AB Only a subset of women with human papillomavirus (HPV) infections will become seropositive, and the factors influencing seroconversion are not well understood. We used a multiplex serology assay in women with mildly abnormal cytology results to examine seroreactivity to oncogenic HPV genotypes. An unbiased subset of women in the atypical squamous cell of undetermined significance /low-grade squamous intraepithelial lesion Triage Study provided blood samples at trial enrollment for serological testing. A Luminex assay based on glutathione s-transferase-L1 fusion proteins as antigens was used to test seroreactivity against eight carcinogenic HPV genotypes (16, 18, 31, 33, 35, 45, 52 and 58). We analyzed the relationship between seroprevalence in women free of precancer (N = 2,464) and HPV DNA status, age, sexual behavior and other HPV-related risk factors. The overall seroprevalence was 24.5% for HPV16 L1 and approximate to 20% for 18L1 and 31L1. Among women free of precancer, seroprevalence peaked in women less than 29 years and decreased with age. Type-specific seroprevalence was associated with baseline DNA detection for HPV16 (OR = 1.36, 95%CI: 1.04-1.79) and HPV18 (OR = 2.31, 95%CI: 1.61-3.32), as well as for HPV52 and HPV58. Correlates of sexual exposure were associated with increased seroprevalence across most genotypes. Women who were current or former smokers were less likely to be seropositive for all eight of the tested oncogenic genotypes. The multiplex assay showed associations between seroprevalence and known risk factors for HPV infection across nearly all tested HPV genotypes but associations between DNA- and serostatus were weak, suggesting possible misclassification of the participants' HPV serostatus. What's new? Not all women infected with human papilloma virus (HPV) develop antibodies to the virus, and the factors that may lead to this seroconversion haven't been well characterized. In addition, there is currently no standardized assay for detecting HPV antibodies. In this study, the authors used a Luminex-based serology assay to measure antibody responses against eight carcinogenic HPV types. In women with mildly abnormal cervical cytology results, the study found an association between HPV-positive antibody titers and several risk factors for HPV infection. Smoking, however, showed a negative association with seroconversion. C1 [Wilson, Lauren E.; Sahasrabuddhe, Vikrant; Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pawlita, Michael; Waterboer, Tim] German Canc Res Ctr, Heidelberg, Germany. [Castle, Phillip E.] Global Canc Initiat, Chestertown, MD USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 5024, Rockville, MD 20852 USA. EM wentzenn@mail.nih.gov RI Pawlita, Labor/C-9720-2011; Waterboer, Tim/G-1252-2010; OI Wilson, Lauren/0000-0002-5953-2293; Pawlita, Michael/0000-0002-4720-8306 FU National Cancer Institute, National Institutes of Health Department of Health and Human Services [CN-55153, CN-55154m CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, CN-55105] FX Grant sponsor: National Cancer Institute, National Institutes of Health Department of Health and Human Services (provided support for ALTS); Grant numbers: CN-55153, CN-55154m CN-55155, CN-55156, CN-55157, CN-55158, CN-55159; CN-55105 NR 43 TC 10 Z9 10 U1 0 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD NOV PY 2013 VL 133 IS 9 BP 2172 EP 2181 DI 10.1002/ijc.28215 PG 10 WC Oncology SC Oncology GA 202XS UT WOS:000323254800016 PM 23588935 ER PT J AU Anderson, WF Rosenberg, PS Petito, L Katki, HA Ejlertsen, B Ewertz, M Rasmussen, BB Jensen, MB Kroman, N AF Anderson, William F. Rosenberg, Philip S. Petito, Lucia Katki, Hormuzd A. Ejlertsen, Bent Ewertz, Marianne Rasmussen, Birgitte B. Jensen, Maj-Britt Kroman, Niels TI Divergent estrogen receptor-positive and -negative breast cancer trends and etiologic heterogeneity in Denmark SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast cancer; estrogen receptor; epidemiology; age-period-cohort models ID COOPERATIVE GROUP; INCIDENCE RATES; POOLED ANALYSIS; UNITED-STATES; RISK-FACTORS; YOUNG-WOMEN; MAMMOGRAPHY; COHORT; AGE; HISTORY AB Long-term breast cancer trends in incidence in the United States (US) show rising estrogen receptor (ER)-positive rates and falling ER-negative rates. We hypothesized that these divergent trends reflect etiologic heterogeneity and that comparable trends should be observed in other countries with similar risk factor profiles. Therefore, we analyzed invasive female breast cancers in Denmark, a country with similar risk factors as the US. We summarized the overall trend in age-standardized rates with the estimated annual percentage change (EAPC) statistic (1993-2010) and used age-period-cohort models to estimate age-specific EAPCs, cohort rate ratios and projections for future time periods (2011-2018). In Denmark, the overall rate of ER-positive cancers rose between 1993 and 2010 by 3.0% per year (95% CI: 2.8-3.3% per year), whereas the overall rate of ER-negative cancers fell by 2.1% per year (95% CI: -2.5 to -1.6% per year). The ER-positive rate increased fastest among postmenopausal women and the ER-negative rate decreased fastest among premenopausal women, reflecting that cohorts born after 1944 were at relatively higher risk of ER-positive tumors and lower risk of ER-negative tumors. If current trends continue, ER-positive cancers will increase at least 13% by 2018 in Denmark, ER-negative cancers will fall 15% by 2018, and breast cancer overall will increase at least 7% by 2018. Divergent ER-specific trends are consistent with distinct etiologic pathways. If trends in known risk factors are responsible, the Danish and US experience may foreshadow a common pattern worldwide. What's new? Estrogen receptor- (ER-)negative breast cancer incidence rates are declining nationwide in Denmark and the United States, whereas rates for ER-positive breast cancers are rising. This report suggests that the divergent trends in ER breast cancers in both countries can be explained by parallel trends in environmental and lifestyle factors that are known to either increase or decrease risk for ER-positive or ER-negative malignancies. The patterns observed in Denmark and the United States may foreshadow a common pattern for many countries worldwide. C1 [Anderson, William F.; Rosenberg, Philip S.; Petito, Lucia; Katki, Hormuzd A.] NCI, DHHS, NIH, Div Canc Epidemiol & Genet,Biostat Branch, Bethesda, MD 20892 USA. [Ejlertsen, Bent; Jensen, Maj-Britt] Rigshosp, Danish Breast Canc Cooperat Grp DBCG, DK-2100 Copenhagen, Denmark. [Ewertz, Marianne] Univ Southern Denmark, Inst Clin Res, Odense Univ Hosp, Dept Oncol, Copenhagen, Denmark. [Rasmussen, Birgitte B.] Herlev Hosp, Dept Pathol, DK-2730 Herlev, Denmark. [Kroman, Niels] Rigshosp, Dept Breast Surg, DK-2100 Copenhagen, Denmark. RP Anderson, WF (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, Room 8036,6120 Execut Blvd, Rockville, MD 20852 USA. EM wanderso@mail.nih.gov RI Katki, Hormuzd/B-4003-2015 FU National Institutes of Health; National Cancer Institute FX Grant sponsor: National Institutes of Health; Grant sponsor: National Cancer Institute NR 29 TC 12 Z9 12 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD NOV PY 2013 VL 133 IS 9 BP 2201 EP 2206 DI 10.1002/ijc.28222 PG 6 WC Oncology SC Oncology GA 202XS UT WOS:000323254800019 PM 23616071 ER PT J AU Jiang, LM Sun, HZ Yuan, AL Zhang, K Li, DW Li, C Shi, C Li, XW Gao, K Zheng, CY Yang, B Sun, HC AF Jiang, Liming Sun, Haizhu Yuan, Anliang Zhang, Kai Li, Daowei Li, Chen Shi, Ce Li, Xiangwei Gao, Kai Zheng, Changyu Yang, Bai Sun, Hongchen TI Enhancement of Osteoinduction by Continual Simvastatin Release from Poly(lactic-co-glycolic acid)-Hydroxyapatite-Simvastatin Nano-Fibrous Scaffold SO JOURNAL OF BIOMEDICAL NANOTECHNOLOGY LA English DT Article DE Bone Regeneration; Simvastatin; Nano-Fibrous Scaffold; Drug Release; Electrospinning ID ALPHA-TRICALCIUM PHOSPHATE; BONE REGENERATION; NANOCOMPOSITE SCAFFOLDS; CALVARIAL DEFECTS; IN-VITRO; DELIVERY; CELLS; DIFFERENTIATION; MICROSPHERES; DEGRADATION AB Simvastatin is considered as a stimulator for bone formation. However, the half-life for simvastatin is generally 2 hours, which means, it is difficult to maintain biologically active simvastatin in vivo. To overcome this limitation, we created a system to slowly release simvastatin in vitro and in vivo. We constructed a poly(lactic-co-glycolic acid)/hydroxyapatite nano-fibrous scaffold to carry sinnvastatin. Releasing assays showed that simvastatin was released from poly(lactic-co-glycolic acid)/hydroxyapatite/simvastatin quickly within 15 days, and small amounts continued to be released through day 56 (experiments terminated). MU assays demonstrated that both poly(lactic-co-glycolic acid)/hydroxyapatite and poly(lactic-co-glycolic acid)/hydroxyapatite/simvastatin promoted MC3T3-E1 cell proliferation. However, Alkaline phosphatase assays showed that only poly(lactic-co-glycolic acid)/hydroxyapatite/simvastatin scaffold significantly promoted the osteogenic differentiation of MC3T3-E1 cells in vitro on day 14. To further test in vivo, we created calvaria bone defect models and implanted either poly(lactic-co-glycolic acid)/hydroxyapatite or poly(lactic-co-glycolic acid)/hydroxyapatite/simvastatin. After 4 or 8 weeks post-implantation, the results indicated that poly(lactic-co-glycolic acid)/hydroxyapatite/simvastatin scaffold induced bone formation more efficiently than poly(lactic-co-glycolic acid)/hydroxyapatite alone. Our data demonstrates that poly(lactic-co-glycolic acid)/hydroxyapatite/simvastatin has the potential to aid in healing bone defects and promoting bone regeneration in the future although we still need to optimize this complex to efficiently promote bone regeneration. C1 [Jiang, Liming; Sun, Haizhu; Yuan, Anliang; Li, Daowei; Li, Chen; Shi, Ce; Li, Xiangwei; Sun, Hongchen] Jilin Univ, Dept Oral Pathol, Sch & Hosp Stomatol, Changchun 130021, Peoples R China. [Sun, Haizhu] NE Normal Univ, Dept Chem, Changchun 130024, Peoples R China. [Zhang, Kai; Yang, Bai] Jilin Univ, Coll Chem, State Key Lab Supramol Struct & Mat, Changchun 130021, Peoples R China. [Gao, Kai] Peking Union Med Coll, Inst Lab Anim Sci, Beijing 100021, Peoples R China. [Zheng, Changyu] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Clarksburg, MD 20871 USA. RP Sun, HC (reprint author), Jilin Univ, Dept Oral Pathol, Sch & Hosp Stomatol, Changchun 130021, Peoples R China. EM hcsun@mail.jlu.edu.cn FU National Natural Science Foundation of China [30830108]; Science Technology Program of Jilin Province [201101051, 200705350, 201201064]; Research Fund for the Doctoral Program of Higher Education of China [233200801830063]; China Postdoctoral Science Foundation FX PLGA was offered by Chinese Academy of Sciences Changchun Institute of Applied Chemistry. This study was supported by the National Natural Science Foundation of China (30830108), the Science Technology Program of Jilin Province (201101051, 200705350, 201201064), Research Fund for the Doctoral Program of Higher Education of China (233200801830063) and China Postdoctoral Science Foundation funded project. NR 35 TC 19 Z9 21 U1 3 U2 52 PU AMER SCIENTIFIC PUBLISHERS PI VALENCIA PA 26650 THE OLD RD, STE 208, VALENCIA, CA 91381-0751 USA SN 1550-7033 J9 J BIOMED NANOTECHNOL JI J. Biomed. Nanotechnol. PD NOV PY 2013 VL 9 IS 11 BP 1921 EP 1928 DI 10.1166/jbn.2013.1692 PG 8 WC Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Science & Technology - Other Topics; Materials Science GA 207TZ UT WOS:000323628800012 PM 24059091 ER PT J AU Goyal, U Blackstone, C AF Goyal, Uma Blackstone, Craig TI Untangling the web: Mechanisms underlying ER network formation SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Atlastin; Endoplasmic reticulum; Hereditary spastic paraplegia; Morphology; REEP; Reticulon ID HEREDITARY SPASTIC PARAPLEGIA; CORTICAL ENDOPLASMIC-RETICULUM; AMYOTROPHIC-LATERAL-SCLEROSIS; MEMBRANE-PROTEINS; NUCLEAR-ENVELOPE; SACCHAROMYCES-CEREVISIAE; ARABIDOPSIS RETICULON; DENDRITIC SPINES; GTPASE ATLASTIN; PLANT RETICULON AB The ER is a continuous membrane system consisting of the nuclear envelope, flat sheets often studded with ribosomes, and a polygonal network of highly-curved tubules extending throughout the cell. Although protein and lipid biosynthesis, protein modification, vesicular transport, Ca(2+)dynamics, and protein quality control have been investigated in great detail, mechanisms that generate the distinctive architecture of the ER have been uncovered only recently. Several protein families including the reticulons and REEPs/DP1/Yop1p harbor hydrophobic hairpin domains that shape high-curvature ER tubules and mediate intramembrane protein interactions. Members of the atlastin/RHD3/Sey1p family of dynamin-related GTPases interact with the ER-shaping proteins and mediate the formation of three-way junctions responsible for the polygonal structure of the tubular ER network, with Lunapark proteins acting antagonistically. Additional classes of tubular ER proteins including some REEPs and the M1 spastin ATPase interact with the microtubule cytoskeleton. Flat ER sheets possess a different complement of proteins such as p180, CLIMP-63 and kinectin implicated in shaping, cisternal stacking and cytoskeletal interactions. The ER is also in constant motion, and numerous signaling pathways as well as interactions among cytoskeletal elements, the plasma membrane, and organelles cooperate to position and shape the ER dynamically. Finally, many proteins involved in shaping the ER network are mutated in the most common forms of hereditary spastic paraplegia, indicating a particular importance for proper ER morphology and distribution in large, highly-polarized cells such as neurons. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum. Published by Elsevier B.V. C1 [Goyal, Uma; Blackstone, Craig] NINDS, Cell Biol Sect, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Blackstone, C (reprint author), NINDS, Cell Biol Sect, Neurogenet Branch, NIH, Bldg 35,Room 2C-913,9000 Rockville Pike, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health; Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program FX Ethan Tyler (NIH Division of Medical Arts) prepared the figures. The authors were supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (C.B.) and the Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program (U.G.). NR 86 TC 40 Z9 40 U1 0 U2 46 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD NOV PY 2013 VL 1833 IS 11 SI SI BP 2492 EP 2498 DI 10.1016/j.bbamcr.2013.04.009 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 204VS UT WOS:000323400000013 PM 23602970 ER PT J AU Gottschalk, RA Martins, AJ Sjoelund, VH Angermann, BR Lin, B Germain, RN AF Gottschalk, Rachel A. Martins, Andrew J. Sjoelund, Virginie H. Angermann, Bastian R. Lin, Bin Germain, Ronald N. TI Recent progress using systems biology approaches to better understand molecular mechanisms of immunity SO SEMINARS IN IMMUNOLOGY LA English DT Review DE Global analysis; High-throughput; Computational modeling; Signaling networks; Transcriptional networks; Single-cell analysis; Heterogeneity ID TO-CELL VARIABILITY; GENE-EXPRESSION; PROTEIN-PHOSPHORYLATION; NEGATIVE REGULATOR; SIGNALING NETWORKS; ACTIVATION; PHOSPHOPROTEOMICS; IDENTIFICATION; TRANSCRIPTION; MACROPHAGES AB The immune system is composed of multiple dynamic molecular and cellular networks, the complexity of which has been revealed by decades of exacting reductionist research. However, understanding of the immune system sufficient to anticipate its response to novel perturbations requires a more integrative or systems approach to immunology. While methods for unbiased high-throughput data acquisition and computational integration of the resulting datasets are still relatively new, they have begun to substantially enhance our understanding of immunological phenomena. Such approaches have expanded our view of interconnected signaling and transcriptional networks and have highlighted the function of non-linear processes such as spatial regulation and feedback loops. In addition, advances in single cell measurement technology have demonstrated potential sources and functions of response heterogeneity in system behavior. The success of the studies reviewed here often depended upon integration of one or more systems biology approaches with more traditional methods. We hope these examples will inspire a broader range of immunologists to probe questions in a quantitative and integrated manner, advancing collective efforts to understand the immune "system". Published by Elsevier Ltd. C1 [Gottschalk, Rachel A.; Martins, Andrew J.; Sjoelund, Virginie H.; Angermann, Bastian R.; Lin, Bin; Germain, Ronald N.] NIAID, NIH, Lab Syst Biol, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, NIH, Lab Syst Biol, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rgermain@nih.gov FU NIAID, NIH FX We thank our many colleagues for the discussion and research interactions responsible for shaping the views advocated in this review. We apologize to those whose papers were not explicitly cited due to space limitations. This work was supported by the Intramural Research Program of NIAID, NIH. NR 80 TC 7 Z9 7 U1 1 U2 14 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD OCT 31 PY 2013 VL 25 IS 3 BP 201 EP 208 DI 10.1016/j.smim.2012.11.002 PG 8 WC Immunology SC Immunology GA 257WS UT WOS:000327419100003 PM 23238271 ER PT J AU Zou, SM Glynn, S Kuritzkes, D Shah, M Cook, N Berliner, N AF Zou, Shimian Glynn, Simone Kuritzkes, Daniel Shah, Monica Cook, Nakela Berliner, Nancy CA NHLBI AIDS Blood Session Working G TI Hematopoietic cell transplantation and HIV cure: where we are and what next? SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; PROGENITOR CELLS; GENE-THERAPY; CORD BLOOD; STEM; ERADICATION; RESERVOIRS; RIBOZYME; ENGRAFTMENT AB The report of the so-called Berlin patient cured of HIV with hematopoietic stem cell transplantation and a few other studies raised tremendous hope, excitement, and curiosity in the field. The National Heart, Lung and Blood Institute of the National Institutes of Health convened a Working Group to address emerging heart, lung, and blood research priorities related to HIV infection. Hematopoietic cells could contribute to HIV cure through allogeneic or autologous transplantation of naturally occurring or engineered cells with anti-HIV moieties. Protection of central memory T cells from HIV infection could be a critical determinant of achieving a functional cure. HIV cure can only be achieved if the virus is eradicated from reservoirs in resting T cells and possibly other hematopoietic cells. The Working Group recommended multidisciplinary efforts leveraging HIV and cell therapy expertise to answer the critical need to support research toward an HIV cure. C1 [Zou, Shimian; Glynn, Simone; Shah, Monica; Cook, Nakela] NHLBI, NIH, Bethesda, MD 20892 USA. [Kuritzkes, Daniel; Berliner, Nancy] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kuritzkes, Daniel; Berliner, Nancy] Harvard Univ, Sch Med, Boston, MA USA. RP Zou, SM (reprint author), NHLBI, NIH, 6701 Rockledge Dr,Room 9144, Bethesda, MD 20892 USA. EM shimian.zou@nih.gov FU NHLBI NIH HHS [R01 HL044851] NR 37 TC 5 Z9 5 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 31 PY 2013 VL 122 IS 18 BP 3111 EP 3115 DI 10.1182/blood-2013-07-518316 PG 5 WC Hematology SC Hematology GA 245ZB UT WOS:000326503200009 PM 24009230 ER PT J AU Bodor, C Grossmann, V Popov, N Okosun, J O'Riain, C Tan, K Marzec, J Araf, S Wang, J Lee, AM Clear, A Montoto, S Matthews, J Iqbal, S Rajnai, H Rosenwald, A Ott, G Campo, E Rimsza, LM Smeland, EB Chan, WC Braziel, RM Staudt, LM Wright, G Lister, TA Elemento, O Hills, R Gribben, JG Chelala, C Matolcsy, A Kohlmann, A Haferlach, T Gascoyne, RD Fitzgibbon, J AF Boedoer, Csaba Grossmann, Vera Popov, Nikolay Okosun, Jessica O'Riain, Ciaran Tan, King Marzec, Jacek Araf, Shamzah Wang, Jun Lee, Abigail M. Clear, Andrew Montoto, Silvia Matthews, Janet Iqbal, Sameena Rajnai, Hajnalka Rosenwald, Andreas Ott, German Campo, Elias Rimsza, Lisa M. Smeland, Erlend B. Chan, Wing C. Braziel, Rita M. Staudt, Louis M. Wright, George Lister, T. Andrew Elemento, Olivier Hills, Robert Gribben, John G. Chelala, Claude Matolcsy, Andras Kohlmann, Alexander Haferlach, Torsten Gascoyne, Randy D. Fitzgibbon, Jude TI EZH2 mutations are frequent and represent an early event in follicular lymphoma SO BLOOD LA English DT Article ID B-CELL LYMPHOMA; SOMATIC MUTATIONS; DNA METHYLATION; HISTONE H3; LYSINE 27; HYPERTRIMETHYLATION; INHIBITION; SURVIVAL; CANCER; GENES AB Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with othermutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy. C1 [Boedoer, Csaba; Popov, Nikolay; Okosun, Jessica; O'Riain, Ciaran; Araf, Shamzah; Lee, Abigail M.; Clear, Andrew; Montoto, Silvia; Matthews, Janet; Iqbal, Sameena; Lister, T. Andrew; Gribben, John G.; Fitzgibbon, Jude] Queen Mary Univ London, Barts Canc Inst, Ctr Haematooncol, London EC1M 6BQ, England. [Boedoer, Csaba; Rajnai, Hajnalka; Matolcsy, Andras] Semmelweis Univ, Dept Pathol & Expt Canc Res, H-1085 Budapest, Hungary. [Grossmann, Vera; Kohlmann, Alexander; Haferlach, Torsten] MLL Munich Leukemia Lab GmbH, Munich, Germany. [Grossmann, Vera] Johannes Gutenberg Univ Mainz, Univ Med Ctr Mainz, Ctr Thrombosis & Hemostasis, D-55122 Mainz, Germany. [Tan, King; Gascoyne, Randy D.] British Columbia Canc Ctr, Dept Pathol, Vancouver, BC, Canada. [Marzec, Jacek; Wang, Jun; Chelala, Claude] Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London EC1M 6BQ, England. [Rosenwald, Andreas; Ott, German] Univ Wurzburg, Inst Pathol, Wurzburg, Germany. [Ott, German] Dept Clin Pathol, Stuttgart, Germany. [Ott, German] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Campo, Elias] Univ Barcelona, Hosp Clin, Dept Pathol, Barcelona, Spain. [Rimsza, Lisa M.] Univ Arizona, Ctr Canc, Dept Pathol, Tucson, AZ USA. [Smeland, Erlend B.] Oslo Univ Hosp, Inst Canc Res, Dept Immunol, Oslo, Norway. [Smeland, Erlend B.] Univ Oslo, Fac Med, Ctr Canc Biomed, Oslo, Norway. [Chan, Wing C.] Univ Nebraska Med Ctr, Dept Pathol, Omaha, NE USA. [Braziel, Rita M.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Staudt, Louis M.; Wright, George] Natl Canc Inst, Metab Branch, Bethesda, MD USA. [Elemento, Olivier] Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY USA. [Elemento, Olivier] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY USA. [Hills, Robert] Cardiff Univ, Sch Med, Dept Haematol, Cardiff CF10 3AX, S Glam, Wales. RP Bodor, C (reprint author), Queen Mary Univ London, Barts Canc Inst, Ctr Haematooncol, Charterhouse Sq, London EC1M 6BQ, England. EM c.bodor@qmul.ac.uk OI Rajnai, Hajnalka/0000-0003-0934-5366; Bodor, Csaba/0000-0002-0729-692X; Hills, Robert/0000-0003-0166-0062; chelala, claude/0000-0002-2488-0669; Campo, elias/0000-0001-9850-9793 FU Leukaemia Lymphoma Research UK [10036]; European Hematology Association [2009/01]; Kay Kendall Leukaemia Fund Junior Clinical Research Fellowship [KKL 557]; OTKA [K-76204]; Cancer Research UK Programme award [C15966/A15968]; European Union; State of Hungary; European Social Fund in the framework of TAMOP National Excellence Program [4.2.4. A/-11-1-2012-0001] FX This work was supported by the Leukaemia Lymphoma Research UK (10036; J.F.), Partner fellowship (2009/01; C. B.) awarded by European Hematology Association, Kay Kendall Leukaemia Fund Junior Clinical Research Fellowship (KKL 557; J.O.), OTKA K-76204 grant (C. B. and A. M.), and Cancer Research UK Programme award (C15966/A15968; J.F.). C. B. was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TAMOP 4.2.4. A/-11-1-2012-0001 National Excellence Program. NR 24 TC 62 Z9 62 U1 1 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 31 PY 2013 VL 122 IS 18 BP 3165 EP 3168 DI 10.1182/blood-2013-04-496893 PG 4 WC Hematology SC Hematology GA 245ZB UT WOS:000326503200016 PM 24052547 ER PT J AU Carter, JW Baker, CM Best, RB De Sancho, D AF Carter, James W. Baker, Christopher M. Best, Robert B. De Sancho, David TI Engineering Folding Dynamics from Two-State to Downhill: Application to lambda-Repressor SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID PROTEIN STABILITY; SPEED LIMIT; TRANSITION-STATES; POINT MUTATIONS; KINETICS; RATES; SIMULATION; PREDICTION; COOPERATIVITY; TEMPERATURE AB One strategy for reaching the downhill folding regime, primarily exploited for the lambda(6-85) protein fragment, consists of cumulatively introducing mutations that speed up folding. This is an experimentally demanding process where chemical intuition usually serves as a guide for the choice of amino acid residues to mutate. Such an approach can be aided by computational methods that screen for protein engineering hot spots. Here we present one such method that involves sampling the energy landscape of the pseudo-wild-type protein and investigating the effect of point mutations on this landscape. Using a novel metric for the cooperativity, we identify those residues leading to the least cooperative folding. The folding dynamics of the selected mutants are then directly characterized and the differences in the kinetics are analyzed within a Markov-state model framework. Although the method is general, here we present results for a coarse-grained topology-based simulation model of lambda-repressor, whose barrier is reduced from an initial value of similar to 4k(B)T at the midpoint to similar to 1k(B)T, thereby reaching the downhill folding regime. C1 [Carter, James W.; Baker, Christopher M.; De Sancho, David] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Best, Robert B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP De Sancho, D (reprint author), Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England. EM dd363@cam.ac.uk RI Baker, Christopher/A-5264-2010; De Sancho, David/C-4995-2009; Best, Robert/H-7588-2016 OI De Sancho, David/0000-0002-8985-2685; Best, Robert/0000-0002-7893-3543 FU Trinity Hall Cambridge; Federation of European Biochemical Societies (FEBS); Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; FEBS; Engineering and Physical Sciences Research Council [EP/J016764/1] FX J.W.C. acknowledges support from Trinity Hall Cambridge. C.M.B. acknowledges the Federation of European Biochemical Societies (FEBS) for a Return to Europe Fellowship. R.B.B. is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. D.D.S. acknowledges support from a FEBS Long Term Postdoctoral Fellowship and from the Engineering and Physical Sciences Research Council [Grant number EP/J016764/1]. NR 61 TC 4 Z9 4 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 31 PY 2013 VL 117 IS 43 BP 13435 EP 13443 DI 10.1021/jp405904g PG 9 WC Chemistry, Physical SC Chemistry GA 247HM UT WOS:000326608500004 PM 24079652 ER PT J AU Chung, HS Eaton, WA AF Chung, Hoi Sung Eaton, William A. TI Single-molecule fluorescence probes dynamics of barrier crossing SO NATURE LA English DT Article ID ULTRAFAST-FOLDING PROTEIN; TRANSITION PATH TIMES; INTERNAL-FRICTION; SOLVENT VISCOSITY; CHAIN DYNAMICS; SPEED LIMIT; SPECTROSCOPY; RATES; DEPENDENCE; KINETICS AB Kramers developed the theory on how chemical reaction rates are influenced by the viscosity of the medium(1,2). At the viscosity of water, the kinetics of unimolecular reactions are described by diffusion of a Brownian particle over a free-energy barrier separating reactants and products. For reactions in solution this famous theory extended Eyring's transition state theory, and is widely applied in physics, chemistry and biology, including to reactions as complex as protein folding(3,4). Because the diffusion coefficient of Kramers' theory is determined by the dynamics in the sparsely populated region of the barrier top, its properties have not been directly measured for any molecular system. Here we show that the Kramers diffusion coefficient and free-energy barrier can be characterized by measuring the temperature- and viscosity-dependence of the transition path time for protein folding. The transition path is the small fraction of an equilibrium trajectory for a single molecule when the free-energy barrier separating two states is actually crossed. Its duration, the transition path time, can now be determined from photon trajectories for single protein molecules undergoing folding/unfolding transitions(5). Our finding of a long transition path time with an unusually small solvent viscosity dependence suggests that internal friction as well as solvent friction determine the Kramers diffusion coefficient for alpha-helical proteins, as opposed to a breakdown of his theory, which occurs for many small-molecule reactions(2). It is noteworthy that the new and fundamental information concerning Kramers' theory and the dynamics of barrier crossings obtained here come from experiments on a protein rather than a much simpler chemical or physical system. C1 [Chung, Hoi Sung; Eaton, William A.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Chung, HS (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM chunghoi@niddk.nih.gov; eaton@helix.nih.gov RI Chung, Hoi Sung/C-2624-2009 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX We are particularly indebted to J. M. Louis for the preparation, dye labelling and purification of the protein used in this work, with technical assistance from A. Aniana. We also thank R. Best, G. Hummer and A. Szabo for discussions and comments on the manuscript, and D. E. Shaw Research for providing access to their molecular dynamics trajectories for the calculations by R. Best. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 38 TC 72 Z9 72 U1 13 U2 174 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 31 PY 2013 VL 502 IS 7473 BP 685 EP + DI 10.1038/nature12649 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 243CC UT WOS:000326293200048 PM 24153185 ER PT J AU Cohen, JI AF Cohen, Jeffrey I. TI Herpes Zoster REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID POSTHERPETIC NEURALGIA; VACCINE; SAFETY; ADULTS C1 NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000430-23] NR 5 TC 9 Z9 9 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 31 PY 2013 VL 369 IS 18 BP 1766 EP 1767 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 243IY UT WOS:000326311300026 PM 24171531 ER PT J AU Wen, H Miao, HX Bennett, EE Adamo, NM Chen, L AF Wen, Han Miao, Houxun Bennett, Eric E. Adamo, Nick M. Chen, Lei TI Flexible Retrospective Phase Stepping in X-Ray Scatter Correction and Phase Contrast Imaging Using Structured Illumination SO PLOS ONE LA English DT Article ID FOURIER-TRANSFORM METHOD; FRINGE-PATTERN ANALYSIS; GRATING INTERFEROMETER; COMPUTED-TOMOGRAPHY; PRIMARY MODULATION; EXPOSURE; CT AB The development of phase contrast methods for diagnostic x-ray imaging is inspired by the potential of seeing the internal structures of the human body without the need to deposit any harmful radiation. An efficient class of x-ray phase contrast imaging and scatter correction methods share the idea of using structured illumination in the form of a periodic fringe pattern created with gratings or grids. They measure the scatter and distortion of the x-ray wavefront through the attenuation and deformation of the fringe pattern via a phase stepping process. Phase stepping describes image acquisition at regular phase intervals by shifting a grating in uniform steps. However, in practical conditions the actual phase intervals can vary from step to step and also spatially. Particularly with the advent of electromagnetic phase stepping without physical movement of a grating, the phase intervals are dependent upon the focal plane of interest. We describe a demodulation algorithm for phase stepping at arbitrary and position-dependent (APD) phase intervals without assuming a priori knowledge of the phase steps. The algorithm retrospectively determines the spatial distribution of the phase intervals by a Fourier transform method. With this ability, grating-based x-ray imaging becomes more adaptable and robust for broader applications. C1 [Wen, Han; Miao, Houxun; Bennett, Eric E.; Adamo, Nick M.] NHLBI, Imaging Phys Lab, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. [Chen, Lei] NIST, Ctr Nanoscale Sci & Technol, Gaithersburg, MD 20899 USA. RP Wen, H (reprint author), NHLBI, Imaging Phys Lab, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wenh@nhlbi.nih.gov RI Miao, Houxun/N-8233-2013; Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 FU Division of Intramural Research of the National Heart, Lung and Blood Institute, National Institutes of Health (NIH) (part of the U.S. Federal Government) FX The work is funded by the Division of Intramural Research of the National Heart, Lung and Blood Institute, National Institutes of Health (NIH) (part of the U.S. Federal Government), with which all but one of the authors are affiliated. The research is performed as official duty in fulfilling the general Mission of NIH. NR 20 TC 5 Z9 5 U1 1 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 31 PY 2013 VL 8 IS 10 AR e78276 DI 10.1371/journal.pone.0078276 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 244FY UT WOS:000326373800017 PM 24205177 ER PT J AU Koola, MM Boggs, DL Kelly, DL Liu, F Linthicum, JA Turner, HE McMahon, RP Gorelick, DA AF Koola, Maju Mathew Boggs, Douglas Lee Kelly, Deanna Lynn Liu, Fang Linthicum, Jared Allen Turner, Hailey Elaine McMahon, Robert Patrick Gorelick, David Alan TI Relief of cannabis withdrawal symptoms and cannabis quitting strategies in people with schizophrenia SO PSYCHIATRY RESEARCH LA English DT Article DE Schizophrenia; Cannabis; Drug withdrawal symptoms; Coping behavior; Abstinence ID SUBSTANCE USE DISORDERS; SERIOUS MENTAL-ILLNESS; MARIJUANA USE; NICOTINE DEPENDENCE; ABSTINENCE SYMPTOMS; POPULATION; PSYCHOSIS; TOBACCO; ABUSE; ONSET AB This study examined the response to cannabis withdrawal symptoms and use of quitting strategies to maintain abstinence in people with schizophrenia. A convenience sample of 120 participants with schizophrenia who had at least weekly cannabis use and a previous quit attempt without formal treatment were administered the 176-item Marijuana Quit Questionnaire to characterize their "most serious" (self-defined) quit attempt. One hundred thirteen participants had withdrawal symptoms, of whom 104 (92.0%) took some action to relieve a symptom, most commonly nicotine use (75%). 90% of withdrawal symptoms evoked an action for relief in a majority of participants experiencing them, most frequently anxiety (95.2% of participants) and cannabis craving (94.4%). 96% of participants used one or more quitting strategies to maintain abstinence during their quit attempt, most commonly getting rid of cannabis (72%) and cannabis paraphernalia (67%). Religious support or prayer was the quitting strategy most often deemed "most helpful" (15%). Use of a self-identified most helpful quitting strategy was associated with significantly higher one-month (80.8% vs. 73.6%) and one-year (54.9% vs. 41.3%) abstinence rates. Actions to relieve cannabis withdrawal symptoms in people with schizophrenia are common. Promotion of effective quitting strategies may aid relapse prevention. Published by Elsevier Ireland Ltd. C1 [Koola, Maju Mathew; Boggs, Douglas Lee; Kelly, Deanna Lynn; Liu, Fang; Linthicum, Jared Allen; Turner, Hailey Elaine; McMahon, Robert Patrick] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Koola, Maju Mathew] Sheppard Pratt Hlth Syst, Clin Res Programs, Baltimore, MD USA. [Boggs, Douglas Lee] Yale Univ, Sch Med, Dept Psychiat, Vet Affairs Connecticut Healthcare Syst, New Haven, CT USA. [Gorelick, David Alan] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gorelick, DA (reprint author), NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM dgorelic@intra.nida.nih.gov FU Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse; NIDA Residential Research Support Services [HHSN271200599091CADB]; National Institute of Mental Health [R03 MH076985-01]; NIMH T32 grant [MH067533-07]; American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry FX Funded by the Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse and NIDA Residential Research Support Services Contract HHSN271200599091CADB, with additional support from National Institute of Mental Health grant R03 MH076985-01 (D. Kelly, PI). Drs. Boggs and Koola were supported by NIMH T32 grant MH067533-07 (Carpenter, PI). Dr. Koola was supported by an American Psychiatric Association/Kempf Fund Award for Research Development in Psychobiological Psychiatry. We thank Ann Marie Kearns for help with regulatory compliance, Stephanie Feldman for study supervision and staff coordination, Heather Raley for participant recruitment, Julie Grim Haines for database design and management, and Melissa Spindler for data entry. NR 44 TC 1 Z9 1 U1 3 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD OCT 30 PY 2013 VL 209 IS 3 BP 273 EP 278 DI 10.1016/j.psychres.2013.07.044 PG 6 WC Psychiatry SC Psychiatry GA 249GS UT WOS:000326766300004 PM 23969281 ER PT J AU Insel, TR Landis, SC AF Insel, Thomas R. Landis, Story C. TI Twenty-Five Years of Progress: The View from NIMH and NINDS SO NEURON LA English DT Review ID DEEP BRAIN-STIMULATION; MULTIPLE-SCLEROSIS; ANIMAL-MODELS; LONG; DISORDERS; EPILEPSY; NEURONS; DISEASE; GENOME; TRANSCRIPTION AB As directors of two NIH institutes supporting neuroscience research, we explore the gap between 25 years of stunning progress in fundamental neuroscience and the persistent needs of those with brain disorders. We conclude that closing this gap will require a more detailed comprehension of brain function, a rethinking of how we approach translational science, a focus on human neurobiology, and a continuing commitment to build a diverse, innovative neuroscience workforce. In contrast to many other areas of medicine, we lack basic knowledge about our organ of interest. The next phase of progress on brain disorders will require a significantly deeper understanding of fundamental neurobiology. C1 [Insel, Thomas R.] NIMH, Bethesda, MD 20892 USA. [Landis, Story C.] NINDS, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, 6001 Execut Blvd,Room 8129,MSC 9669, Bethesda, MD 20892 USA. EM tinsel@mail.nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 51 TC 16 Z9 17 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 30 PY 2013 VL 80 IS 3 BP 561 EP 567 DI 10.1016/j.neuron.2013.09.041 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 247IA UT WOS:000326609900003 PM 24183009 ER PT J AU Meisel, C Olbrich, E Shriki, O Achermann, P AF Meisel, Christian Olbrich, Eckehard Shriki, Oren Achermann, Peter TI Fading Signatures of Critical Brain Dynamics during Sustained Wakefulness in Humans SO JOURNAL OF NEUROSCIENCE LA English DT Article ID RANGE TEMPORAL CORRELATIONS; SELF-ORGANIZED CRITICALITY; NEURONAL AVALANCHES; SYNAPTIC HOMEOSTASIS; CORTICAL NETWORKS; TIME-SERIES; SLEEP; ELECTROENCEPHALOGRAM; OSCILLATIONS; EEG AB Sleep encompasses approximately a third of our lifetime, yet its purpose and biological function are not well understood. Without sleep optimal brain functioning such as responsiveness to stimuli, information processing, or learning may be impaired. Such observations suggest that sleep plays a crucial role in organizing or reorganizing neuronal networks of the brain toward states where information processing is optimized. Increasing evidence suggests that cortical neuronal networks operate near a critical state characterized by balanced activity patterns, which supports optimal information processing. However, it remains unknown whether critical dynamics is affected in the course of wake and sleep, which would also impact information processing. Here, we show that signatures of criticality are progressively disturbed during wake and restored by sleep. We demonstrate that the precise power-laws governing the cascading activity of neuronal avalanches and the distribution of phase-lock intervals in human electroencephalographic recordings are increasingly disarranged during sustained wakefulness. These changes are accompanied by a decrease in variability of synchronization. Interpreted in the context of a critical branching process, these seemingly different findings indicate a decline of balanced activity and progressive distance from criticality toward states characterized by an imbalance toward excitation where larger events prevail dynamics. Conversely, sleep restores the critical state resulting in recovered power-law characteristics in activity and variability of synchronization. These findings support the intriguing hypothesis that sleep may be important to reorganize cortical network dynamics to a critical state thereby assuring optimal computational capabilities for the following time awake. C1 [Meisel, Christian] Max Planck Inst Phys Komplexer Syst, D-01187 Dresden, Germany. [Meisel, Christian] Univ Clin Carl Gustav Carus, Dept Neurol, D-01307 Dresden, Germany. [Meisel, Christian; Shriki, Oren] NIMH, Sect Crit Brain Dynam, Bethesda, MD 20892 USA. [Olbrich, Eckehard] Max Planck Inst Math Sci, D-04103 Leipzig, Germany. [Achermann, Peter] Univ Zurich, Inst Pharmacol & Toxicol, CH-8057 Zurich, Switzerland. [Achermann, Peter] Univ Zurich, Zurich Ctr Integrat Human Psychol, CH-8057 Zurich, Switzerland. [Achermann, Peter] Univ Zurich, Neurosci Ctr Zurich, Zurich, Switzerland. [Achermann, Peter] Swiss Fed Inst Technol, Zurich, Switzerland. RP Meisel, C (reprint author), Univ Clin Carl Gustav Carus, Dept Neurol, Fetscherstr 74, D-01307 Dresden, Germany. EM christian@meisel.de RI Achermann, Peter/N-1215-2014; Olbrich, Eckehard/A-2339-2010; OI Achermann, Peter/0000-0002-0208-3511; Olbrich, Eckehard/0000-0002-3987-1271; Shriki, Oren/0000-0003-1129-4799 FU Swiss National Science Foundation Grant [320030-130766]; European Community [258749] FX The study was supported by the Swiss National Science Foundation Grant 320030-130766 (P. A.) and by the European Community's Seventh Framework Programme (FP7/2007-2013) under Grant agreement no. 258749 (E. O.). We thank Thilo Gross for comments on an earlier version of this manuscript. NR 51 TC 19 Z9 19 U1 0 U2 13 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 30 PY 2013 VL 33 IS 44 BP 17363 EP 17372 DI 10.1523/JNEUROSCI.1516-13.2013 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 246BB UT WOS:000326509800014 PM 24174669 ER PT J AU Jiang, ZP de Messieres, M Lee, JC AF Jiang, Zhiping de Messieres, Michel Lee, Jennifer C. TI Membrane Remodeling by alpha-Synuclein and Effects on Amyloid Formation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID N-TERMINAL ACETYLATION; PARKINSONS-DISEASE; CURVATURE GENERATION; HELICAL CONFORMATION; FIBRIL FORMATION; LIPID-BILAYERS; BINDING; PROTEIN; ASSOCIATION; PHOSPHATIDYLCHOLINE AB alpha-Synuclein (alpha-Syn), an intrinsically disordered protein, is associated with Parkinson's disease. Though molecular pathogenic mechanisms are ill-defined, mounting evidence connects its amyloid forming and membrane binding propensities to disease etiology. Contrary to recent data suggesting that membrane remodeling by alpha-syn involves anionic phospholipids and helical structure, we discovered that the protein deforms vesicles with no net surface charge (phosphatidylcholine, PC) into tubules (average diameter similar to 20 nm). No discernible secondary structural changes were detected by circular dichroism spectroscopy upon the addition of vesicles. Notably, membrane remodeling inhibits alpha-syn amyloid formation affecting both lag and growth phases. Using five single tryptophan variants and time-resolved fluorescence anisotropy measurements, we determined that alpha-syn influences bilayer structure with surprisingly weak interaction and no site specificity (partition constant, K-P similar to 300 M-1). Vesicle deformation by alpha-syn under a variety of different lipid/protein conditions is characterized via transmission electron microscopy. As cellular membranes are enriched in PC lipids, these results support possible biological consequences for alpha-syn induced membrane remodeling related to both function and pathogenesis. C1 [Jiang, Zhiping; de Messieres, Michel; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bethesda, MD 20892 USA. RP Lee, JC (reprint author), NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM leej4@mail.nih.gov RI Lee, Jennifer/E-9658-2015 OI Lee, Jennifer/0000-0003-0506-8349 FU NIH, NHLBI FX Supported by the Intramural Research Program at the NIH, NHLBI. We thank the NHLBI EM, Biophysics, and Biochemistry Cores and Yi He for the use of equipment and technical expertise. We also thank Dan Mulvihill (University of Kent) for the gift of pNatB plasmid and Jian Liu (NHLBI) for helpful discussions. NR 43 TC 21 Z9 21 U1 3 U2 42 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 EI 1520-5126 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 30 PY 2013 VL 135 IS 43 BP 15970 EP 15973 DI 10.1021/ja405993r PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 245TX UT WOS:000326487800002 PM 24099487 ER PT J AU Deshmukh, L Schwieters, CD Grishaev, A Ghirlando, R Baber, JL Clore, GM AF Deshmukh, Lalit Schwieters, Charles D. Grishaev, Alexander Ghirlando, Rodolfo Baber, James L. Clore, G. Marius TI Structure and Dynamics of Full-Length HIV-1 Capsid Protein in Solution SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; MOLECULAR-STRUCTURE DETERMINATION; N-TERMINAL DOMAIN; ANALYTICAL ULTRACENTRIFUGATION; SEDIMENTATION-VELOCITY; PERDEUTERATED PROTEINS; DIMERIZATION DOMAIN; INTERDOMAIN MOTION; NMR STRUCTURES; CA PROTEIN AB The HIV-1 capsid protein plays a crucial role in viral infectivity, assembling into a cone that encloses the viral RNA. In the mature virion, the N-terminal domain of the capsid protein forms hexameric and pentameric rings, while C-terminal domain homodimers connect adjacent N-terminal domain rings to one another. Structures of disulfide-linked hexamer and pentamer assemblies, as well as structures of the isolated domains, have been solved previously. The dimer configuration in C-terminal domain constructs differs in solution (residues 144-231) and crystal (residues 146-231) structures by similar to 30 degrees, and it has been postulated that the former connects the hexamers while the latter links pentamers to hexamers. Here we study the structure and dynamics of full-length capsid protein in solution, comprising a mixture of monomeric and dimeric forms in dynamic equilibrium, using ensemble simulated annealing driven by experimental NMR residual dipolar couplings and X-ray scattering data. The complexity of the system necessitated the development of a novel computational framework that should be generally applicable to many other challenging systems that currently escape structural characterization by standard application of mainstream techniques of structural biology. We show that the orientation of the C-terminal domains in dimeric full-length capsid and isolated C-terminal domain constructs is the same in solution, and we obtain a quantitative description of the conformational space sampled by the N-terminal domain relative to the C-terminal domain on the nano- to millisecond time scale. The positional distribution of the N-terminal domain relative to the C-terminal domain is large and modulated by the oligomerization state of the C-terminal domain. We also show that a model of the hexamer/pentamer assembly can be readily generated with a single configuration of the C-terminal domain dimer, and that capsid assembly likely proceeds via conformational selection of sparsely populated configurations of the N-terminal domain within the capsid protein dimer. C1 [Deshmukh, Lalit; Grishaev, Alexander; Baber, James L.; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008; Deshmukh, Lalit/C-5073-2015 OI Clore, G. Marius/0000-0003-3809-1027; FU NIH, NIDDK; CIT; Office of the Director of the NIH FX We thank Vincenzo Venditti, Marvin Bayro, and Mengli Cai for useful discussions, Rob Tycko for generously giving us the full-length capsid DNA, Dan Garrett for technical support, and Mark Yeager (Scripps Research Institute) for providing the fullerene cone model coordinates. Use of the Advanced Photon Source (DOE W-31-109-ENG-38) and the shared scattering beamline resource (PUP-77 agreement between NCI, NIH, and Argonne National Laboratory) is acknowledged. This work was supported by funds from the Intramural Program of the NIH, NIDDK (G.M.C.), and CIT (C.D.S.), and from the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). NR 60 TC 43 Z9 46 U1 1 U2 36 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 EI 1520-5126 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 30 PY 2013 VL 135 IS 43 BP 16133 EP 16147 DI 10.1021/ja406246z PG 15 WC Chemistry, Multidisciplinary SC Chemistry GA 245TX UT WOS:000326487800035 PM 24066695 ER PT J AU Weathers, J Brotman, MA Deveney, CM Kim, P Zarate, C Fromm, S Pine, D Leibenluft, E AF Weathers, Judah Brotman, Melissa A. Deveney, Christen M. Kim, Pilyoung Zarate, Carlos, Jr. Fromm, Stephen Pine, Daniel Leibenluft, Ellen TI A developmental study on the neural circuitry mediating response flexibility in bipolar disorder SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Bipolar disorder; Neuroimaging; Response flexibility; Cross-sectional; Stop-change task ID EVENT-RELATED FMRI; NEUROIMAGING FINDINGS; ANTERIOR CINGULATE; PREFRONTAL CORTEX; INHIBITION TASK; RATING-SCALE; MANIA; RELIABILITY; MEDICATION; VALIDITY AB Cross-sectional neuroimaging studies are an important first step in examining developmental differences in brain function between adults and youth with bipolar disorder (BD). Impaired response flexibility may contribute to reduced ability to modify goal-directed behavior in BD appropriately. We compared neural circuitry mediating this process in child (CBD) vs. adult BD (ABD) and age-matched healthy subjects. fMRI data from 15 CBD, 23 ABD, 20 healthy children, and 27 healthy adults were acquired during a response flexibility paradigm, a task where subjects inhibit a prepotent response and execute an alternative response. When successfully executing an alternate response, CBD showed frontal, parietal, and temporal hyperactivation relative to healthy children and ABD, while ABD hypoactivated these regions relative to healthy adults. Previous studies of response flexibility in healthy volunteers revealed frontal, temporal, and parietal cortex hyperactivation in children and hypoactivation in adults. Relative to age-matched healthy subjects, we found hyperactivation in these regions in CBD and hypoactivation in ABD. This suggests that our findings in patients may represent the extreme extension of the age-related response flexibility activation differences found in healthy subjects. Future studies should use longitudinal fMRI to examine the developmental trajectory of the neural circuitry mediating response flexibility in BD. Published by Elsevier Ireland Ltd. C1 [Weathers, Judah; Brotman, Melissa A.; Deveney, Christen M.; Kim, Pilyoung; Leibenluft, Ellen] NIMH, NIH, US Dept Hlth & Human Serv, Emot & Dev Branch,Sect Bipolar Spectrum Disorders, Bethesda, MD 20892 USA. [Zarate, Carlos, Jr.] NIMH, NIH, US Dept Hlth & Human Serv, Div Intramural Res,Sect Neurobio & Treatment Mood, Bethesda, MD 20892 USA. [Fromm, Stephen] NIMH, NIH, US Dept Hlth & Human Serv, Emot & Dev Branch, Bethesda, MD 20892 USA. [Pine, Daniel] NIMH, NIH, US Dept Hlth & Human Serv, Emot & Dev Branch,Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. RP Weathers, J (reprint author), NIMH, NIH, US Dept Hlth & Human Serv, Emot & Dev Branch,Sect Bipolar Spectrum Disorders, Bethesda, MD 20892 USA. EM judah.weathers@yale.edu RI Brotman, Melissa/H-7409-2013 FU National Institute of Mental Health; National Institutes of Health; Department of Health and Human Services FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Dr. Zarate is listed as a co-inventor on a patent application for the use of ketamine in major depression. Dr. Zarate has assigned his rights in the patent to the U.S. government but will share a percentage of any royalties that may be received by the government. We thank the participants and their families who made this research possible and the staff of the Emotion and Development Branch at NIMH. NR 47 TC 5 Z9 5 U1 3 U2 18 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD OCT 30 PY 2013 VL 214 IS 1 BP 56 EP 65 DI 10.1016/j.pscychresns.2013.05.002 PG 10 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 211UC UT WOS:000323935600008 PM 23958598 ER PT J AU Masur, D Shinnar, S Cnaan, A Shinnar, RC Clark, P Wang, JC Weiss, EF Hirtz, DG Glauser, TA AF Masur, David Shinnar, Shlomo Cnaan, Avital Shinnar, Ruth C. Clark, Peggy Wang, Jichuan Weiss, Erica F. Hirtz, Deborah G. Glauser, Tracy A. CA Childhood Absence Epilepsy Study TI Pretreatment cognitive deficits and treatment effects on attention in childhood absence epilepsy SO NEUROLOGY LA English DT Article ID HYPERACTIVITY DISORDER; VALPROIC ACID; CHILDREN; ADHD; ETHOSUXIMIDE; LAMOTRIGINE; DIAGNOSIS AB Objective: To determine the neurocognitive deficits associated with newly diagnosed untreated childhood absence epilepsy (CAE), develop a model describing the factorial structure of items measuring academic achievement and 3 neuropsychological constructs, and determine short-term differential neuropsychological effects on attention among ethosuximide, valproic acid, and lamotrigine. Methods: Subjects with newly diagnosed CAE entering a double-blind, randomized controlled clinical trial had neuropsychological testing including assessments of general intellectual functioning, attention, memory, executive function, and achievement. Attention was reassessed at the week 16-20 visit. Results: At study entry, 36% of the cohort exhibited attention deficits despite otherwise intact neurocognitive functioning. Structural equation modeling of baseline neuropsychological data revealed a direct sequential effect among attention, memory, executive function, and academic achievement. At the week 16-20 visit, attention deficits persisted even if seizure freedom was attained. More subjects receiving valproic acid (49%) had attention deficits than subjects receiving ethosuximide (32%) or lamotrigine (24%) (p = 0.0006). Parental assessment did not reliably detect attention deficits before or after treatment (p < 0.0001). Conclusions: Children with CAE have a high rate of pretreatment attentional deficits that persist despite seizure freedom. Rates are disproportionately higher for valproic acid treatment compared with ethosuximide or lamotrigine. Parents do not recognize these attentional deficits. These deficits present a threat to academic achievement. Vigilant cognitive and behavioral assessment of these children is warranted. Classification of evidence: This study provides Class I evidence that valproic acid is associated with more significant attentional dysfunction than ethosuximide or lamotrigine in children with newly diagnosed CAE. C1 [Masur, David; Shinnar, Shlomo; Shinnar, Ruth C.; Weiss, Erica F.] Albert Einstein Coll Med, Montefiore Med Ctr, New York, NY USA. [Cnaan, Avital; Wang, Jichuan] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Hirtz, Deborah G.] NINDS, Bethesda, MD 20892 USA. [Clark, Peggy; Glauser, Tracy A.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Clark, Peggy; Glauser, Tracy A.] Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. RP Glauser, TA (reprint author), Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. EM tracy.glauser@cchmc.org FU NIH [U01-NS045911, U01-NS045803] FX Supported by the NIH (U01-NS045911and U01-NS045803). NR 40 TC 43 Z9 44 U1 4 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 29 PY 2013 VL 81 IS 18 BP 1572 EP 1580 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA AA0FB UT WOS:000330769800012 PM 24089388 ER PT J AU Tuchman, R Hirtz, D Mamounas, LA AF Tuchman, Roberto Hirtz, Deborah Mamounas, Laura A. TI NINDS epilepsy and autism spectrum disorders workshop report SO NEUROLOGY LA English DT Review ID FRAGILE-X-SYNDROME; TUBEROUS SCLEROSIS COMPLEX; TARGETED TREATMENT TRIALS; RETT-SYNDROME; INTELLECTUAL DISABILITY; CHILDREN; BRAIN; DYSFUNCTION; SEIZURES; MECP2 AB The association of epilepsy and autism spectrum disorders (ASD), although well-recognized, is poorly understood. The purpose of this report is to summarize the discussion of a workshop sponsored by the National Institute of Neurological Disorders and Stroke, with support from the National Institute of Child Health and Human Development, Autism Speaks, and Citizens United for Research in Epilepsy, that took place in Bethesda, Maryland, on May 29 and 30, 2012. The goals of this workshop were to highlight the clinical and biological relationships between ASD and epilepsy, to determine both short- and long-term goals that address research and treatment conundrums in individuals with both ASD and epilepsy, and to identify resources that can further both clinical and basic research. Topics discussed included epidemiology, genetics, environmental factors, common mechanisms, neuroimaging, neuropathology, neurophysiology, treatment, and research gaps and challenges in this unique population. C1 [Tuchman, Roberto] Miami Childrens Hosp Dan Marino Ctr, Dept Neurol, Weston, FL 33331 USA. [Hirtz, Deborah; Mamounas, Laura A.] NINDS, NIH, Bethesda, MD 20892 USA. RP Tuchman, R (reprint author), Miami Childrens Hosp Dan Marino Ctr, Dept Neurol, Weston, FL 33331 USA. EM roberto.tuchman@gmail.com NR 60 TC 20 Z9 21 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 29 PY 2013 VL 81 IS 18 BP 1630 EP 1636 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA AA0FB UT WOS:000330769800020 PM 24089385 ER PT J AU Henry, TD Traverse, JH Pepine, CJ Willerson, JT Ellis, S Zhao, DX Simpson, L Perin, E Penn, M Baran, KW Chambers, J Lambert, C Raveendran, G Simon, D Gee, AP Forder, JR Taylor, DA Cogle, CR Olson, RE Smith, D Geither, C Skarlatos, SI Moye, LA Simari, RD AF Henry, Timothy D. Traverse, Jay H. Pepine, Carl J. Willerson, James T. Ellis, Stephen Zhao, David X. Simpson, Lara Perin, Emerson Penn, Marc Baran, Kenneth W. Chambers, Jeffrey Lambert, Charles Raveendran, Ganesh Simon, Daniel Gee, Adrian P. Forder, John R. Taylor, Doris A. Cogle, Christopher R. Olson, Rachel E. Smith, Deirdre Geither, Carrie Skarlatos, Sonia I. Moye, Lemuel A. Simari, Robert D. TI Results from LateTIME: A Randomized, Placebo Controlled Trial of Intracoronary Stem Cell Delivery Two to Three Weeks Following Acute Myocardial Infarction from the Cardiovascular Cell Therapy Research Network SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 25th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 27-NOV 01, 2013 CL San Francisco, CA C1 [Henry, Timothy D.; Traverse, Jay H.; Olson, Rachel E.] Abbott NW Hosp, Minneapolis Heart Inst Fdn, Minneapolis, MN 55407 USA. [Pepine, Carl J.; Forder, John R.; Cogle, Christopher R.] Univ Florida, Coll Med, Gainesville, FL USA. [Willerson, James T.; Perin, Emerson; Taylor, Doris A.; Smith, Deirdre] St Lukes Episcopal Hosp, Texas Heart Inst, Houston, TX USA. [Ellis, Stephen; Geither, Carrie] Cleveland Clin, Cleveland, OH 44106 USA. [Zhao, David X.] Vanderbilt Heart & Vasc Inst, Nashville, TN USA. [Simpson, Lara; Moye, Lemuel A.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Penn, Marc] Summa Cardiovasc Inst, Akron, OH USA. [Baran, Kenneth W.] United Heart & Vasc Clin, St Paul, MN USA. [Chambers, Jeffrey] Metropolitan Heart & Vasc Inst, Minneapolis, MN USA. [Lambert, Charles] Florida Hosp Pepin Heart Inst, Tampa, FL USA. [Raveendran, Ganesh] Univ Minnesota, Lillehei Heart Inst, Minneapolis, MN USA. [Simon, Daniel] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Gee, Adrian P.] Baylor Coll Med, Houston, TX 77030 USA. [Skarlatos, Sonia I.] NHLBI, Bethesda, MD 20892 USA. [Simari, Robert D.] Mayo Clin, Rochester, MN USA. NR 0 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 29 PY 2013 VL 62 IS 18 SU 1 BP B249 EP B249 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 291RA UT WOS:000329845601110 ER PT J AU Kim, JH Sung, SC Park, J Heo, J Park, YH Kim, JP Kim, JH Lederman, RJ AF Kim, June-Hong Sung, Si Chan Park, Jongha Heo, Jeong Park, Yong-Hyun Kim, Jin-Pyong Kim, Jun-Ho Lederman, Robert J. TI A novel appliance for transcatheter mitral cerclage annuloplasty SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 25th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 27-NOV 01, 2013 CL San Francisco, CA C1 [Kim, June-Hong; Sung, Si Chan; Park, Jongha; Park, Yong-Hyun; Kim, Jun-Ho] Pusan Natl Univ, Yangsan Hosp, Yangsan, South Korea. [Heo, Jeong] Pusan Natl Univ Hosp, Pusan, South Korea. [Kim, Jin-Pyong] Koswire RND Ctr, Pusan, South Korea. [Lederman, Robert J.] 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 29 PY 2013 VL 62 IS 18 SU 1 BP B40 EP B40 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 291RA UT WOS:000329845600121 ER PT J AU Rogers, T Ratnayaka, K Schenke, WH Faranesh, AZ Sonmez, M Franson, DN Lederman, RJ AF Rogers, Toby Ratnayaka, Kanishka Schenke, William H. Faranesh, Anthony Z. Sonmez, Merdim Franson, Dominique N. Lederman, Robert J. TI Trans-Auricular Intra-Pericardial Tricuspid Annuloplasty (TRAIPTA) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 25th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT) CY OCT 27-NOV 01, 2013 CL San Francisco, CA C1 [Rogers, Toby; Ratnayaka, Kanishka; Schenke, William H.; Faranesh, Anthony Z.; Sonmez, Merdim; Franson, Dominique N.; Lederman, Robert J.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 29 PY 2013 VL 62 IS 18 SU 1 BP B41 EP B41 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 291RA UT WOS:000329845600124 ER PT J AU Yewdell, JW David, A AF Yewdell, Jonathan W. David, Alexandre TI Nuclear translation for immunosurveillance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID MESSENGER-RNA TRANSLATION; PROTEIN-SYNTHESIS; MAMMALIAN-CELLS; QUALITY-CONTROL; REVEALS; HYPOTHESIS; PATHWAY; CYCLE C1 [Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [David, Alexandre] CNRS, Unite Mixte Rech UMR 5203, Inst Genom Fonct, F-34094 Montpellier, France. [David, Alexandre] CNRS, INSERM, U661, F-34094 Montpellier, France. [David, Alexandre] Univ Montpellier I, Unite Mixte Rech UMR 5203, F-34094 Montpellier, France. [David, Alexandre] Univ Montpellier 2, Unite Mixte Rech UMR 5203, F-34094 Montpellier, France. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov FU Intramural NIH HHS NR 20 TC 5 Z9 5 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 29 PY 2013 VL 110 IS 44 BP 17612 EP 17613 DI 10.1073/pnas.1318259110 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 242LJ UT WOS:000326243100017 PM 24143809 ER PT J AU Falk, EB Hyde, LW Mitchell, C Faul, J Gonzalez, R Heitzeg, MM Keating, DP Langa, KM Martz, ME Maslowsky, J Morrison, FJ Noll, DC Patrick, ME Pfeffer, FT Reuter-Lorenz, PA Thomason, ME Davis-Kean, P Monk, CS Schulenberg, J AF Falk, Emily B. Hyde, Luke W. Mitchell, Colter Faul, Jessica Gonzalez, Richard Heitzeg, Mary M. Keating, Daniel P. Langa, Kenneth M. Martz, Meghan E. Maslowsky, Julie Morrison, Frederick J. Noll, Douglas C. Patrick, Megan E. Pfeffer, Fabian T. Reuter-Lorenz, Patricia A. Thomason, Moriah E. Davis-Kean, Pamela Monk, Christopher S. Schulenberg, John TI What is a representative brain? Neuroscience meets population science SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neuroimaging; life course; statistics; survey methodology; physics ID HUMAN PREFRONTAL CORTEX; SOCIOECONOMIC-STATUS; SOCIAL-STATUS; ENVIRONMENT INTERACTIONS; FUNCTIONAL CONNECTIVITY; ANTISOCIAL-BEHAVIOR; AMYGDALA REACTIVITY; ALZHEIMERS-DISEASE; DECISION-MAKING; CLINICAL-TRIALS AB The last decades of neuroscience research have produced immense progress in the methods available to understand brain structure and function. Social, cognitive, clinical, affective, economic, communication, and developmental neurosciences have begun to map the relationships between neuro-psychological processes and behavioral outcomes, yielding a new understanding of human behavior and promising interventions. However, a limitation of this fast moving research is that most findings are based on small samples of convenience. Furthermore, our understanding of individual differences may be distorted by unrepresentative samples, undermining findings regarding brain-behavior mechanisms. These limitations are issues that social demographers, epidemiologists, and other population scientists have tackled, with solutions that can be applied to neuroscience. By contrast, nearly all social science disciplines, including social demography, sociology, political science, economics, communication science, and psychology, make assumptions about processes that involve the brain, but have incorporated neural measures to differing, and often limited, degrees; many still treat the brain as a black box. In this article, we describe and promote a perspective-population neuroscience-that leverages interdisciplinary expertise to (i) emphasize the importance of sampling to more clearly define the relevant populations and sampling strategies needed when using neuroscience methods to address such questions; and (ii) deepen understanding of mechanisms within population science by providing insight regarding underlying neural mechanisms. Doing so will increase our confidence in the generalizability of the findings. We provide examples to illustrate the population neuroscience approach for specific types of research questions and discuss the potential for theoretical and applied advances from this approach across areas. C1 [Falk, Emily B.] Univ Michigan, Dept Commun Studies, Ann Arbor, MI 48109 USA. [Hyde, Luke W.; Gonzalez, Richard; Keating, Daniel P.; Martz, Meghan E.; Morrison, Frederick J.; Reuter-Lorenz, Patricia A.; Davis-Kean, Pamela; Monk, Christopher S.; Schulenberg, John] Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. [Gonzalez, Richard] Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA. [Heitzeg, Mary M.; Keating, Daniel P.; Monk, Christopher S.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Keating, Daniel P.] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Langa, Kenneth M.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Noll, Douglas C.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [Reuter-Lorenz, Patricia A.; Monk, Christopher S.] Univ Michigan, Neurosci Grad Program, Ann Arbor, MI 48109 USA. [Falk, Emily B.; Gonzalez, Richard; Davis-Kean, Pamela] Univ Michigan, Res Ctr Grp Dynam, Ann Arbor, MI 48109 USA. [Hyde, Luke W.; Mitchell, Colter; Faul, Jessica; Keating, Daniel P.; Langa, Kenneth M.; Patrick, Megan E.; Pfeffer, Fabian T.; Reuter-Lorenz, Patricia A.; Davis-Kean, Pamela; Monk, Christopher S.; Schulenberg, John] Univ Michigan, Survey Res Ctr, Ann Arbor, MI 48109 USA. [Mitchell, Colter; Pfeffer, Fabian T.] Univ Michigan, Inst Social Res, Populat Studies Ctr, Ann Arbor, MI 48109 USA. [Hyde, Luke W.; Davis-Kean, Pamela; Monk, Christopher S.; Schulenberg, John] Univ Michigan, Ctr Human Growth & Dev, Ann Arbor, MI 48109 USA. [Falk, Emily B.] Univ Penn, Annenberg Sch Commun, Philadelphia, PA 19104 USA. [Langa, Kenneth M.] Vet Affairs Ctr Clin Management Res, Ann Arbor, MI 48105 USA. [Maslowsky, Julie] Univ Wisconsin, Robert Wood Johnson Fdn Hlth & Soc Scholars Progr, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Thomason, Moriah E.] Wayne State Univ, Sch Med Pediat, Detroit, MI 48202 USA. [Thomason, Moriah E.] Wayne State Univ, Merrill Palmer Skillman Inst Child & Family Dev, Detroit, MI 48202 USA. [Thomason, Moriah E.] NIH, Perinatol Res Branch, Detroit, MI 48202 USA. RP Mitchell, C (reprint author), Univ Michigan, Dept Commun Studies, Ann Arbor, MI 48109 USA. EM cmsm@umich.edu RI Noll, Douglas/D-8124-2014; Monk, Christopher/J-1805-2014; Schulenberg, John/A-2212-2008; OI Noll, Douglas/0000-0002-0983-3805; Schulenberg, John/0000-0003-2129-8486; Patrick, Megan/0000-0003-3594-4944 FU National Institutes of Health (NIH) [DP2 DA035156-01, U01AG009740, R01 DA027261, R01 AA12217, U01 AG09740]; Robert Wood Johnson Foundation Health and Society Scholars program FX This paper was made possible by the collective efforts of the Social Environment and Neural Development (SEND) working group within the Survey Research Center (SRC) at the University of Michigan. We gratefully acknowledge the SRC for support of this group, as well as funding supporting group members: National Institutes of Health (NIH)-1 Grants DP2 DA035156-01 (to E.B.F.), U01AG009740 (to. J.F.), R01 DA027261 (to M.M.H.), R01 AA12217 (to M.M.H.), and U01 AG09740 (to. K.L.), and the Robert Wood Johnson Foundation Health and Society Scholars program (J.M.). NR 126 TC 19 Z9 19 U1 2 U2 38 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 OCT 29 PY 2013 VL 110 IS 44 BP 17615 EP 17622 DI 10.1073/pnas.1310134110 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 242LJ UT WOS:000326243100018 PM 24151336 ER PT J AU Best, RB Hummer, G Eaton, WA AF Best, Robert B. Hummer, Gerhard Eaton, William A. TI Native contacts determine protein folding mechanisms in atomistic simulations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE funnel; internal friction; frustration; reaction coordinate; Go models ID TRANSITION-STATE ENSEMBLE; 3-HELIX BUNDLE PROTEIN; NONNATIVE INTERACTIONS; ENERGY LANDSCAPE; MOLECULAR-DYNAMICS; KINETICS; MODEL; RATES; FRUSTRATION; THERMODYNAMICS AB The recent availability of long equilibrium simulations of protein folding in atomistic detail for more than 10 proteins allows us to identify the key interactions driving folding. We find that the collective fraction of native amino acid contacts, Q, captures remarkably well the transition states for all the proteins with a folding free energy barrier. Going beyond this global picture, we devise two different measures to quantify the importance of individual interresidue contacts in the folding mechanism: (i) the log-ratio of lifetimes of contacts during folding transition paths and in the unfolded state and (ii) a Bayesian measure of how predictive the formation of each contact is for being on a transition path. Both of these measures indicate that native, or near-native, contacts are important for determining mechanism, as might be expected. More remarkably, however, we found that for almost all the proteins, with the designed protein alpha D-3 being a notable exception, nonnative contacts play no significant part in determining folding mechanisms. C1 [Best, Robert B.; Hummer, Gerhard; Eaton, William A.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Best, RB (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertbe@helix.nih.gov RI Hummer, Gerhard/A-2546-2013; Best, Robert/H-7588-2016 OI Hummer, Gerhard/0000-0001-7768-746X; Best, Robert/0000-0002-7893-3543 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX We thank D.E. Shaw Research for making this work possible by giving us access to the MD trajectories; Prof. Eugene Shakhnovich, Dr. Attila Szabo, and Dr. Eric Henry for many insightful discussions; and Prof. Kresten Lindorff-Larson and Dr. Stefano Piana for their comments on the manuscript. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 70 TC 99 Z9 100 U1 13 U2 84 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 OCT 29 PY 2013 VL 110 IS 44 BP 17874 EP 17879 DI 10.1073/pnas.1311599110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 242LJ UT WOS:000326243100061 PM 24128758 ER PT J AU Henry, ER Best, RB Eaton, WA AF Henry, Eric R. Best, Robert B. Eaton, William A. TI Comparing a simple theoretical model for protein folding with all-atom molecular dynamics simulations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE stochastic kinetics; funneled energy landscape; Ising-like model; statistical mechanics ID TRANSITION PATH TIMES; ENERGY LANDSCAPE; MICROSCOPIC THEORY; KINETICS; RATES; PHYSICS; HELIX; THERMODYNAMICS; COOPERATIVITY; COEFFICIENTS AB Advances in computing have enabled microsecond all-atom molecular dynamics trajectories of protein folding that can be used to compare with and test critical assumptions of theoretical models. We show that recent simulations by the Shaw group (10, 11, 14, 15) are consistent with a key assumption of an Ising-like theoretical model that native structure grows in only a few regions of the amino acid sequence as folding progresses. The distribution of mechanisms predicted by simulating the master equation of this native-centric model for the benchmark villin subdomain, with only two adjustable thermodynamic parameters and one temperature-dependent kinetic parameter, is remarkably similar to the distribution in the molecular dynamics trajectories. C1 [Henry, Eric R.; Best, Robert B.; Eaton, William A.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Henry, ER (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM eric@helix.nih.gov; robertbe@helix.nih.gov; eaton@helix.nih.gov RI Best, Robert/H-7588-2016; Henry, Eric/J-3414-2013 OI Best, Robert/0000-0002-7893-3543; Henry, Eric/0000-0002-5648-8696 FU Intramural Research Program of the National Institutes of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX We thank D.E. Shaw Research for making this work possible by giving us access to their MD trajectories, Gerhard Hummer and Attila Szabo for many insightful discussions, and Kresten Lindorff-Larsen and Stefano Piana for their comments on the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. NR 64 TC 29 Z9 32 U1 3 U2 51 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 OCT 29 PY 2013 VL 110 IS 44 BP 17880 EP 17885 DI 10.1073/pnas.1317105110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 242LJ UT WOS:000326243100062 PM 24128764 ER PT J AU Parker, SCJ Stitzel, ML Taylor, DL Orozco, JM Erdos, MR Akiyama, JA van Bueren, KL Chines, PS Narisu, N Black, BL Visel, A Pennacchio, LA Collins, FS AF Parker, Stephen C. J. Stitzel, Michael L. Taylor, D. Leland Orozco, Jose Miguel Erdos, Michael R. Akiyama, Jennifer A. van Bueren, Kelly Lammerts Chines, Peter S. Narisu, Narisu Black, Brian L. Visel, Axel Pennacchio, Len A. Collins, Francis S. CA NISC Comparative Sequencing TI Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SUPER-ENHANCERS; SNP RS6983267; HUMAN GENOME; DISCOVERY; ELEMENTS; DNA; ANNOTATION; EXPRESSION; COHESIN; ISLETS AB Chromatin-based functional genomic analyses and genomewide association studies (GWASs) together implicate enhancers as critical elements influencing gene expression and risk for common diseases. Here, we performed systematic chromatin and transcriptome profiling in human pancreatic islets. Integrated analysis of islet data with those from nine cell types identified specific and significant enrichment of type 2 diabetes and related quantitative trait GWAS variants in islet enhancers. Our integrated chromatin maps reveal that most enhancers are short (median = 0.8 kb). Each cell type also contains a substantial number of more extended (>= 3 kb) enhancers. Interestingly, these stretch enhancers are often tissue-specific and overlap locus control regions, suggesting that they are important chromatin regulatory beacons. Indeed, we show that (i) tissue specificity of enhancers and nearby gene expression increase with enhancer length; (ii) neighborhoods containing stretch enhancers are enriched for important cell type-specific genes; and (iii) GWAS variants associated with traits relevant to a particular cell type are more enriched in stretch enhancers compared with short enhancers. Reporter constructs containing stretch enhancer sequences exhibited tissue-specific activity in cell culture experiments and in transgenic mice. These results suggest that stretch enhancers are critical chromatin elements for coordinating cell type-specific regulatory programs and that sequence variation in stretch enhancers affects risk of major common human diseases. C1 [Parker, Stephen C. J.; Stitzel, Michael L.; Taylor, D. Leland; Orozco, Jose Miguel; Erdos, Michael R.; Chines, Peter S.; Narisu, Narisu; Collins, Francis S.; NISC Comparative Sequencing] Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. [Akiyama, Jennifer A.; Visel, Axel; Pennacchio, Len A.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Genom Div, Berkeley, CA 94720 USA. [van Bueren, Kelly Lammerts; Black, Brian L.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 95158 USA. [Visel, Axel; Pennacchio, Len A.] Joint Genome Inst, Dept Energy, Walnut Creek, CA 94598 USA. RP Collins, FS (reprint author), Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. EM collinsf@od.nih.gov RI Visel, Axel/A-9398-2009; OI Visel, Axel/0000-0002-4130-7784; Black, Brian/0000-0002-6664-8913; Taylor, Leland/0000-0001-6498-6970 FU Postdoctoral Research Associate (PRAT) fellowship [1ZIAHG000024, K99DK092251, K99DK099240, R01HL64658, R01DE019118]; E.O. Lawrence Berkeley National Laboratory [R01HG003988]; Department of Energy, University of California [DEAC02-05CH11231] FX We thank the Finland United States Investigation of NIDDM Genetics Consortium and National Institutes of Health (NIH) Chromatin community for valuable critiques and discussion. We thank Lori Bonnycastle, Laura Elnitski, Andrea Ramirez, Mario Morken, and Adam Woolfe for helpful comments. Human islets were obtained from organ donors through the ICR Basic Science Islet Distribution Program (Universities of Illinois, Washington, Miami, and Alabama at Birmingham) and the National Disease Research Interchange. We thank the reviewers for excellent feedback and suggestions. This work was supported by Postdoctoral Research Associate (PRAT) fellowship (to S.C.J.P.); Grants 1ZIAHG000024 (to F.S.C.), K99DK092251 (to M.L.S.), K99DK099240 (to S.C.J.P.), R01HL64658 (to B.L.B.), and R01DE019118 (to B.L.B.). A.V. and L.A.P. are supported by Grant R01HG003988 and conducted research at the E.O. Lawrence Berkeley National Laboratory, performed under Department of Energy Contract DEAC02-05CH11231, University of California. NR 33 TC 150 Z9 150 U1 2 U2 23 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 29 PY 2013 VL 110 IS 44 BP 17921 EP 17926 DI 10.1073/pnas.1317023110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 242LJ UT WOS:000326243100069 PM 24127591 ER PT J AU Song, YR Zhang, Q Kutlu, B Difilippantonio, S Bash, R Gilbert, D Yin, CY O'Sullivan, TN Yang, CY Kozlov, S Bullitt, E McCarthy, KD Kafri, T Louis, DN Miller, CR Hood, L Van Dyke, T AF Song, Yurong Zhang, Qian Kutlu, Burak Difilippantonio, Simone Bash, Ryan Gilbert, Debra Yin, Chaoying O'Sullivan, T. Norene Yang, Chunyu Kozlov, Serguei Bullitt, Elizabeth McCarthy, Ken D. Kafri, Tal Louis, David N. Miller, C. Ryan Hood, Leroy Van Dyke, Terry TI Evolutionary etiology of high-grade astrocytomas SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mouse model preclinical; cancer progression; cancer initiation ID INTEGRATED GENOMIC ANALYSIS; DISEASE PROGRESSION; G(1) CONTROL; PTEN; GLIOBLASTOMA; GLIOMA; MICE; BRAIN; MUTATIONS; RAS AB Glioblastoma (GBM), the most common brain malignancy, remains fatal with no effective treatment. Analyses of common aberrations in GBM suggest major regulatory pathways associated with disease etiology. However, 90% of GBMs are diagnosed at an advanced stage (primary GBMs), providing no access to early disease stages for assessing disease progression events. As such, both understanding of disease mechanisms and the development of biomarkers and therapeutics for effective disease management are limited. Here, we describe an adult-inducible astrocyte-specific system in genetically engineered mice that queries causation in disease evolution of regulatory networks perturbed in human GBM. Events yielding disease, both engineered and spontaneous, indicate ordered grade-specific perturbations that yield high-grade astrocytomas (anaplastic astrocytomas and GBMs). Impaired retinoblastoma protein RB tumor suppression yields grade II histopathology. Additional activation of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) network drives progression to grade III disease, and further inactivation of phosphatase and tensin homolog (PTEN) yields GBM. Spontaneous missense mutation of tumor suppressor Trp53 arises subsequent to KRAS activation, but before grade III progression. The stochastic appearance of mutations identical to those observed in humans, particularly the same spectrum of p53 amino acid changes, supports the validity of engineered lesions and the ensuing interpretations of etiology. Absence of isocitrate dehydrogenase 1 (IDH1) mutation, asymptomatic low grade disease, and rapid emergence of GBM combined with a mesenchymal transcriptome signature reflect characteristics of primary GBM and provide insight into causal relationships. C1 [Song, Yurong; Gilbert, Debra; O'Sullivan, T. Norene; Van Dyke, Terry] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Zhang, Qian] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. [Kutlu, Burak; Hood, Leroy] Inst Syst Biol, Seattle, WA 98103 USA. [Difilippantonio, Simone; Kozlov, Serguei] Sci Applicat Int Corp, Ctr Adv Preclin Res, Frederick, MD 21702 USA. [Bash, Ryan] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pathol & Lab Med & Neurol, Chapel Hill, NC 27599 USA. [Bash, Ryan; Miller, C. Ryan] Univ N Carolina, Neurosci Ctr, Chapel Hill, NC 27599 USA. [Yin, Chaoying; Kafri, Tal] Univ N Carolina, Gene Therapy Ctr, Chapel Hill, NC 27599 USA. [Yang, Chunyu] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Bullitt, Elizabeth] Univ N Carolina, Dept Neurosurg, Chapel Hill, NC 27599 USA. [McCarthy, Ken D.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Louis, David N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Louis, David N.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Louis, David N.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Van Dyke, T (reprint author), NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. EM vandyket@mail.nih.gov RI Miller, Ryan/B-9365-2008 OI Miller, Ryan/0000-0002-0096-8762 FU Intramural Research Program of the NCI-Center for Cancer Research [CA084314, CA046283]; Goldhirsh Foundation; Brain Tumor Society; Waxman Cancer Research Foundation [NCI CA124608]; National Institutes of Health [NS020212, NS033938]; Luxembourg Centre for Systems Biomedicine; University of Luxembourg FX We thank A. Wolthusen, D. Roth, S. Sweeney, S. Henderson, S. Rausch, and D. Swing for excellent animal care; the Laboratory Animal Medicine and the Histopathology Core Facility at the University of North Carolina-Chapel Hill and the transgenic core at the National Cancer Institute (NCI)-Frederick and Pathology/Histotechnology Laboratory at Science Applications International Corporation (SAIC)-Frederick for mouse husbandry and histopathological service; S. Lockett for confocal images; L. Ileva for assistance with MRI; the Laboratory of Molecular Technology (LMT) at SAIC-Frederick for sequencing; and LMT and the Institute for Systems Biology microarray core for microarray studies. We thank S. Jansen, P. Martin, L. Cleveland, L. Lu, A. Adhikari, T. Sullivan, N. K. Collins, D. Householder, T. Guerin, H. Duong, and O. Pacheco-Velez for technical assistance; P. Duke for providing a plasmid containing VEGF-A165 cDNA; and G. Merlino for critical evaluation of the manuscript. This research was supported by the Intramural Research Program of the NCI-Center for Cancer Research, NCI Grants CA084314 and CA046283, the Goldhirsh Foundation, the Brain Tumor Society, and the Waxman Cancer Research Foundation (T. V. D.), NCI CA124608 (E. B.), National Institutes of Health NS020212 and NS033938 (K. D. M.), and the Luxembourg Centre for Systems Biomedicine and the University of Luxembourg (B. K. and L. H.). C. R. M. is a Damon Runyon-Genentech Clinical Investigator (CI-45-09). NR 41 TC 14 Z9 14 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 29 PY 2013 VL 110 IS 44 BP 17933 EP 17938 DI 10.1073/pnas.1317026110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 242LJ UT WOS:000326243100071 PM 24114272 ER PT J AU Majoul, IV Gao, L Betzig, E Onichtchouk, D Butkevich, E Kozlov, Y Bukauskas, F Bennett, MVL Lippincott-Schwartz, J Duden, R AF Majoul, Irina V. Gao, Liang Betzig, Eric Onichtchouk, Daria Butkevich, Eugenia Kozlov, Yuri Bukauskas, Feliksas Bennett, Michael V. L. Lippincott-Schwartz, Jennifer Duden, Rainer TI Fast structural responses of gap junction membrane domains to AB5 toxins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE membrane traffic; connexin actin; cell-cell junctions; cholesterol ID CHOLERA-TOXIN; LIVING CELLS; MAMMALIAN BRAIN; LIPID RAFTS; SHIGA TOXIN; INTERNALIZATION; CHOLESTEROL; FILIPIN; INHIBITION; TRANSPORT AB Gap junctions (GJs) represent connexin-rich membrane domains that connect interiors of adjoining cells in mammalian tissues. How fast GJs can respond to bacterial pathogens has not been known previously. Using Bessel beam plane illumination and confocal spinning disk microscopy, we found fast (similar to 500 ms) formation of connexin-depleted regions (CDRs) inside GJ plaques between cells exposed to AB5 toxins. CDR formation appears as a fast redistribution of connexin channels within GJ plaques with minor changes in outline or geometry. CDR formation does not depend on membrane trafficking or submembrane cytoskeleton and has no effect on GJ conductance. However, CDR responses depend on membrane lipids, can be modified by cholesterol-clustering agents and extracellular K+ ion concentration, and influence cAMP signaling. The CDR response of GJ plaques to bacterial toxins is a phenomenon observed for all tested connexin isoforms. Through signaling, the CDR response may enable cells to sense exposure to AB5 toxins. CDR formation may reflect lipid-phase separation events in the biological membrane of the GJ plaque, leading to increased connexin packing and lipid reorganization. Our data demonstrate very fast dynamics (in the millisecond-to-second range) within GJ plaques, which previously were considered to be relatively stable, long-lived structures. C1 [Majoul, Irina V.; Duden, Rainer] Med Univ Lubeck, Inst Biol, Ctr Struct & Cell Biol Med, D-23562 Lubeck, Germany. [Gao, Liang; Betzig, Eric] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Onichtchouk, Daria] Univ Freiburg, Ctr Biol Signaling Studies, D-79104 Freiburg, Germany. [Butkevich, Eugenia] Univ Gottingen, Drittes Phys Inst, D-37077 Gottingen, Germany. [Kozlov, Yuri] Russian Acad Sci, VA Engelhardt Inst Mol Biol, Moscow 119991, Russia. [Bukauskas, Feliksas; Bennett, Michael V. L.] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Bronx, NY 10461 USA. [Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Majoul, IV (reprint author), Med Univ Lubeck, Inst Biol, Ctr Struct & Cell Biol Med, D-23562 Lubeck, Germany. EM irina.majoul@bio.uni-luebeck.de; lippincj@mail.nih.gov; duden@bio.uni-luebeck.de FU Deutsche Forschungsgemeinschaft Excellence Cluster "Inflammation at Interfaces''; National Institutes of Health [NS55363, NS72238, HL84464] FX We thank Dr. Christian Hubner for help with fluorescence spectroscopy measurements; Dr. Klaus Aktories for providing CNF toxin; Dr. Anna Akhmanova for the actin- and EB3-mCherry constructs; Dr. Manuela Zaccolo for cytosolic and membrane- attached Epac-based cAMP sensors; Drs. James Pawley, Michael Berridge, Richard Blumberg, Werner W. Franke, and Rolf Hilgenfeld for discussions; and Robert Schnherr and Dr. Enno Hartmann for comments on versions of the manuscript. This study was supported by a Deutsche Forschungsgemeinschaft Excellence Cluster "Inflammation at Interfaces'' grant (to R.D.) and by National Institutes of Health Grants NS55363 (to M.V.L.B.) and NS72238 and HL84464 (to F.B.). M.V.L.B. is the Sylvia and Robert S. Olnick Professor of Neuroscience and Distinguished Professor of the Albert Einstein College of Medicine. NR 45 TC 5 Z9 5 U1 1 U2 33 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 OCT 29 PY 2013 VL 110 IS 44 BP E4125 EP E4133 DI 10.1073/pnas.1315850110 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 242LJ UT WOS:000326243100007 PM 24133139 ER PT J AU Louis, JM Tozser, J Roche, J Matuz, K Aniana, A Sayer, JM AF Louis, John M. Toezser, Jozsef Roche, Julien Matuz, Krisztina Aniana, Annie Sayer, Jane M. TI Enhanced Stability of Monomer Fold Correlates with Extreme Drug Resistance of HIV-1 Protease SO BIOCHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CLINICAL INHIBITORS; CLEAVAGE SITES; MUTATIONS; BINDING; GAG; MATURATION; GENERATION; PRECURSOR; FITNESS AB During treatment, mutations in HIV-1 protease (PR) are selected rapidly that confer resistance by decreasing affinity to clinical protease inhibitors (PIs). As these unique drug resistance mutations can compromise the fitness of the virus to replicate, mutations that restore conformational stability and activity while retaining drug resistance are selected on further evolution. Here we identify several compensating mechanisms by which an extreme drug-resistant mutant bearing 20 mutations (PR20) with >5-fold increased K-d and >4000-fold decreased affinity to the PI darunavir functions. (1) PR20 cleaves, albeit poorly, Gag polyprotein substrates essential for viral maturation. (2) PR20 dimer, which exhibits distinctly enhanced thermal stability, has highly attenuated autoproteolysis, thus likely prolonging its lifetime in vivo. (3) The enhanced stability of PR20 results from stabilization of the monomer fold. Both monomeric PR20(T26A), and dimeric PR20 exhibit T-m values 6-7.5 degrees C higher than those for their PR counterparts. Two specific mutations in PR20, L33F and L63P at sites of autoproteolysis, increase the T-m of monomeric PRT26A by similar to 8 degrees C, similar to PR20(T26A). However, without other compensatory mutations as seen in PR20, L33F and L63P substitutions, together, neither restrict autoproteolysis nor significantly reduce binding affinity to darunavir. To determine whether dimer stability contributes to binding affinity for inhibitors, we examined single-chain dimers of PR and PRD25N in which the corresponding identical monomer units were covalently linked by GGSSG sequence. Linking of the subunits did not appreciably change the Delta T-m on inhibitor binding; thus stabilization by tethering appears to have little direct effect on enhancing inhibitor affinity. C1 [Louis, John M.; Roche, Julien; Aniana, Annie; Sayer, Jane M.] NIDDK, Lab Chem Phys, NIH, DHHS, Bethesda, MD 20892 USA. [Toezser, Jozsef; Matuz, Krisztina] Univ Debrecen, Fac Med, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. RP Louis, JM (reprint author), NIDDK, LCP, NIH, Bldg 5,Room B2-29, Bethesda, MD 20892 USA. EM johnl@intra.niddk.nih.gov RI Roche, Julien/O-3204-2013; Tozser, Jozsef/A-7840-2008 OI Roche, Julien/0000-0003-3892-0200; Tozser, Jozsef/0000-0003-0274-0056 FU NIDDK, National Institutes of Health; Office of the Director, NIH; Hungarian Science and Research Fund [OTKA 101591]; [TAMOP 4.2.2.A-11/1/KONV-2012-0023] FX This research was supported by the Intramural Research Program of the NIDDK, National Institutes of Health and the Intramural AIDS-Targeted Program of the Office of the Director, NIH, and in, part by the TAMOP 4.2.2.A-11/1/KONV-2012-0023 "VED-ELEM" and by the Hungarian Science and Research Fund (OTKA 101591). NR 42 TC 5 Z9 5 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 29 PY 2013 VL 52 IS 43 BP 7678 EP 7688 DI 10.1021/bi400962r PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 244ZS UT WOS:000326429300016 PM 24079831 ER PT J AU Bedognetti, D Spivey, TL Zhao, Y Uccellini, L Tomei, S Dudley, ME Ascierto, ML De Giorgi, V Liu, Q Delogu, LG Sommariva, M Sertoli, MR Simon, R Wang, E Rosenberg, SA Marincola, FM AF Bedognetti, D. Spivey, T. L. Zhao, Y. Uccellini, L. Tomei, S. Dudley, M. E. Ascierto, M. L. De Giorgi, V. Liu, Q. Delogu, L. G. Sommariva, M. Sertoli, M. R. Simon, R. Wang, E. Rosenberg, S. A. Marincola, F. M. TI CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2 SO BRITISH JOURNAL OF CANCER LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; IMMUNOLOGICAL CONSTANT; CANCER-IMMUNOTHERAPY; OVARIAN-CANCER; T-CELLS; CCR5; EXPRESSION; REJECTION; SURVIVAL; IMPACT AB Background: Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in similar to 20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression. Methods: Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-triangle 32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N = 50). Results: The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-triangle 32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P = 0.0009, and P = 0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio = 6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR. Conclusion: Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-triangle 32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response. C1 [Bedognetti, D.; Spivey, T. L.; Uccellini, L.; Tomei, S.; Ascierto, M. L.; De Giorgi, V.; Liu, Q.; Sommariva, M.; Wang, E.; Marincola, F. M.] CHI, NIH, Clin Ctr & Trans NIH, Dept Transfus Med,IDIS, Bethesda, MD 20892 USA. [Bedognetti, D.; Sertoli, M. R.] Univ Genoa, Dept Oncol Biol Genet DOBIG, I-16132 Genoa, Italy. [Bedognetti, D.; Sertoli, M. R.] Natl Inst Canc Res, I-16132 Genoa, Italy. [Bedognetti, D.; Sertoli, M. R.] Univ Genoa, Dept Internal Med DiMI, I-16132 Genoa, Italy. [Spivey, T. L.] CRTP, NIH, Bethesda, MD 20892 USA. [Spivey, T. L.] Rush Univ, Rush Med Coll, Med Ctr, Chicago, IL 60612 USA. [Zhao, Y.; Simon, R.] NCI, NIH, Div Canc Treatment & Diag, Biometr Res Branch, Bethesda, MD 20892 USA. [Uccellini, L.] Univ Milan, Dept Clin Sci, Infect Dis & Trop Med Sect, Milan, Italy. [Dudley, M. E.; Rosenberg, S. A.] NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. [Ascierto, M. L.] Univ Genoa, CEBR, I-16132 Genoa, Italy. [Delogu, L. G.] Univ Sassari, Dept Chem & Pharm, I-07100 Sassari, Italy. [Sommariva, M.] Univ Milan, Dept Biomed Sci Hlth, I-20133 Milan, Italy. [Marincola, F. M.] Sidra Med & Res Ctr, Res Branch, Doha, Qatar. RP Bedognetti, D (reprint author), CHI, NIH, Clin Ctr & Trans NIH, Dept Transfus Med,IDIS, Bethesda, MD 20892 USA. EM davide.bedognetti@nih.gov; fmarincola@sidra.org RI Sommariva, Michele/C-1174-2017; De Giorgi, Valeria/D-4582-2017; OI Sommariva, Michele/0000-0002-7622-0996; Bedognetti, Davide/0000-0002-5857-773X FU Intramural Research program of the US National Institutes of Health; Conquer Cancer Foundation of the American Society of Clinical Oncology; Italian Association of Medical Oncology (AIOM) Foundation FX This study was supported by the Intramural Research program of the US National Institutes of Health and by the Conquer Cancer Foundation of the American Society of Clinical Oncology (2011 Young Investigator Award Grant, granted to Davide Bedognetti). Dr Bedognetti's fellowship was initially supported by the Italian Association of Medical Oncology (AIOM) Foundation. NR 51 TC 34 Z9 36 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 29 PY 2013 VL 109 IS 9 BP 2412 EP 2423 DI 10.1038/bjc.2013.557 PG 12 WC Oncology SC Oncology GA 244LT UT WOS:000326390800015 PM 24129241 ER PT J AU Posokhova, E Ng, D Opel, A Masuho, I Tinker, A Biesecker, LG Wickman, K Martemyanov, KA AF Posokhova, Ekaterina Ng, David Opel, Aaisha Masuho, Ikuo Tinker, Andrew Biesecker, Leslie G. Wickman, Kevin Martemyanov, Kirill A. TI Essential Role of the m(2)R-RGS6-I-KACh Pathway in Controlling Intrinsic Heart Rate Variability SO PLOS ONE LA English DT Article ID ENDOGENOUS RGS PROTEINS; I-KACH; ATRIAL-FIBRILLATION; SINOATRIAL NODE; GATING KINETICS; POINCARE PLOT; K+-CHANNEL; PACEMAKER; MOUSE; MICE AB Normal heart function requires generation of a regular rhythm by sinoatrial pacemaker cells and the alteration of this spontaneous heart rate by the autonomic input to match physiological demand. However, the molecular mechanisms that ensure consistent periodicity of cardiac contractions and fine tuning of this process by autonomic system are not completely understood. Here we examined the contribution of the m(2)R-I-KACh intracellular signaling pathway, which mediates the negative chronotropic effect of parasympathetic stimulation, to the regulation of the cardiac pacemaking rhythm. Using isolated heart preparations and single-cell recordings we show that the m(2)R-I-KACh signaling pathway controls the excitability and firing pattern of the sinoatrial cardiomyocytes and determines variability of cardiac rhythm in a manner independent from the autonomic input. Ablation of the major regulator of this pathway, Rgs6, in mice results in irregular cardiac rhythmicity and increases susceptibility to atrial fibrillation. We further identify several human subjects with variants in the RGS6 gene and show that the loss of function in RGS6 correlates with increased heart rate variability. These findings identify the essential role of the m(2)R-I-KACh signaling pathway in the regulation of cardiac sinus rhythm and implicate RGS6 in arrhythmia pathogenesis. C1 [Posokhova, Ekaterina; Masuho, Ikuo; Martemyanov, Kirill A.] Scripps Res Inst, Dept Neurosci, Jupiter, FL USA. [Ng, David; Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Opel, Aaisha] UCL, Dept Med, London, England. [Tinker, Andrew] Barts & London Queen Marys Sch Med & Dent, Ctr Heart, William Harvey Res Inst, London, England. [Wickman, Kevin] Univ Minnesota, Dept Pharmacol, Minneapolis, MN 55455 USA. RP Martemyanov, KA (reprint author), Scripps Res Inst, Dept Neurosci, Jupiter, FL USA. EM kirill@scripps.edu RI Masuho, Ikuo/J-6115-2014 FU NIH [HL105550]; British Heart Foundation [FS/09/042/27860]; Welcome Trust [081475/Z/06/Z]; NHGRI FX This work was supported by the NIH grant HL105550 (KW and KAM), the British Heart Foundation, FS/09/042/27860 (AT) and Welcome Trust, 081475/Z/06/Z (AT). DN and LB are supported by the Intramural Research Program of the NHGRI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 13 Z9 14 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 29 PY 2013 VL 8 IS 10 AR e76973 DI 10.1371/journal.pone.0076973 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 242VF UT WOS:000326270700014 PM 24204714 ER PT J AU Benjamin, RM Yanovski, SZ Simons-Morton, DG AF Benjamin, Regina M. Yanovski, Susan Z. Simons-Morton, Denise G. TI Can Primary Care Physician-Driven Community Programs Address the Obesity Epidemic Among High-Risk Populations? SO JAMA INTERNAL MEDICINE LA English DT Editorial Material C1 [Benjamin, Regina M.] US Dept HHS, Washington, DC 20201 USA. [Yanovski, Susan Z.] NIDDK, Bethesda, MD 20892 USA. [Simons-Morton, Denise G.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Benjamin, RM (reprint author), US Dept HHS, 200 Independence Ave SW, Washington, DC 20201 USA. EM reginabenjamin@comcast.net NR 4 TC 0 Z9 0 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD OCT 28 PY 2013 VL 173 IS 19 BP 1778 EP 1779 DI 10.1001/jamainternmed.2013.7776 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 302EO UT WOS:000330584900005 PM 23979565 ER PT J AU McMahon, GM Zeng, XX Waikar, SS AF McMahon, Gearoid M. Zeng, Xiaoxi Waikar, Sushrut S. TI A Risk Prediction Score for Kidney Failure or Mortality in Rhabdomyolysis SO JAMA INTERNAL MEDICINE LA English DT Article ID ACUTE-RENAL-FAILURE; EXERTIONAL MUSCLE DAMAGE; SERUM CREATINE-KINASE; VALIDATION; EXERCISE; INJURY AB IMPORTANCE Rhabdomyolysis ranges in severity from asymptomatic elevations in creatine phosphokinase levels to a life-threatening disorder characterized by severe acute kidney injury requiring hemodialysis or continuous renal replacement therapy (RRT). OBJECTIVE To develop a risk prediction tool to identify patients at greatest risk of RRT or in-hospital mortality. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of 2371 patients admitted between January 1, 2000, and March 31, 2011, to 2 large teaching hospitals in Boston, Massachusetts, with creatine phosphokinase levels in excess of 5000 U/L within 3 days of admission. The derivation cohort consisted of 1397 patients from Massachusetts General Hospital, and the validation cohort comprised 974 patients from Brigham and Women's Hospital. MAIN OUTCOMES AND MEASURES The composite of RRT or in-hospital mortality. RESULTS The causes and outcomes of rhabdomyolysis were similar between the derivation and validation cohorts. In total, the composite outcome occurred in 19.0% of patients (8.0% required RRT and 14.1% died during hospitalization). The highest rates of the composite outcome were from compartment syndrome (41.2%), sepsis (39.3%), and following cardiac arrest (58.5%). The lowest rates were from myositis (1.7%), exercise (3.2%), and seizures (6.0%). The independent predictors of the composite outcome were age, female sex, cause of rhabdomyolysis, and values of initial creatinine, creatine phosphokinase, phosphate, calcium, and bicarbonate. We developed a risk-prediction score from these variables in the derivation cohort and subsequently applied it in the validation cohort. The C statistic for the prediction model was 0.82 (95% CI, 0.80-0.85) in the derivation cohort and 0.83 (0.80-0.86) in the validation cohort. The Hosmer-Lemeshow P values were .14 and .28, respectively. In the validation cohort, among the patients with the lowest risk score (<5), 2.3% died or needed RRT. Among the patients with the highest risk score (>10), 61.2% died or needed RRT. CONCLUSIONS AND RELEVANCE Outcomes from rhabdomyolysis vary widely depending on the clinical context. The risk of RRT or in-hospital mortality in patients with rhabdomyolysis can be estimated using commonly available demographic, clinical, and laboratory variables on admission. C1 [McMahon, Gearoid M.; Zeng, Xiaoxi; Waikar, Sushrut S.] Harvard Univ, Brigham & Womens Hosp, Div Renal, Dept Med,Med Sch, Boston, MA 02115 USA. [McMahon, Gearoid M.] NHLBI, Framingham Heart Study, Framingham, MA USA. [McMahon, Gearoid M.] Ctr Populat Studies, Framingham, MA USA. [Zeng, Xiaoxi] Sichuan Univ, Dept Nephrol, West China Hosp Sichuan, Chengdu 610064, Peoples R China. RP McMahon, GM (reprint author), Brigham & Womens Hosp, Div Renal, 75 Francis St, Boston, MA 02115 USA. EM gearoidmm@gmail.com OI McMahon, Gearoid/0000-0002-7723-2198 FU China Scholarship Council; [DK093574]; [DK085660] FX Dr Zeng was supported by the China Scholarship Council. Dr Waikar is supported by grants DK093574 and DK085660. NR 21 TC 31 Z9 32 U1 0 U2 18 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD OCT 28 PY 2013 VL 173 IS 19 BP 1821 EP 1828 DI 10.1001/jamainternmed.2013.9774 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 302EO UT WOS:000330584900014 PM 24000014 ER PT J AU Xiao, Q Park, Y AF Xiao, Qian Park, Yikyung TI Dietary and Supplemental Calcium Intake and Mortality Reply SO JAMA INTERNAL MEDICINE LA English DT Letter ID BREAST-CANCER RISK; CHINESE WOMEN; CONSUMPTION C1 [Xiao, Qian; Park, Yikyung] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Rockville, MD 20850 USA. RP Xiao, Q (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM qian.xiao@nih.gov NR 5 TC 0 Z9 0 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD OCT 28 PY 2013 VL 173 IS 19 BP 1841 EP 1842 DI 10.1001/jamainternmed.2013.9232 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 302EO UT WOS:000330584900024 PM 24165843 ER PT J AU Fang, YP Gao, S Tai, D Middaugh, CR Fang, JW AF Fang, Yaping Gao, Shan Tai, David Middaugh, C. Russell Fang, Jianwen TI Identification of properties important to protein aggregation using feature selection SO BMC BIOINFORMATICS LA English DT Article DE Aggregation; Amyloid; Peptide; Prediction; Feature selection; Machine learning ID FIBRIL-FORMING SEGMENTS; SIGNAL PEPTIDES; PREDICTION; RATES; CLASSIFICATION; MACHINE; PROPENSITY; SEQUENCE; PACKAGE; REGIONS AB Background: Protein aggregation is a significant problem in the biopharmaceutical industry (protein drug stability) and is associated medically with over 40 human diseases. Although a number of computational models have been developed for predicting aggregation propensity and identifying aggregation-prone regions in proteins, little systematic research has been done to determine physicochemical properties relevant to aggregation and their relative importance to this important process. Such studies may result in not only accurately predicting peptide aggregation propensities and identifying aggregation prone regions in proteins, but also aid in discovering additional underlying mechanisms governing this process. Results: We use two feature selection algorithms to identify 16 features, out of a total of 560 physicochemical properties, presumably important to protein aggregation. Two predictors (ProA-SVM and ProA-RF) using selected features are built for predicting peptide aggregation propensity and identifying aggregation prone regions in proteins. Both methods are compared favourably to other state-of-the-art algorithms in cross validation. The identified important properties are fairly consistent with previous studies and bring some new insights into protein and peptide aggregation. One interesting new finding is that aggregation prone peptide sequences have similar properties to signal peptide and signal anchor sequences. Conclusions: Both predictors are implemented in a freely available web application (http://www.abl.ku. edu/ProA/). We suggest that the quaternary structure of protein aggregates, especially soluble oligomers, may allow the formation of new molecular recognition signals that guide aggregate targeting to specific cellular sites. C1 [Fang, Yaping] Huazhong Agr Univ, Inst Comp Applicat, Coll Sci, Wuhan 430070, Peoples R China. [Fang, Yaping; Gao, Shan; Tai, David; Fang, Jianwen] Univ Kansas, Appl Bioinformat Lab, Lawrence, KS 66047 USA. [Middaugh, C. Russell] Univ Kansas, Dept Pharmaceut Chem, Lawrence, KS 66047 USA. [Fang, Jianwen] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Rockville, MD 20850 USA. RP Fang, JW (reprint author), Univ Kansas, Appl Bioinformat Lab, 2034 Becker Dr, Lawrence, KS 66047 USA. EM jianwen.fang@nih.gov OI Fang, Yaping/0000-0001-6075-0768 FU National Institutes of Health (NIH) [P01 AG12993] FX We are indebted to Professor Amedeo Caflisch, Professor Luis Serrano, and their research groups for providing the PAGE and TANGO programs. We also thank Dr. Max Kuhn for his help in using the caret package, and Dr. David Volkin for his review of the manuscript. This work was supported in part by the National Institutes of Health (NIH) Grant P01 AG12993 (PI: E. Michaelis). NR 45 TC 9 Z9 9 U1 2 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 28 PY 2013 VL 14 AR 314 DI 10.1186/1471-2105-14-314 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 259LQ UT WOS:000327528800001 PM 24165390 ER PT J AU Oddoux, S Zaal, KJ Tate, V Kenea, A Nandkeolyar, SA Reid, E Liu, WH Ralston, E AF Oddoux, Sarah Zaal, Kristien J. Tate, Victoria Kenea, Aster Nandkeolyar, Shuktika A. Reid, Ericka Liu, Wenhua Ralston, Evelyn TI Microtubules that form the stationary lattice of muscle fibers are dynamic and nucleated at Golgi elements SO JOURNAL OF CELL BIOLOGY LA English DT Article ID SKELETAL-MUSCLE; ORGANIZING CENTERS; TARGETING MOTIF; GAMMA-TUBULIN; GENE-TRANSFER; LIVING CELLS; PROTEIN 4; COMPLEX; MYOGENESIS; ORGANIZATION AB Skeletal muscle microtubules (MTs) form a nonclassic grid-like network, which has so far been documented in static images only. We have now observed and analyzed dynamics of GFP constructs of MT and Golgi markers in single live fibers and in the whole mouse muscle in vivo. Using confocal, intravital, and superresolution microscopy, we find that muscle MTs are dynamic, growing at the typical speed of similar to 9 mu m/min, and forming small bundles that build a durable network. We also show that static Golgi elements, associated with the MT-organizing center proteins gamma-tubulin and pericentrin, are major sites of muscle MT nucleation, in addition to the previously identified sites (i.e., nuclear membranes). These data give us a framework for understanding how muscle MTs organize and how they contribute to the pathology of muscle diseases such as Duchenne muscular dystrophy. C1 [Oddoux, Sarah; Zaal, Kristien J.; Tate, Victoria; Kenea, Aster; Nandkeolyar, Shuktika A.; Reid, Ericka; Liu, Wenhua; Ralston, Evelyn] NIAMSD, Light Imaging Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. RP Ralston, E (reprint author), NIAMSD, Light Imaging Sect, Off Sci & Technol, NIH, Bethesda, MD 20892 USA. EM evelyn.ralston@nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases FX This work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. NR 55 TC 30 Z9 33 U1 1 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD OCT 28 PY 2013 VL 203 IS 2 BP 205 EP 213 DI 10.1083/jcb.201304063 PG 9 WC Cell Biology SC Cell Biology GA 242YB UT WOS:000326281200007 PM 24145165 ER PT J AU Schwartz, LM Persson, EC Weinstein, SJ Graubard, BI Freedman, ND Mannisto, S Albanes, D McGlynn, KA AF Schwartz, Lauren M. Persson, E. Christina Weinstein, Stephanie J. Graubard, Barry I. Freedman, Neal D. Mannisto, Satu Albanes, Demetrius McGlynn, Katherine A. TI Alcohol Consumption, One-Carbon Metabolites, Liver Cancer and Liver Disease Mortality SO PLOS ONE LA English DT Article ID HEPATOCELLULAR-CARCINOMA; CIGARETTE-SMOKING; UNITED-STATES; FOLATE INTAKE; COHORT; RISK; CARCINOGENESIS; BURDEN; REPRODUCIBILITY; VITAMIN-B-12 AB Background: Excess alcohol consumption adversely affects one-carbon metabolism and increases the risk of liver disease and liver cancer. Conversely, higher folate levels have been inversely associated with liver damage. The current study investigated the effects of alcohol and one-carbon metabolite intake on liver cancer incidence and liver disease mortality within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Methods: Cox proportional hazards modeling was used to calculate hazard ratios and 95% confidence intervals (CIs) in a population of 27,086 Finnish males with 194 incident liver cancers and 213 liver disease deaths. In a nested case-control subset (95 liver cancers, 103 controls), logistic regression was used to calculate odds ratios and 95% CIs for serum one-carbon metabolites in relation to liver cancer risk. Results: Daily alcohol consumption of more than 20.44 g was associated with an increased risk of both liver cancer incidence (Hazard Ratio (HR) 1.52, 95% CI 1.06-2.18) and liver disease mortality (HR 6.68, 95% CI 4.16-10.71). These risks were unaffected by one-carbon metabolite intake. Similarly, in the case-control study, none of the serum one-carbon metabolites were associated with liver cancer. Conclusions: The current study provided no convincing evidence for a protective association of one-carbon metabolite intake or serum level on the risk of liver cancer or liver disease mortality. C1 [Schwartz, Lauren M.; Persson, E. Christina; Weinstein, Stephanie J.; Graubard, Barry I.; Freedman, Neal D.; Albanes, Demetrius; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Persson, E. Christina] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Mannisto, Satu] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RP McGlynn, KA (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. EM mcglynnk@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Freedman, Neal/B-9741-2015; OI Freedman, Neal/0000-0003-0074-1098; Mannisto, Satu/0000-0002-8668-3046 FU National Cancer Institute, NIH FX The study was financially supported by the Intramural Research Program of the National Cancer Institute, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 2 Z9 2 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 28 PY 2013 VL 8 IS 10 AR e78156 DI 10.1371/journal.pone.0078156 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 242KW UT WOS:000326241200054 PM 24205137 ER PT J AU Wu, X Peng, MY Huang, BQ Zhang, H Wang, HF Huang, B Xue, ZY Zhang, LJ Da, YR Yang, D Yao, Z Zhang, RX AF Wu, Xi Peng, Meiyu Huang, Bingqing Zhang, Huan Wang, Huafeng Huang, Biao Xue, Zhenyi Zhang, Lijuan Da, Yurong Yang, De Yao, Zhi Zhang, Rongxin TI Immune microenvironment profiles of tumor immune equilibrium and immune escape states of mouse sarcoma SO CANCER LETTERS LA English DT Article DE Immunoediting; Immune equilibrium; Immune escape; Immune microenvironment; Dormant sarcomas ID REGULATORY T-CELLS; MYELOID SUPPRESSOR-CELLS; COLORECTAL-CANCER; NKT CELLS; INFILTRATING LYMPHOCYTES; PROGNOSTIC-SIGNIFICANCE; CARCINOMA PATIENTS; ANTITUMOR VACCINE; OVARIAN-CANCER; BEARING MICE AB Cancer immunoediting consists of three distinct phases: elimination, equilibrium and escape. Here, for the first time, we investigated the immune microenvironment profiles of tumor immune equilibrium and immune escape states in 3'-methylcholanthrene-induced murine sarcoma model. Our study indicates the relative balance of monocytic MDSCs and antitumor immunity cells (especially CTLs, NK cells and gamma delta T cells) may involve in maintaining tumor cells in a state of immune-mediated dormancy. In addition, high percentages of Treg cells and PMN-MDSCs are associated with the tumor immune escape state - mice with progressing sarcomas. In summary, the relative balance of immune effector cells and suppressive populations in the tumor microenvironment may involve in determining the fate of tumors. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Wu, Xi; Peng, Meiyu; Huang, Bingqing; Zhang, Huan; Wang, Huafeng; Huang, Biao; Xue, Zhenyi; Zhang, Lijuan; Da, Yurong; Yang, De; Zhang, Rongxin] Tianjin Med Univ, Res Ctr Basic Med Sci, Lab Immunol & Inflammat, Tianjin 300070, Peoples R China. [Wu, Xi; Peng, Meiyu; Xue, Zhenyi; Zhang, Lijuan; Da, Yurong; Yao, Zhi; Zhang, Rongxin] Tianjin Med Univ, Basic Med Coll, Dept Immunol, Tianjin 300070, Peoples R China. [Wu, Xi; Peng, Meiyu; Xue, Zhenyi; Zhang, Lijuan; Da, Yurong; Yao, Zhi; Zhang, Rongxin] Tianjin Med Univ, Tianjin Key Lab Cellular & Mol Immunol, Tianjin 300070, Peoples R China. [Wu, Xi; Peng, Meiyu; Xue, Zhenyi; Zhang, Lijuan; Da, Yurong; Yao, Zhi; Zhang, Rongxin] Tianjin Med Univ, Educ Minist China, Key Lab Immune Microenvironm & Dis, Tianjin 300070, Peoples R China. [Yang, De] NCI, Mol Immunoregulat Lab, NIH, Frederick, MD 21702 USA. RP Yao, Z (reprint author), Tianjin Med Univ, Basic Med Coll, Dept Immunol, Qi Xiang Tai Rd 22, Tianjin 300070, Peoples R China. EM yaozhi@tijmu.edu.cn; rongxinz@yahoo.com FU Ministry of Science and Technology of China [2012CB932503, 2012CBA01305, 2011CB933100]; National Natural Science Foundation of China [91029705, 81172864, 81272317, 81072019] FX This work is supported by the Ministry of Science and Technology of China through Grant Nos. 2012CB932503, 2012CBA01305 and 2011CB933100; the National Natural Science Foundation of China through Grants Nos. 91029705, 81172864, 81272317 and 81072019. NR 49 TC 9 Z9 9 U1 1 U2 17 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD OCT 28 PY 2013 VL 340 IS 1 BP 124 EP 133 DI 10.1016/j.canlet.2013.07.038 PG 10 WC Oncology SC Oncology GA 233RP UT WOS:000325587500014 PM 23920127 ER PT J AU Harvie, M Wright, C Pegington, M McMullan, D Mitchell, E Martin, B Cutler, RG Evans, G Whiteside, S Maudsley, S Camandola, S Wang, R Carlson, OD Egan, JM Mattson, MP Howell, A AF Harvie, Michelle Wright, Claire Pegington, Mary McMullan, Debbie Mitchell, Ellen Martin, Bronwen Cutler, Roy G. Evans, Gareth Whiteside, Sigrid Maudsley, Stuart Camandola, Simonetta Wang, Rui Carlson, Olga D. Egan, Josephine M. Mattson, Mark P. Howell, Anthony TI The effect of intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss and metabolic disease risk markers in overweight women SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Intermittent energy restriction; Low-carbohydrate diets; Weight loss; Daily energy restriction; Insulin resistance ID RANDOMIZED CONTROLLED-TRIAL; LOW-FAT DIET; BREAST-CANCER; HIGH-PROTEIN; CALORIE RESTRICTION; OXIDATIVE STRESS; GLYCEMIC CONTROL; OBESE MEN; INTERVENTION; METAANALYSIS AB Intermittent energy restriction may result in greater improvements in insulin sensitivity and weight control than daily energy restriction (DER). We tested two intermittent energy and carbohydrate restriction (IECR) regimens, including one which allowed ad libitum protein and fat (IECR + PF). Overweight women (n 115) aged 20 and 69 years with a family history of breast cancer were randomised to an overall 25% energy restriction, either as an IECR (2500-2717 kJ/d, <40 g carbohydrate/d for 2 d/week) or a 25% DER (approximately 6000 kJ/d for 7 d/week) or an IECR + PF for a 3-month weight-loss period and 1 month of weight maintenance (IECR or IECR + PF for 1 d/week). Insulin resistance reduced with the IECR diets (mean -0.34 (95% CI -0.66, -0.02) units) and the IECR + PF diet (mean -0.38 (95% CI -0.75, -0.01) units). Reductions with the IECR diets were significantly greater compared with the DER diet (mean 0.2 (95% CI -0.19, 0.66) mu U/unit, P=0.02). Both IECR groups had greater reductions in body fat compared with the DER group (IECR: mean -3.7 (95% CI -2.5, -4.9) kg, P=0.007; IECR + PF: mean -3.7 (95% CI -2.8, -4.7) kg, P=0.019; DER: mean -2.0 (95% CI -1.0, 3.0)kg). During the weight maintenance phase, 1 d of IECR or IECR + PF per week maintained the reductions in insulin resistance and weight. In the short term, IECR is superior to DER with respect to improved insulin sensitivity and body fat reduction. Longer-term studies into the safety and effectiveness of IECR diets are warranted. C1 [Harvie, Michelle; Pegington, Mary; McMullan, Debbie; Mitchell, Ellen; Evans, Gareth; Howell, Anthony] Univ Hosp South Manchester NHS Fdn Trust, Genesis Breast Canc Prevent Ctr, Manchester M23 9LT, Lancs, England. [Wright, Claire] Univ Chester, Dept Clin Sci & Nutr, Chester, Cheshire, England. [Martin, Bronwen; Camandola, Simonetta; Wang, Rui; Carlson, Olga D.; Egan, Josephine M.] NIA, Lab Clin Invest, Intramural Res Program, Baltimore, MD 21224 USA. [Cutler, Roy G.; Maudsley, Stuart; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Whiteside, Sigrid] Univ Hosp South Manchester NHS Fdn Trust, Dept Stat, Manchester M23 9LT, Lancs, England. RP Harvie, M (reprint author), Univ Hosp South Manchester NHS Fdn Trust, Genesis Breast Canc Prevent Ctr, Southmoor Rd, Manchester M23 9LT, Lancs, England. EM michelle.harvie@manchester.ac.uk OI Evans, Gareth/0000-0002-8482-5784 FU Genesis Breast Cancer Prevention [1109839]; National Institute on Aging, Baltimore, USA FX The present study was supported by the Genesis Breast Cancer Prevention (Registered Charity no. 1109839) and, in part, by the Intramural Research Program of the National Institute on Aging, Baltimore, USA. NR 66 TC 27 Z9 28 U1 6 U2 35 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 EI 1475-2662 J9 BRIT J NUTR JI Br. J. Nutr. PD OCT 28 PY 2013 VL 110 IS 8 BP 1534 EP 1547 DI 10.1017/S0007114513000792 PG 14 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 234YZ UT WOS:000325681900019 PM 23591120 ER PT J AU Choe, SW Terman, DS Rivers, AE Rivera, J Lottenberg, R Sorg, BS AF Choe, Se-woon Terman, David S. Rivers, Angela E. Rivera, Jose Lottenberg, Richard Sorg, Brian S. TI Drug-loaded sickle cells programmed ex vivo for delayed hemolysis target hypoxic tumor microvessels and augment tumor drug delivery SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Blood; Cancer; Carrier; Chemotherapy; Particle; Photosensitizer ID RED-BLOOD-CELLS; CARRIER HUMAN ERYTHROCYTES; SENSITIVE LIPOSOMES; MOUSE MODEL; RELEASE; DISEASE; ANEMIA; TRANSFUSION; ALLOIMMUNIZATION; PHOTOHEMOLYSIS AB Selective drug delivery to hypoxic tumor niches remains a significant therapeutic challenge that calls for new conceptual approaches. Sickle red blood cells (SSRBCs) have shown an ability to target such hypoxic niches and induce tumoricidal effects when used together with exogenous pro-oxidants. Here we determine whether the delivery of a model therapeutic encapsulated in murine SSRBCs can be enhanced by ex vivo photosensitization under conditions that delay autohemolysis to a time that coincides with maximal localization of SSRBCs in a hypoxic tumor. Hyperspectral imaging of 4T1 carcinomas shows oxygen saturation levels <10% in a large fraction (commonly 50% or more) of the tumor. Using video microscopy of dorsal skin window chambers implanted with 4T1 tumors, we demonstrate that allogeneic SSRBCs, but not normal RBCs (nRBCs), selectively accumulate in hypoxic 4T1 tumors between 12 and 24 h after systemic administration. We further show that ex vivo photo-oxidation can program SSRBCs to postpone hemolysis/release of a model therapeutic to a point that coincides with their maximum sequestration in hypoxic tumor microvessels. Under these conditions, drug-loaded photosensitized SSRBCs show a 3-4 fold greater drug delivery to tumors compared to non-photosensitized SSRBCs, drug-loaded photosensitized nRBCs, and free drug. These results demonstrate that photo-oxidized SSRBCs, but not photo-oxidized nRBCs, sequester and hemolyze in hypoxic tumors and release substantially more drug than photo-oxidized nRBCs and non-photo-oxidized SSRBCs. Photo-oxidation of drug-loaded SSRBCs thus appears to exploit the unique tumor targeting and carrier properties of SSRBCs to optimize drug delivery to hypoxic tumors. Such programmed and drug-loaded SSRBCs therefore represent a novel and useful tool for augmenting drug delivery to hypoxic solid tumors. Published by Elsevier B.V. C1 [Choe, Se-woon] Gumi Elect & Informat Technol Res Inst, Gumi, South Korea. [Terman, David S.] Jenom Res Inst, Mol Genet Program, Carmel, VA USA. [Rivers, Angela E.] Univ Illinois, Coll Med, Div Pediat Hematol Oncol, Chicago, IL USA. [Rivera, Jose] Univ Illinois, Dept Bioengn, Urbana, IL 61801 USA. [Lottenberg, Richard] Univ Florida, Coll Med, Div Hematol Oncol, Gainesville, FL USA. [Sorg, Brian S.] NCI, NIH, Bethesda, MD 20892 USA. RP Sorg, BS (reprint author), NCI, Canc Diag Program, Div Canc Treatment & Diag, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM brian.sorg@nih.gov FU Bankhead-Coley Cancer Research Program, Florida Department of Health; National Institutes of Health (NHLBI) [7K01HL103172] FX The authors would like to thank Mark W. Dewhirst (Duke University, Durham, NC), Linda Jones (College of Charleston, Charleston, SC), and M-Ali H. Al-Akhras (Jordan University of Science and Technology, Irbid, Jordan) for insightful discussions, and Chul Han (University of Florida, Department of Physiology and Functional Genomics), and Yonghwan Kim (University of Florida, Department of Physiology and Functional Genomics) for technical support. This work was supported in part by a grant from the Bankhead-Coley Cancer Research Program, Florida Department of Health (to BSS), and the National Institutes of Health (NHLBI, 7K01HL103172 to AER). NR 67 TC 9 Z9 9 U1 1 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD OCT 28 PY 2013 VL 171 IS 2 BP 184 EP 192 DI 10.1016/j.jconrel.2013.07.008 PG 9 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 215YK UT WOS:000324247000011 PM 23871960 ER PT J AU Maltsev, AV Yaniv, Y Stern, MD Lakatta, EG Maltsev, VA AF Maltsev, Anna V. Yaniv, Yael Stern, Michael D. Lakatta, Edward G. Maltsev, Victor A. TI RyR-NCX-SERCA Local Cross-Talk Ensures Pacemaker Cell Function at Rest and During the Fight-or-Flight Reflex SO CIRCULATION RESEARCH LA English DT Article DE calcium; sarcoplasmic reticulum; sinoatrial node; sodium-calcium exchanger ID EXCHANGER KNOCKOUT MICE; SINOATRIAL NODE; CA2+ RELEASE; RYANODINE RECEPTOR; DIASTOLIC DEPOLARIZATION; NA+-CA2+ EXCHANGER; HEART-RATE; AUTOMATICITY; CLOCK; MODEL AB Rationale: A recent study published in Circulation Research by Gao et al used sinoatrial node (SAN)-targeted, incomplete Ncx1 knockout in mice to explore the role of the Na+/Ca2+ exchanger (NCX) in cardiac pacemaker. The authors concluded that NCX is required for increasing sinus rates, but not for maintaining resting heart rate. This conclusion was based, in part, on numeric model simulations performed by Gao et al that reproduced their experimental results of unchanged action potentials in the knockout SAN cells. The authors, however, did not simulate the NCX current (I-NCX), that is, the subject of the study. Objective: We extended numeric examinations to simulate I-NCX in their incomplete knockout SAN cells that is crucial to interpret the study results. Methods and Results: I-NCX and Ca2+ dynamics were simulated using different contemporary numeric models of SAN cells. We found that minimum diastolic Ca2+ levels and I-NCX amplitudes generated by remaining NCX molecules (only 20% of control) remained almost unchanged. Simulations using a new local Ca2+ control model indicate that these powerful compensatory mechanisms involve complex local cross-talk of Ca2+ cycling proteins and NCX. Specifically, lower NCX expression facilitates Ca2+-induced Ca2+ release and larger local Ca2+ releases that stabilize diastolic I-NCX. Further reduction of NCX expression results in arrhythmia and halt of automaticity. Conclusions: Remaining NCX molecules in the incomplete knockout model likely produce almost the same diastolic I-NCX as in wild-type cells. I-NCX contribution is crucially important for both basal automaticity of SAN cells and during the fight-or-flight reflex. C1 [Maltsev, Anna V.] Univ Bristol, Dept Math, Bristol BS8 1TW, Avon, England. [Maltsev, Anna V.] Pace Biol LLC, Bethesda, MD USA. [Yaniv, Yael; Stern, Michael D.; Lakatta, Edward G.; Maltsev, Victor A.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Maltsev, VA (reprint author), NIA, Cardiovasc Sci Lab, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM MaltsevVi@mail.nih.gov RI Yaniv, Yael/B-3311-2015 OI Yaniv, Yael/0000-0002-5183-6284 FU National Institutes of Health, National Institute on Aging; Pace Biologics, LLC FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, and, in part, by Pace Biologics, LLC (A.V.M.). NR 23 TC 8 Z9 8 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD OCT 25 PY 2013 VL 113 IS 10 BP E94 EP E100 DI 10.1161/CIRCRESAHA.113.302465 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 298VE UT WOS:000330351800001 PM 24158576 ER PT J AU George, SM McTiernan, A Villasenor, A Alfano, CM Irwin, ML Neuhouser, ML Baumgartner, RN Baumgartner, KB Bernstein, L Smith, AW Ballard-Barbash, R AF George, Stephanie M. McTiernan, Anne Villasenor, Adriana Alfano, Catherine M. Irwin, Melinda L. Neuhouser, Marian L. Baumgartner, Richard N. Baumgartner, Kathy B. Bernstein, Leslie Smith, Ashley W. Ballard-Barbash, Rachel TI Disentangling the body weight-bone mineral density association among breast cancer survivors: an examination of the independent roles of lean mass and fat mass SO BMC CANCER LA English DT Article DE Body composition; Bone mineral density; Breast cancer survivor; Epidemiology; Bone loss ID RECEIVING ADJUVANT CHEMOTHERAPY; PHYSICAL-ACTIVITY; CONTROLLED-TRIAL; ENERGY-BALANCE; FRACTURE RISK; WOMEN; HEALTH; OBESITY; DIAGNOSIS; LIFE AB Background: Bone mineral density (BMD) and lean mass (LM) may both decrease in breast cancer survivors, thereby increasing risk of falls and fractures. Research is needed to determine whether lean mass (LM) and fat mass (FM) independently relate to BMD in this patient group. Methods: The Health, Eating, Activity, and Lifestyle Study participants included 599 women, ages 29-87 years, diagnosed from 1995-1999 with stage 0-IIIA breast cancer, who underwent dual-energy X-ray absorptiometry scans approximately 6-months postdiagnosis. We calculated adjusted geometric means of total body BMD within quartiles (Q) of LM and FM. We also stratified LM-BMD associations by a fat mass index threshold that tracks with obesity (lower body fat: <= 12.9 kg/m(2); higher body fat: > 12.9 kg/m(2)) and stratified FM-BMD associations by appendicular lean mass index level corresponding with sarcopenia (non-sarcopenic: >= 5.45 kg/m(2) and sarcopenic: < 5.45 kg/m(2)). Results: Higher LM (Q4 vs. Q1) was associated with higher total body BMD overall (1.12 g/cm(2) vs. 1.07 g/cm(2), p-trend < 0.0001), and among survivors with lower body fat (1.13 g/cm(2) vs. 1.07 g/cm(2), p-trend <0.0001) and higher body fat (1.15 g/cm(2) vs. 1.08 g/cm(2), p-trend = 0.004). Higher FM (Q4 vs. Q1) was associated with higher total body BMD overall (1.12 g/cm(2) vs. 1.07 g/cm(2), p-trend < 0.0001) and among non-sarcopenic survivors (1.15 g/cm(2) vs. 1.08 g/cm(2), p <0.0001), but the association was not significant among sarcopenic survivors (1.09 g/cm(2) vs. 1.04 g/cm(2), p-trend = 0.18). Conclusion: Among breast cancer survivors, higher LM and FM were independently related to higher total body BMD. Future exercise interventions to prevent bone loss among survivors should consider the potential relevance of increasing and preserving LM. C1 [George, Stephanie M.; Smith, Ashley W.; Ballard-Barbash, Rachel] NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. [McTiernan, Anne; Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Villasenor, Adriana] Univ Calif San Diego, Canc Prevent & Control Program, Moores UCSD Canc Ctr, San Diego, CA 92103 USA. [Alfano, Catherine M.] NCI, Div Canc Control & Populat Sci, Off Canc Survivorship, Bethesda, MD 20892 USA. [Irwin, Melinda L.] MD Yale Sch Publ Hlth, Div Chron Dis Epidemiol, New Haven, CT USA. [Baumgartner, Richard N.; Baumgartner, Kathy B.] Univ Louisville, Dept Epidemiol & Populat Hlth, Louisville, KY 40292 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA. RP George, SM (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. EM Stephanie.george@nih.gov FU National Cancer Institute [N01-CN-75036-20, NO1-CN-05228, NO1-PC-67010] FX We would like to thank the HEAL study participants, the HEAL study staff, and Todd Gibson of Information Management Systems. This study was funded by National Cancer Institute Grants N01-CN-75036-20, NO1-CN-05228, and NO1-PC-67010. NR 42 TC 0 Z9 1 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD OCT 25 PY 2013 VL 13 AR 497 DI 10.1186/1471-2407-13-497 PG 6 WC Oncology SC Oncology GA 280JJ UT WOS:000329024700003 PM 24161130 ER PT J AU Thierry-Carstensen, B Dalby, T Stevner, MA Robbins, JB Schneerson, R Trollfors, B AF Thierry-Carstensen, Birgit Dalby, Tine Stevner, Michael A. Robbins, John B. Schneerson, Rachel Trollfors, Birger TI Experience with monocomponent acellular pertussis combination vaccines for infants, children, adolescents and adults-A review of safety, immunogenicity, efficacy and effectiveness studies and 15 years of field experience SO VACCINE LA English DT Review DE Clinical trial; Hydrogen peroxide inactivated pertussis toxoid; aP vaccine; Whooping cough; Statens Serum Institut ID PERSISTENT ITCHING NODULES; ANTIGEN-CONTENT DIPHTHERIA; BORDETELLA-PERTUSSIS; TOXOID VACCINE; BOOSTER IMMUNIZATION; HYDROGEN-PEROXIDE; ADSORBED VACCINES; CONTROLLED TRIAL; DELAYED-HYPERSENSITIVITY; ANTIBODY-RESPONSES AB Combination vaccines containing a monocomponent acellular pertussis (aP) vaccine, manufactured at Statens Serum Institut (SSI), Denmark, have successfully controlled Bordetella pertussis infections in Denmark since 1997. The efficacy of this aP vaccine was 71% in a double-blind, randomised and controlled clinical trial. Its safety and immunogenicity have been demonstrated in infants, children, adolescents and adults. In approximately 500,000 children it was effective against pertussis requiring hospitalisation (VE: 93% after 3 doses) and against pertussis not requiring hospitalisation (VE: 78% after 3 doses). IgG antibodies against pertussis toxin (IgG anti-PT) response rates after booster vaccination of adults with tetanus, diphtheria and aP combination vaccine (TdaP) were considerably higher for this monocornponent aP vaccine containing 20 mu g pertussis toxoid, inactivated by hydrogen peroxide (92.0%), than for two multicomponent aP vaccines inactivated by formaldehyde and/or glutaraldehyde: 3-component aP with 8 p.g pertussis toxoid (77.2%) and 5-component aP with 2.5 mu g pertussis toxoid (47.1%), without compromising the safety profile. In Denmark where this monocomponent aP vaccine has been the only pertussis vaccine in use for 15 years, there has been no pertussis epidemic since 2002 (population incidence 36 per 100,000), in contrast to neighbouring countries, where epidemics have occurred. This monocomponent aP vaccine can be used in combination vaccines for primary and booster vaccination against pertussis in all age groups and is an important tool for successful pertussis control. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved. C1 [Thierry-Carstensen, Birgit; Dalby, Tine; Stevner, Michael A.] Statens Serum Inst, DK-2300 Copenhagen, Denmark. [Robbins, John B.; Schneerson, Rachel] NICHHD, NIH, Bethesda, MD 20892 USA. [Trollfors, Birger] Sahlgrenska Univ Hosp East, Dept Pediat Med, S-4168S Gothenburg, Sweden. RP Thierry-Carstensen, B (reprint author), Statens Serum Inst, 5 Artillerivej, DK-2300 Copenhagen, Denmark. EM btc@ssi.dk NR 75 TC 17 Z9 19 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD OCT 25 PY 2013 VL 31 IS 45 BP 5178 EP 5191 DI 10.1016/j.vaccine.2013.08.034 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 252HR UT WOS:000326996300005 PM 23994021 ER PT J AU Murphy, RA Schairer, C Gierach, GL Byrne, C Sherman, ME Register, TC Ding, JZ Kritchevsky, SB Harris, TB AF Murphy, Rachel A. Schairer, Catherine Gierach, Gretchen L. Byrne, Celia Sherman, Mark E. Register, Thomas C. Ding, Jingzhong Kritchevsky, Stephen B. Harris, Tamara B. TI Beyond Breast Cancer: Mammographic Features and Mortality Risk in a Population of Healthy Women SO PLOS ONE LA English DT Article ID BODY-MASS INDEX; TYPE-2 DIABETES-MELLITUS; SKELETAL-MUSCLE; FOLLOW-UP; INSULIN-RESISTANCE; UNITED-STATES; WHITE WOMEN; DENSITY; OBESITY; TISSUE AB Background: Breast fibroglandular (dense) tissue is a risk factor for breast cancer. Beyond breast cancer, little is known regarding the prognostic significance of mammographic features. Methods: We evaluated relationships between nondense (fatty) breast area and dense area with all-cause mortality in 4,245 initially healthy women from the Breast Cancer Detection Demonstration Project; 1,361 died during a mean follow-up of 28.2 years. Dense area and total breast area were assessed using planimeter measurements from screening mammograms. Percent density reflects dense area relative to breast area and nondense area was calculated as the difference between total breast area and dense area. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression. Results: In age-adjusted models, greater nondense and total breast area were associated with increased risk of death (HR 1.17, 95% CI 1.10-1.24 and HR 1.13, 95% CI 1.06-1.19, per SD difference) while greater dense area and percent density were associated with lower risk of death (HR 0.91, 95% CI 0.86-0.95 and HR 0.87, 95% CI 0.83-0.92, per SD difference). Associations were not attenuated with adjustment for race, education, mammogram type (x-ray or xerogram), smoking status, diabetes and heart disease. With additional adjustment for body mass index, associations were diminished for all features but remained statistically significant for dense area (HR 0.94, 95% CI 0.89-0.99, per SD difference) and percent density (HR 0.93, 95% CI 0.87-0.98, per SD difference). Conclusions: These data indicate that dense area and percent density may relate to survival in healthy women and suggest the potential utility of mammograms beyond prediction of breast cancer risk. C1 [Murphy, Rachel A.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Schairer, Catherine; Gierach, Gretchen L.; Sherman, Mark E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Byrne, Celia] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Register, Thomas C.] Sticht Ctr Aging, Sect Comparat Med Pathol, Winston Salem, NC USA. [Ding, Jingzhong; Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging Sect Gerontol & Geriatr, Winston Salem, NC USA. RP Murphy, RA (reprint author), NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. EM Rachel.murphy@nih.gov RI Gierach, Gretchen/E-1817-2016; Byrne, Celia/K-2964-2015 OI Gierach, Gretchen/0000-0002-0165-5522; Byrne, Celia/0000-0001-8289-4252 FU NIH, National Institute on Aging; Banting Postdoctoral Fellowship FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. RAM is supported by a Banting Postdoctoral Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 1 Z9 1 U1 2 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 OCT 25 PY 2013 VL 8 IS 10 AR e78722 DI 10.1371/journal.pone.0078722 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241GW UT WOS:000326155400101 PM 24205300 ER PT J AU Belkaid, Y Grainger, J AF Belkaid, Yasmine Grainger, John TI Mucus Coat, a Dress Code for Tolerance SO SCIENCE LA English DT Editorial Material ID REGULATORY T-CELLS; DENDRITIC CELLS; RETINOIC-ACID; SMALL-INTESTINE; INFLAMMATION; MICROBIOTA; INFECTION C1 [Belkaid, Yasmine; Grainger, John] NIAID, Program Barrier Immun & Repair, Mucosal Immunol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Belkaid, Y (reprint author), NIAID, Program Barrier Immun & Repair, Mucosal Immunol Sect, Parasit Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov FU Intramural NIH HHS NR 14 TC 2 Z9 3 U1 0 U2 13 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD OCT 25 PY 2013 VL 342 IS 6157 BP 432 EP 433 DI 10.1126/science.1246252 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239RH UT WOS:000326042600029 PM 24159036 ER PT J AU Shan, MM Gentile, M Yeiser, JR Walland, AC Bornstein, VU Chen, K He, B Cassis, L Bigas, A Cols, M Comerma, L Huang, BH Blander, JM Xiong, HB Mayer, L Berin, C Augenlicht, LH Velcich, A Cerutti, A AF Shan, Meimei Gentile, Maurizio Yeiser, John R. Walland, A. Cooper Bornstein, Victor U. Chen, Kang He, Bing Cassis, Linda Bigas, Anna Cols, Montserrat Comerma, Laura Huang, Bihui Blander, J. Magarian Xiong, Huabao Mayer, Lloyd Berin, Cecilia Augenlicht, Leonard H. Velcich, Anna Cerutti, Andrea TI Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals SO SCIENCE LA English DT Article ID T-CELL DIFFERENTIATION; DENDRITIC CELLS; EPITHELIAL-CELLS; RETINOIC-ACID; BETA-CATENIN; DECTIN-1; INTESTINE; IMMUNITY; ASSOCIATION; COLITIS AB A dense mucus layer in the large intestine prevents inflammation by shielding the underlying epithelium from luminal bacteria and food antigens. This mucus barrier is organized around the hyperglycosylated mucin MUC2. Here we show that the small intestine has a porous mucus layer, which permitted the uptake of MUC2 by antigen-sampling dendritic cells (DCs). Glycans associated with MUC2 imprinted DCs with anti-inflammatory properties by assembling a galectin-3-Dectin-1-Fc gamma RIIB receptor complex that activated beta-catenin. This transcription factor interfered with DC expression of inflammatory but not tolerogenic cytokines by inhibiting gene transcription through nuclear factor kappa B. MUC2 induced additional conditioning signals in intestinal epithelial cells. Thus, mucus does not merely form a nonspecific physical barrier, but also constrains the immunogenicity of gut antigens by delivering tolerogenic signals. C1 [Shan, Meimei; Yeiser, John R.; Walland, A. Cooper; Bornstein, Victor U.; Chen, Kang; He, Bing; Cols, Montserrat; Blander, J. Magarian; Xiong, Huabao; Mayer, Lloyd; Cerutti, Andrea] Icahn Sch Med Mt Sinai, Inst Immunol, Dept Med, New York, NY USA. [Gentile, Maurizio; Cassis, Linda; Comerma, Laura; Cerutti, Andrea] Inst Hosp Mar Invest Med IMIM, Program Inflammatory & Cardiovasc Disorders, Barcelona, Spain. [Chen, Kang] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Bigas, Anna] IMIM, Program Canc Res, Barcelona, Spain. [Comerma, Laura] Hosp del Mar, Dept Pathol, Barcelona, Spain. [Huang, Bihui] Yale Univ, Dept Pharmacol, New Haven, CT USA. [Blander, J. Magarian] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY USA. [Berin, Cecilia] Icahn Sch Med Mt Sinai, Inst Immunol, Dept Pediat, New York, NY USA. [Augenlicht, Leonard H.; Velcich, Anna] Albert Einstein Coll Med, Dept Med, New York, NY USA. [Cerutti, Andrea] NIH, Mucosal Immunol Studies Team MIST, Bethesda, MD 20892 USA. [Cerutti, Andrea] Catalan Inst Res & Adv Studies ICREA, Barcelona, Spain. RP Cerutti, A (reprint author), Icahn Sch Med Mt Sinai, Inst Immunol, Dept Med, New York, NY USA. EM andrea.cerutti@mssm.edu RI BIGAS, ANNA/A-7457-2014; Cassis, Linda/K-9633-2014 OI Cassis, Linda/0000-0003-4544-9816 FU National Institute of Allergy and Infectious Diseases, NIH [AI61093, AI57653, AI95613, AI96187, AI74378, AI073899, DK072201, AI095245]; Redes Tematicas de Investigacion Cooperativa en Salud/Fondo Europeo de Desarrollo Regional [RD12/0036/0054] FX This study was supported by the National Institute of Allergy and Infectious Diseases, NIH (AI61093, AI57653, AI95613, AI96187 and AI74378 to A. C. and AI073899, DK072201 and AI095245 to J.M.B.) and by Redes Tematicas de Investigacion Cooperativa en Salud/Fondo Europeo de Desarrollo Regional (RD12/0036/0054 to A. B). pRSETb-mRFP used for red bacteria is under a materials transfer agreement with R. Y. Tsien at the University of California, San Francisco, and Howard Hughes Medical Institute. The data presented in this manuscript are tabulated in the main paper and the supplementary materials. NR 28 TC 145 Z9 148 U1 0 U2 61 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD OCT 25 PY 2013 VL 342 IS 6157 BP 447 EP 453 DI 10.1126/science.1237910 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239RH UT WOS:000326042600034 PM 24072822 ER PT J AU Palaniyandi, S Mitra, A Herren, CD Zhu, XP Mukhopadhyay, S AF Palaniyandi, Senthilkumar Mitra, Arindam Herren, Christopher D. Zhu, Xiaoping Mukhopadhyay, Suman TI LuxS contributes to virulence in avian pathogenic Escherichia coli O78:K80:H9 SO VETERINARY MICROBIOLOGY LA English DT Article DE APEC; LPS; Pathogenicity; Bacteria; Quorum sensing ID BIOFILM FORMATION; SYSTEM; PNEUMONIAE; EXPRESSION; BACTERIA; DISEASE; GENE; COMMUNICATION; MODULATION; MACROPHAGE AB Avian pathogenic Escherichia coli (APEC) cause avian colibacillosis, a poultry disease characterized by multiple organ infections resulting in significant economic loss in the poultry industry. Several virulence factors are important for disease manifestation in APEC of which, role of quorum sensing has not been investigated. Quorum sensing is a population dependent cell-cell signaling system which modulates numerous physiological processes such as biofilm formation and virulence in multiple species. LuxS, a well-known controller in the QS, plays a role in regulating virulence in various bacterial species. Here we investigated the role of LuxS in regulating virulence in APEC O78:K80:H9. Mutation of luxS resulted in a significant reduction of virulence in APEC O78:K80:H9, evidenced by both in vivo and in vitro assays such as decreased invasion of internal organs in chicken embryo, reduced lethality in chicken embryo lethality assay, and altered lipopolysaccharide (LPS) profile. In addition, the abilities of the knockout strain to survive in chicken macrophage cell lines and to invade in chicken embryo fibroblast cells were significantly diminished. Further, structure and expression level of the LPS profile was significantly altered in the knockout strain, which may be one of the contributing factors for the persistence and virulence of APEC. Complementation of luxS gene in trans restored the virulence of the knockout strain to the level of wild-type bacteria. Taken together, these results show that LuxS contributes to the virulence in APEC O78:K80:H9 strain and partly explain the role played by LuxS in the pathogenesis of APEC strains. (C) 2013 Elsevier B.V. All rights reserved. C1 [Palaniyandi, Senthilkumar; Mitra, Arindam; Herren, Christopher D.; Zhu, Xiaoping; Mukhopadhyay, Suman] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Palaniyandi, Senthilkumar; Zhu, Xiaoping] Univ Maryland, Maryland Pathogen Res Inst, College Pk, MD 20742 USA. [Mitra, Arindam] SASTRA Univ, Sch Chem & Biotechnol, Thanjavur 613401, Tamil Nadu, India. RP Mukhopadhyay, S (reprint author), NIAID, Bacteriol & Mycol Branch, Div Microbiol & Infect Dis, 6610 Room 4226 MSC6604,Rockledge Dr, Bethesda, MD 20892 USA. EM mukhopadhyays@mail.nih.gov RI Palaniyandi, Senthilkumar/B-9575-2016 FU USDA-NRI-CSREES [2004-35204-14749]; USDA-Animal Health [2002-1106-0195318]; Maryland Agriculture Experimental Station; National Institutes of Health [R21 AI101752] FX We are grateful to Dr. Siba K. Samal for supplying the DF1 and HD11 cell lines. This work was supported by USDA-NRI-CSREES Competitive Grant 2004-35204-14749, USDA-Animal Health 2002-1106-0195318, and a Maryland Agriculture Experimental Station grant to S.M. and a National Institutes of Health Grant R21 AI101752 (to X.Z.). We acknowledge the technical help from Dr. Adam Coleman. NR 36 TC 5 Z9 6 U1 3 U2 28 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1135 EI 1873-2542 J9 VET MICROBIOL JI Vet. Microbiol. PD OCT 25 PY 2013 VL 166 IS 3-4 BP 567 EP 575 DI 10.1016/j.vetmic.2013.07.009 PG 9 WC Microbiology; Veterinary Sciences SC Microbiology; Veterinary Sciences GA 225JW UT WOS:000324960200028 PM 23958403 ER PT J AU Maurizi, MR Stan, G AF Maurizi, Michael R. Stan, George TI ClpX Shifts into High Gear to Unfold Stable Proteins SO CELL LA English DT Editorial Material ID ATP; MACHINE AB Protein degradation by the ClpXP protease requires collaboration among the six AAA+ domains of ClpX. Using single-molecule optical tweezers, Sen et al. show that ClpX uses a coordinated succession of power strokes to translocate polypeptides in ATP-tunable bursts before reloading with nucleotide. This strategy allows ClpX to kinetically capture transiently unfolded intermediates. C1 [Maurizi, Michael R.] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. [Stan, George] Univ Cincinnati, Dept Chem, Cincinnati, OH 45221 USA. RP Maurizi, MR (reprint author), NCI, Cell Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM mmaurizi@helix.nih.gov FU Intramural NIH HHS NR 10 TC 2 Z9 2 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 24 PY 2013 VL 155 IS 3 BP 502 EP 504 DI 10.1016/j.cell.2013.10.007 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 246WQ UT WOS:000326571800005 PM 24243009 ER PT J AU Saharia, KK Koup, RA AF Saharia, Kapil K. Koup, Richard A. TI T Cell Susceptibility to HIV Influences Outcome of Opportunistic Infections SO CELL LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN-PAPILLOMAVIRUS INFECTION; MYCOBACTERIUM-TUBERCULOSIS INFECTION; CERVICAL INTRAEPITHELIAL NEOPLASIA; ACTIVE ANTIRETROVIRAL THERAPY; CYTOMEGALOVIRUS-SPECIFIC CD4(+); INTERFERON-GAMMA-RECEPTOR; MEDIATED IMMUNE-RESPONSES; END-ORGAN DISEASE; LANGERHANS CELLS AB During HIV infection, the timing of opportunistic infections is not always associated with severity of CD4 T cell depletion, and different opportunistic pathogens reactivate at different CD4 T cell thresholds. Here, we examine how differences in the phenotype and function of pathogen-specific CD4 T cells influence susceptibility to HIV infection. By focusing on three common opportunistic infections (Mycobacterium tuberculosis, human papillomavirus, and cytomegalovirus), we investigate how differential depletion of pathogen-specific CD4 T cells impacts the natural history of these pathogens in HIV infection. A broader understanding of this relationship can better inform treatment strategies against copathogens. C1 [Saharia, Kapil K.] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Saharia, Kapil K.] Univ Maryland, Sch Med, Div Infect Dis, Baltimore, MD 21201 USA. [Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Koup, RA (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM rkoup@mail.nih.gov FU Intramural NIH HHS [ZIA AI005014-12] NR 113 TC 9 Z9 9 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 24 PY 2013 VL 155 IS 3 BP 505 EP 514 DI 10.1016/j.cell.2013.09.045 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 246WQ UT WOS:000326571800006 PM 24243010 ER PT J AU Barouch, DH Stephenson, KE Borducchi, EN Smith, K Stanley, K McNally, AG Liu, JY Abbink, P Maxfield, LF Seaman, MS Dugast, AS Alter, G Ferguson, M Li, WJ Earl, PL Moss, B Giorgi, EE Szinger, JJ Eller, LA Billings, EA Rao, M Tovanabutra, S Sanders-Buell, E Weijtens, M Pau, MG Schuitemaker, H Robb, ML Kim, JH Korber, BT Michael, NL AF Barouch, Dan H. Stephenson, Kathryn E. Borducchi, Erica N. Smith, Kaitlin Stanley, Kelly McNally, Anna G. Liu, Jinyan Abbink, Peter Maxfield, Lori F. Seaman, Michael S. Dugast, Anne-Sophie Alter, Galit Ferguson, Melissa Li, Wenjun Earl, Patricia L. Moss, Bernard Giorgi, Elena E. Szinger, James J. Eller, Leigh Anne Billings, Erik A. Rao, Mangala Tovanabutra, Sodsai Sanders-Buell, Eric Weijtens, Mo Pau, Maria G. Schuitemaker, Hanneke Robb, Merlin L. Kim, Jerome H. Korber, Bette T. Michael, Nelson L. TI Protective Efficacy of a Global HIV-1 Mosaic Vaccine against Heterologous SHIV Challenges in Rhesus Monkeys SO CELL LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; T-LYMPHOCYTE RESPONSES; NEUTRALIZING ANTIBODIES; IMMUNE CONTROL; REPLICATION; DIVERSITY; MACAQUES; BREADTH; AIDS; IMMUNOGENICITY AB The global diversity of HIV-1 represents a critical challenge facing HIV-1 vaccine development. HIV-1 mosaic antigens are bioinformatically optimized immunogens designed for improved coverage of HIV-1 diversity. However, the protective efficacy of such global HIV-1 vaccine antigens has not previously been evaluated. Here, we demonstrate the capacity of bivalent HIV-1 mosaic antigens to protect rhesus monkeys against acquisition of infection following heterologous challenges with the difficult-to-neutralize simian-human immunodeficiency virus SHIV-SF162P3. Adenovirus/poxvirus and adenovirus/adenovirus vector-based vaccines expressing HIV-1 mosaic Env, Gag, and Pol afforded a significant reduction in the per-exposure acquisition risk following repetitive, intrarectal SHIV-SF162P3 challenges. Protection against acquisition of infection correlated with vaccine-elicited binding, neutralizing, and functional nonneutralizing antibodies, suggesting that the coordinated activity of multiple antibody functions may contribute to protection against difficult-to-neutralize viruses. These data demonstrate the protective efficacy of HIV-1 mosaic antigens and suggest a potential strategy for the development of a global HIV-1 vaccine. C1 [Barouch, Dan H.; Stephenson, Kathryn E.; Borducchi, Erica N.; Smith, Kaitlin; Stanley, Kelly; McNally, Anna G.; Liu, Jinyan; Abbink, Peter; Maxfield, Lori F.; Seaman, Michael S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Barouch, Dan H.; Dugast, Anne-Sophie; Alter, Galit] Ragon Inst MGH Massachusetts Inst Technol & Harva, Boston, MA 02114 USA. [Ferguson, Melissa] Alpha Genesis Inc, Yemassee, SC 29945 USA. [Li, Wenjun] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Earl, Patricia L.; Moss, Bernard] NIAID, Bethesda, MD 20892 USA. [Giorgi, Elena E.; Szinger, James J.; Korber, Bette T.] Los Alamos Natl Lab, Los Alamos, NM 87545 USA. [Eller, Leigh Anne; Billings, Erik A.; Rao, Mangala; Tovanabutra, Sodsai; Sanders-Buell, Eric; Robb, Merlin L.; Kim, Jerome H.; Michael, Nelson L.] Walter Reed Army Inst Res, US Mil HIV Res Program, Rockville, MD 20850 USA. [Weijtens, Mo; Pau, Maria G.; Schuitemaker, Hanneke] Crucell Holland BV, NL-2301 CA Leiden, Netherlands. RP Barouch, DH (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu RI Li, Wenjun/F-5634-2015; Dugast, AnneSophie/L-9541-2015 OI Li, Wenjun/0000-0001-5335-7386; FU U.S. Military Research and Material Command; U.S. Military HIV Research Program [W81XWH-07-2-0067]; National Institutes of Health [AI052074, AI060354, AI078526, AI084794, AI095985, AI096040, AI100645]; NIAID Division of Intramural Research; Ragon Institute of MGH, MIT, and Harvard; Bill and Melinda Gates Foundation [OPP1033091, OPP1040741] FX We thank M. Pensiero, S. Blackmore, R. Bradsky, C. Cabral, A. Cheung, J. Goudsmit, R. Hamel, B. Hibl, S. Howell, M. Iampietro, K. Kelly, D. Lynch, M. Marovich, C. Miller, J. Nkolola, A. O'Sullivan, L. Parenteau, J. Perry, W. Rinaldi, J. Sadoff, A. SanMiguel, N. Simmons, J. Smith, F. Stephens, D. van Manen, G. Westergaard, and L. Wyatt for generous advice, assistance, and reagents. The HIV-1 PTE peptides were obtained from the NIH AIDS Research and Reference Reagent Program. We acknowledge support from the U.S. Military Research and Material Command and the U.S. Military HIV Research Program (W81XWH-07-2-0067); the National Institutes of Health (AI052074, AI060354, AI078526, AI084794, AI095985, AI096040, and AI100645); the NIAID Division of Intramural Research; the Ragon Institute of MGH, MIT, and Harvard; and the Bill and Melinda Gates Foundation (OPP1033091 and OPP1040741). M. W., M. G. P., and H. S. are employees of Crucell. Beth Israel Deaconess Medical Center and Los Alamos National Laboratory are co-owners of an HIV-1 mosaic antigen patent that has been licensed to Crucell. The opinions in this manuscript are those of the authors and do not reflect the views of the U.S. Department of the Army or the Department of Defense. NR 37 TC 103 Z9 103 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 24 PY 2013 VL 155 IS 3 BP 531 EP 539 DI 10.1016/j.cell.2013.09.061 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 246WQ UT WOS:000326571800009 PM 24243013 ER PT J AU Fang, XY Wang, JB O'Carroll, IP Mitchell, M Zuo, XB Wang, Y Yu, P Liu, Y Rausch, JW Dyba, MA Kjems, J Schwieters, CD Seifert, S Winans, RE Watts, NR Stahl, SJ Wingfield, PT Byrd, RA Le Grice, SFJ Rein, A Wang, YX AF Fang, Xianyang Wang, Jinbu O'Carroll, Ina P. Mitchell, Michelle Zuo, Xiaobing Wang, Yi Yu, Ping Liu, Yu Rausch, Jason W. Dyba, Marzena A. Kjems, Jorgen Schwieters, Charles D. Seifert, Soenke Winans, Randall E. Watts, Norman R. Stahl, Stephen J. Wingfield, Paul T. Byrd, R. Andrew Le Grice, Stuart F. J. Rein, Alan Wang, Yun-Xing TI An Unusual Topological Structure of the HIV-1 Rev Response Element SO CELL LA English DT Article ID SMALL-ANGLE SCATTERING; X-RAY-SCATTERING; GENE-EXPRESSION REQUIRES; RICH-BINDING MOTIF; BIOLOGICAL MACROMOLECULES; SECONDARY STRUCTURE; ZINC-FINGER; VIRION EXPRESSION; TRANS-ACTIVATOR; TARGET SEQUENCE AB Nuclear export of unspliced and singly spliced viral mRNA is a critical step in the HIV life cycle. The structural basis by which the virus selects its own mRNA among more abundant host cellular RNAs for export has been a mystery for more than 25 years. Here, we describe an unusual topological structure that the virus uses to recognize its own mRNA. The viral Rev response element (RRE) adopts an "A"-like structure in which the two legs constitute two tracks of binding sites for the viral Rev protein and position the two primary known Rev-binding sites similar to 55 angstrom apart, matching the distance between the two RNAbinding motifs in the Rev dimer. Both the legs of the "A" and the separation between them are required for optimal RRE function. This structure accounts for the specificity of Rev for the RRE and thus the specific recognition of the viral RNA. C1 [Fang, Xianyang; Wang, Jinbu; Zuo, Xiaobing; Yu, Ping; Liu, Yu; Wang, Yun-Xing] NCI, Prot Nucle Acid Interact Sect, Struct Biophys Lab, HIV Drug Resistance Program,Ctr Canc Res,NIH, Frederick, MD 21702 USA. [O'Carroll, Ina P.; Rein, Alan] NCI, Retroviral Assembly Sect, HIV Drug Resistance Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Mitchell, Michelle; Wang, Yi; Rausch, Jason W.; Le Grice, Stuart F. J.] NCI, RT Biochem Sect, HIV Drug Resistance Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. [Yu, Ping; Dyba, Marzena A.] SAIC Frederick, Struct Biophys Lab, Frederick, MD 21702 USA. [Kjems, Jorgen] Univ Aarhus, Dept Mol Biol, DK-8000 Aarhus C, Denmark. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Seifert, Soenke; Winans, Randall E.] Argonne Natl Lab, Xray Sci Div, Argonne, IL 60439 USA. [Watts, Norman R.; Stahl, Stephen J.; Wingfield, Paul T.] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. [Byrd, R. Andrew] NCI, Macromol NMR Sect, Struct Biophys Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Rein, A (reprint author), NCI, Retroviral Assembly Sect, HIV Drug Resistance Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM reina@mail.nih.gov; wangyunx@mail.nih.gov RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI) Center for Cancer Research; National Institute of Arthritis, Musculoskeletal and Skin Diseases; Center for Information Technology; SAIC-Frederick [HHSN26120080001E]; U.S. DOE [DE-AC02-06CH11357] FX We thank Drs. Stephen Hughes, Alexander Wlodawer, and Prof. James Williamson for discussion. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI) Center for Cancer Research; National Institute of Arthritis, Musculoskeletal and Skin Diseases; Center for Information Technology; and SAIC-Frederick under contract HHSN26120080001E. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. NR 57 TC 52 Z9 52 U1 3 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 24 PY 2013 VL 155 IS 3 BP 594 EP 605 DI 10.1016/j.cell.2013.10.008 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 246WQ UT WOS:000326571800014 PM 24243017 ER PT J AU Basudhar, D Bharadwaj, G Cheng, RY Jain, S Shi, S Heinecke, JL Holland, RJ Ridnour, LA Caceres, VM Spadari-Bratfisch, RC Paolocci, N Velazquez-Martinez, CA Wink, DA Miranda, KM AF Basudhar, Debashree Bharadwaj, Gaurav Cheng, Robert Y. Jain, Sarthak Shi, Sa Heinecke, Julie L. Holland, Ryan J. Ridnour, Lisa A. Caceres, Viviane M. Spadari-Bratfisch, Regina C. Paolocci, Nazareno Velazquez-Martinez, Carlos A. Wink, David A. Miranda, Katrina M. TI Synthesis and Chemical and Biological Comparison of Nitroxyl- and Nitric Oxide-Releasing Diazeniumdiolate-Based Aspirin Derivatives SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; TUMOR ANGIOGENESIS; CANCER PREVENTION; BREAST-CANCER; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; CARDIOVASCULAR-SYSTEM; THERAPEUTIC TARGETS; AQUEOUS-SOLUTION; UP-REGULATION; ANGELIS SALT AB Structural modifications of nonsteroidal anti-inflammatory drugs (NSAIDs) have successfully reduced the side effect of gastrointestinal ulceration without affecting anti-inflammatory activity, but they may increase the risk of myocardial infarction with chronic use. The fact that nitroxyl (HNO) reduces platelet aggregation, preconditions against myocardial infarction, and enhances contractility led us to synthesize a diazeniumdiolate-based HNO-releasing aspirin and to compare it to an NO-releasing analogue. Here, the decomposition mechanisms are described for these compounds. In addition to protection against stomach ulceration, these prodrugs exhibited significantly enhanced cytotoxcity compared to either aspirin or the parent diazeniumdiolate toward nonsmall cell lung carcinoma cells (A549), but they were not appreciably toxic toward endothelial cells (HUVECs). The HNO-NSAID prodrug inhibited cylcooxgenase-2 and glyceraldehyde 3-phosphate dehydrogenase activity and triggered significant sarcomere shortening on murine ventricular myocytes compared to control. Together, these anti-inflammatory, antineoplasic, and contractile properties suggest the potential of HNO-NSAIDs in the treatment of inflammation, cancer, or heart failure. C1 [Basudhar, Debashree; Bharadwaj, Gaurav; Miranda, Katrina M.] Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA. [Cheng, Robert Y.; Heinecke, Julie L.; Ridnour, Lisa A.; Wink, David A.] NIH, Radiat Biol Branch, Bethesda, MD 20892 USA. [Jain, Sarthak; Velazquez-Martinez, Carlos A.] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2E1, Canada. [Shi, Sa; Caceres, Viviane M.; Paolocci, Nazareno] Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21287 USA. [Shi, Sa] Harbin Med Univ, Dept Pathophysiol, Harbin 150081, Heilongjiang, Peoples R China. [Holland, Ryan J.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Caceres, Viviane M.; Spadari-Bratfisch, Regina C.] Fed Univ Sao Paulo UNIFESP, Dept Biosci, BR-04021001 Santos, SP, Brazil. [Paolocci, Nazareno] Univ Perugia, Dept Clin & Expt Med, I-06100 Perugia, Italy. RP Miranda, KM (reprint author), Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA. EM kmiranda@email.arizona.edu OI Paolocci, Nazareno/0000-0001-7011-997X FU National Institutes of Health [R01-GM076247]; Intramural Research Program of the National Institutes of Health; Center for Cancer Research; Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta; National Cancer Institute FX This work is supported in part by a National Institutes of Health grant (R01-GM076247 to K.M.M.), the Intramural Research Program of the National Institutes of Health, National Cancer Institute and Center for Cancer Research (D.A.W.), and start-up funds from the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta (C.A.V.-M.). NR 96 TC 21 Z9 21 U1 4 U2 38 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD OCT 24 PY 2013 VL 56 IS 20 BP 7804 EP 7820 DI 10.1021/jm400196q PG 17 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 242RO UT WOS:000326259900010 PM 24102516 ER PT J AU Whittredge, PB Taraska, JW AF Whittredge, Paul B. Taraska, Justin W. TI Bridging the Spectral Gap in Fluorescent Proteins through Directed Evolution SO CHEMISTRY & BIOLOGY LA English DT Editorial Material ID YFP; PHOTOCONVERSION; ZFP538 AB Fluorescent proteins are used as noninvasive tags for protein trafficking, structure, and action. In this issue of Chemistry & Biology, Hoi and colleagues present a new optimized zFP538 yellow fluorescent protein called mPapaya1 that is bright, monomeric, and an excellent fusion partner for cellular proteins. C1 [Whittredge, Paul B.; Taraska, Justin W.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Taraska, JW (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM justin.taraska@nih.gov RI Taraska, Justin/H-8876-2016 OI Taraska, Justin/0000-0001-5355-9535 FU Intramural NIH HHS [ZIA HL006099-02] NR 13 TC 0 Z9 0 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 EI 1879-1301 J9 CHEM BIOL JI Chem. Biol. PD OCT 24 PY 2013 VL 20 IS 10 BP 1203 EP 1205 DI 10.1016/j.chembiol.2013.10.004 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 244ZT UT WOS:000326429400004 PM 24210004 ER PT J AU Qian, WJ Park, JE Lim, D Park, SY Lee, KW Yaffe, MB Lee, KS Burke, TR AF Qian, Wen-Jian Park, Jung-Eun Lim, Dan Park, Suk-Youl Lee, Ki-Won Yaffe, Michael B. Lee, Kyung S. Burke, Terrence R., Jr. TI Peptide-Based Inhibitors of Plk1 Polo-box Domain Containing Mono-anionic Phosphothreonine Esters and Their Pivaloyloxymethyl Prodrugs SO CHEMISTRY & BIOLOGY LA English DT Article ID SMALL-MOLECULE INHIBITOR; KINASE 1 PLK1; CANCER-THERAPY; SIGNAL-TRANSDUCTION; CRYSTAL-STRUCTURE; HOT-SPOT; POLO-LIKE-KINASE-1; PHOSPHOPEPTIDES; POSITION; TARGET AB Binding of polo-like kinase 1 (Plk1) polo-box domains (PBDs) to phosphothreonine (pThr)/phosphoserine (pSer)-containing sequences is critical for the proper function of Plk1. Although high-affinity synthetic pThr-containing peptides may be used to disrupt PBD function, the efficacy of such peptides in whole cell assays has been poor. This potentially reflects limited cell membrane permeability arising in part from the di-anionic nature of the phosphoryl group. We report five-mer peptides containing mono-anionic pThr phosphoryl esters that exhibit single-digit nanomolar PBD binding affinities in extracellular assays and improved antimitotic efficacies in whole cell assays. The cellular efficacies of these peptides have been further enhanced by the application of bio-reversible pivaloyloxymethyl (POM) phosphoryl protection to a pThr-containing polypeptide. Our findings may redefine structural parameters for the development of PBD-binding peptides and peptide mimetics. C1 [Qian, Wen-Jian; Burke, Terrence R., Jr.] NCI, Chem Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lim, Dan; Yaffe, Michael B.] MIT, Ctr Canc Res, Dept Biol & Biol Engn, Cambridge, MA 02139 USA. [Park, Suk-Youl; Lee, Ki-Won] Seoul Natl Univ, Adv Inst Convergence Technol, Suwon 443270, South Korea. [Lee, Ki-Won] Seoul Natl Univ, World Class Univ Biomodulat Major, Seoul 151742, South Korea. [Lee, Ki-Won] Seoul Natl Univ, Dept Agr Biotechnol, Seoul 151742, South Korea. RP Lee, KS (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kyunglee@mail.nih.gov; tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 FU National Institutes of Health, Center for Cancer Research, NCI-Frederick; National Cancer Institute, National Institutes of Health; NCI Director's Innovation Career Development award; National Institutes of Health [S015339, CA112967, GM104047] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, NCI-Frederick and the National Cancer Institute, National Institutes of Health (to W.-J.Q., J.-E.P., K.S.L., and T.R.B.), an NCI Director's Innovation Career Development award (to W.-J.Q.), and National Institutes of Health grants S015339, CA112967, and GM104047 (to M.B.Y.). Appreciation is expressed to Wei Dai, New York University School of Medicine for reagents. NR 60 TC 6 Z9 6 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 EI 1879-1301 J9 CHEM BIOL JI Chem. Biol. PD OCT 24 PY 2013 VL 20 IS 10 BP 1255 EP 1264 DI 10.1016/j.chembiol.2013.09.005 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 244ZT UT WOS:000326429400011 PM 24120332 ER PT J AU Johnson, ME Hummer, G AF Johnson, Margaret E. Hummer, Gerhard TI Evolutionary Pressure on the Topology of Protein Interface Interaction Networks SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID ENERGY LANDSCAPE; COMPLEX NETWORKS; BINDING-SITES; SPECIFICITY; SCALE; YEAST; INFORMATION; FRUSTRATION; INTEGRATION; PATHWAYS AB The densely connected structure of protein-protein interaction (PPI) networks reflects the functional need of proteins to cooperate in cellular processes. However, PPI networks do not adequately capture the competition in protein binding. By contrast, the interface interaction network (IN) studied here resolves the modular character of protein-protein binding and distinguishes between simultaneous and exclusive interactions that underlie both cooperation and competition. We show that the topology of the IIN is under evolutionary pressure, and we connect topological features of the UN to specific biological functions. To reveal the forces shaping the network topology, we use a sequence-based computational model of interface binding along with network analysis. We find that the more fragmented structure of IINs, in contrast to the dense PPI networks, arises in large part from the competition between specific and nonspecific binding. The need to minimize nonspecific binding favors specific network motifs, including a minimal number of cliques (i.e., fully connected subgraphs) and many disconnected fragments. Validating the model, we find that these network characteristics are closely mirrored in the UN of clathrin-mediated endocytosis. Features unexpected on the basis of our motif analysis are found to indicate either exceptional binding selectivity or important regulatory functions. C1 [Johnson, Margaret E.; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Johnson, ME (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM johnsonme@niddk.nih.gov; Gerhard.Hummer@nih.gov RI Hummer, Gerhard/A-2546-2013; Johnson, Margaret/M-4708-2016 OI Hummer, Gerhard/0000-0001-7768-746X; Johnson, Margaret/0000-0001-9881-291X FU Intramural Research Program of the NIDDK, NIH; NIH K99 Award [GM098371] FX This work was supported by the Intramural Research Program of the NIDDK, NIH, and by an NIH K99 Award (GM098371 to M.E.J.). The research used the Biowulf Linux duster at the NIH. NR 44 TC 0 Z9 0 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 EI 1520-5207 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 24 PY 2013 VL 117 IS 42 BP 13098 EP 13106 DI 10.1021/jp402944e PG 9 WC Chemistry, Physical SC Chemistry GA 242RN UT WOS:000326259800044 PM 23701316 ER PT J AU Berezhkovskii, AM Szabo, A AF Berezhkovskii, Alexander M. Szabo, Attila TI Diffusion along the Splitting/Commitment Probability Reaction Coordinate SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID TRANSITION-PATH THEORY; PROTEIN; MODEL; KINETICS; DYNAMICS; STATES AB The splitting or commitment probabilities of states in the region of configuration space that separates reactants and products play an important role in the theory of chemical reactions. Assuming that the splitting probability changes more slowly than any other coordinate, we project multidimensional diffusive dynamics onto it. The resulting one-dimensional diffusion equation is not exact because the assumed separation of time scales does not hold in general. Nevertheless, this equation has the remarkable property that it always predicts the exact value of the number of transitions between reactants and products per unit time at equilibrium and hence the exact reaction rate. In the special case of two deep basins separated by a harmonic saddle, this equation is equivalent to the one that describes diffusion along a coordinate perpendicular to the transition state, defined as the surface starting from which reactants and products are reached with equal probability. C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Szabo, Attila] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM alexanderb@mail.nih.gov RI Szabo, Attila/H-3867-2012 FU Intramural Research Program of the NIH, Center for Information Technology; National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Sergei Krivov for many discussions and Margaret Johnson, Alexander Grosberg, and Eric Vanden-Eijnden for their comments on our manuscript. In addition, we thank Eric Vanden-Eijnden for sending us a draft of an unpublished manuscript which arrives at similar conclusions. This study was supported by the Intramural Research Program of the NIH, Center for Information Technology and National Institute of Diabetes and Digestive and Kidney Diseases. NR 22 TC 15 Z9 15 U1 1 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 EI 1520-5207 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 24 PY 2013 VL 117 IS 42 BP 13115 EP 13119 DI 10.1021/jp403043a PG 5 WC Chemistry, Physical SC Chemistry GA 242RN UT WOS:000326259800046 PM 23777371 ER PT J AU Li, MH Shoemaker, BA Thangudu, RR Ferraris, JD Burg, MB Panchenko, AR AF Li, Minghui Shoemaker, Benjamin A. Thangudu, Ratna R. Ferraris, Joan D. Burg, Maurice B. Panchenko, Anna R. TI Mutations in DNA-Binding Loop of NFAT5 Transcription Factor Produce Unique Outcomes on Protein-DNA Binding and Dynamics SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID MOLECULAR-DYNAMICS; PHOSPHORYLATION SITES; NUCLEAR-LOCALIZATION; ENERGY LANDSCAPE; RECOGNITION; MUTAGENESIS; PREDICTION; COMPLEXES; SERVER AB The nuclear factor of activated T cells 5 (NFAT5 or TonEBP) is a Rel family transcriptional activator and is activated by hypertonic conditions. Several studies point to a possible connection between nuclear translocation and DNA binding; however, the mechanism of NFAT5 nuclear translocation and the effect of DNA binding on retaining NFAT5 in the nucleus are largely unknown. Recent experiments showed that different mutations introduced in the DNA-binding loop and dimerization interface were important for DNA binding and some of them decreased the nuclear cytoplasm ratio of NFAT5. To understand the mechanisms of these mutations, we model their effect on protein dynamics and DNA binding. We show that the NFATS complex without DNA is much more flexible than the complex with DNA. Moreover, DNA binding considerably stabilizes the overall dimeric complex and the NFATS dimer is only marginally stable in the absence of DNA. Two sets of NFAT5 mutations from the same DNA-binding loop are found to have different mechanisms of specific and nonspecific binding to DNA. The R217A/E223A/R226A (R293A/E299A/R302A using isoform c numbering) mutant is characterized by significantly compromised binding to DNA and higher complex flexibility. On the contrary, the T222D (T298D in isoform c) mutation, a potential phosphomimetic mutation, makes the overall complex more rigid and does not significantly affect the DNA binding. Therefore, the reduced nuclear cytoplasm ratio of NFAT5 can be attributed to reduced binding to DNA for the triple mutant, while the T222D mutant suggests an additional mechanism at work. C1 [Li, Minghui; Shoemaker, Benjamin A.; Thangudu, Ratna R.; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Ferraris, Joan D.; Burg, Maurice B.] NHLBI, Renal Cellular & Mol Biol Sect, NIH, Bethesda, MD 20892 USA. RP Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM panch@ncbi.nlm.nih.gov RI Li, Minghui/M-9209-2014; Li, Minghui/E-4339-2016 OI Li, Minghui/0000-0002-2056-1249; FU Intramural Research Program of the National Library of Medicine; Intramural Research Program of the National Heart, Lung, and Blood Institute at the U.S. National Institutes of Health FX We thank Hafumi Nishi for help during the initial stage of this project. This work was supported by the Intramural Research Program of the National Library of Medicine and Intramural Research Program of the National Heart, Lung, and Blood Institute at the U.S. National Institutes of Health. NR 40 TC 5 Z9 5 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 EI 1520-5207 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 24 PY 2013 VL 117 IS 42 BP 13226 EP 13234 DI 10.1021/jp403310a PG 9 WC Chemistry, Physical SC Chemistry GA 242RN UT WOS:000326259800058 PM 23734591 ER PT J AU Best, RB AF Best, Robert B. TI How Well Does a Funneled Energy Landscape Capture the Folding Mechanism of Spectrin Domains? SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; PROTEIN ENGINEERING ANALYSIS; TRANSITION-STATE ENSEMBLE; COARSE-GRAINED MODELS; NONNATIVE INTERACTIONS; INTERNAL-FRICTION; ELECTROSTATIC INTERACTIONS; DEPENDENT DIFFUSION; REACTION COORDINATE; NATIVE-STATE AB Three structurally similar domains from alpha-spectrin have been shown to fold very differently. First, there is a contrast in the folding mechanism, as probed by Phi-value analysis, between the R15 domain and the R16 and R17 domains. Second, there are very different contributions from internal friction to folding: the folding rate of the R15 domain was found to be inversely proportional to solvent viscosity, showing no apparent frictional contribution from the protein, but in the other two domains, a large internal friction component was evident. Non-native misdocking of helices has been suggested to be responsible for this phenomenon. Here, I study the folding of these three proteins with minimalist coarse-grained models based on a funneled energy landscape. Remarkably, I find that, despite the absence of non-native interactions, the differences in folding mechanism of the domains are well captured by the model, and the agreement of the Phi-values with experiment is fairly good. On the other hand, within the context of this model, there are no significant differences in diffusion coefficient along the chosen folding coordinate, and the model cannot explain the large differences in folding rates between the proteins found experimentally. These results are nonetheless consistent with the expectations from the energy landscape perspective of protein folding, namely, that the folding mechanism is primarily determined by the native-like interactions present in the Go-like model, with missing non-native interactions being required to explain the differences in "internal friction" seen in experiment. C1 [Best, Robert B.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Best, Robert B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Best, RB (reprint author), Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England. EM robertbe@helix.nih.gov RI Best, Robert/H-7588-2016 OI Best, Robert/0000-0002-7893-3543 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health; Royal Society University Research Fellowship at Cambridge FX I would like to thank Alessandro Borgia and William Eaton for helpful comments on the manuscript. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. R.B.B. was supported by a Royal Society University Research Fellowship while at Cambridge. NR 66 TC 7 Z9 7 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 24 PY 2013 VL 117 IS 42 BP 13235 EP 13244 DI 10.1021/jp403305a PG 10 WC Chemistry, Physical SC Chemistry GA 242RN UT WOS:000326259800059 PM 23947368 ER PT J AU Cruz, CRY Micklethwaite, KP Savoldo, B Ramos, CA Lam, S Ku, S Diouf, O Liu, EL Barrett, AJ Ito, S Shpall, EJ Krance, RA Kamble, RT Carrum, G Hosing, CM Gee, AP Mei, ZY Grilley, BJ Heslop, HE Rooney, CM Brenner, MK Bollard, CM Dotti, G AF Cruz, Conrad Russell Y. Micklethwaite, Kenneth P. Savoldo, Barbara Ramos, Carlos A. Lam, Sharon Ku, Stephanie Diouf, Oumar Liu, Enli Barrett, A. John Ito, Sawa Shpall, Elizabeth J. Krance, Robert A. Kamble, Rammurti T. Carrum, George Hosing, Chitra M. Gee, Adrian P. Mei, Zhuyong Grilley, Bambi J. Heslop, Helen E. Rooney, Cliona M. Brenner, Malcolm K. Bollard, Catherine M. Dotti, Gianpietro TI Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study SO BLOOD LA English DT Article ID CHIMERIC ANTIGEN RECEPTOR; ACUTE LYMPHOCYTIC-LEUKEMIA; ADOPTIVE IMMUNOTHERAPY; ANTITUMOR-ACTIVITY; PERIPHERAL-BLOOD; RECIPIENTS; INFECTION; LYMPHOMA; RECONSTITUTION; PERSISTENCE AB Autologous T cells expressing a CD19-specific chimeric antigen receptor (CD19.CAR) are active against B-cellmalignancies, but it is unknown whether allogeneic CD19.CART cells are safe or effective. After allogeneic hematopoietic stem cell transplantation (HSCT), infused donor-derived virus-specific T cells (VSTs) expand in vivo, persist long term, and display antiviral activity without inducing graft-vs-host disease; therefore, we determined whether donor VSTs, engineered to express CD19.CAR, retained the characteristics of nonmanipulated allogeneic VSTs while gaining antitumor activity. We treated 8 patients with allogeneic (donor-derived) CD19.CAR-VSTs 3 months to 13 years after HSCT. There were no infusion-related toxicities. VSTs persisted for a median of 8 weeks in blood and up to 9 weeks at disease sites. Objective antitumor activity was evident in 2 of 6 patients with relapsed disease during the period of CD19.CAR-VST persistence, whereas 2 patients who received cells while in remission remain disease free. In 2 of 3 patients with viral reactivation, donor CD19.CAR-VSTs expanded concomitantly with VSTs. Hence CD19.CAR-VSTs display antitumor activity and, because their number may be increased in the presence of viral stimuli, earlier treatment post-HSCT (when lymphodepletion is greater and the incidence of viral infection is higher) or planned vaccination with viral antigens may enhance disease control. This study is registered at clinicaltrials.gov as #NCT00840853. C1 [Cruz, Conrad Russell Y.; Micklethwaite, Kenneth P.; Savoldo, Barbara; Ramos, Carlos A.; Lam, Sharon; Ku, Stephanie; Diouf, Oumar; Liu, Enli; Krance, Robert A.; Kamble, Rammurti T.; Carrum, George; Gee, Adrian P.; Mei, Zhuyong; Grilley, Bambi J.; Heslop, Helen E.; Rooney, Cliona M.; Brenner, Malcolm K.; Bollard, Catherine M.; Dotti, Gianpietro] Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Barrett, A. John; Ito, Sawa] NHLBI, NIH, Bethesda, MD 20892 USA. [Shpall, Elizabeth J.; Hosing, Chitra M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Krance, Robert A.; Kamble, Rammurti T.; Carrum, George; Heslop, Helen E.; Brenner, Malcolm K.; Bollard, Catherine M.] Methodist Hosp, Houston, TX 77030 USA. RP Dotti, G (reprint author), Baylor Coll Med, Ctr Cell & Gene Therapy, 1102 Bates St,Feigin Ctr Suite 1750, Houston, TX 77030 USA. EM gxdotti@txch.org OI Ramos, Carlos/0000-0002-4004-7837; Hosing, Chitra/0000-0003-0409-5556 FU Leukemia and Lymphoma Society Specialized Center of Research [7018-04, RP100484 CPRIT]; William Lawrence & Blanche Hughes Foundation Grant; Cancer Institute of New South Wales International Clinical and Research Fellowship FX This work was supported in part by the Leukemia and Lymphoma Society Specialized Center of Research 7018-04, RP100484 CPRIT, and a William Lawrence & Blanche Hughes Foundation Grant; and the Cancer Institute of New South Wales International Clinical and Research Fellowship (K.P.M.). NR 40 TC 135 Z9 139 U1 8 U2 31 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 24 PY 2013 VL 122 IS 17 BP 2965 EP 2973 DI 10.1182/blood-2013-06-506741 PG 9 WC Hematology SC Hematology GA 240FS UT WOS:000326081000012 PM 24030379 ER PT J AU Lau, SM Cha, KM Karunatillake, A Stokes, RA Cheng, K McLean, M Cheung, NW Gonzalez, FJ Gunton, JE AF Lau, Sue Mei Cha, Kuan Minn Karunatillake, Ayesha Stokes, Rebecca A. Cheng, Kim McLean, Mark Cheung, N. W. Gonzalez, Frank J. Gunton, Jenny E. TI Beta-Cell ARNT Is Required for Normal Glucose Tolerance in Murine Pregnancy SO PLOS ONE LA English DT Article ID GESTATIONAL DIABETES-MELLITUS; PLACENTAL-LACTOGEN; ENDOCRINE PANCREAS; INSULIN-SECRETION; GENE-EXPRESSION; ISLET MASS; PROLIFERATION; PROLACTIN; ADAPTATION; RECEPTORS AB Aims: Insulin secretion increases in normal pregnancy to meet increasing demands. Inability to increase beta-cell function results in gestational diabetes mellitus (GDM). We have previously shown that the expression of the transcription factor ARNT (Aryl-hydrocarbon Receptor Nuclear Translocator) is reduced in the islets of humans with type 2 diabetes. Mice with a beta-cell specific deletion of ARNT (beta-ARNT mice) have impaired glucose tolerance secondary to defective insulin secretion. We hypothesised that ARNT is required to increase beta-cell function during pregnancy, and that beta-ARNT mice would be unable to compensate for the beta-cell stress of pregnancy. The aims of this study were to investigate the mechanisms of ARNT regulation of beta-cell function and glucose tolerance in pregnancy. Methods: beta-ARNT females were mated with floxed control (FC) males and FC females with beta-ARNT males. Results: During pregnancy, beta-ARNT mice had a marked deterioration in glucose tolerance secondary to defective insulin secretion. There was impaired beta-cell proliferation in late pregnancy, associated with decreased protein and mRNA levels of the islet cell-cycle regulator cyclinD2. There was also reduced expression of Irs2 and G6PI. In contrast, in control mice, pregnancy was associated with a 2.1-fold increase in ARNT protein and a 1.6-fold increase in cyclinD2 protein, and with increased beta-cell proliferation. Conclusions: Islet ARNT increases in normal murine pregnancy and beta-cell ARNT is required for cyclinD2 induction and increased beta-cell proliferation in pregnancy. C1 [Lau, Sue Mei; Cha, Kuan Minn; Karunatillake, Ayesha; Stokes, Rebecca A.; Cheng, Kim; Gunton, Jenny E.] Garvan Inst Med Res, Diabet & Transcript Factors Grp, Sydney, NSW, Australia. [Lau, Sue Mei] Univ New S Wales, Fac Med, Prince Wales Clin Sch, Sydney, NSW, Australia. [McLean, Mark; Cheung, N. W.; Gunton, Jenny E.] Westmead Hosp, Dept Endocrinol & Diabet, Sydney, NSW, Australia. [McLean, Mark] Univ Western Sydney, Fac Med, Sydney, NSW, Australia. [Cheung, N. W.; Gunton, Jenny E.] Univ Sydney, Fac Med, Sydney, NSW 2006, Australia. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. [Gunton, Jenny E.] Univ New S Wales, St Vincents Clin Sch, Sydney, NSW, Australia. RP Gunton, JE (reprint author), Garvan Inst Med Res, Diabet & Transcript Factors Grp, Sydney, NSW, Australia. EM j.gunton@garvan.org.au FU National Health and Medical Research Council; Diabetes Australia Research Trust; Australasian Diabetes in Pregnancy Society FX The funders were peer-reviewed granting bodies: National Health and Medical Research Council, Diabetes Australia Research Trust, and Australasian Diabetes in Pregnancy Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 5 Z9 5 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 OCT 24 PY 2013 VL 8 IS 10 AR e77419 DI 10.1371/journal.pone.0077419 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241FR UT WOS:000326152300024 PM 24204824 ER PT J AU Smith, LK Tandon, A Shah, RR Mav, D Scoltock, AB Cidlowski, JA AF Smith, Lindsay K. Tandon, Arpit Shah, Ruchir R. Mav, Deepak Scoltock, Alyson B. Cidlowski, John A. TI Deep Sequencing Identification of Novel Glucocorticoid-Responsive miRNAs in Apoptotic Primary Lymphocytes SO PLOS ONE LA English DT Article ID RNA SECONDARY STRUCTURE; BH3-ONLY PROTEIN BIM; LEUKEMIA CELLS; LYMPHOBLASTIC-LEUKEMIA; MESSENGER-RNA; HUMAN GENOME; MICRORNAS; EXPRESSION; RESISTANCE; REVEALS AB Apoptosis of lymphocytes governs the response of the immune system to environmental stress and toxic insult. Signaling through the ubiquitously expressed glucocorticoid receptor, stress-induced glucocorticoid hormones induce apoptosis via mechanisms requiring altered gene expression. Several reports have detailed the changes in gene expression mediating glucocorticoid-induced apoptosis of lymphocytes. However, few studies have examined the role of non-coding miRNAs in this essential physiological process. Previously, using hybridization-based gene expression analysis and deep sequencing of small RNAs, we described the prevalent post-transcriptional repression of annotated miRNAs during glucocorticoid-induced apoptosis of lymphocytes. Here, we describe the development of a customized bioinformatics pipeline that facilitates the deep sequencing-mediated discovery of novel glucocorticoid-responsive miRNAs in apoptotic primary lymphocytes. This analysis identifies the potential presence of over 200 novel glucocorticoid-responsive miRNAs. We have validated the expression of two novel glucocorticoid-responsive miRNAs using small RNA-specific qPCR. Furthermore, through the use of Ingenuity Pathways Analysis (IPA) we determined that the putative targets of these novel validated miRNAs are predicted to regulate cell death processes. These findings identify two and predict the presence of additional novel glucocorticoid-responsive miRNAs in the rat transcriptome, suggesting a potential role for both annotated and novel miRNAs in glucocorticoid-induced apoptosis of lymphocytes. C1 [Smith, Lindsay K.; Scoltock, Alyson B.; Cidlowski, John A.] NIEHS, Mol Endocrinol Grp, Lab Signal Transduct, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Tandon, Arpit; Shah, Ruchir R.; Mav, Deepak] SRA Int, Durham, NC USA. RP Cidlowski, JA (reprint author), NIEHS, Mol Endocrinol Grp, Lab Signal Transduct, NIH,Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 6 Z9 6 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 24 PY 2013 VL 8 IS 10 AR e78316 DI 10.1371/journal.pone.0078316 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 241FR UT WOS:000326152300048 PM 24250753 ER PT J AU Lauer, MS D'Agostino, RB AF Lauer, Michael S. D'Agostino, Ralph B., Sr. TI The Randomized Registry Trial - The Next Disruptive Technology in Clinical Research? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material AB The registry-based randomized trial may make less expensive, more efficient clinical studies possible. But before the new study design can be widely used, questions about the quality of the underlying data sets must be addressed. The randomized trial is one of the most powerful tools clinical researchers possess, a tool that enables them to evaluate the effectiveness of new (or established) therapies while accounting for the effects of unmeasured confounders and selection bias by indication. Randomized trials, especially huge megatrials, have transformed medical practice. Thanks to randomized trials, we no longer, for example, treat acute myocardial infarction with lidocaine and nitrates. Instead we use rapid revascularization, anticoagulants, and antiplatelet agents, and during long-term follow-up we routinely prescribe statins, beta-blockers, and angiotensin-converting-enzyme inhibitors. But the reputation of randomized trials has suffered of late,(1) owing to reasonable ... C1 [Lauer, Michael S.] NHLBI, Off Director, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [D'Agostino, Ralph B., Sr.] Harvard Clin Res Inst, Boston, MA USA. RP Lauer, MS (reprint author), NHLBI, Off Director, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 175 Z9 176 U1 1 U2 18 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 OCT 24 PY 2013 VL 369 IS 17 BP 1579 EP 1581 DI 10.1056/NEJMp1310102 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 239MZ UT WOS:000326031100004 PM 23991657 ER PT J AU Hedge, J Lycett, SJ Rambaut, A AF Hedge, J. Lycett, S. J. Rambaut, A. TI Real-time characterization of the molecular epidemiology of an influenza pandemic SO BIOLOGY LETTERS LA English DT Article DE Bayesian phylogenetics; influenza; pandemic; parameter estimation; real-time ID POPULATION-DYNAMICS; GROWTH-RATES; PHYLOGENETICS; TRANSMISSION; INFERENCE; SKYLINE; VIRUS AB Early characterization of the epidemiology and evolution of a pandemic is essential for determining the most appropriate interventions. During the 2009 H1N1 influenza A pandemic, public databases facilitated widespread sharing of genetic sequence data from the outset. We use Bayesian phylogenetics to simulate real-time estimates of the evolutionary rate, date of emergence and intrinsic growth rate (r(0)) of the pandemic from whole-genome sequences. We investigate the effects of temporal range of sampling and dataset size on the precision and accuracy of parameter estimation. Parameters can be accurately estimated as early as two months after the first reported case, from 100 genomes and the choice of growth model is important for accurate estimation of r(0). This demonstrates the utility of simple coalescent models to rapidly inform intervention strategies during a pandemic. C1 [Hedge, J.; Lycett, S. J.; Rambaut, A.] Univ Edinburgh, Inst Evolutionary Biol, Ashworth Labs, Edinburgh, Midlothian, Scotland. [Rambaut, A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Hedge, J (reprint author), Univ Edinburgh, Inst Evolutionary Biol, Ashworth Labs, Edinburgh, Midlothian, Scotland. EM jessica.hedge@ndm.ox.ac.uk; a.rambaut@ed.ac.uk OI Hedge, Jessica/0000-0002-4343-4146; Rambaut, Andrew/0000-0003-4337-3707; Lycett, Samantha/0000-0003-3159-596X FU Wellcome Trust [092807]; European Research Council under the European Community [278433-PRE-DEMICS]; ERC [260864]; Biotechnology Biological Sciences Research Council (UK); Interdisciplinary Centre for Human and Avian Influenza Research (ICHAIR); University of Edinburgh Centre for Infection Immunity and Evolution (CIIE) FX The research leading to these results has received funding from the Wellcome Trust (grant no. 092807), the European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 278433-PRE-DEMICS and ERC grant agreement no. 260864 and the Biotechnology Biological Sciences Research Council (UK). We acknowledge funding and resources from the Interdisciplinary Centre for Human and Avian Influenza Research (ICHAIR) and the University of Edinburgh Centre for Infection Immunity and Evolution (CIIE). NR 25 TC 10 Z9 10 U1 0 U2 12 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1744-9561 EI 1744-957X J9 BIOL LETTERS JI Biol. Lett. PD OCT 23 PY 2013 VL 9 IS 5 AR UNSP 20130331 DI 10.1098/rsbl.2013.0331 PG 5 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 297XY UT WOS:000330289600039 PM 23883574 ER PT J AU Simmons, RP Scully, EP Groden, EE Arnold, KB Chang, JJ Lane, K Lifson, J Rosenberg, E Lauffenburger, DA Altfeld, M AF Simmons, Rachel P. Scully, Eileen P. Groden, Erin E. Arnold, Kelly B. Chang, J. Judy Lane, Kim Lifson, Jeff Rosenberg, Eric Lauffenburger, Douglas A. Altfeld, Marcus TI HIV-1 infection induces strong production of IP-10 through TLR7/9-dependent pathways SO AIDS LA English DT Article DE immune activation; IP-10; mDCs; monocytes; Toll-like receptor ID ACTIVE ANTIRETROVIRAL THERAPY; T-CELL-ACTIVATION; DISEASE PROGRESSION; IMMUNE ACTIVATION; DENDRITIC CELLS; VIRAL SUPPRESSION; GENE-EXPRESSION; LIFE EXPECTANCY; INCREASED RISK; IFN-ALPHA AB Objective:To study the cytokine/chemokine profiles in response to HIV-1 viremia, and elucidate the pathways leading to HIV-1-induced inflammation.Design/methods:Plasma levels of 19 cytokines in individuals with early HIV-1 infection and individuals undergoing treatment interruptions were evaluated via multiplex assay. To investigate the cellular sources of relevant cytokines, sorted cells from HIV-1 infected individuals were assessed for mRNA expression. Relevant signaling pathways were assessed by comparing cytokine production patterns of peripheral blood mononuclear cells stimulated with intact HIV-1 or specific Toll-like receptor (TLR) stimulants with and without a TLR7/9 antagonist.Results:IP-10 plasma concentration was most significantly associated with HIV-1 viral load and was the most significant contributor in a multivariate model. IP-10 mRNA was highly expressed in monocytes and mDCs and these cells were the dominant producers after in-vitro stimulation with TLR7/8 ligands (CL097 and ssRNAGag1166), AT-2 HIV-1, and HIV-1NL43 virus. Partial least square discriminant analysis of culture supernatants revealed distinct cytokine/chemokine secretion profiles associated with intact viruses compared with TLR7/8 ligands alone, with IP-10 production linked to the former. A TLR7/9 antagonist blocked IP-10 production following whole virus stimulation, suggesting the involvement of TLR7/9 in the recognition of HIV-1 by these cells.Conclusion:Monocytes and mDCs produce significant amounts of IP-10 in response to HIV-1 viremia and after in-vitro stimulation with HIV-1. Stimulation with HIV-1-derived TLR7/8-ligands versus HIV-1 resulted in distinct cytokine/chemokine profiles, indicating additional pathways other than TLR7/8 that lead to the activation of innate immune cells by HIV-1. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Simmons, Rachel P.] Boston Univ, Infect Dis Sect, Boston, MA 02215 USA. [Simmons, Rachel P.; Scully, Eileen P.; Groden, Erin E.; Chang, J. Judy; Lane, Kim; Altfeld, Marcus] MIT, MGH, Ragon Inst, Boston, MA USA. [Simmons, Rachel P.; Scully, Eileen P.; Groden, Erin E.; Chang, J. Judy; Lane, Kim; Altfeld, Marcus] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Arnold, Kelly B.; Lauffenburger, Douglas A.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Lifson, Jeff] NCI, Sci Applicat Int Corp Frederick, AIDS & Canc Virus Program, Frederick, MD USA. [Rosenberg, Eric] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. [Scully, Eileen P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Infect Dis, Boston, MA 02115 USA. [Altfeld, Marcus] Leibniz Inst Expt Virol, Heinrich Pette Inst, Hamburg, Germany. RP Altfeld, M (reprint author), Harvard Univ, MIT, MGH, Med Sch,Ragon Inst, 400 Technol Sq, Cambridge, MA 02139 USA. EM maltfeld@partners.org FU NIH/NIAID [R01 AI078784]; Harvard University Center for AIDS Research (CFAR), NIH [P30 AI060354]; NIAID; NCI; NICHD; NHLBI; NIDA; NIMH NIA; NCCAM; FIC; OAR FX This publication was supported by the NIH/NIAID (R01 AI078784) and resulted (in part) from research supported by the Harvard University Center for AIDS Research (CFAR), an NIH funded program (P30 AI060354), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH NIA, NCCAM, FIC, and OAR. NR 46 TC 25 Z9 25 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD OCT 23 PY 2013 VL 27 IS 16 BP 2505 EP 2517 DI 10.1097/01.aids.0000432455.06476.bc PG 13 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 250HD UT WOS:000326840300002 PM 24096630 ER PT J AU Yutin, N Koonin, EV AF Yutin, Natalya Koonin, Eugene V. TI Pandoraviruses are highly derived phycodnaviruses SO BIOLOGY DIRECT LA English DT Article ID NUCLEOCYTOPLASMIC DNA VIRUSES; ORTHOLOGOUS GENES; GENOME SEQUENCE; GIANT VIRUS; EVOLUTION; MIMIVIRUS; ORIGIN; EUKARYOTES; RECONSTRUCTION; SELECTION AB The recently discovered Pandoraviruses are by far the largest viruses known, with their 2 megabase genomes exceeding in size the genomes of numerous bacteria and archaea. Pandoraviruses show a distant relationship with other nucleocytoplasmic large DNA viruses (NCLDV) of eukaryotes, lack some of the NCLDV core genes and in particular do not appear to be specifically related to the other, better characterized family of giant viruses, the Mimiviridae. Here we report phylogenetic analysis of 6 core NCLDV genes that confidently places Pandoraviruses within the family Phycodnaviridae, with an apparent specific affinity with Coccolithoviruses. We conclude that, despite their many unusual characteristics, Pandoraviruses are highly derived phycodnaviruses. These findings imply that giant viruses have independently evolved from smaller NCLDV on at least two occasions. This article was reviewed by Patrick Forterre and Lakshminarayan Iyer. For the full reviews, see the Reviewers' reports section. C1 [Yutin, Natalya; 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 FU US Department of Health and Human Services intramural funds FX The authors thank members of the Koonin group for useful discussions. The authors' research is supported by the US Department of Health and Human Services intramural funds (to National Library of Medicine). NR 32 TC 20 Z9 21 U1 0 U2 29 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD OCT 23 PY 2013 VL 8 AR 25 DI 10.1186/1745-6150-8-25 PG 8 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 247NY UT WOS:000326626200001 PM 24148757 ER PT J AU Li, HH Doiron, K Patterson, AD Gonzalez, FJ Fornace, AJ AF Li, Heng-Hong Doiron, Kathryn Patterson, Andrew D. Gonzalez, Frank J. Fornace, Albert J., Jr. TI Identification of serum insulin-like growth factor binding protein 1 as diagnostic biomarker for early-stage alcohol-induced liver disease SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Alcohol-induced liver disease; Transcriptomics; Biomarker; Igfbp1; IGFBP1 protein ID PPARA-NULL MOUSE; GENE-EXPRESSION; INTRAGASTRIC INFUSION; BETA-HEXOSAMINIDASE; HEAVY DRINKING; FACTOR SYSTEM; RAT MODEL; ETHANOL; INJURY; MICROARRAY AB Background: Alcohol consumption is a major cause of liver disease in humans. The use and monitoring of biomarkers associated with early, pre-clinical stages of alcohol-induced liver disease (pre-ALD) could facilitate diagnosis and treatment, leading to improved outcomes. Methods: We investigated the pathological, transcriptomic and protein changes in early stages of pre-ALD in mice fed the Lieber-Decarli liquid diet with or without alcohol for four months to identify biomarkers for the early stage of alcohol induced liver injury. Mice were sampled after 1, 2 and 4 months treatment. Results: Pathological examination revealed a modest increase in fatty liver changes in alcohol-treated mice. Transcriptomics revealed gene alterations at all time points. Most notably, the Igfbp1 (Insulin-Like Growth Factor Binding Protein 1) was selected as the best candidate gene for early detection of liver damage since it showed early and continuously enhanced induction during the treatment course. Consistent with the microarray data, both Igfbp1mRNA expression in the liver tissue and the IGFBP1 serum protein levels showed progressive and significant increases over the course of pre-ALD development. Conclusions: The results suggest that in conjunction with other tests, serum IGFBPI protein could provide an easily measured biomarker for early detection of alcohol-induced liver injury in humans. C1 [Li, Heng-Hong; Doiron, Kathryn; Fornace, Albert J., Jr.] Georgetown Univ, Dept Biochem & Mol & Cellular Biol, Washington, DC 20057 USA. [Patterson, Andrew D.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Patterson, Andrew D.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20852 USA. RP Fornace, AJ (reprint author), Georgetown Univ, Dept Biochem & Mol & Cellular Biol, 3970 Reservoir Rd NW,New Res Bldg,Room E504, Washington, DC 20057 USA. EM af294@georgetown.edu RI Patterson, Andrew/G-3852-2012; OI Patterson, Andrew/0000-0003-2073-0070; Fornace, Albert/0000-0001-9695-085X FU NIEHS, NIH [U01ES016013]; NIAAA, NIH [R01AA018863] FX This study was funded by grant U01ES016013 from NIEHS, NIH, and grant R01AA018863 from NIAAA, NIH. NR 38 TC 10 Z9 10 U1 1 U2 3 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 OCT 23 PY 2013 VL 11 AR 266 DI 10.1186/1479-5876-11-266 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 245JO UT WOS:000326460100001 PM 24152801 ER PT J AU Good, CH Wang, H Chen, YH Mejias-Aponte, CA Hoffman, AF Lupica, CR AF Good, Cameron H. Wang, Huikun Chen, Yuan-Hao Mejias-Aponte, Carlos A. Hoffman, Alexander F. Lupica, Carl R. TI Dopamine D-4 Receptor Excitation of Lateral Habenula Neurons via Multiple Cellular Mechanisms SO JOURNAL OF NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; ACTIVATED CATION CHANNELS; I-H; SUBSTANTIA-NIGRA; MESSENGER-RNA; RAT-BRAIN; GLOBUS-PALLIDUS; SYNAPTIC-TRANSMISSION; EFFERENT CONNECTIONS; DEPENDENT REGULATION AB Glutamatergic lateral habenula (LHb) output communicates negative motivational valence to ventral tegmental area (VTA) dopamine (DA) neurons via activation of the rostromedial tegmental nucleus (RMTg). However, the LHb also receives a poorly understood DA input from the VTA, which we hypothesized constitutes an important feedback loop regulating DA responses to stimuli. Using whole-cell electrophysiology in rat brain slices, we find that DA initiates a depolarizing inward current (I-DAi) and increases spontaneous firing in 32% of LHb neurons. I-DAi was also observed upon application of amphetamine or the DA uptake blockers cocaine or GBR12935, indicating involvement of endogenous DA. I-DAi was blocked by D-4 receptor (D4R) antagonists (L745,870 or L741,742), and mimicked by a selective D4R agonist (A412997). I-DAi was associated with increased whole-cell conductance and was blocked by Cs+ or a selective blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel, ZD7288. I-DAi was also associated with a depolarizing shift in half-activation voltage for the hyperpolarization-activated cation current (I-h) mediated by HCN channels. Recordings from LHb neurons containing fluorescent retrograde tracers revealed that I-DAi was observed only in cells projecting to the RMTg and not the VTA. In parallel with direct depolarization, DA also strongly increased synaptic glutamate release and reduced synaptic GABA release onto LHb cells. These results demonstrate that DA can excite glutamatergic LHb output to RMTg via multiple cellular mechanisms. Since the RMTg strongly inhibits midbrain DA neurons, activation of LHb output to RMTg by DA represents a negative feedback loop that may dampen DA neuron output following activation. C1 [Good, Cameron H.; Wang, Huikun; Hoffman, Alexander F.; Lupica, Carl R.] NIDA, Natl Inst Hlth, US Dept HHS, Intramural Res Program,Cellular Neurobiol Res Bra, Baltimore, MD 21224 USA. [Good, Cameron H.; Wang, Huikun; Hoffman, Alexander F.; Lupica, Carl R.] NIDA, Natl Inst Hlth, US Dept HHS, Intramural Res Program,Electrophysiol Res Sect, Baltimore, MD 21224 USA. [Mejias-Aponte, Carlos A.] NIDA, Natl Inst Hlth, US Dept HHS, Intramural Res Program,Integrat Neurosci Res Bran, Baltimore, MD 21224 USA. [Chen, Yuan-Hao] Tri Serv Gen Hosp, Natl Def Med Ctr, Dept Neurosurg, Taipei 114, Taiwan. RP Lupica, CR (reprint author), NIDA, Triad Technol Ctr, Intramural Res Program, Electrophysiol Res Sect, 333 Cassell Dr, Baltimore, MD 21224 USA. EM clupica@intra.nida.nih.gov RI Hoffman, Alexander/H-3035-2012 OI Hoffman, Alexander/0000-0002-2676-0628 FU National Institutes of Health, National Institute on Drug Abuse Intramural Research Program FX This work was supported by the National Institutes of Health, National Institute on Drug Abuse Intramural Research Program. We thank Dr. Thomas C. Jhou for critical reading of the manuscript and Daniel D. Brauer for assistance with some experiments. NR 66 TC 17 Z9 17 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 OCT 23 PY 2013 VL 33 IS 43 BP 16853 EP 16864 DI 10.1523/JNEUROSCI.1844-13.2013 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 240II UT WOS:000326088500001 PM 24155292 ER PT J AU Robertson, CE Kravitz, DJ Freyberg, J Baron-Cohen, S Baker, CI AF Robertson, Caroline E. Kravitz, Dwight J. Freyberg, Jan Baron-Cohen, Simon Baker, Chris I. TI Slower Rate of Binocular Rivalry in Autism SO JOURNAL OF NEUROSCIENCE LA English DT Article ID STIMULUS COMPLEXITY; BISTABLE PERCEPTION; SPECTRUM DISORDERS; VISUAL-PERCEPTION; MODEL; EXCITATION/INHIBITION; SENSITIVITY; ADAPTATION; ATTENTION; DYNAMICS AB An imbalance between cortical excitation and inhibition is a central component of many models of autistic neurobiology. We tested a potential behavioral footprint of this proposed imbalance using binocular rivalry, a visual phenomenon in which perceptual experience is thought to mirror the push and pull of excitatory and inhibitory cortical dynamics. In binocular rivalry, two monocularly presented images compete, leading to a percept that alternates between them. In a series of trials, we presented separate images of objects (e.g., a baseball and a broccoli) to each eye using a mirror stereoscope and asked human participants with autism and matched control subjects to continuously report which object they perceived, or whether they perceived a mixed percept. Individuals with autism demonstrated a slower rate of binocular rivalry alternations than matched control subjects, with longer durations of mixed percepts and an increased likelihood to revert to the previously perceived object when exiting a mixed percept. Critically, each of these findings was highly predictive of clinical measures of autistic symptomatology. Control "playback" experiments demonstrated that differences in neither response latencies nor response criteria could account for the atypical dynamics of binocular rivalry we observed in autistic spectrum conditions. Overall, these results may provide an index of atypical cortical dynamics that may underlie both the social and nonsocial symptoms of autism. C1 [Robertson, Caroline E.; Kravitz, Dwight J.; Baker, Chris I.] NIMH, NIH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Robertson, Caroline E.; Freyberg, Jan; Baron-Cohen, Simon] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge CB2 8AH, England. RP Robertson, CE (reprint author), Harvard Soc Fellows, 78 Mt Auburn St, Cambridge, MA 02138 USA. EM carolinerobertson@fas.harvard.edu OI , Caroline/0000-0002-1858-6594; Baker, Chris/0000-0001-6861-8964; Freyberg, Jan/0000-0003-2386-8243 FU National Institute of Mental Health; Gates-Cambridge Trust; National Institutes of Health-Cambridge Fellowship; Medical Research Council; Wellcome Trust FX This work was supported in part by the Intramural Research Program of the National Institute of Mental Health, and was conducted in association with the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Cambridgeshire and Peterborough NHS Foundation Trust. This work was also supported by the Gates-Cambridge Trust and the National Institutes of Health-Cambridge Fellowship (C.E.R.). S.B.-C. was supported by the Medical Research Council and the Wellcome Trust during the period of this work. We thank John Mollon for the use of his mirror stereoscope; David Leopold, Carson Chow, Shashaank Vattikuti, Alex Martin, and Kate Plaisted-Grant for comments; and Carrie Allison for help with recruitment. NR 41 TC 28 Z9 30 U1 3 U2 20 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 OCT 23 PY 2013 VL 33 IS 43 BP 16983 EP 16991 DI 10.1523/JNEUROSCI.0448-13.2013 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 240II UT WOS:000326088500012 PM 24155303 ER PT J AU Basta, NE Stuart, JM Nascimento, MC Manigart, O Trotter, C Hassan-King, M Chandramohan, D Sow, SO Berthe, A Bedru, A Tekletsion, YK Collard, JM Jusot, JF Diallo, A Bassene, H Daugla, DM Gamougam, K Hodgson, A Forgor, AA Omotara, BA Gadzama, GB Watkins, ER Rebbetts, LS Diallo, K Weiss, NS Halloran, ME Maiden, MCJ Greenwood, B AF Basta, Nicole E. Stuart, James M. Nascimento, Maria C. Manigart, Olivier Trotter, Caroline Hassan-King, Musa Chandramohan, Daniel Sow, Samba O. Berthe, Abdoulaye Bedru, Ahmed Tekletsion, Yenenesh K. Collard, Jean-Marc Jusot, Jean-Francois Diallo, Aldiouma Bassene, Hubert Daugla, Doumagoum M. Gamougam, Khadidja Hodgson, Abraham Forgor, Abudulai A. Omotara, Babatunji A. Gadzama, Galadima B. Watkins, Eleanor R. Rebbetts, Lisa S. Diallo, Kanny Weiss, Noel S. Halloran, M. Elizabeth Maiden, Martin C. J. Greenwood, Brian TI Methods for Identifying Neisseria meningitidis Carriers: A Multi-Center Study in the African Meningitis Belt SO PLOS ONE LA English DT Article ID MENINGOCOCCAL CONJUGATE VACCINE; DIAGNOSTIC-TESTS; CARRIAGE; SEROGROUP; DISEASE; SPECIFICITY; SENSITIVITY; EPIDEMIC; IMMUNITY; IMPACT AB Objective: Detection of meningococcal carriers is key to understanding the epidemiology of Neisseria meningitidis, yet no gold standard has been established. Here, we directly compare two methods for collecting pharyngeal swabs to identify meningococcal carriers. Methods: We conducted cross-sectional surveys of schoolchildren at multiple sites in Africa to compare swabbing the posterior pharynx behind the uvula (U) to swabbing the posterior pharynx behind the uvula plus one tonsil (T). Swabs were cultured immediately and analyzed using molecular methods. Results: One thousand and six paired swab samples collected from schoolchildren in four countries were analyzed. Prevalence of meningococcal carriage was 6.9% (95% CI: 5.4-8.6%) based on the results from both swabs, but the observed prevalence was lower based on one swab type alone. Prevalence based on the T swab or the U swab alone was similar (5.2% (95% CI: 3.8-6.7%) versus 4.9% (95% CI: 3.6-6.4%) respectively (p=0.6)). The concordance between the two methods was 96.3% and the kappa was 0.61 (95% CI: 0.50-0.73), indicating good agreement. Conclusions: These two commonly used methods for collecting pharyngeal swabs provide consistent estimates of the prevalence of carriage, but both methods misclassified carriers to some degree, leading to underestimates of the prevalence. C1 [Basta, Nicole E.] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Basta, Nicole E.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Basta, Nicole E.; Weiss, Noel S.; Halloran, M. Elizabeth] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Stuart, James M.; Nascimento, Maria C.; Manigart, Olivier; Hassan-King, Musa; Chandramohan, Daniel; Greenwood, Brian] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Dis Control, London WC1, England. [Trotter, Caroline] Univ Cambridge, Dept Vet Med, Cambridge, England. [Sow, Samba O.; Berthe, Abdoulaye; Diallo, Kanny] Ctr Dev Vaccins, Bamako, Mali. [Bedru, Ahmed; Tekletsion, Yenenesh K.] Armauer Hansen Res Inst, Addis Ababa, Ethiopia. [Tekletsion, Yenenesh K.; Watkins, Eleanor R.; Rebbetts, Lisa S.; Diallo, Kanny; Maiden, Martin C. J.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Collard, Jean-Marc; Jusot, Jean-Francois] Ctr Rech Med & Sanit, Niamey, Niger. [Diallo, Aldiouma; Bassene, Hubert] Inst Rech Dev, Dakar, Senegal. [Hodgson, Abraham] Ghana Hlth Serv, Div Res & Dev, Accra, Ghana. [Forgor, Abudulai A.] War Mem Hosp, Navrongo, Ghana. [Omotara, Babatunji A.] Univ Maiduguri, Dept Community Med, Maiduguri, Borno State, Nigeria. [Gadzama, Galadima B.] Univ Maiduguri, Dept Med Microbiol, Maiduguri, Borno State, Nigeria. [Weiss, Noel S.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Halloran, M. Elizabeth] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. RP Basta, NE (reprint author), Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. EM nbasta@princeton.edu RI Trotter, Caroline/H-5077-2013; OI Trotter, Caroline/0000-0003-4000-2708; Maiden, Martin/0000-0001-6321-5138 FU Bill & Melinda Gates Foundation [51251]; Wellcome Trust [086546]; NIH [R37A1032042]; NIH Early Independence Award [1DP5OD009162]; RAPIDD program of the Science & Technology Directorate (Department of Homeland Security and the Fogarty International Centre) FX This research was funded by the Bill & Melinda Gates Foundation Grant 51251 (www.gatesfoundation.org), the Wellcome Trust Grant 086546 (www.wellcome.ac.uk), NIH Grant R37A1032042 (support for MEH, NEB), NIH Early Independence Award 1DP5OD009162 (Office of the Director and the National Institute of Dental and Craniofacial Research; support for NEB) (www.nih.gov), and the RAPIDD program of the Science & Technology Directorate (Department of Homeland Security and the Fogarty International Centre; support for NEB)(http://www.fic.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 6 Z9 6 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 OCT 23 PY 2013 VL 8 IS 10 AR e78336 DI 10.1371/journal.pone.0078336 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239PE UT WOS:000326037000100 PM 24194921 ER PT J AU Wood, E Samet, JH Volkow, ND AF Wood, Evan Samet, Jeffrey H. Volkow, Nora D. TI Physician Education in Addiction Medicine SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID DEPENDENCE; HEALTH; BURDEN; CARE C1 [Wood, Evan] Univ British Columbia, Dept Med, Vancouver, BC V6Z 1Y6, Canada. [Samet, Jeffrey H.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Volkow, Nora D.] US Natl Inst Drug Abuse, Bethesda, MD USA. RP Wood, E (reprint author), Univ British Columbia, Div Aids, 608-1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada. EM uhri-ew@cfenet.ubc.ca FU Intramural NIH HHS [Z99 DA999999] NR 9 TC 25 Z9 26 U1 2 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 23 PY 2013 VL 310 IS 16 BP 1673 EP 1674 DI 10.1001/jama.2013.280377 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 238LR UT WOS:000325948500019 PM 24150462 ER PT J AU Metsch, LR Feaster, DJ Gooden, L Schackman, BR Matheson, T Das, M Golden, MR Huffaker, S Haynes, LF Tross, S Malotte, CK Douaihy, A Korthuis, PT Duffus, WA Henn, S Bolan, R Philip, SS Castro, JG Castellon, PC McLaughlin, G Mandler, RN Branson, B Colfax, GN AF Metsch, Lisa R. Feaster, Daniel J. Gooden, Lauren Schackman, Bruce R. Matheson, Tim Das, Moupali Golden, Matthew R. Huffaker, Shannon Haynes, Louise F. Tross, Susan Malotte, C. Kevin Douaihy, Antoine Korthuis, P. Todd Duffus, Wayne A. Henn, Sarah Bolan, Robert Philip, Susan S. Castro, Jose G. Castellon, Pedro C. McLaughlin, Gayle Mandler, Raul N. Branson, Bernard Colfax, Grant N. TI Effect of Risk-Reduction Counseling With Rapid HIV Testing on Risk of Acquiring Sexually Transmitted Infections The AWARE Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HEALTH-CARE SETTINGS; SERVICES-TASK-FORCE; MEN; SEX; EFFICACY; ADOLESCENTS; BEHAVIORS; COHORT; ADULTS; VIRUS AB IMPORTANCE To increase human immunodeficiency virus (HIV) testing rates, many institutions and jurisdictions have revised policies to make the testing process rapid, simple, and routine. A major issue for testing scale-up efforts is the effectiveness of HIV risk-reduction counseling, which has historically been an integral part of the HIV testing process. OBJECTIVE To assess the effect of brief patient-centered risk-reduction counseling at the time of a rapid HIV test on the subsequent acquisition of sexually transmitted infections (STIs). DESIGN, SETTING, AND PARTICIPANTS From April to December 2010, Project AWARE randomized 5012 patients from 9 sexually transmitted disease (STD) clinics in the United States to receive either brief patient-centered HIV risk-reduction counseling with a rapid HIV test or the rapid HIV test with information only. Participants were assessed for multiple STIs at both baseline and 6-month follow-up. INTERVENTIONS Participants randomized to counseling received individual patient-centered risk-reduction counseling based on an evidence-based model. The core elements included a focus on the patient's specific HIV/STI risk behavior and negotiation of realistic and achievable risk-reduction steps. All participants received a rapid HIV test. MAIN OUTCOMES AND MEASURES The prespecified outcome was a composite end point of cumulative incidence of any of the measured STIs over 6 months. All participants were tested for Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum (syphilis), herpes simplex virus 2, and HIV. Women were also tested for Trichomonas vaginalis. RESULTS There was no significant difference in 6-month composite STI incidence by study group (adjusted risk ratio, 1.12; 95% CI, 0.94-1.33). There were 250 of 2039 incident cases (12.3%) in the counseling group and 226 of 2032 (11.1%) in the information-only group. CONCLUSION AND RELEVANCE Risk-reduction counseling in conjunction with a rapid HIV test did not significantly affect STI acquisition among STD clinic patients, suggesting no added benefit from brief patient-centered risk-reduction counseling. C1 [Metsch, Lisa R.; Gooden, Lauren; Castellon, Pedro C.] Columbia Univ, Dept Sociomed Sci, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Metsch, Lisa R.; Feaster, Daniel J.; Gooden, Lauren; Castellon, Pedro C.] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Miami, FL 33136 USA. [Schackman, Bruce R.] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY USA. [Matheson, Tim; Das, Moupali; Huffaker, Shannon; Colfax, Grant N.] San Francisco Dept Publ Hlth, HIV Prevent Sect, San Francisco, CA USA. [Das, Moupali; Colfax, Grant N.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Golden, Matthew R.] Univ Washington, Ctr AIDS & STD, Seattle, WA 98195 USA. [Golden, Matthew R.] Publ Hlth Seattle & King Cty, Seattle, WA USA. [Haynes, Louise F.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. [Tross, Susan] Columbia Univ, HIV Ctr Clin & Behav Studies, Dept Psychiat, New York, NY 10032 USA. [Tross, Susan] Columbia Univ, Subst Use Res Ctr, Dept Psychiat, New York, NY 10032 USA. [Malotte, C. Kevin] Calif State Univ Long Beach, Dept Hlth Sci, Long Beach, CA 90840 USA. [Douaihy, Antoine] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Duffus, Wayne A.] Univ S Carolina, Div Infect Dis, Dept Med, Sch Med, Columbia, SC 29208 USA. [Henn, Sarah] Whitman Walker Hlth, Elizabeth Taylor Med Ctr, Washington, DC USA. [Bolan, Robert] Los Angeles Gay & Lesbian Ctr, Jeffrey Goodman Special Care Clin, Los Angeles, CA USA. [Philip, Susan S.] San Francisco Dept Publ Hlth, STD Prevent & Control, San Francisco, CA USA. [Castro, Jose G.] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [McLaughlin, Gayle] Duval Cty Hlth Dept, Jacksonville, FL USA. [Mandler, Raul N.] NIDA, NIH, Bethesda, MD 20892 USA. [Branson, Bernard] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Natl Ctr HIV Hepatitis STD & TB Prevent, Atlanta, GA USA. RP Metsch, LR (reprint author), Columbia Univ, Dept Sociomed Sci, Mailman Sch Publ Hlth, 722 W 168th St, New York, NY 10032 USA. EM lm2892@cumc.columbia.edu FU National Institute on Drug Abuse [RC2DA028973]; University of Miami Center for AIDS Research (CFAR) [P30 AI073961] FX Funding for this study and analysis was provided by the National Institute on Drug Abuse (RC2DA028973). The infrastructure of the National Drug Abuse Treatment Clinical Trials Network was used as a platform in conducting this trial (U10-DA13720). Support from the University of Miami Center for AIDS Research (CFAR) is also acknowledged (P30 AI073961). NR 32 TC 43 Z9 44 U1 4 U2 20 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 OCT 23 PY 2013 VL 310 IS 16 BP 1701 EP 1710 DI 10.1001/jama.2013.280034 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 238LR UT WOS:000325948500026 PM 24150466 ER PT J AU Hassan, R Miller, AC Sharon, E Thomas, A Reynolds, JC Ling, A Kreitman, RJ Miettinen, MM Steinberg, SM Fowler, DH Pastan, I AF Hassan, Raffit Miller, Andrew C. Sharon, Elad Thomas, Anish Reynolds, James C. Ling, Alexander Kreitman, Robert J. Miettinen, Markku M. Steinberg, Seth M. Fowler, Daniel H. Pastan, Ira TI Major Cancer Regressions in Mesothelioma After Treatment with an Anti-Mesothelin Immunotoxin and Immune Suppression SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID MALIGNANT PLEURAL MESOTHELIOMA; RESPONSE CRITERIA; SOLID TUMORS; RECOMBINANT IMMUNOTOXIN; PLUS CYCLOPHOSPHAMIDE; PHASE-I; THERAPY; RECIST; CHEMOTHERAPY; PENTOSTATIN AB Immunotoxins are potent anticancer agents with an unusual mechanism of action: inhibition of protein synthesis resulting in apoptotic cell death. Immunotoxins have produced many durable complete responses in refractory hairy cell leukemia, where patients rarely form antibodies to the bacterial toxin component of the immunotoxin. Patients with mesothelioma, however, have normal immune systems and form antibodies after one cycle, and tumor responses to the immunotoxin have not been observed in this disease. We describe the results of a trial in which major antitumor responses were seen in patients with advanced mesothelioma who received the anti-mesothelin immunotoxin SS1P, together with pentostatin and cyclophosphamide, to deplete T and B cells. Of 10 patients with chemotherapy-refractory mesothelioma, 3 have had major tumor regressions with 2 ongoing at 15 months, and 2 others responded to chemotherapy after discontinuing immunotoxin therapy. Antibody formation was markedly delayed, allowing more SS1P cycles to be given, but this alone does not appear to account for the marked antitumor activity observed. C1 [Hassan, Raffit; Kreitman, Robert J.; Pastan, Ira] NIH, NCI, CCR, Lab Mol Biol, Bethesda, MD 20892 USA. [Miller, Andrew C.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Sharon, Elad] NIH, NCI, Div Canc Treatment & Diag, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Thomas, Anish] NIH, NCI, CCR, Med Oncol Branch, Bethesda, MD 20892 USA. [Reynolds, James C.; Ling, Alexander] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Miettinen, Markku M.] NIH, NCI, CCR, Pathol Lab, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NIH, NCI, CCR, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Fowler, Daniel H.] NIH, NCI, CCR, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. RP Hassan, R (reprint author), NIH, NCI, CCR, Lab Mol Biol, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov OI Thomas, Anish/0000-0003-3293-3115; Miller, Andrew/0000-0001-8474-5090 FU NIH, NCI, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. NR 25 TC 75 Z9 75 U1 2 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 23 PY 2013 VL 5 IS 208 AR 208ra147 DI 10.1126/scitranslmed.3006941 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 240IX UT WOS:000326090200004 PM 24154601 ER PT J AU Li, J Lu, ZY AF Li, Jiao Lu, Zhiyong TI Pathway-based drug repositioning using causal inference SO BMC BIOINFORMATICS LA English DT Article ID DISEASE; DISCOVERY; NETWORKS; KNOWLEDGEBASE; EXPRESSION; VIEW AB Background: Recent in vivo studies showed new hopes of drug repositioning through causality inference from drugs to disease. Inspired by their success, here we present an in silico method for building a causal network (CauseNet) between drugs and diseases, in an attempt to systematically identify new therapeutic uses of existing drugs. Methods: Unlike the traditional 'one drug-one target-one disease' causal model, we simultaneously consider all possible causal chains connecting drugs to diseases via target-and gene-involved pathways based on rich information in several expert-curated knowledge-bases. With statistical learning, our method estimates transition likelihood of each causal chain in the network based on known drug-disease treatment associations (e. g. bexarotene treats skin cancer). Results: To demonstrate its validity, our method showed high performance (AUC = 0.859) in cross validation. Moreover, our top scored prediction results are highly enriched in literature and clinical trials. As a showcase of its utility, we show several drugs for potential re-use in Crohn's Disease. Conclusions: We successfully developed a computational method for discovering new uses of existing drugs based on casual inference in a layered drug-target-pathway-gene-disease network. The results showed that our proposed method enables hypothesis generation from public accessible biological data for drug repositioning. C1 [Li, Jiao] Chinese Acad Med Sci, Inst Med Informat, Beijing 100730, Peoples R China. [Lu, Zhiyong] NIH, NCBI, Bethesda, MD 20892 USA. RP Lu, ZY (reprint author), NIH, NCBI, Bldg 10, Bethesda, MD 20892 USA. EM zhiyong.lu@nih.gov FU Intramural Research Program of the National Institutes of Health; National Key Technology R&D Program of China [2013BAI06B01]; Peking Union Medical College Youth Fund FX This research was supported by the Intramural Research Program of the National Institutes of Health, the National Key Technology R&D Program of China (Grant No. 2013BAI06B01) and the Peking Union Medical College Youth Fund. The authors would like to thank the Pathway Commons team for discussing meaning use of their data, and Bethany Harris for proofreading our manuscript. NR 31 TC 13 Z9 13 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 22 PY 2013 VL 14 SU 16 AR S3 DI 10.1186/1471-2105-14-S16-S3 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 286CC UT WOS:000329441100002 PM 24564553 ER PT J AU Nazarov, C Lo Surdo, J Bauer, SR Wei, CH AF Nazarov, Cristina Lo Surdo, Jessica Bauer, Steven R. Wei, Cheng-Hong TI Assessment of immunosuppressive activity of human mesenchymal stem cells using murine antigen specific CD4 and CD8 T cells in vitro SO STEM CELL RESEARCH & THERAPY LA English DT Article ID STROMAL CELLS; LYMPHOCYTE-PROLIFERATION; CEREBRAL-ISCHEMIA; INTERFERON-GAMMA; INHIBIT; EXPRESSION; RESPONSES; SUPPRESS; REPAIR; DIFFERENTIATION AB Introduction: Mesenchymal stem cells (MSCs) have immunosuppressive activity. They do not induce allospecific T cell responses, making them promising tools for reducing the severity of graft versus host disease (GVHD) as well as treating various immune diseases. Currently, there is a need in the MSC field to develop a robust in vitro bioassay which can characterize the immunosuppressive function of MSCs. Methods: Murine clonal CD4 and CD8 T cells were stimulated with cognate peptide antigen and antigen presenting cells (APCs) in the absence or presence of human MSCs, different aspects of T cell activation were monitored and analyzed using flow cytometery, real time RT-PCR and cytokine measurement. Results: Human MSCs (hMSCs) can alter multiple aspects of murine T cell activation induced by stimulation with specific antigen, including: reduced proliferation, inhibited or stimulated cell surface marker expression (CD25, CD69, CD44 and CD62L), inhibited mRNA expression of transcription factors (T-bet and GATA-3) and decreased cytokine expression (interferon-gamma, interleukin-10). Disappearance of activation-induced cluster formation and decreased apoptosis of CD8 T cells were also observed. Moreover, the effects are specific to MSCs; incubating the T cells with non-MSC control cell lines had no effect on T cell proliferation and activation. Conclusions: Clonal murine T cells can be used to measure, characterize, and quantify the in vitro immunosuppressive activity of human MSCs, representing a promising approach to improve bioassays for immunosuppression. C1 [Nazarov, Cristina; Wei, Cheng-Hong] US FDA, Gene Transfer & Immunogen Branch, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies,Ctr Biol Eva, Bethesda, MD 20892 USA. [Lo Surdo, Jessica; Bauer, Steven R.] US FDA, Cellular & Tissue Therapies Branch, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies,Ctr Biol Eva, Bethesda, MD 20892 USA. [Wei, Cheng-Hong] US FDA, Ctr Biol Evaluat & Res, NIH, Bethesda, MD 20892 USA. RP Wei, CH (reprint author), US FDA, Gene Transfer & Immunogen Branch, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies,Ctr Biol Eva, Bethesda, MD 20892 USA. EM chenghong.wei@fda.hhs.gov FU FDA Modernizing Science grant program; FDA medical countermeasures initiative (MCMi); Division of Cellular and Gene Therapies; Oak Ridge Institute for Science and Education FX This work was supported by the FDA Modernizing Science grant program, the FDA medical countermeasures initiative (MCMi) as well as the Division of Cellular and Gene Therapies. Cristina Nazarov and Jessica Lo Surdo were supported through fellowship administered by the Oak Ridge Institute for Science and Education. The authors would like to thank Drs. Andrew Byrnes and Graeme Price for critically reviewing this manuscript and Jean Manirarora for assistance with the breeding and typing of the TCR transgenic mice. NR 48 TC 8 Z9 9 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-6512 J9 STEM CELL RES THER JI Stem Cell Res. Ther. PD OCT 22 PY 2013 VL 4 AR 128 DI 10.1186/scrt339 PG 15 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 282PD UT WOS:000329183300001 PM 24406271 ER PT J AU Narouz, MR Soliman, SE Bassily, RW El-Sokkary, RI Nasr, AZ Nashed, MA AF Narouz, Mina R. Soliman, Sameh E. Bassily, Rafik W. El-Sokkary, Ramadan I. Nasr, Adel Z. Nashed, Mina A. TI Improved Synthesis of 6-Azido-6-deoxy- and 6,6 '-Diazido-dideoxya-alpha,alpha- trehaloses SO SYNLETT LA English DT Article DE carbohydrate chemistry; regioselectivity; azides; protecting groups ID ALPHA-TREHALOSE; ANALOGS; DESIGN AB An efficient synthesis of 6-azido-6-deoxy and 6,6-diazido-dideoxy-,-trehalose derivatives was achieved by reaction of trifluoromethanesulfonic anhydride with partially trimethylsilylated heptakis- and hexakis-O-(trimethylsilyl)-,-trehalose in the presence of pyridine and 4-(N,N-dimethylamino)pyridine. Displacement with azide and desilylation afforded the title compounds, which represent potential precursors for the corresponding 6-amino- and 6,6-diamino-trehaloses. C1 [Narouz, Mina R.; Nasr, Adel Z.] Damanhour Univ, Fac Sci, Dept Chem, Damanhour, Beheira, Egypt. [Soliman, Sameh E.; Bassily, Rafik W.; El-Sokkary, Ramadan I.; Nashed, Mina A.] Univ Alexandria, Dept Chem, Fac Sci, Alexandria 21321, Egypt. [Soliman, Sameh E.] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. RP Nashed, MA (reprint author), Univ Alexandria, Dept Chem, Fac Sci, POB 426, Alexandria 21321, Egypt. EM mina4na@yahoo.com NR 11 TC 0 Z9 0 U1 1 U2 5 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0936-5214 EI 1437-2096 J9 SYNLETT JI Synlett PD OCT 22 PY 2013 VL 24 IS 17 BP 2271 EP 2273 DI 10.1055/s-0033-1339843 PG 3 WC Chemistry, Organic SC Chemistry GA 232GP UT WOS:000325480800017 ER PT J AU Ibarrondo, FJ Yang, OO Chodon, T Avramis, E Lee, Y Sazegar, H Jalil, J Chmielowski, B Koya, RC Schmid, I Gomez-Navarro, J Jamieson, BD Ribas, A Comin-Anduix, BA AF Ibarrondo, F. Javier Yang, Otto O. Chodon, Thinle Avramis, Earl Lee, Yohan Sazegar, Hooman Jalil, Jason Chmielowski, Bartosz Koya, Richard C. Schmid, Ingrid Gomez-Navarro, Jesus Jamieson, Beth D. Ribas, Antoni Comin-Anduix, Begon A. TI Natural Killer T Cells in Advanced Melanoma Patients Treated with Tremelimumab SO PLOS ONE LA English DT Article ID ACTIVATION-INDUCED EXPRESSION; INVARIANT NKT CELLS; METASTATIC MELANOMA; DENDRITIC CELLS; IN-VITRO; PHASE-I; CANCER-IMMUNOTHERAPY; MONOCLONAL-ANTIBODY; CYTOKINE SECRETION; CYTOLYTIC ACTIVITY AB A significant barrier to effective immune clearance of cancer is loss of antitumor cytotoxic T cell activity. Antibodies to block pro-apoptotic/downmodulatory signals to T cells are currently being tested. Because invariant natural killer T cells (iNKT) can regulate the balance of Th1/Th2 cellular immune responses, we characterized the frequencies of circulating iNKT cell subsets in 21 patients with melanoma who received the anti-CTLA4 monoclonal antibody tremelimumab alone and 8 patients who received the antibody in combination with MART-1(26-35) peptide-pulsed dendritic cells (MART-1/DC). Blood T cell phenotypes and functionality were characterized by flow cytometry before and after treatment. iNKT cells exhibited the central memory phenotype and showed polyfunctional cytokine production. In the combination treatment group, high frequencies of pro-inflammatory Th1 iNKT CD8(+) cells correlated with positive clinical responses. These results indicate that iNKT cells play a critical role in regulating effective antitumor T cell activity. C1 [Ibarrondo, F. Javier] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Ibarrondo, F. Javier; Yang, Otto O.; Jamieson, Beth D.] Univ Calif Los Angeles, David Geffen Sch Med, UCLA AIDS Inst, Los Angeles, CA 90095 USA. [Yang, Otto O.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. [Chodon, Thinle; Avramis, Earl; Sazegar, Hooman; Jalil, Jason; Chmielowski, Bartosz; Koya, Richard C.; Schmid, Ingrid; Jamieson, Beth D.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. [Lee, Yohan] NIMH, Dept Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Gomez-Navarro, Jesus] PGRD, Dept Clin Res, New London, CT USA. [Ribas, Antoni; Comin-Anduix, Begon A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Ribas, Antoni; Comin-Anduix, Begon A.] Univ Calif Los Angeles, Dept Med, Dept Surg, Div Surg Oncol, Los Angeles, CA 90024 USA. RP Ibarrondo, FJ (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. EM fibarrondo@mednet.ucla.edu; bcomin@mednet.ucla.edu OI Chmielowski, Bartosz/0000-0002-2374-3320 FU Pfizer Inc.; NIH [U54 CA119347]; National Institutes of Health [CA-16042, AI-28697] FX The authors are grateful to the generosity of a grant from Mr. Gerald Oppenheimer and Ambassador Holden. The conduct of both clinical trials was supported by research grants from Pfizer Inc., and the ex vivo cellular analysis by the NIH grant U54 CA119347. Flow cytometry was performed at the UCLA Jonsson Comprehensive Cancer Center (JCCC) Flow Cytometry Core Facility supported by National Institutes of Health awards CA-16042 and AI-28697. None of those companies funded the present study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 6 Z9 6 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 OCT 22 PY 2013 VL 8 IS 10 AR e76829 DI 10.1371/journal.pone.0076829 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239OF UT WOS:000326034500009 PM 24167550 ER PT J AU Zhuang, J Wang, PY Huang, XL Chen, XY Kang, JG Hwang, PM AF Zhuang, Jie Wang, Ping-yuan Huang, Xinglu Chen, Xiaoyuan Kang, Ju-Gyeong Hwang, Paul M. TI Mitochondrial disulfide relay mediates translocation of p53 and partitions its subcellular activity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mitochondrial DNA; DNA repair; mutant p53 ID LI-FRAUMENI-SYNDROME; IN-VIVO; DNA; PROTEIN; METABOLISM; OXIDATION; TRANSPORT; BINDING; SYSTEM; CELLS AB p53, a critical tumor suppressor, regulates mitochondrial respiration, but how a nuclear protein can orchestrate the function of an organelle encoded by two separate genomes, both of which require p53 for their integrity, remains unclear. Here we report that the mammalian homolog of the yeast mitochondrial disulfide relay protein Mia40 (CHCHD4) is necessary for the respiratory-dependent translocation of p53 into the mitochondria. In the setting of oxidative stress, increased CHCHD4 expression partitions p53 into the mitochondria and protects its genomic integrity while decreasing p53 nuclear localization and transcriptional activity. Conversely, decreased CHCHD4 expression prevents the mitochondrial translocation of p53 while augmenting its nuclear localization and activity. Thus, the mitochondrial disulfide relay system allows p53 to regulate two spatially segregated genomes depending on oxidative metabolic activity. C1 [Zhuang, Jie; Wang, Ping-yuan; Kang, Ju-Gyeong; Hwang, Paul M.] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Huang, Xinglu; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Hwang, PM (reprint author), NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. EM hwangp@mail.nih.gov FU Division of Intramural Research of the National Heart, Lung, and Blood Institute, National Institutes of Health FX We thank Alicia M. Evangelista for her kind assistance with adenovirus preparation, members of our laboratory Cory U. Lago and Jie Li for support, and Toren Finkel for helpful advice. This work was supported by the Division of Intramural Research of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 32 TC 26 Z9 26 U1 1 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 OCT 22 PY 2013 VL 110 IS 43 BP 17356 EP 17361 DI 10.1073/pnas.1310908110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 238JU UT WOS:000325943300048 PM 24101517 ER PT J AU Zhu, J Wu, XL Zhang, BS McKee, K O'Dell, S Soto, C Zhou, TQ Casazza, JP Mullikin, JC Kwong, PD Mascola, JR Shapiro, L AF Zhu, Jiang Wu, Xueling Zhang, Baoshan McKee, Krisha O'Dell, Sijy Soto, Cinque Zhou, Tongqing Casazza, Joseph P. Mullikin, James C. Kwong, Peter D. Mascola, John R. Shapiro, Lawrence CA NISC Comparative Sequencing Progra TI De novo identification of VRC01 class HIV-1-neutralizing antibodies by next-generation sequencing of B-cell transcripts SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antibodyomics; cross-donor phylogenetic analysis; DNA sequencing; humoral immune response; sequence signature ID STRUCTURAL BASIS; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; HIV-1 NEUTRALIZATION; NUCLEOTIDE-SEQUENCE; IMMUNOGEN DESIGN; INFLUENZA-VIRUS; BINDING-SITE; GENE USAGE; BROAD AB Next-generation sequencing of antibody transcripts provides a wealth of data, but the ability to identify function-specific antibodies solely on the basis of sequence has remained elusive. We previously characterized the VRC01 class of antibodies, which target the CD4-binding site on gp120, appear in multiple donors, and broadly neutralize HIV-1. Antibodies of this class have developmental commonalities, but typically share only similar to 50% amino acid sequence identity among different donors. Here we apply next-generation sequencing to identify VRC01 class antibodies in a new donor, C38, directly from B cell transcript sequences. We first tested a lineage rank approach, but this was unsuccessful, likely because VRC01 class antibody sequences were not highly prevalent in this donor. We next identified VRC01 class heavy chains through a phylogenetic analysis that included thousands of sequences from C38 and a few known VRC01 class sequences from other donors. This "cross-donor analysis" yielded heavy chains with little sequence homology to previously identified VRC01 class heavy chains. Nonetheless, when reconstituted with the light chain from VRC01, half of the heavy chain chimeric antibodies showed substantial neutralization potency and breadth. We then identified VRC01 class light chains through a five-amino-acid sequence motif necessary for VRC01 light chain recognition. From over a million light chain sequences, we identified 13 candidate VRC01 class members. Pairing of these light chains with the phylogenetically identified C38 heavy chains yielded functional antibodies that effectively neutralized HIV-1. Bioinformatics analysis can thus directly identify functional HIV-1-neutralizing antibodies of the VRC01 class from a sequenced antibody repertoire. C1 [Zhu, Jiang; Wu, Xueling; Zhang, Baoshan; McKee, Krisha; O'Dell, Sijy; Soto, Cinque; Zhou, Tongqing; Casazza, Joseph P.; Kwong, Peter D.; Mascola, John R.] NHGRI, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; Shapiro, Lawrence; NISC Comparative Sequencing Progra] NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. RP Kwong, PD (reprint author), NHGRI, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM pdkwong@nih.gov; jmascola@nih.gov; lss8@columbia.edu RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute, National Institutes of Health; International AIDS Vaccine Initiative's Neutralizing Antibody Consortium FX We thank J. Almeida and D. Douek for protocols of PBMC cDNA preparation and for helpful discussions; H. Coleman, S. Ho, M. Park, B. Schmidt, and A. Young for 454 pyrosequencing at the National Institutes of Health Intramural Sequencing Center; and J. Stuckey for assistance with figures. We also thank Rahul Kohli and members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions or comments on the manuscript. Support for this work was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases and the National Human Genome Research Institute, National Institutes of Health, and grants from the International AIDS Vaccine Initiative's Neutralizing Antibody Consortium. NR 48 TC 28 Z9 28 U1 0 U2 19 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 OCT 22 PY 2013 VL 110 IS 43 BP E4088 EP E4097 DI 10.1073/pnas.1306262110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 238JU UT WOS:000325943300008 PM 24106303 ER PT J AU Guyton, JR Slee, AE Anderson, T Fleg, JL Goldberg, RB Kashyap, ML Marcovina, SM Nash, SD O'Brien, KD Weintraub, WS Xu, P Zhao, XQ Boden, WE AF Guyton, John R. Slee, April E. Anderson, Todd Fleg, Jerome L. Goldberg, Ronald B. Kashyap, Moti L. Marcovina, Santica M. Nash, Stephen D. O'Brien, Kevin D. Weintraub, William S. Xu, Ping Zhao, Xue-Qiao Boden, William E. TI Relationship of Lipoproteins to Cardiovascular Events The AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular events; clinical trial; GPR109A; lipoproteins; niacin ID RELEASE NICOTINIC-ACID; CHOLESTEROL LEVELS; HEART-DISEASE; NIACIN; COMBINATION; PREVENTION; THERAPY; STRESS; CELLS AB Objectives This study sought to examine the relationship between niacin treatment, lipoproteins, and cardiovascular (CV) outcomes in this secondary analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial. Background During a 3-year follow-up in 3,414 patients with established CV disease and low high-density lipoprotein cholesterol (HDL-C) levels, combined niacin + low-density lipoprotein cholesterol (LDL-C)-lowering therapy did not reduce CV events compared with LDL-C-lowering therapy alone. Methods Subjects taking simvastatin and/or ezetimibe were randomized to receive extended-release (ER) niacin 1,500 to 2,000 mg or minimal immediate-release niacin (<= 150 mg) as placebo at bedtime. LDL-C levels in both groups were maintained from 40 to 80 mg/dl. Hazard ratios were estimated by using Cox proportional hazards models for relationships between lipoproteins and the composite endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. Results CV outcomes were not associated with ER niacin in any baseline lipoprotein tertile. In a subset of patients in both the highest triglyceride (>= 198 mg/dl) and lowest HDL-C (<33 mg/dl) tertiles, ER niacin showed a trend toward benefit (hazard ratio: 0.74, p = 0.073). In-trial LDL-C levels, non-HDL-C levels, and the total cholesterol/HDL-C ratio were positively associated with CV events in the control group, but these relationships were absent in the ER niacin group. Conclusions Baseline lipoprotein tertiles did not predict differential benefit or harm with ER niacin added to LDL-C-lowering therapy, but a small dyslipidemic subgroup may benefit. ER niacin attenuated expected relationships of lipoprotein risk factors with CV events, raising the possibility that nonlipoprotein actions of niacin could affect risk. (Niacin Plus Statin to Prevent Vascular Events [AIM-HIGH]; NCT00120289) (C) 2013 by the American College of Cardiology Foundation C1 [Guyton, John R.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Slee, April E.; Xu, Ping] Axio Res, Seattle, WA USA. [Anderson, Todd] Univ Calgary, Libin Cardiovasc Inst, Calgary, AB, Canada. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Goldberg, Ronald B.] Univ Miami, Leonard M Miller Sch Med, Dept Med, Hollywood, FL USA. [Kashyap, Moti L.] Vet Affairs Med Ctr, Long Beach, CA USA. [Kashyap, Moti L.] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Marcovina, Santica M.; O'Brien, Kevin D.; Zhao, Xue-Qiao] Univ Washington, Dept Med, Seattle, WA USA. [Nash, Stephen D.] SUNY Hlth Sci Ctr, Dept Med, Syracuse, NY 13210 USA. [Weintraub, William S.] Ctr Heart & Vasc Hlth, Newark, DE USA. [Boden, William E.] Samuel S Stratton VA Med Ctr, Dept Med, Albany, NY USA. RP Guyton, JR (reprint author), Duke Univ, Med Ctr, Box 3510,200 Trent Dr, Durham, NC 27710 USA. EM john.guyton@duke.edu FU National Heart, Lung, and Blood Institute [U01-HL-081616, U01-HL-081649]; Abbott Laboratories; Merck Co.; Kowa Pharmaceuticals America; Regeneron Pharmaceuticals; Sanofi US; Genzyme Corporation; Isis Pharmaceuticals; Amgen; Amarin Corporation; GlaxoSmithKline USA; Roche; Daiichi Sankyo; GlaxoSmithKline; AstraZeneca; Eli Lilly and Company; Sanofi; Amarin Pharmaceuticals; Pfizer FX This work was supported by the National Heart, Lung, and Blood Institute (U01-HL-081616 and U01-HL-081649) and by an unrestricted grant from Abbott Laboratories. Abbott Laboratories donated the extended-release niacin, the matching placebo, and the ezetimibe; Merck & Co. donated the simvastatin. Neither of these companies had any role in the oversight or design of the study, or in the analysis or interpretation of the data. Dr. Guyton has received consultation fees from Merck & Co. and Kowa Pharmaceuticals America; research grants from Merck & Co., Regeneron Pharmaceuticals, Sanofi US, Genzyme Corporation, Isis Pharmaceuticals, Amgen, Amarin Corporation, and GlaxoSmithKline USA; and owns $14,000 common stock in Eli Lilly and Company. Dr. Anderson has received clinical trials research funding from Merck & Co., Roche, and Abbott Laboratories. Dr. Goldberg has received research funding from Abbott Laboratories, Daiichi Sankyo, GlaxoSmithKline, and Roche. Dr. Kashyap has received research grants from Abbott Laboratories, Amgen, AstraZeneca, Eli Lilly and Company, Roche, and Sanofi; and honoraria as a speaker/consultant for Abbott Laboratories, Amarin Pharmaceuticals, Kos (was bought by Abbott Laboratories in 2006), and Merck & Co. Dr. Nash is a member of the speaker's bureau for Daiichi Sankyo, Takeda Pharmaceutical, and Amarin Pharmaceuticals; and has received research funding from Amarin Pharmaceuticals, AstraZeneca, Merck & Co., and Roche. Dr. Zhao has received research funding from Pfizer, Merck & Co., Abbott Laboratories, and Daiichi Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 22 TC 67 Z9 68 U1 1 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 22 PY 2013 VL 62 IS 17 BP 1580 EP 1584 DI 10.1016/j.jacc.2013.07.023 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 238HY UT WOS:000325937400007 PM 23916935 ER PT J AU Peprah, E Wonkam, A AF Peprah, Emmanuel Wonkam, Ambroise TI Biomedical research, a tool to address the health issues that affect African populations SO GLOBALIZATION AND HEALTH LA English DT Article DE Genomics; Biomedical; Research; Africa; Development; Policy ID GENOME-WIDE ASSOCIATION; SICKLE-CELL-DISEASE; SUB-SAHARAN AFRICA; SYSTEMATIC ANALYSIS; GLOBAL BURDEN; DEVELOPING-COUNTRIES; FUTURE OPPORTUNITIES; SOUTH-AFRICA; BRAIN-DRAIN; PLASMODIUM-FALCIPARUM AB Traditionally, biomedical research endeavors in low to middle resources countries have focused on communicable diseases. However, data collected over the past 20 years by the World Health Organization (WHO) show a significant increase in the number of people suffering from non-communicable diseases (e. g. heart disease, diabetes, cancer and pulmonary diseases). Within the coming years, WHO predicts significant decreases in communicable diseases while non-communicable diseases are expected to double in low and middle income countries in sub-Saharan Africa. The predicted increase in the non-communicable diseases population could be economically burdensome for the basic healthcare infrastructure of countries that lack resources to address this emerging disease burden. Biomedical research could stimulate development of healthcare and biomedical infrastructure. If this development is sustainable, it provides an opportunity to alleviate the burden of both communicable and non-communicable diseases through diagnosis, prevention and treatment. In this paper, we discuss how research using biomedical technology, especially genomics, has produced data that enhances the understanding and treatment of both communicable and non-communicable diseases in sub-Saharan Africa. We further discuss how scientific development can provide opportunities to pursue research areas responsive to the African populations. We limit our discussion to biomedical research in the areas of genomics due to its substantial impact on the scientific community in recent years however, we also recognize that targeted investments in other scientific disciplines could also foster further development in African countries. C1 [Wonkam, Ambroise] Univ Cape Town, Fac Hlth Sci, Div Human Genet, ZA-7925 Cape Town, South Africa. RP Peprah, E (reprint author), NIH, Bldg 1,RM 256A, Bethesda, MD 20892 USA. EM peprahek@mail.nih.gov NR 89 TC 4 Z9 4 U1 5 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8603 J9 GLOBALIZATION HEALTH JI Global. Health PD OCT 21 PY 2013 VL 9 AR UNSP 50 DI 10.1186/1744-8603-9-50 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 246LM UT WOS:000326539700001 PM 24143865 ER PT J AU Sawai, CM Sisirak, V Ghosh, HS Hou, EZ Ceribelli, M Staudt, LM Reizis, B AF Sawai, Catherine M. Sisirak, Vanja Ghosh, Hiyaa S. Hou, Esther Z. Ceribelli, Michele Staudt, Louis M. Reizis, Boris TI Transcription factor Runx2 controls the development and migration of plasmacytoid dendritic cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID FACTOR NETWORKS; FACTOR E2-2; EXPRESSION; RECRUITMENT; LY49Q; MONOCYTES; INFECTION; RECEPTOR; SUBSETS; LINEAGE AB Plasmacytoid dendritic cells (pDCs) rapidly produce type I interferon (IFN-I) in response to viruses and are essential for antiviral immune responses. Although related to classical DCs (cDCs) in their development and expression profile, pDCs possess many distinct features. Unlike cDCs, pDCs develop in the bone marrow (BM) and emerge into peripheral lymphoid organs and tissues as fully differentiated cells. We now report that pDCs specifically express Runx2, a Runt family transcription factor that is essential for bone development. pDCs in Runx2-deficient mice developed normally in the BM but were greatly reduced in the periphery. The defect was cell-intrinsic and was associated with the retention of mature Ly49Q(+) pDCs in the BM. Runx2 was required for the expression of several pDC-enriched genes, including the chemokine receptors Ccr2 and Ccr5. Mature pDCs expressed high levels of Ccr5 at the cell surface, and Ccr5-deficient pDCs in a competitive setting were reduced in the periphery relative to the BM. Thus, Runx2 is required for the emergence of mature BM pDCs into the periphery, in a process that is partially dependent on Ccr5. These results establish Runx2 as a lineage-specific regulator of immune system development. C1 [Sawai, Catherine M.; Sisirak, Vanja; Ghosh, Hiyaa S.; Hou, Esther Z.; Reizis, Boris] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. [Ceribelli, Michele; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Reizis, B (reprint author), Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10032 USA. EM bvr2101@columbia.edu RI Sisirak, Vanja/O-9393-2016; OI Sisirak, Vanja/0000-0003-3070-6533; Reizis, Boris/0000-0003-1140-7853 FU New York State Department of Health [N09G-22]; National Institutes of Health [AI072571]; Leona M. and Harry B. Helmsley Charitable Trust; Irvington Institute Fellowship of the Cancer Research Institute; American Society of Hematology FX This work was supported by the New York State Department of Health grant N09G-22, National Institutes of Health grant AI072571, and Leona M. and Harry B. Helmsley Charitable Trust (B. Reizis), Irvington Institute Fellowship of the Cancer Research Institute (V. Sisirak), and American Society of Hematology (H.S. Ghosh). NR 33 TC 22 Z9 25 U1 0 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD OCT 21 PY 2013 VL 210 IS 11 BP 2151 EP 2159 DI 10.1084/jem.20130443 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 239BX UT WOS:000325997600002 PM 24101375 ER PT J AU Bouchlaka, MN Sckisel, GD Chen, MY Mirsoian, A Zamora, AE Maverakis, E Wilkins, DEC Alderson, KL Hsiao, HH Weiss, JM Monjazeb, AM Hesdorffer, C Ferrucci, L Longo, DL Blazar, BR Wiltrout, RH Redelman, D Taub, DD Murphy, WJ AF Bouchlaka, Myriam N. Sckisel, Gail D. Chen, Mingyi Mirsoian, Annie Zamora, Anthony E. Maverakis, Emanual Wilkins, Danice E. C. Alderson, Kory L. Hsiao, Hui-Hua Weiss, Jonathan M. Monjazeb, Arta M. Hesdorffer, Charles Ferrucci, Luigi Longo, Dan L. Blazar, Bruce R. Wiltrout, Robert H. Redelman, Doug Taub, Dennis D. Murphy, William J. TI Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NECROSIS-FACTOR-ALPHA; VERSUS-HOST-DISEASE; TNF-ALPHA; RHEUMATOID-ARTHRITIS; IFN-GAMMA; ALLOGRAFT-REJECTION; MONOCLONAL-ANTIBODY; INSULIN-RESISTANCE; CELL RESPONSES; IN-VIVO AB Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knock-out mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immuno-stimulation and underscore the importance of performing preclinical assessments in aged mice. C1 [Bouchlaka, Myriam N.; Wilkins, Danice E. C.; Alderson, Kory L.] Univ Nevada, Dept Microbiol & Immunol, Reno Sch Med, Reno, NV 89557 USA. [Redelman, Doug] Univ Nevada, Dept Physiol & Cell Biol, Reno Sch Med, Reno, NV 89557 USA. [Sckisel, Gail D.; Mirsoian, Annie; Zamora, Anthony E.; Hsiao, Hui-Hua; Murphy, William J.] Univ Calif Davis, Dept Dermatol, Davis, CA 95817 USA. [Chen, Mingyi] Univ Calif Davis, Dept Pathol & Lab Med, Davis, CA 95817 USA. [Monjazeb, Arta M.] Univ Calif Davis, Dept Radiat Oncol, Davis, CA 95817 USA. [Murphy, William J.] Univ Calif Davis, Dept Internal Med, Davis, CA 95817 USA. [Maverakis, Emanual] VA Northern Calif Hlth Care Syst, Mather, CA 95655 USA. [Weiss, Jonathan M.; Wiltrout, Robert H.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Hesdorffer, Charles; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Longo, Dan L.; Taub, Dennis D.] NIA, Lab Immunol, Baltimore, MD 21224 USA. [Blazar, Bruce R.] Univ Minnesota, Div Blood & Marrow Transplantat, Dept Pediat, Minneapolis, MN 55455 USA. RP Murphy, WJ (reprint author), Univ Calif Davis, Dept Dermatol, Davis, CA 95817 USA. EM wmjmurphy@ucdavis.edu OI Bouchlaka, Myriam/0000-0003-2865-0817; Maverakis, Emanual/0000-0002-6294-6294 FU National Institutes of Health [CA0905572, AG034874]; Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work was supported by grants from the National Institutes of Health (CA0905572 and AG034874) and by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 62 TC 29 Z9 29 U1 0 U2 15 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD OCT 21 PY 2013 VL 210 IS 11 BP 2223 EP 2237 DI 10.1084/jem.20131219 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 239BX UT WOS:000325997600008 PM 24081947 ER PT J AU Sirois, CM Jin, TC Miller, AL Bertheloot, D Nakamura, H Horvath, GL Mian, A Jiang, JS Schrum, J Bossaller, L Pelka, K Garbi, N Brewah, Y Tian, J Chang, CS Chowdhury, PS Sims, GP Kolbeck, R Coyle, AJ Humbles, AA Xiao, TS Latz, E AF Sirois, Cherilyn M. Jin, Tengchuan Miller, Allison L. Bertheloot, Damien Nakamura, Hirotaka Horvath, Gabor L. Mian, Abubakar Jiang, Jiansheng Schrum, Jacob Bossaller, Lukas Pelka, Karin Garbi, Natalio Brewah, Yambasu Tian, Jane Chang, ChewShun Chowdhury, Partha S. Sims, Gary P. Kolbeck, Roland Coyle, Anthony J. Humbles, Alison A. Xiao, T. Sam Latz, Eicke TI RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID GLYCATION END-PRODUCTS; TOLL-LIKE RECEPTORS; X-RAY-DIFFRACTION; CYTOPLASMIC DOMAIN; IMMUNE-RESPONSES; STRUCTURAL BASIS; DENDRITIC CELLS; OXIDANT STRESS; IN-VIVO; KAPPA-B AB Recognition of DNA and RNA molecules derived from pathogens or self-antigen is one way the mammalian immune system senses infection and tissue damage. Activation of immune signaling receptors by nucleic acids is controlled by limiting the access of DNA and RNA to intracellular receptors, but the mechanisms by which endosome-resident receptors encounter nucleic acids from the extracellular space are largely undefined. In this study, we show that the receptor for advanced glycation end-products (RAGE) promoted DNA uptake into endosomes and lowered the immune recognition threshold for the activation of Toll-like receptor 9, the principal DNA-recognizing transmembrane signaling receptor. Structural analysis of RAGE-DNA complexes indicated that DNA interacted with dimers of the outer-most RAGE extracellular domains, and could induce formation of higher-order receptor complexes. Furthermore, mice deficient in RAGE were unable to mount a typical inflammatory response to DNA in the lung, indicating that RAGE is important for the detection of nucleic acids in vivo. C1 [Sirois, Cherilyn M.; Nakamura, Hirotaka; Horvath, Gabor L.; Schrum, Jacob; Bossaller, Lukas; Latz, Eicke] Univ Massachusetts, Dept Med, Div Infect Dis & Immunol, Sch Med, Worcester, MA 01605 USA. [Jin, Tengchuan; Mian, Abubakar; Jiang, Jiansheng; Xiao, T. Sam] NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Miller, Allison L.; Brewah, Yambasu; Tian, Jane; Sims, Gary P.; Kolbeck, Roland; Coyle, Anthony J.; Humbles, Alison A.] MedImmune LLC, Div Resp Inflammat & Autoimmun, Gaithersburg, MD 20878 USA. [Chang, ChewShun; Chowdhury, Partha S.] MedImmune LLC, Dept Antibody Discovery & Prot Engn, Gaithersburg, MD 20878 USA. [Bertheloot, Damien; Horvath, Gabor L.] Univ Bonn, Inst Innate Immun, D-53127 Bonn, Germany. [Coyle, Anthony J.] Pfizer Inc, Ctr Therapeut Innovat, Boston, MA 02115 USA. [Latz, Eicke] German Ctr Neurodegenerat Dis DZNE, D-53175 Bonn, Germany. RP Latz, E (reprint author), Univ Massachusetts, Dept Med, Div Infect Dis & Immunol, Sch Med, Worcester, MA 01605 USA. EM xiaot@niaid.nih.gov; eicke.latz@uni-bonn.de RI Xiao, Tsan/A-8590-2010; Garbi, Natalio/H-7666-2014; Jin, Tengchuan/B-5883-2014; Horvath, Gabor/J-3917-2014; Latz, Eicke/H-3951-2014; OI Jin, Tengchuan/0000-0002-1395-188X; Horvath, Gabor/0000-0003-0309-595X; Latz, Eicke/0000-0003-1488-5666; Sirois, Cherilyn M./0000-0002-5472-4288 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); NIH; Deutsche Forschungsgesellschaft (DFG) [SFB704] FX T.S. Xiao is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). E. Latz is supported in part by grants from the NIH and the Deutsche Forschungsgesellschaft (DFG, SFB704). E. Latz is a member of the ImmunoSensation Excellence cluster of the DFG and a member of the German Center for Infectious Diseases (DZIF). NR 68 TC 41 Z9 42 U1 1 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD OCT 21 PY 2013 VL 210 IS 11 BP 2447 EP 2463 DI 10.1084/jem.20120201 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 239BX UT WOS:000325997600022 PM 24081950 ER PT J AU Henry, HF Burken, JG Maier, RM Newman, LA Rock, S Schnoor, JL Suk, WA AF Henry, Heather F. Burken, Joel G. Maier, Raina M. Newman, Lee A. Rock, Steven Schnoor, Jerald L. Suk, William A. TI Phytotechnologies Preventing Exposures, Improving Public Health SO INTERNATIONAL JOURNAL OF PHYTOREMEDIATION LA English DT Article; Proceedings Paper CT 8th Annual Conference, International Phytotechnology Society, Putting Plants to Work, Where We Live, Labor, Breathe, and Play CY SEP 13-16, 2011 CL Portland, OR DE phytotechnologies; sustainability; exposure prevention; primary prevention; public health; airborne pollution; water contamination; food safety; developing countries ID SOIL; DENDROCHEMISTRY; REMEDIATION; PHYTOSTABILIZATION; CONTAMINANTS; TAILINGS AB Phytotechnologies have potential to reduce the amount or toxicity of deleterious chemicals and agents, and thereby, can reduce human exposures to hazardous substances. As such, phytotechnologies are tools for primary prevention in public health. Recent research demonstrates phytotechnologies can be uniquely tailored for effective exposure prevention in a variety of applications. In addition to exposure prevention, plants can be used as sensors to identify environmental contamination and potential exposures. In this paper, we have presented applications and research developments in a framework to illustrate how phytotechnologies can meet basic public health needs for access to clean water, air, and food. Because communities can often integrate plant-based technologies at minimal cost and with low infrastructure needs, the use of these technologies can be applied broadly to minimize potential contaminant exposure and improve environmental quality. These natural treatment systems also provide valuable ecosystem services to communities and society. In the future, integrating and coordinating phytotechnology activities with public health research will allow technology development focused on prevention of environmental exposures to toxic compounds. Hence, phytotechnologies may provide sustainable solutions to environmental exposure challenges, improving public health and potentially reducing the burden of disease. C1 [Henry, Heather F.; Suk, William A.] NIEHS, Superfund Res Program, Res Triangle Pk, NC 27709 USA. [Burken, Joel G.] Missouri Univ Sci & Technol, Rolla, MO USA. [Maier, Raina M.] Univ Arizona, Ctr Environm Sustainable Min, Dept Soil Water & Environm Sci, Tucson, AZ USA. [Newman, Lee A.] SUNY Syracuse, Coll Environm Sci & Technol, Syracuse, NY USA. [Rock, Steven] US EPA, Remediat & Contaminant Branch, Natl Risk Management Res Lab, Cincinnati, OH USA. [Schnoor, Jerald L.] Univ Iowa, Coll Engn, Dept Civil & Environm Engn, Iowa City, IA 52242 USA. RP Henry, HF (reprint author), NIEHS, Superfund Res Program, POB 12233 K 304, Res Triangle Pk, NC 27709 USA. EM henryh@niehs.nih.gov RI Burken, Joel /C-2099-2016 OI Burken, Joel /0000-0002-7774-5364 FU National Institute of Environmental Health Sciences (NIEHS) FX This manuscript is based on a series of presentations and breakout sessions linking human health and phytotechnologies initiated at the 2009 International Phytotechnologies Society Conference in St. Louis, MO, USA. 2011 Health Sessions: Tracy Punshon, Dartmouth College; Raina M. Maier, University of Arizona; Stanislaw Gawronski, Warsaw University of Life Sciences, Poland; Mackenzie J. Denyes, The Royal Military College of Canada; Lee Newman, SUNY - ESF; Heather Henry, NIEHS; 2010 Health Sessions: Joel G. Burken, Missouri University of Science and Technology; Steven Rock, USEPA; Jerald L. Schnoor, University of Iowa; Jean-Christophe Balouet, Environment International; Lee A Newman, SUNY-ESF; Nelson Marmiroli, University of Parma; Peter Schroder, Helmholtz Zentrum Munchen (Marimoli 2012). 2009 Health Plenary: William A. Suk, NIEHS. These sessions were funded, in part, by the National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program (SRP) which advances its mission to reduce the public health burden of hazardous substances through interdisciplinary research. This paper is not intended to be a comprehensive review; rather, the phytotechnology research presented herein are examples to illustrate the linkages of plant-based remediation to primary prevention in the context of public health. The authors would like to thank Jason White, Thaddeus Schug, Kimberly Thigpen-Tart, Mary Lou Guerinot, and Payal Chokshi for their assistance in editing and formatting (PC) this document. 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 45 TC 12 Z9 12 U1 0 U2 223 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1522-6514 EI 1549-7879 J9 INT J PHYTOREMEDIAT JI Int. J. Phytoremediat. PD OCT 21 PY 2013 VL 15 IS 9 SI SI BP 889 EP 899 DI 10.1080/15226514.2012.760521 PG 11 WC Environmental Sciences SC Environmental Sciences & Ecology GA 097NJ UT WOS:000315480500006 PM 23819283 ER PT J AU Guy, GP Ekwueme, DU Yabroff, KR Dowling, EC Li, CY Rodriguez, JL de Moor, JS Virgo, KS AF Guy, Gery P., Jr. Ekwueme, Donatus U. Yabroff, K. Robin Dowling, Emily C. Li, Chunyu Rodriguez, Juan L. de Moor, Janet S. Virgo, Katherine S. TI Economic Burden of Cancer Survivorship Among Adults in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID EXPENDITURE PANEL SURVEY; 2ND PRIMARY CANCERS; BREAST-CANCER; PRODUCTIVITY COSTS; LESS-THAN-65 YEARS; MEDICAL-CARE; PREVALENCE; CALIFORNIA; AGE; MORTALITY AB Purpose To present nationally representative estimates of the impact of cancer survivorship on medical expenditures and lost productivity among adults in the United States. Methods Using the 2008 to 2010 Medical Expenditure Panel Survey, we identified 4,960 cancer survivors and 64,431 individuals without a history of cancer age >= 18 years. Direct medical costs were measured using annual health care expenditures and examined by source of payment and service type. Indirect morbidity costs were estimated from lost productivity as a result of employment disability, missed work days, and lost household productivity. We evaluated the economic burden of cancer survivorship by estimating excess costs among cancer survivors, stratified by time since diagnosis (recently diagnosed [<= 1 year] and previously diagnosed [> 1 year]), compared with individuals without a history of cancer using multivariable regression models stratified by age (18 to 64 and >= 65 years), controlling for age, sex, race/ethnicity, education, and comorbidities. Results In 2008 to 2010, the annual excess economic burden of cancer survivorship among recently diagnosed cancer survivors was $16,213 per survivor age 18 to 64 years and $16,441 per survivor age >= 65 years. Among previously diagnosed cancer survivors, the annual excess burden was $4,427 per survivor age 18 to 64 years and $4,519 per survivor age >= 65 years. Excess medical expenditures composed the largest share of the economic burden among cancer survivors, particularly among those recently diagnosed. Conclusion The economic impact of cancer survivorship is considerable and is also high years after a cancer diagnosis. Efforts to reduce the economic burden caused by cancer will be increasingly important given the growing population of cancer survivors. C1 [Guy, Gery P., Jr.; Ekwueme, Donatus U.; Li, Chunyu; Rodriguez, Juan L.] Ctr Res Dis Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Virgo, Katherine S.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Yabroff, K. Robin; de Moor, Janet S.] NCI, Bethesda, MD 20892 USA. [Dowling, Emily C.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. RP Guy, GP (reprint author), Ctr Res Dis Prevent, Div Canc Prevent & Control, 4770 Buford Highway,NE,F76, Atlanta, GA 30341 USA. EM irm2@cdc.gov OI Yabroff, K. Robin/0000-0003-0644-5572 NR 42 TC 44 Z9 44 U1 1 U2 9 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 OCT 20 PY 2013 VL 31 IS 30 BP 3749 EP 3757 DI 10.1200/JCO.2013.49.1241 PG 9 WC Oncology SC Oncology GA 301OA UT WOS:000330540400011 PM 24043731 ER PT J AU Fowkes, FGR Rudan, D Rudan, I Aboyans, V Denenberg, JO McDermott, MM Norman, PE Sampson, UKA Williams, LJ Mensah, GA Criqui, MH AF Fowkes, F. Gerald R. Rudan, Diana Rudan, Igor Aboyans, Victor Denenberg, Julie O. McDermott, Mary M. Norman, Paul E. Sampson, Uchechukwe K. A. Williams, Linda J. Mensah, George A. Criqui, Michael H. TI Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis SO LANCET LA English DT Article ID ANKLE-BRACHIAL INDEX; NUTRITION EXAMINATION SURVEY; C-REACTIVE PROTEIN; CARDIOVASCULAR RISK; NATIONAL-HEALTH; INTERMITTENT CLAUDICATION; GENERAL-POPULATION; ELDERLY CHINESE; LEG SYMPTOMS; MORTALITY AB Background Lower extremity peripheral artery disease is the third leading cause of atherosclerotic cardiovascular morbidity, following coronary artery disease and stroke. This study provides the first comparison of the prevalence of peripheral artery disease between high-income countries (HIC) and low-income or middle-income countries (LMIC), establishes the primary risk factors for peripheral artery disease in these settings, and estimates the number of people living with peripheral artery disease regionally and globally. Methods We did a systematic review of the literature on the prevalence of peripheral artery disease in which we searched for community-based studies since 1997 that defined peripheral artery disease as an ankle brachial index (ABI) lower than or equal to 0.90. We used epidemiological modelling to defi ne age-specific and sex-specific prevalence rates in HIC and in LMIC and combined them with UN population numbers for 2000 and 2010 to estimate the global prevalence of peripheral artery disease. Within a subset of studies, we did meta-analyses of odds ratios (ORs) associated with 15 putative risk factors for peripheral artery disease to estimate their effect size in HIC and LMIC. We then used the risk factors to predict peripheral artery disease numbers in eight WHO regions (three HIC and five LMIC). Findings 34 studies satisfied the inclusion criteria, 22 from HIC and 12 from LMIC, including 112 027 participants, of which 9347 had peripheral artery disease. Sex-specific prevalence rates increased with age and were broadly similar in HIC and LMIC and in men and women. The prevalence in HIC at age 45-49 years was 5.28% (95% CI 3.38-8.17%) in women and 5.41% (3.41-8.49%) in men, and at age 85-89 years, it was 18.38% (11.16-28.76%) in women and 18.83% (12.03-28.25%) in men. Prevalence in men was lower in LMIC than in HIC (2.89% [2.04-4.07%] at 45-49 years and 14.94% [9.58-22.56%] at 85-89 years). In LMIC, rates were higher in women than in men, especially at younger ages (6.31% [4.86-8.15%] of women aged 45-49 years). Smoking was an important risk factor in both HIC and LMIC, with meta-OR for current smoking of 2.72 (95% CI 2.39-3.09) in HIC and 1.42 (1.25-1.62) in LMIC, followed by diabetes (1.88 [1.66-2.14] vs 1.47 [1.29-1.68]), hypertension (1.55 [1.42-1.71] vs 1.36 [1.24-1.50]), and hypercholesterolaemia (1.19 [1.07-1.33] vs 1.14 [1.03-1.25]). Globally, 202 million people were living with peripheral artery disease in 2010, 69.7% of them in LMIC, including 54.8 million in southeast Asia and 45.9 million in the western Pacific Region. During the preceding decade the number of individuals with peripheral artery disease increased by 28.7% in LMIC and 13.1% in HIC. Interpretation In the 21st century, peripheral artery disease has become a global problem. Governments, non-governmental organisations, and the private sector in LMIC need to address the social and economic consequences, and assess the best strategies for optimum treatment and prevention of this disease. C1 [Fowkes, F. Gerald R.; Rudan, Diana; Rudan, Igor; Williams, Linda J.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Rudan, Diana] Univ Hosp Dubrava, Zagreb, Croatia. [Aboyans, Victor] Dupuytren Univ Hosp, Dept Cardiol, Limoges, France. [Aboyans, Victor] INSERM, U1094, Limoges, France. [Denenberg, Julie O.; Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [McDermott, Mary M.] Northwestern Univ, Feinberg Sch, Dept Med & Prevent Med, Chicago, IL 60611 USA. [Norman, Paul E.] Univ Western Australia, Sch Surg, Fremantle, WA, Australia. [Sampson, Uchechukwe K. A.] Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville, TN USA. [Mensah, George A.] NHLBI, Immediate Off Director, NIH, Bethesda, MD 20892 USA. RP Fowkes, FGR (reprint author), Univ Edinburgh, Ctr Populat Hlth Sci, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland. EM gerry.fowkes@ed.ac.uk RI Rudan, Igor/I-1467-2012; OI Rudan, Igor/0000-0001-6993-6884; Mensah, George/0000-0002-0387-5326; Aboyans, Victor/0000-0002-0322-9818 FU Peripheral Arterial Disease Research Coalition (Europe) FX Peripheral Arterial Disease Research Coalition (Europe). NR 71 TC 295 Z9 311 U1 10 U2 55 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 19 PY 2013 VL 382 IS 9901 BP 1329 EP 1340 DI 10.1016/S0140-6736(13)61249-0 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 238UG UT WOS:000325975700023 PM 23915883 ER PT J AU Furman, C Mehla, J Ananthaswamy, N Arya, N Kulesh, B Kovach, I Ambudkar, SV Golin, J AF Furman, Christopher Mehla, Jitender Ananthaswamy, Neeti Arya, Nidhi Kulesh, Bridget Kovach, Ildiko Ambudkar, Suresh V. Golin, John TI The Deviant ATP-binding Site of the Multidrug Efflux Pump Pdr5 Plays an Active Role in the Transport Cycle SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE ABC Transporter; ATPases; Drug Transport; Membrane Proteins; Multidrug Transporters ID DOUBLE-MUTANT CYCLES; CANDIDA-ALBICANS; ABC TRANSPORTER; DRUG TRANSPORTER; RESISTANCE; HYDROLYSIS; YEAST; DOMAIN; MECHANISMS; INTERFACE AB Pdr5 is the founding member of a large subfamily of evolutionarily distinct, clinically important fungal ABC transporters containing a characteristic, deviant ATP-binding site with altered Walker A, Walker B, Signature (C-loop), and Q-loop residues. In contrast to these motifs, the D-loops of the two ATP-binding sites have similar sequences, including a completely conserved aspartate residue. Alanine substitution mutants in the deviant Walker A and Signature motifs retain significant, albeit reduced, ATPase activity and drug resistance. The D-loop residue mutants D340A and D1042A showed a striking reduction in plasma membrane transporter levels. The D1042N mutation localized properly had nearly WT ATPase activity but was defective in transport and was profoundly hypersensitive to Pdr5 substrates. Therefore, there was a strong uncoupling of ATPase activity and drug efflux. Taken together, the properties of the mutants suggest an additional, critical intradomain signaling role for deviant ATP-binding sites. C1 [Furman, Christopher; Mehla, Jitender; Ananthaswamy, Neeti; Arya, Nidhi; Kulesh, Bridget; Kovach, Ildiko; Golin, John] Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. Catholic Univ Amer, Dept Chem, Washington, DC 20064 USA. [Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Golin, J (reprint author), Catholic Univ Amer, Dept Biol, 620 Michigan Ave NE, Washington, DC 20064 USA. EM golin@cua.edu RI Mehla, Jitender/M-6165-2016 OI Mehla, Jitender/0000-0002-7829-557X FU National Institutes of Health [GM07721]; National Science Foundation [MCB1048838]; Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research FX This work was supported, in whole or in part, by National Institutes of Health Grant GM07721 (to J.G.). This work was also supported by National Science Foundation Grant MCB1048838 and funds from the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research (to S. V. A.). NR 33 TC 13 Z9 13 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 18 PY 2013 VL 288 IS 42 BP 30420 EP 30431 DI 10.1074/jbc.M113.494682 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 291YF UT WOS:000329868100038 PM 24019526 ER PT J AU Dorelien, AM Ballesteros, S Grenfell, BT AF Dorelien, Audrey M. Ballesteros, Sebastien Grenfell, Bryan T. TI Impact of Birth Seasonality on Dynamics of Acute Immunizing Infections in Sub-Saharan Africa SO PLOS ONE LA English DT Article ID TIME-SERIES; MEASLES; EPIDEMICS; DISEASES; RATES; TRANSMISSION; VACCINATION; RESONANCE; PATTERNS; MODEL AB We analyze the impact of birth seasonality (seasonal oscillations in the birth rate) on the dynamics of acute, immunizing childhood infectious diseases. Previous research has explored the effect of human birth seasonality on infectious disease dynamics using parameters appropriate for the developed world. We build on this work by including in our analysis an extended range of baseline birth rates and amplitudes, which correspond to developing world settings. Additionally, our analysis accounts for seasonal forcing both in births and contact rates. We focus in particular on the dynamics of measles. In the absence of seasonal transmission rates or stochastic forcing, for typical measles epidemiological parameters, birth seasonality induces either annual or biennial epidemics. Changes in the magnitude of the birth fluctuations (birth amplitude) can induce significant changes in the size of the epidemic peaks, but have little impact on timing of disease epidemics within the year. In contrast, changes to the birth seasonality phase (location of the peak in birth amplitude within the year) significantly influence the timing of the epidemics. In the presence of seasonality in contact rates, at relatively low birth rates (20 per 1000), birth amplitude has little impact on the dynamics but does have an impact on the magnitude and timing of the epidemics. However, as the mean birth rate increases, both birth amplitude and phase play an important role in driving the dynamics of the epidemic. There are stronger effects at higher birth rates. C1 [Dorelien, Audrey M.] Univ Michigan, Ctr Social Epidemiol & Populat Hlth, Ann Arbor, MI 48109 USA. [Ballesteros, Sebastien; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Dorelien, AM (reprint author), Univ Michigan, Ctr Social Epidemiol & Populat Hlth, Ann Arbor, MI 48109 USA. EM dorelien@umich.edu OI Dorelien, Audrey/0000-0002-0618-4782 FU National Institute for Child Health and Human Development [R24HD047879]; National Science Foundation [EF-0742373]; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Department of Homeland Security Science and Technology Directorate; Fogarty International Center, National Institutes of Health FX Audrey M. Dorelien was supported by the National Institute for Child Health and Human Development, Grant No. R24HD047879, to the Office of Population Research at Princeton University. Bryan Grenfell was supported by the National Science Foundation grant EF-0742373 and the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Department of Homeland Security Science and Technology Directorate and the Fogarty International Center, 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 32 TC 10 Z9 10 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 OCT 18 PY 2013 VL 8 IS 10 AR e75806 DI 10.1371/journal.pone.0075806 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239MM UT WOS:000326029300004 PM 24204580 ER PT J AU Godiksen, S Soendergaard, C Friis, S Jensen, JK Bornholdt, J Sales, KU Huang, MD Bugge, TH Vogel, LK AF Godiksen, Sine Soendergaard, Christoffer Friis, Stine Jensen, Jan K. Bornholdt, Jette Sales, Katiuchia Uzzun Huang, Mingdong Bugge, Thomas H. Vogel, Lotte K. TI Detection of Active Matriptase Using a Biotinylated Chloromethyl Ketone Peptide SO PLOS ONE LA English DT Article ID TISSUE-PLASMINOGEN-ACTIVATOR; SERINE-PROTEASE MATRIPTASE; NEURAL-TUBE CLOSURE; ZYMOGEN ACTIVATION; PLACENTAL DEVELOPMENT; EPITHELIAL-CELLS; BARRIER FUNCTION; IN-VITRO; INHIBITOR; COMPLEX AB Matriptase is a member of the family of type II transmembrane serine proteases that is essential for development and maintenance of several epithelial tissues. Matriptase is synthesized as a single-chain zymogen precursor that is processed into a two-chain disulfide-linked form dependent on its own catalytic activity leading to the hypothesis that matriptase functions at the pinnacle of several protease induced signal cascades. Matriptase is usually found in either its zymogen form or in a complex with its cognate inhibitor hepatocyte growth factor activator inhibitor 1 (HAI-1), whereas the active non-inhibited form has been difficult to detect. In this study, we have developed an assay to detect enzymatically active non-inhibitor-complexed matriptase by using a biotinylated peptide substrate-based chloromethyl ketone (CMK) inhibitor. Covalently CMK peptide-bound matriptase is detected by streptavidin pull-down and subsequent analysis by Western blotting. This study presents a novel assay for detection of enzymatically active matriptase in living human and murine cells. The assay can be applied to a variety of cell systems and species. C1 [Godiksen, Sine; Soendergaard, Christoffer; Friis, Stine; Bornholdt, Jette; Vogel, Lotte K.] Univ Copenhagen, Dept Cellular & Mol Med, Copenhagen, Denmark. [Godiksen, Sine] Univ Copenhagen, Dept Biol, Copenhagen, Denmark. [Godiksen, Sine; Friis, Stine; Sales, Katiuchia Uzzun; Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Bethesda, MD USA. [Jensen, Jan K.] Aarhus Univ, Dept Mol Biol & Genet, Aarhus, Denmark. [Jensen, Jan K.; Huang, Mingdong] Danish Chinese Ctr Proteases & Canc, Fuzhou, Fujian, Peoples R China. [Huang, Mingdong] Fujian Inst Res Struct Matter, State Key Lab Struct Chem, Fuzhou, Fujian, Peoples R China. RP Vogel, LK (reprint author), Univ Copenhagen, Dept Cellular & Mol Med, Copenhagen, Denmark. EM vogel@sund.ku.dk OI Soendergaard, Christoffer/0000-0002-2943-6911 FU Faculty of Science, University of Copenhagen; Grocer Kristian Kjaer and wife's Foundation; Kjaer-Foundation; Dagmar Marshalls Foundation; Master Cabinetmaker Sophus Jacobsen and wife Astrid Jacobsen's Foundation; Wholesale Dealer Valdemar Foersom and wife Thyra Foersom's Foundation; Manufacturer Einar Willumsen's Foundation; Lundbeck Foundation; Architect Holger Hjortenberg and wife Dagmar Hjortenberg's Foundation FX This work was supported by Faculty of Science, University of Copenhagen, Architect Holger Hjortenberg and wife Dagmar Hjortenberg's Foundation; Grocer Kristian Kjaer and wife's Foundation, the Kjaer-Foundation; Dagmar Marshalls Foundation; Master Cabinetmaker Sophus Jacobsen and wife Astrid Jacobsen's Foundation; Wholesale Dealer Valdemar Foersom and wife Thyra Foersom's Foundation; Manufacturer Einar Willumsen's Foundation; and the Lundbeck Foundation. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 3 Z9 3 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 18 PY 2013 VL 8 IS 10 AR e77146 DI 10.1371/journal.pone.0077146 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239MM UT WOS:000326029300085 PM 24204759 ER PT J AU Mori, T Hayashi, T Hayashi, E Su, TP AF Mori, Tomohisa Hayashi, Teruo Hayashi, Eri Su, Tsung-Ping TI Sigma-1 Receptor Chaperone at the ER-Mitochondrion Interface Mediates the Mitochondrion-ER-Nucleus Signaling for Cellular Survival SO PLOS ONE LA English DT Article ID UNFOLDED-PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; DIMERIZATION DOMAIN; DYNAMIC INTERACTION; OXIDATIVE STRESS; MESSENGER-RNA; IRE1; IRE1-ALPHA; ACTIVATION; APOPTOSIS AB The membrane of the endoplasmic reticulum (ER) of a cell forms contacts directly with mitochondria whereby the contact is referred to as the mitochondrion-associated ER membrane or the MAM. Here we found that the MAM regulates cellular survival via an MAM-residing ER chaperone the sigma-1 receptor (Sig-1R) in that the Sig-1R chaperones the ER stress sensor IRE1 to facilitate inter-organelle signaling for survival. IRE1 is found in this study to be enriched at the MAM in CHO cells. We found that IRE1 is stabilized at the MAM by Sig-1Rs when cells are under ER stress. Sig-1Rs stabilize IRE1 and thus allow for conformationally correct IRE1 to dimerize into the long-lasting, activated endonuclease. The IRE1 at the MAM also responds to reactive oxygen species derived from mitochondria. Therefore, the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-responding signaling between mitochondria, ER, and nucleus. C1 [Mori, Tomohisa; Hayashi, Teruo; Hayashi, Eri; Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Sect, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. EM TSU@intra.nida.nih.gov FU Intramural Research Program, NIDA, NIH, DHHS FX This study was supported by the Intramural Research Program, NIDA, NIH, DHHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 37 Z9 40 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 18 PY 2013 VL 8 IS 10 AR e76941 DI 10.1371/journal.pone.0076941 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239MM UT WOS:000326029300070 PM 24204710 ER PT J AU Sastalla, I Fattah, R Coppage, N Nandy, P Crown, D Pomerantsev, AP Leppla, SH AF Sastalla, Inka Fattah, Rasem Coppage, Nicole Nandy, Poulomi Crown, Devorah Pomerantsev, Andrei P. Leppla, Stephen H. TI The Bacillus cereus Hbl and Nhe Tripartite Enterotoxin Components Assemble Sequentially on the Surface of Target Cells and Are Not Interchangeable SO PLOS ONE LA English DT Article ID 3 EXOPROTEIN COMPONENTS; PLCR VIRULENCE REGULON; RAY CRYSTAL-STRUCTURE; HEMOLYSIN E HLYE; PHOSPHOLIPASE-C; ESCHERICHIA-COLI; TOXINS; BL; ANTHRACIS; ENDOPHTHALMITIS AB Bacillus cereus is a spore-forming, Gram-positive bacterium commonly associated with outbreaks of food poisoning. It is also known as an opportunistic pathogen causing clinical infections such as bacteremia, meningitis, pneumonia, and gas gangrene-like cutaneous infections, mostly in immunocompromised patients. B. cereus secretes a plethora of toxins of which four are associated with the symptoms of food poisoning. Two of these, the non-hemolytic enterotoxin Nhe and the hemolysin BL (Hbl) toxin, are predicted to be structurally similar and are unique in that they require the combined action of three toxin proteins to induce cell lysis. Despite their dominant role in disease, the molecular mechanism of their toxic function is still poorly understood. We report here that B. cereus strain ATCC 10876 harbors not only genes encoding Nhe, but also two copies of the hbl genes. We identified Hbl as the major secreted toxin responsible for inducing rapid cell lysis both in cultured cells and in an intraperitoneal mouse toxicity model. Antibody neutralization and deletion of Hbl-encoding genes resulted in significant reductions of cytotoxic activity. Microscopy studies with Chinese Hamster Ovary cells furthermore showed that pore formation by both Hbl and Nhe occurs through a stepwise, sequential binding of toxin components to the cell surface and to each other. This begins with binding of Hbl-B or NheC to the eukaryotic membrane, and is followed by the recruitment of Hbl-L-1 or NheB, respectively, followed by the corresponding third protein. Lastly, toxin component complementation studies indicate that although Hbl and Nhe can be expressed simultaneously and are predicted to be structurally similar, they are incompatible and cannot complement each other. C1 [Sastalla, Inka; Fattah, Rasem; Coppage, Nicole; Nandy, Poulomi; Crown, Devorah; Pomerantsev, Andrei P.; Leppla, Stephen H.] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Sastalla, I (reprint author), NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sastallai@niaid.nih.gov FU Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 9 Z9 9 U1 2 U2 14 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 OCT 18 PY 2013 VL 8 IS 10 AR e76955 DI 10.1371/journal.pone.0076955 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239MM UT WOS:000326029300071 PM 24204713 ER PT J AU Zhao, HY Casillas, E Shroff, H Patterson, GH Schuck, P AF Zhao, Huaying Casillas, Ernesto, Jr. Shroff, Hari Patterson, George H. Schuck, Peter TI Tools for the Quantitative Analysis of Sedimentation Boundaries Detected by Fluorescence Optical Analytical Ultracentrifugation SO PLOS ONE LA English DT Article ID VELOCITY DATA; PROTEIN AB Fluorescence optical detection in sedimentation velocity analytical ultracentrifugation allows the study of macromolecules at nanomolar concentrations and below. This has significant promise, for example, for the study of systems of high-affinity protein interactions. Here we describe adaptations of the direct boundary modeling analysis approach implemented in the software SEDFIT that were developed to accommodate unique characteristics of the confocal fluorescence detection system. These include spatial gradients of signal intensity due to scanner movements out of the plane of rotation, temporal intensity drifts due to instability of the laser and fluorophores, and masking of the finite excitation and detection cone by the sample holder. In an extensive series of experiments with enhanced green fluorescent protein ranging from low nanomolar to low micromolar concentrations, we show that the experimental data provide sufficient information to determine the parameters required for first-order approximation of the impact of these effects on the recorded data. Systematic deviations of fluorescence optical sedimentation velocity data analyzed using conventional sedimentation models developed for absorbance and interference optics are largely removed after these adaptations, resulting in excellent fits that highlight the high precision of fluorescence sedimentation velocity data, thus allowing a more detailed quantitative interpretation of the signal boundaries that is otherwise not possible for this system. C1 [Zhao, Huaying; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. [Casillas, Ernesto, Jr.; Patterson, George H.] Natl Inst Biomed Imaging & Bioengn, Sect Biophoton, NIH, Bethesda, MD USA. [Shroff, Hari] Natl Inst Biomed Imaging & Bioengn, Sect High Resolut Opt Imaging, NIH, Bethesda, MD USA. RP Schuck, P (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. EM schuckp@mail.nih.gov RI Shroff, Hari/E-7247-2016; OI Shroff, Hari/0000-0003-3613-8215; Schuck, Peter/0000-0002-8859-6966 FU National Institute of Biomedical Imaging and Bioengineering; National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Biomedical Imaging and Bioengineering and the National Institute of Child Health and Human Development, 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 21 TC 14 Z9 14 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 18 PY 2013 VL 8 IS 10 AR e77245 DI 10.1371/journal.pone.0077245 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239MM UT WOS:000326029300093 PM 24204779 ER PT J AU Poorey, K Viswanathan, R Carver, MN Karpova, TS Cirimotich, SM McNally, JG Bekiranov, S Auble, DT AF Poorey, Kunal Viswanathan, Ramya Carver, Melissa N. Karpova, Tatiana S. Cirimotich, Shana M. McNally, James G. Bekiranov, Stefan Auble, David T. TI Measuring Chromatin Interaction Dynamics on the Second Time Scale at Single-Copy Genes SO SCIENCE LA English DT Article ID TRANSCRIPTION ACTIVATION; GAL4 TURNOVER; GENOME; PROMOTER; LOCALIZATION; ORGANIZATION; KINETICS; MOT1 AB The chromatin immunoprecipitation (ChIP) assay is widely used to capture interactions between chromatin and regulatory proteins, but it is unknown how stable most native interactions are. Although live-cell imaging suggests short-lived interactions at tandem gene arrays, current methods cannot measure rapid binding dynamics at single-copy genes. We show, by using a modified ChIP assay with subsecond temporal resolution, that the time dependence of formaldehyde cross-linking can be used to extract in vivo on and off rates for site-specific chromatin interactions varying over a similar to 100-fold dynamic range. By using the method, we show that a regulatory process can shift weakly bound TATA-binding protein to stable promoter interactions, thereby facilitating transcription complex formation. This assay provides an approach for systematic, quantitative analyses of chromatin binding dynamics in vivo. C1 [Poorey, Kunal; Viswanathan, Ramya; Carver, Melissa N.; Cirimotich, Shana M.; Bekiranov, Stefan; Auble, David T.] Univ Virginia Hlth Syst, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. [Karpova, Tatiana S.; McNally, James G.] NCI, Ctr Canc Res Core Fluorescence Imaging Facil, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Bekiranov, S (reprint author), Univ Virginia Hlth Syst, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. EM sb3de@virginia.edu; auble@virginia.edu FU NIH, National Cancer Institute, Center for Cancer Research; NIH [GM55763] FX We thank K. Struhl, F. Pugh, S. Hahn, and P. deHaseth for discussion; R. Nakamoto and M. Galkin for discussions and help with the KinTek instrument; and J. Muldoon, J. Hopper, F. Pugh, and S. Hahn for strains and plasmids. J. G. M. and T. S. K. were supported by the intramural program of the NIH, National Cancer Institute, Center for Cancer Research. Supported by NIH grant GM55763 to D.T.A. NR 17 TC 39 Z9 39 U1 1 U2 20 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD OCT 18 PY 2013 VL 342 IS 6156 BP 369 EP 372 DI 10.1126/science.1242369 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 235XG UT WOS:000325755100048 PM 24091704 ER PT J AU Restifo, NP AF Restifo, Nicholas P. TI A "Big Data" View of the Tumor "Immunome" SO IMMUNITY LA English DT Editorial Material ID ADOPTIVE IMMUNOTHERAPY; T-CELLS; CANCER AB Tumors are complex masses containing not just neoplastic cells but also stromal cells, neovasculature, and a gamut of immune cells. In this issue, Bindea et al. (2013) identify a surprising new "immune landscape" associated with prolonged disease-free survival. C1 [Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Restifo, Nicholas P.] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM restifo@nih.gov OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [ZIA BC010763-07] NR 10 TC 8 Z9 8 U1 0 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD OCT 17 PY 2013 VL 39 IS 4 BP 631 EP 632 DI 10.1016/j.immuni.2013.10.002 PG 2 WC Immunology SC Immunology GA AA2UP UT WOS:000330950000005 PM 24138879 ER PT J AU Deeks, SG Tracy, R Douek, DC AF Deeks, Steven G. Tracy, Russell Douek, Daniel C. TI Systemic Effects of Inflammation on Health during Chronic HIV Infection SO IMMUNITY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; RECEIVING ANTIRETROVIRAL THERAPY; CARDIOVASCULAR-DISEASE EVENTS; MUCOSAL IMMUNE RECONSTITUTION; INTESTINAL EPITHELIAL BARRIER; RANDOMIZED CONTROLLED-TRIAL; MICROBIAL TRANSLOCATION; D-DIMER; MONOCYTE ACTIVATION AB Combination antiretroviral therapy for HIV infection improves immune function and eliminates the risk of AIDS-related complications but does not restore full health. HIV-infected adults have excess risk of cardiovascular, liver, kidney, bone, and neurologic diseases. Many markers of inflammation are elevated in HIV disease and strongly predictive of the risk of morbidity and mortality. A conceptual model has emerged to explain this syndrome of diseases where HIV-mediated destruction of gut mucosa leads to local and systemic inflammation. Translocated microbial products then pass through the liver, contributing to hepatic damage, impaired microbial clearance, and impaired protein synthesis. Chronic activation of monocytes and altered liver protein synthesis subsequently contribute to a hypercoagulable state. The combined effect of systemic inflammation and excess clotting on tissue function leads to end-organ disease. Multiple therapeutic interventions designed to reverse these pathways are now being tested in the clinic. It is likely that knowledge gained on how inflammation affects health in HIV disease could have implications for our understanding of other chronic inflammatory diseases and the biology of aging. C1 [Deeks, Steven G.] Univ Calif San Francisco, San Francisco, CA 94114 USA. [Tracy, Russell] Univ Vermont, Colchester, VT 05405 USA. [Douek, Daniel C.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Deeks, SG (reprint author), Univ Calif San Francisco, San Francisco, CA 94114 USA. EM sdeeks@php.ucsf.edu FU National Institute of Allergy and Infectious Diseases [K24 AI069994]; DARE: Delaney AIDS Research Enterprise (DARE) [U19AI096109]; National Institute of Allergy and Infectious Diseases FX This work was supported by grants from the National Institute of Allergy and Infectious Diseases (K24 AI069994), the DARE: Delaney AIDS Research Enterprise (DARE; U19AI096109), and the Intramural Program of the National Institute of Allergy and Infectious Diseases. NR 125 TC 137 Z9 138 U1 4 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD OCT 17 PY 2013 VL 39 IS 4 BP 633 EP 645 DI 10.1016/j.immuni.2013.10.001 PG 13 WC Immunology SC Immunology GA AA2UP UT WOS:000330950000006 PM 24138880 ER PT J AU He, J Tsai, LM Leong, YA Hu, X Ma, CS Chevalier, N Sun, XL Vandenberg, K Rockman, S Ding, Y Zhu, L Wei, W Wang, CQ Karnowski, A Belz, GT Ghali, JR Cook, MC Riminton, DS Veillette, A Schwartzberg, PL Mackay, F Brink, R Tangye, SG Vinuesa, CG Mackay, CR Li, ZG Yu, D AF He, Jing Tsai, Louis M. Leong, Yew Ann Hu, Xin Ma, Cindy S. Chevalier, Nina Sun, Xiaolin Vandenberg, Kirsten Rockman, Steve Ding, Yan Zhu, Lei Wei, Wei Wang, Changqi Karnowski, Alexander Belz, Gabrielle T. Ghali, Joanna R. Cook, Matthew C. Riminton, D. Sean Veillette, Andre Schwartzberg, Pamela L. Mackay, Fabienne Brink, Robert Tangye, Stuart G. Vinuesa, Carola G. Mackay, Charles R. Li, Zhanguo Yu, Di TI Circulating Precursor CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T Cells Indicate Tfh Cell Activity and Promote Antibody Responses upon Antigen Reexposure SO IMMUNITY LA English DT Article ID FOLLICULAR HELPER-CELL; CENTER B-CELL; CXC CHEMOKINE RECEPTOR-5; SYSTEMIC AUTOIMMUNITY; BCL6 EXPRESSION; CENTRAL MEMORY; HIV-INFECTION; EFFECTOR; DIFFERENTIATION; GENERATION AB Follicular B helper T (Tfh) cells support high affinity and long-term antibody responses. Here we found that within circulating CXCR5(+) CD4(+) T cells in humans and mice, the CCR7(lo)PD-1(hi) subset has a partial Tfh effector phenotype, whereas CCR7(hi) PD-1(lo) cells have a resting phenotype. The circulating CCR7(lo)PD-1(hi) subset was indicative of active Tfh differentiation in lymphoid organs and correlated with clinical indices in autoimmune diseases. Thus the CCR7(lo)PD-1(hi) subset provides a biomarker to monitor protective antibody responses during infection or vaccination and pathogenic antibody responses in autoimmune diseases. Differentiation of both CCR7(hi)PD-1(lo) and CCR7(lo)PD-1(hi) subsets required ICOS and BCL6, but not SAP, suggesting that circulating CXCR5(+) helper T cells are primarily generated before germinal centers. Upon antigen reencounter, CCR7(lo)PD-1(hi) CXCR5(+) precursors rapidly differentiate into mature Tfh cells to promote anti-body responses. Therefore, circulating CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells are generated during active Tfh differentiation and represent a new mechanism of immunological early memory. C1 [He, Jing; Sun, Xiaolin; Ding, Yan; Zhu, Lei; Li, Zhanguo] Peking Univ, Peoples Hosp, Dept Rheumatol & Immunol, Beijing 100044, Peoples R China. [Tsai, Louis M.; Leong, Yew Ann; Hu, Xin; Mackay, Charles R.; Yu, Di] Monash Univ, Sch Biomed Sci, Mol Immunomodulat Lab, Clayton, Vic 3800, Australia. [Hu, Xin; Cook, Matthew C.; Vinuesa, Carola G.] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 2601, Australia. [Ma, Cindy S.; Chevalier, Nina; Brink, Robert; Tangye, Stuart G.] Garvan Inst Med Res, Program Immunol, Darlinghurst, NSW 2010, Australia. [Ma, Cindy S.; Chevalier, Nina; Brink, Robert; Tangye, Stuart G.] Univ New S Wales, St Vincents Clin Sch, Darlinghurst, NSW 2010, Australia. [Chevalier, Nina] Univ Med Ctr Freiburg, Dept Rheumatol & Clin Immunol, D-79106 Freiburg, Germany. [Vandenberg, Kirsten; Rockman, Steve] BioCSL, Influenza Res & Dev, Parkville, Vic 3052, Australia. [Wei, Wei] Chinese Acad Sci, Inst Proc Engn, Natl Key Lab Biochem Engn, Beijing 100190, Peoples R China. [Wang, Changqi] Shandong Acad Sci, Shandong Anal & Test Ctr, Lab Immunol Environm & Hlth, Jinan 250014, Shandong, Peoples R China. [Karnowski, Alexander; Belz, Gabrielle T.] Walter & Eliza Hall Inst Med Res, Div Mol Immunol, Parkville, Vic 3052, Australia. [Ghali, Joanna R.] Monash Univ, Ctr Inflammatory Dis, Clayton, Vic 3800, Australia. [Cook, Matthew C.] Australian Natl Univ, Sch Med, Canberra, ACT 2601, Australia. [Riminton, D. Sean] Concord Hosp, Dept Immunol, Concord, NSW 2139, Australia. [Veillette, Andre] Clin Res Inst Montreal, Montreal, PQ H2W 1R7, Canada. [Schwartzberg, Pamela L.] NHGRI, Bethesda, MD 20892 USA. [Mackay, Fabienne] Monash Univ, Dept Immunol, Clayton, Vic 3800, Australia. RP Li, ZG (reprint author), Peking Univ, Peoples Hosp, Dept Rheumatol & Immunol, Beijing 100044, Peoples R China. EM li99@bjmu.edu.cn; di.yu@monash.edu RI Mackay, Fabienne/B-7440-2008; Brink, Robert/B-7910-2010; Yu, Di/C-2163-2009; Tangye, Stuart/H-4023-2014; Mackay, Charles/A-9673-2008 OI Mackay, Fabienne/0000-0002-6074-2693; Brink, Robert/0000-0002-9586-3655; Yu, Di/0000-0003-1721-8922; Mackay, Charles/0000-0002-6338-7340 FU National Basic Research Program of China (973 Program) [2010CB529100]; National Health and Medical Research Council (NHMRC) [1010761]; Australian Research Council [DP110105024]; Ramaciotti Foundation; National Natural Science Foundation of China (NSFC) [81128012]; Beijing Natural Science Foundation [7131015]; NSFC [3107088]; NHMRC program; NHMRC Fellowship [GNT1011947]; Monash Fellowship; Viertel Senior Medical Research Fellowship; NHMRC Australian Fellowship FX We thank FlowCore, Monash University, and Garvan MLC Flow Cytometry Facility for cell sorting and providing analytical instruments, Monash and Garvan animal facilities for animal husbandry and technical services, Karen Laurie and Anne Kelso for suggestion on influenza vaccination, Andrew Wei for suggestion on immune response after hematopoietic stem cell transplantation, and Zdenka Prodanovic (the Tissue Bank Southern Health) for collecting human tissue samples. This work was funded by National Basic Research Program of China (973 Program, 2010CB529100) To Z.L. and D.Y. National Health and Medical Research Council (NHMRC, 1010761), Australian Research Council (DP110105024), Ramaciotti Foundation and National Natural Science Foundation of China (NSFC, 81128012) to D.Y., Beijing Natural Science Foundation (7131015) to Z.L. NSFC (3107088) to J.H., and NHMRC program to C. R. M., C. G. V., S. G. T., R. B., and F. M. D.Y. is supported by a NHMRC Fellowship (GNT1011947) and a Monash Fellowship. C. S. M. is supported by a NHMRC Fellowship. C. G. V. is supported by a Viertel Senior Medical Research Fellowship. C. R. M. is supported by a NHMRC Australian Fellowship. NR 50 TC 133 Z9 141 U1 4 U2 30 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD OCT 17 PY 2013 VL 39 IS 4 BP 770 EP 781 DI 10.1016/j.immuni.2013.09.007 PG 12 WC Immunology SC Immunology GA AA2UP UT WOS:000330950000017 PM 24138884 ER PT J AU McShane, LM Cavenagh, MM Lively, TG Eberhard, DA Bigbee, WL Williams, PM Mesirov, JP Polley, MYC Kim, KY Tricoli, JV Taylor, JMG Shuman, DJ Simon, RM Doroshow, JH Conley, BA AF McShane, Lisa M. Cavenagh, Margaret M. Lively, Tracy G. Eberhard, David A. Bigbee, William L. Williams, P. Mickey Mesirov, Jill P. Polley, Mei-Yin C. Kim, Kelly Y. Tricoli, James V. Taylor, Jeremy M. G. Shuman, Deborah J. Simon, Richard M. Doroshow, James H. Conley, Barbara A. TI Criteria for the use of omics-based predictors in clinical trials: explanation and elaboration SO BMC MEDICINE LA English DT Article DE Analytical validation; Biomarker; Diagnostic test; Genomic classifier; Model validation; Molecular profile; Omics; Personalized medicine; Precision Medicine; Treatment selection ID OLIGONUCLEOTIDE MICROARRAY DATA; TANDEM MASS-SPECTROMETRY; GENE-EXPRESSION ANALYSIS; PROBE LEVEL DATA; BREAST-CANCER; REPORTING RECOMMENDATIONS; INDIVIDUALIZED OPTIONS; DIAGNOSTIC-ACCURACY; QUALITY ASSESSMENT; RNA-SEQ AB High-throughput 'omics' technologies that generate molecular profiles for biospecimens have been extensively used in preclinical studies to reveal molecular subtypes and elucidate the biological mechanisms of disease, and in retrospective studies on clinical specimens to develop mathematical models to predict clinical endpoints. Nevertheless, the translation of these technologies into clinical tests that are useful for guiding management decisions for patients has been relatively slow. It can be difficult to determine when the body of evidence for an omics-based test is sufficiently comprehensive and reliable to support claims that it is ready for clinical use, or even that it is ready for definitive evaluation in a clinical trial in which it may be used to direct patient therapy. Reasons for this difficulty include the exploratory and retrospective nature of many of these studies, the complexity of these assays and their application to clinical specimens, and the many potential pitfalls inherent in the development of mathematical predictor models from the very high-dimensional data generated by these omics technologies. Here we present a checklist of criteria to consider when evaluating the body of evidence supporting the clinical use of a predictor to guide patient therapy. Included are issues pertaining to specimen and assay requirements, the soundness of the process for developing predictor models, expectations regarding clinical study design and conduct, and attention to regulatory, ethical, and legal issues. The proposed checklist should serve as a useful guide to investigators preparing proposals for studies involving the use of omics-based tests. The US National Cancer Institute plans to refer to these guidelines for review of proposals for studies involving omics tests, and it is hoped that other sponsors will adopt the checklist as well. C1 [McShane, Lisa M.; Polley, Mei-Yin C.; Simon, Richard M.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Cavenagh, Margaret M.; Lively, Tracy G.; Kim, Kelly Y.; Tricoli, James V.; Conley, Barbara A.] NCI, Canc Diag Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Eberhard, David A.] Univ N Carolina, Dept Pathol, Chapel Hill, NC 27599 USA. [Eberhard, David A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Bigbee, William L.] Hillman Canc Ctr, Dept Pathol, Pittsburgh, PA 15213 USA. [Bigbee, William L.] Univ Pittsburgh Canc Inst, Pittsburgh, PA 15213 USA. [Williams, P. Mickey] NCI, Frederick Natl Lab Canc Res, NIH, Frederick, MD 21702 USA. [Mesirov, Jill P.] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA. [Taylor, Jeremy M. G.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Shuman, Deborah J.; Doroshow, James H.] NCI, Off Director, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP McShane, LM (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Room 5W130,MSC 9735,9609 Med Ctr Dr, Bethesda, MD 20892 USA. EM mcshanel@ctep.nci.nih.gov FU NCI NIH HHS [R01 CA109467] NR 103 TC 39 Z9 39 U1 1 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD OCT 17 PY 2013 VL 11 AR 220 DI 10.1186/1741-7015-11-220 PG 22 WC Medicine, General & Internal SC General & Internal Medicine GA 241QG UT WOS:000326181600001 PM 24228635 ER PT J AU Cardone, A Pant, H Hassan, SA AF Cardone, Antonio Pant, Harish Hassan, Sergio A. TI Specific and Non-Specific Protein Association in Solution: Computation of Solvent Effects and Prediction of First-Encounter Modes for Efficient Configurational Bias Monte Carlo Simulations SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID PARAMAGNETIC RELAXATION ENHANCEMENT; SCREENED COULOMB POTENTIALS; SIDE-CHAIN INTERACTIONS; LIQUID-STRUCTURE FORCES; SURFACE-AREA; DYNAMICS SIMULATIONS; SECONDARY STRUCTURE; INTERACTION NETWORK; NEUTRON-SCATTERING; LIGAND-BINDING AB Weak and ultraweak protein protein association play a role in molecular recognition and can drive spontaneous self-assembly and aggregation. Such interactions are difficult to detect experimentally, and are a challenge to the force field and sampling technique. A method is proposed to identify low-population protein protein binding modes in aqueous solution. The method is designed to identify preferential first-encounter complexes from which the final complex(es) at equilibrium evolve. A continuum model is used to represent the effects of the solvent, which accounts for short- and long-range effects of water exclusion and for liquid-structure forces at protein/liquid interfaces. These effects control the behavior of proteins in close proximity and are optimized on the basis of binding enthalpy data and simulations. An algorithm is described to construct a biasing function for self-adaptive configurational-bias Monte Carlo of a set of interacting proteins. The function allows mixing large and local changes in the spatial distribution of proteins, thereby enhancing sampling of relevant microstates. The method is applied to three binary systems. Generalization to multiprotein complexes is discussed. C1 [Cardone, Antonio] Univ Maryland, Inst Adv Comp Sci, College Pk, MD 20742 USA. [Cardone, Antonio] NIST, Software & Syst Div, Gaithersburg, MD 20899 USA. [Pant, Harish] NINDS, Lab Neurochem, Bethesda, MD 20892 USA. [Hassan, Sergio A.] NIH, Ctr Mol Modeling, Div Computat Biosci, CIT, Bethesda, MD 20892 USA. RP Hassan, SA (reprint author), NIH, Ctr Mol Modeling, Div Computat Biosci, CIT, Bldg 10, Bethesda, MD 20892 USA. EM hassan@mail.nih.gov FU NIH Intramural Research Program through the CIT; NINDS; Internal NIST Research Fund FX This study utilized the high-performance computer capabilities of the Biowulf PC/Linux cluster at the NIH. This work was supported by the NIH Intramural Research Program through the CIT and NINDS and by the Internal NIST Research Fund. NR 99 TC 8 Z9 8 U1 2 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 17 PY 2013 VL 117 IS 41 BP 12360 EP 12374 DI 10.1021/jp4050594 PG 15 WC Chemistry, Physical SC Chemistry GA 240VO UT WOS:000326126000003 PM 24044772 ER PT J AU Curtis, KA Longosz, AF Kennedy, MS Keating, S Heitman, J Laeyendecker, O Owen, SM AF Curtis, Kelly A. Longosz, Andrew F. Kennedy, M. Susan Keating, Sheila Heitman, John Laeyendecker, Oliver Owen, S. Michele TI Inter-Laboratory Assessment of a Prototype Multiplex Kit for Determination of Recent HIV-1 Infection SO PLOS ONE LA English DT Article ID BED-ENZYME-IMMUNOASSAY; PERFORMANCE-CHARACTERISTICS; TYPE-1 SEROCONVERSION; VACCINE PREPAREDNESS; UNITED-STATES; ASSAY; IDENTIFICATION; SEROINCIDENCE; TRIALS AB Background: Accurate and reliable laboratory-based assays are needed for estimating HIV-1 incidence from cross-sectional samples. We recently described the development of a customized, HIV-1-specific Bio-Plex assay that allows for the measurement of HIV-specific antibody levels and avidity to multiple analytes for improved HIV-1 incidence estimates. Methods: To assess intra-and inter-laboratory assay performance, prototype multiplex kits were developed and evaluated by three distinct laboratories. Longitudinal seroconversion specimens were tested in parallel by each laboratory and kit performance was compared to that of an in-house assay. Additionally, the ability of the kit to distinguish recent from long-term HIV-1 infection, as compared to the in-house assay, was determined by comparing the reactivity of known recent (infected <6 months) and long-term (infected >12 months) drug naive specimens. Results: Although the range of reactivity for each analyte varied between the prototype kit and in-house assay, a measurable distinction in reactivity between recent and long-term specimens was observed with both assays in all three laboratories. Additionally, kit performance was consistent between all three laboratories. The intra-assay coefficient of variation (CV), between sample replicates for all laboratories, ranged from 0.5% to 6.1%. The inter-laboratory CVs ranged from 8.5% to 21.3% for gp160-avidity index (a) and gp120-normalized mean fluorescent intensity (MFI) value (n), respectively. Conclusion: We demonstrate the feasibility of producing a multiplex kit for measuring HIV antibody levels and avidity, with the potential for improved incidence estimates based on multi-analyte algorithms. The availability of a commercial kit will facilitate the transfer of technology among diverse laboratories for widespread assay use. C1 [Curtis, Kelly A.; Kennedy, M. Susan; Owen, S. Michele] Ctr Dis Control & Prevent, Branch Lab, Div HIV AIDS Prevent, Natl Ctr HIV AIDS Hepatitis STD & TB Prevent, Atlanta, GA 30329 USA. [Longosz, Andrew F.; Laeyendecker, Oliver] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. [Keating, Sheila; Heitman, John] Blood Syst Res Inst, San Francisco, CA USA. [Laeyendecker, Oliver] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. RP Curtis, KA (reprint author), Ctr Dis Control & Prevent, Branch Lab, Div HIV AIDS Prevent, Natl Ctr HIV AIDS Hepatitis STD & TB Prevent, Atlanta, GA 30329 USA. EM czv2@cdc.gov OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Centers for Disease Control; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); HIV Prevention Trials Network; NIAID, National Institutes of Child Health and Human Development, National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research, of the NIH, Department of Health and Human Services (DHHS) [U01-AI46745, U01-AI48054, UM1-AI068613, R01-AI095068] FX Funding for this research was provided in part through intramural funding from the Centers for Disease Control. Additional funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Additional funders included: The Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); the HIV Prevention Trials Network sponsored by NIAID, National Institutes of Child Health and Human Development, National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research, of the NIH, Department of Health and Human Services (DHHS, U01-AI46745, U01-AI48054, and UM1-AI068613), R01-AI095068. NR 28 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 OCT 17 PY 2013 VL 8 IS 10 AR e77765 DI 10.1371/journal.pone.0077765 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239KL UT WOS:000326022200073 PM 24147075 ER PT J AU Song, HF Josleyn, N Janosko, K Skinner, J Reeves, RK Cohen, M Jett, C Johnson, R Blaney, JE Bollinger, L Jennings, G Jahrling, PB AF Song, Haifeng Josleyn, Nicole Janosko, Krisztina Skinner, Jeff Reeves, R. Keith Cohen, Melanie Jett, Catherine Johnson, Reed Blaney, Joseph E. Bollinger, Laura Jennings, Gerald Jahrling, Peter B. TI Monkeypox Virus Infection of Rhesus Macaques Induces Massive Expansion of Natural Killer Cells but Suppresses Natural Killer Cell Functions SO PLOS ONE LA English DT Article ID NK CELLS; VIRAL-INFECTION; LYMPH-NODES; CYNOMOLGUS MACAQUES; ACTIVATION RECEPTOR; MEDIATED RESISTANCE; ECTROMELIA VIRUS; SMALLPOX VACCINE; DENDRITIC CELLS; INNATE IMMUNITY AB Natural killer (NK) cells play critical roles in innate immunity and in bridging innate and adaptive immune responses against viral infection. However, the response of NK cells to monkeypox virus (MPXV) infection is not well characterized. In this intravenous challenge study of MPXV infection in rhesus macaques (Macaca mulatta), we analyzed blood and lymph node NK cell changes in absolute cell numbers, cell proliferation, chemokine receptor expression, and cellular functions. Our results showed that the absolute number of total NK cells in the blood increased in response to MPXV infection at a magnitude of 23-fold, manifested by increases in CD56+, CD16+, CD16-CD56-double negative, and CD16+ CD56+ double positive NK cell subsets. Similarly, the frequency and NK cell numbers in the lymph nodes also largely increased with the total NK cell number increasing 46.1-fold. NK cells both in the blood and lymph nodes massively proliferated in response to MPXV infection as measured by Ki67 expression. Chemokine receptor analysis revealed reduced expression of CXCR3, CCR7, and CCR6 on NK cells at early time points (days 2 and 4 after virus inoculation), followed by an increased expression of CXCR3 and CCR5 at later time points (days 7-8) of infection. In addition, MPXV infection impaired NK cell degranulation and ablated secretion of interferon-gamma and tumor necrosis factor-alpha. Our data suggest a dynamic model by which NK cells respond to MPXV infection of rhesus macaques. Upon virus infection, NK cells proliferated robustly, resulting in massive increases in NK cell numbers. However, the migrating capacity of NK cells to tissues at early time points might be reduced, and the functions of cytotoxicity and cytokine secretion were largely compromised. Collectively, the data may explain, at least partially, the pathogenesis of MPXV infection in rhesus macaques. C1 [Song, Haifeng; Josleyn, Nicole; Janosko, Krisztina; Cohen, Melanie; Jett, Catherine; Bollinger, Laura; Jennings, Gerald; Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Frederick, MD USA. [Skinner, Jeff] NIAID, Computat Biol Sect, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. [Reeves, R. Keith] Harvard Univ, Sch Med, New England Primate Res Ctr, Southborough, MA 01772 USA. [Johnson, Reed; Blaney, Joseph E.; Jahrling, Peter B.] NIAID, Emerging Viral Pathogens Sect, NIH, Bethesda, MD 20892 USA. RP Song, HF (reprint author), NIAID, Integrated Res Facil, NIH, Frederick, MD USA. EM haifengsong2003@yahoo.com OI Skinner, Jeff/0000-0001-5697-0442 FU National Institute of Allergy and Infectious Diseases (NIAID) under Battelle Memorial [HHSN272200200016I]; NIAID Division of Intramural Research funds FX The study was supported under Battelle Memorial contract with National Institute of Allergy and Infectious Diseases (NIAID) (contract number HHSN272200200016I) and was also supported in part by NIAID Division of Intramural Research funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 0 Z9 0 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 OCT 17 PY 2013 VL 8 IS 10 AR UNSP e77804 DI 10.1371/journal.pone.0077804 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239KL UT WOS:000326022200078 PM 24147080 ER PT J AU Townsley, DM Young, NS AF Townsley, Danielle M. Young, Neal S. TI Blood consult: paroxysmal nocturnal hemoglobinuria and its complications SO BLOOD LA English DT Editorial Material ID ECULIZUMAB; COMPLEMENT C1 [Townsley, Danielle M.; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Townsley, DM (reprint author), NIH, 10 Ctr Dr,CRC 3-5140, Bethesda, MD 20892 USA. EM Danielle.townsley@nih.gov FU Intramural NIH HHS NR 14 TC 4 Z9 4 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 17 PY 2013 VL 122 IS 16 BP 2795 EP 2798 DI 10.1182/blood-2013-07-360081 PG 4 WC Hematology SC Hematology GA 240FL UT WOS:000326080200011 PM 24021672 ER PT J AU McShane, LM Cavenagh, MM Lively, TG Eberhard, DA Bigbee, WL Williams, PM Mesirov, JP Polley, MYC Kim, KY Tricoli, JV Taylor, JMG Shuman, DJ Simon, RM Doroshow, JH Conley, BA AF McShane, Lisa M. Cavenagh, Margaret M. Lively, Tracy G. Eberhard, David A. Bigbee, William L. Williams, P. Mickey Mesirov, Jill P. Polley, Mei-Yin C. Kim, Kelly Y. Tricoli, James V. Taylor, Jeremy M. G. Shuman, Deborah J. Simon, Richard M. Doroshow, James H. Conley, Barbara A. TI Criteria for the use of omics-based predictors in clinical trials SO NATURE LA English DT Article ID MICROARRAY; BIOMARKERS AB The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to 'omics'-based test development, has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy. C1 [McShane, Lisa M.; Cavenagh, Margaret M.; Lively, Tracy G.; Polley, Mei-Yin C.; Kim, Kelly Y.; Tricoli, James V.; Shuman, Deborah J.; Simon, Richard M.; Doroshow, James H.; Conley, Barbara A.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Eberhard, David A.] Univ N Carolina, Dept Pathol, Chapel Hill, NC 27599 USA. [Eberhard, David A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Bigbee, William L.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15213 USA. [Bigbee, William L.] Univ Pittsburgh, Sch Med, Inst Canc, Hillman Canc Ctr, Pittsburgh, PA 15213 USA. [Williams, P. Mickey] NCI, Frederick Natl Lab Canc Res, NIH, Frederick, MD 21702 USA. [Mesirov, Jill P.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Mesirov, Jill P.] Harvard Univ, Cambridge, MA 02142 USA. [Taylor, Jeremy M. G.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. RP McShane, LM (reprint author), NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. EM mcshanel@ctep.nci.nih.gov FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [R01 CA129102, P30 CA046592] NR 18 TC 72 Z9 73 U1 1 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 17 PY 2013 VL 502 IS 7471 BP 317 EP 320 DI 10.1038/nature12564 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 235GY UT WOS:000325706300042 PM 24132288 ER PT J AU Adgent, MA Flake, GP Umbach, DM Stallings, VA Bernbaum, JC Rogan, WJ AF Adgent, Margaret A. Flake, Gordon P. Umbach, David M. Stallings, Virginia A. Bernbaum, Judy C. Rogan, Walter J. TI Urogenital Epithelial Cells as Simple Markers of Estrogen Response in Infants: Methods and Applications SO PLOS ONE LA English DT Article ID URINARY SEDIMENT; CHILDHOOD; CYTOLOGY; SMEARS AB Exposure to estrogen-mimicking chemicals during critical periods of development, such as infancy, may have adverse effects. However, these effects can be difficult to characterize in most epidemiologic studies. For example, growth of reproductive organs may be susceptible to estrogenic chemicals, but measuring it requires skilled ultrasound examination; timing of pubertal onset may be altered, but observing it requires long-term follow up. To address the need for a simple marker of response to estrogenic exposures in infants, we propose a novel application of a classic marker of estrogen response in adult women: cytological evaluation of urogenital epithelial cells. In this cross-sectional study of 34 female and 41 male infants, we demonstrate that epithelial cells can be obtained from swabs of the vaginal introitus (females) and urethral meatus (males), as well as from spun urine, and that these cells respond to differential estrogenic conditions, as indicated by the relative abundance of the superficial epithelial cell type. To model varying estrogen exposure, we sampled from infants who were either newborn (highly exposed to maternal estrogens), or 12 weeks old (12W) (negligibly exposed to estrogen). Newborns had a higher percentage of superficial cells (%S), as compared to 12W (mean +/- standard error: 8.3 +/- 1.8 vs. 0.9 +/- 0.2) (p < 0.01), consistent with an estrogen response. This difference in %S from newborn to 12W was observed similarly for swab (-7.6 +/- 1.7) and urine (-7.3 +/- 2.6) specimens and for males (-9.6 +/- 2.9) and females (-5.2 +/- 2.1). Examination of urogenital epithelial cells can successfully demonstrate estrogen response in both sexes, using cell specimens collected from either swab or urine sampling. In future studies, this simple, non-invasive method may be applied to assess whether estrogen-mimicking chemicals produce an estrogenic response in infants. C1 [Adgent, Margaret A.; Rogan, Walter J.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Flake, Gordon P.] NIEHS, Cellular & Mol Pathol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Stallings, Virginia A.; Bernbaum, Judy C.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Stallings, Virginia A.; Bernbaum, Judy C.] Univ Penn, Philadelphia, PA 19104 USA. RP Rogan, WJ (reprint author), NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. EM rogan@niehs.nih.gov RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 FU NIH, National Institute of Environmental Health Sciences; National Institutes of Health [ES044006] FX This research was supported (in part) by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The funding for this study was provided by the intramural research program of the National Institutes of Health (Intramural Project ES044006), where Drs. Rogan, Adgent, Umbach and Flake work. Drs. Stallings and Bernbaum and the data collection activities were supported by a contract between Children's Hospital of Philadelphia and NIH. The work was carried out collaboratively. NR 23 TC 1 Z9 1 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 OCT 16 PY 2013 VL 8 IS 10 AR e77061 DI 10.1371/journal.pone.0077061 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239JR UT WOS:000326019400092 PM 24146956 ER PT J AU Antonio, T Childers, SR Rothman, RB Dersch, CM King, C Kuehne, M Bornmann, WG Eshleman, AJ Janowsky, A Simon, ER Reith, MEA Alper, K AF Antonio, Tamara Childers, Steven R. Rothman, Richard B. Dersch, Christina M. King, Christine Kuehne, Martin Bornmann, William G. Eshleman, Amy J. Janowsky, Aaron Simon, Eric R. Reith, Maarten E. A. Alper, Kenneth TI Effect of Iboga Alkaloids on mu-Opioid Receptor-Coupled G Protein Activation SO PLOS ONE LA English DT Article ID NALOXONE-PRECIPITATED WITHDRAWAL; ALPHA-3-BETA-4 NICOTINIC RECEPTORS; INDUCED LOCOMOTOR-ACTIVITY; MORPHINE-DEPENDENT RATS; ANTINOCICEPTIVE ACTION; ADENYLYL-CYCLASE; ACETYLCHOLINE-RECEPTOR; TABERNANTHE-IBOGA; ACUTE SIGNS; NORIBOGAINE AB Objective: The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of mu-opioid receptor (MOR)-related G proteins by iboga alkaloids. Methods: Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5'-O-(gamma-thio)-triphosphate ([S-35]GTP gamma S) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices. Results And Significance: In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [S-35]GTP gamma S binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [S-35]GTP gamma S binding in any MOR expressing cells. Noribogaine did not stimulate [S-35]GTP gamma S binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids. C1 [Antonio, Tamara; King, Christine; Simon, Eric R.; Reith, Maarten E. A.; Alper, Kenneth] NYU, Sch Med, Dept Psychiat, New York, NY USA. [Antonio, Tamara; King, Christine; Simon, Eric R.; Reith, Maarten E. A.] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USA. [Childers, Steven R.] Wake Forest Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC USA. [Rothman, Richard B.; Dersch, Christina M.] NIDA, Translat Pharmacol Res Sect, Intramural Res Program, Baltimore, MD USA. [Kuehne, Martin] Univ Vermont, Dept Chem, Burlington, VT 05405 USA. [Bornmann, William G.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Eshleman, Amy J.; Janowsky, Aaron] Oregon Hlth & Sci Univ, Res Serv, VA Med Ctr, Portland, OR 97201 USA. [Eshleman, Amy J.; Janowsky, Aaron] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Eshleman, Amy J.; Janowsky, Aaron] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA. [Alper, Kenneth] NYU, Dept Neurol, Sch Med, New York, NY 10016 USA. RP Alper, K (reprint author), NYU, Sch Med, Dept Psychiat, New York, NY USA. EM Kenneth.Alper@nyumc.org FU New York University School of Medicine Addiction Center of Excellence; Methamphetamine Abuse Research Center [P50 DA018165]; NIDA-VA [ADA12013]; VA Research Career Scientist and Merit Review programs NIDA grant, Intramural Research Program, NIDA, National Institute of health, Baltimore, MD [DA-06634] FX Funding was provided by New York University School of Medicine Addiction Center of Excellence (MEAR, KA, TA), The Methamphetamine Abuse Research Center (P50 DA018165), NIDA-VA Interagency agreement ADA12013, and VA Research Career Scientist and Merit Review programs (AJ, AJE) NIDA grant DA-06634 (SRC) Intramural Research Program, NIDA, National Institute of health, Baltimore, MD (RBR, CMD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 93 TC 11 Z9 11 U1 3 U2 19 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 OCT 16 PY 2013 VL 8 IS 10 AR UNSP e77262 DI 10.1371/journal.pone.0077262 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239JR UT WOS:000326019400097 PM 24204784 ER PT J AU Gordon, M El-Kalla, M Zhao, YW Fiteih, Y Law, J Volodko, N Mohamed, A El-Kadi, AOS Liu, L Odenbach, J Thiesen, A Onyskiw, C Abu Ghazaleh, H Park, J Lee, SB Yu, VC Fernandez-Patron, C Alexander, RT Wine, E Baksh, S AF Gordon, Marilyn El-Kalla, Mohamed Zhao, Yuewen Fiteih, Yahya Law, Jennifer Volodko, Natalia Mohamed, Anwar El-Kadi, Ayman O. S. Liu, Lei Odenbach, Jeff Thiesen, Aducio Onyskiw, Christina Abu Ghazaleh, Haya Park, Jikyoung Lee, Sean Bong Yu, Victor C. Fernandez-Patron, Carlos Alexander, R. Todd Wine, Eytan Baksh, Shairaz TI The Tumor Suppressor Gene, RASSF1A, Is Essential for Protection against Inflammation -Induced Injury SO PLOS ONE LA English DT Article ID YES-ASSOCIATED PROTEIN; STEM-CELL PROLIFERATION; NF-KAPPA-B; INTESTINAL INFLAMMATION; BOWEL-DISEASE; C-ABL; TYROSINE PHOSPHORYLATION; DNA METHYLTRANSFERASE-1; COLORECTAL-CANCER; INDUCED APOPTOSIS AB Ras association domain family protein 1A (RASSF1A) is a tumor suppressor gene silenced in cancer. Here we report that RASSF1A is a novel regulator of intestinal inflammation as Rassf1a(+/-), Rassf1a(-/-) and an intestinal epithelial cell specific knockout mouse (Rassf1a(IEC-KO)) rapidly became sick following dextran sulphate sodium (DSS) administration, a chemical inducer of colitis. Rassf1a knockout mice displayed clinical symptoms of inflammatory bowel disease including: increased intestinal permeability, enhanced cytokine/chemokine production, elevated nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF kappa B) activity, elevated colonic cell death and epithelial cell injury. Furthermore, epithelial restitution/repair was inhibited in DSS-treated Rassf1a(-/-) mice with reduction of several makers of proliferation including Yes associated protein (YAP)-driven proliferation. Surprisingly, tyrosine phosphorylation of YAP was detected which coincided with increased nuclear p73 association, Bax-driven epithelial cell death and p53 accumulation resulting in enhanced apoptosis and poor survival of DSS-treated Rassf1a knockout mice. We can inhibit these events and promote the survival of DSS-treated Rassf1a knockout mice with intraperitoneal injection of the c-Abl and c-Abl related protein tyrosine kinase inhibitor, imatinib/gleevec. However, p53 accumulation was not inhibited by imatinib/gleevec in the Rassf1a(-/-) background which revealed the importance of p53-dependent cell death during intestinal inflammation. These observations suggest that tyrosine phosphorylation of YAP (to drive p73 association and up-regulation of pro-apoptotic genes such as Bax) and accumulation of p53 are consequences of inflammation-induced injury in DSS-treated Rassf1a(-/-) mice. Mechanistically, we can detect robust associations of RASSF1A with membrane proximal Toll-like receptor (TLR) components to suggest that RASSF1A may function to interfere and restrict TLR-driven activation of NF kappa B. Failure to restrict NF kappa B resulted in the inflammation-induced DNA damage driven tyrosine phosphorylation of YAP, subsequent p53 accumulation and loss of intestinal epithelial homeostasis. C1 [Gordon, Marilyn; El-Kalla, Mohamed; Fiteih, Yahya; Volodko, Natalia; Onyskiw, Christina; Abu Ghazaleh, Haya; Alexander, R. Todd; Wine, Eytan; Baksh, Shairaz] Univ Alberta, Dept Pediat, Edmonton, AB, Canada. [Zhao, Yuewen; Law, Jennifer; Odenbach, Jeff; Fernandez-Patron, Carlos; Baksh, Shairaz] Univ Alberta, Dept Biochem, Edmonton, AB, Canada. [Mohamed, Anwar; El-Kadi, Ayman O. S.] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. [Liu, Lei; Wine, Eytan] Univ Alberta, Fac Med & Dent, CEGIIR, Edmonton, AB, Canada. [Thiesen, Aducio] Univ Alberta, Dept Lab Med & Pathol, Fac Med & Dent, Edmonton, AB, Canada. [Park, Jikyoung; Lee, Sean Bong] NIDDK, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. [Yu, Victor C.] Natl Univ Singapore, Dept Pharm, Fac Sci, Singapore 117548, Singapore. [Alexander, R. Todd] Univ Alberta, Dept Nephrol, Edmonton, AB, Canada. [Wine, Eytan; Baksh, Shairaz] Cross Canc Inst, Dept Oncol, Edmonton, AB T6G 1Z2, Canada. RP Baksh, S (reprint author), Univ Alberta, Dept Pediat, Edmonton, AB, Canada. EM sbaksh@ualberta.ca RI Alexander, R. Todd/G-1373-2012; Yu, Victor /A-7899-2015 OI Yu, Victor /0000-0003-3270-4734 FU Canadian Institutes of Health Research; Women and Children's Health Research Institute; Canadian Breast Cancer Foundation (Prairies/NWT); Alberta Heritage Foundation for Medical Research; Canadian Foundation for Innovation/Alberta Small Equipment Grants Program; Stollery Children's Foundation/Hair Massacure Donation Fund FX This work was supported by grants from Canadian Institutes of Health Research, The Women and Children's Health Research Institute, the Canadian Breast Cancer Foundation (Prairies/NWT), the Alberta Heritage Foundation for Medical Research, the Canadian Foundation for Innovation/Alberta Small Equipment Grants Program and The Stollery Children's Foundation/Hair Massacure Donation Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 13 Z9 14 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 16 PY 2013 VL 8 IS 10 AR e75483 DI 10.1371/journal.pone.0075483 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239JR UT WOS:000326019400008 PM 24146755 ER PT J AU Luger, D Yang, YA Raviv, A Weinberg, D Banerjee, S Lee, MJ Trepel, J Yang, L Wakefield, LM AF Luger, Dror Yang, Yu-an Raviv, Asaf Weinberg, Douglas Banerjee, Subhadra Lee, Min-Jung Trepel, Jane Yang, Li Wakefield, Lalage M. TI Expression of the B-Cell Receptor Component CD79a on Immature Myeloid Cells Contributes to Their Tumor Promoting Effects SO PLOS ONE LA English DT Article ID SUPPRESSOR-CELLS; IG-ALPHA; BONE-MARROW; TYROSINE PHOSPHORYLATION; CYTOPLASMIC DOMAIN; CANCER-PATIENTS; ACUTE-LEUKEMIA; BEARING HOST; BETA; LINEAGE AB The role of myeloid derived suppressor cells (MDSCs) in promoting tumorigenesis is well-established, and significant effort is being made to further characterize surface markers on MDSCs both for better diagnosis and as potential targets for therapy. Here we show that the B cell receptor adaptor molecule CD79a is unexpectedly expressed on immature bone marrow myeloid cells, and is upregulated on MDSCs generated in multiple different mouse models of metastatic but not nonmetastatic cancer. CD79a on MDSCs is upregulated and activated in response to soluble factors secreted by tumor cells. Activation of CD79a on mouse MDSCs, by crosslinking with a specific antibody, maintained their immature phenotype (CD11b+Gr1+), enhanced their migration, increased their suppressive effect on T cell proliferation, and increased secretion of pro-tumorigenic cytokines such as IL-6 and CCL22. Furthermore, crosslinking CD79a on myeloid cells activated signaling through Syk, BLNK, ERK and STAT3 phosphorylation. In vivo, CD79+ myeloid cells showed enhanced ability to promote primary tumor growth and metastasis. Finally we demonstrate that CD79a is upregulated on circulating myeloid cells from lung cancer patients, and that CD79a+ myeloid cells infiltrate human breast tumors. We propose that CD79a plays a functional role in the tumor promoting effects of myeloid cells, and may represent a novel target for cancer therapy. C1 [Luger, Dror; Yang, Yu-an; Raviv, Asaf; Weinberg, Douglas; Banerjee, Subhadra; Yang, Li; Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Lee, Min-Jung; Trepel, Jane] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Luger, D (reprint author), NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. EM lugerd@mail.nih.gov; lw34g@nih.gov FU National Institutes of Health (NIH), NCI, Center for Cancer Research, Intramural Research Program [ZIA BC 010881] FX This work was supported by the National Institutes of Health (NIH), NCI, Center for Cancer Research, Intramural Research Program (Grant# ZIA BC 010881). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 7 Z9 7 U1 1 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 OCT 16 PY 2013 VL 8 IS 10 AR e76115 DI 10.1371/journal.pone.0076115 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239JR UT WOS:000326019400038 PM 24146823 ER PT J AU Wei, JS Johansson, P Chen, L Song, YK Tolman, C Li, S Hurd, L Patidar, R Wen, XY Badgett, TC Cheuk, ATC Marshall, JC Steeg, PS Diez, JPV Yu, YL Gutkind, JS Khan, J AF Wei, Jun S. Johansson, Peter Chen, Li Song, Young K. Tolman, Catherine Li, Samuel Hurd, Laura Patidar, Rajesh Wen, Xinyu Badgett, Thomas C. Cheuk, Adam T. C. Marshall, Jean-Claude Steeg, Patricia S. Diez, Jose P. Vaque Yu, Yanlin Gutkind, J. Silvio Khan, Javed TI Massively Parallel Sequencing Reveals an Accumulation of De Novo Mutations and an Activating Mutation of LPAR1 in a Patient with Metastatic Neuroblastoma SO PLOS ONE LA English DT Article ID ARTIFICIAL NEURAL-NETWORKS; LYSOPHOSPHATIDIC ACID LPA; ACUTE MYELOID-LEUKEMIA; CLINICAL CHARACTERIZATION; PANCREATIC-CANCER; BREAST-CANCER; CELL MOTILITY; HUMAN COLON; ALK KINASE; N-MYC AB Neuroblastoma is one of the most genomically heterogeneous childhood malignances studied to date, and the molecular events that occur during the course of the disease are not fully understood. Genomic studies in neuroblastoma have showed only a few recurrent mutations and a low somatic mutation burden. However, none of these studies has examined the mutations arising during the course of disease, nor have they systemically examined the expression of mutant genes. Here we performed genomic analyses on tumors taken during a 3.5 years disease course from a neuroblastoma patient (bone marrow biopsy at diagnosis, adrenal primary tumor taken at surgical resection, and a liver metastasis at autopsy). Whole genome sequencing of the index liver metastasis identified 44 non-synonymous somatic mutations in 42 genes (0.85 mutation/MB) and a large hemizygous deletion in the ATRX gene which has been recently reported in neuroblastoma. Of these 45 somatic alterations, 15 were also detected in the primary tumor and bone marrow biopsy, while the other 30 were unique to the index tumor, indicating accumulation of de novo mutations during therapy. Furthermore, transcriptome sequencing on the 3 tumors demonstrated only 3 out of the 15 commonly mutated genes (LPAR1, GATA2, and NUFIP1) had high level of expression of the mutant alleles, suggesting potential oncogenic driver roles of these mutated genes. Among them, the druggable G-protein coupled receptor LPAR1 was highly expressed in all tumors. Cells expressing the LPAR1 R163W mutant demonstrated a significantly increased motility through elevated Rho signaling, but had no effect on growth. Therefore, this study highlights the need for multiple biopsies and sequencing during progression of a cancer and combinatorial DNA and RNA sequencing approach for systematic identification of expressed driver mutations. C1 [Wei, Jun S.; Johansson, Peter; Chen, Li; Song, Young K.; Tolman, Catherine; Li, Samuel; Hurd, Laura; Patidar, Rajesh; Wen, Xinyu; Badgett, Thomas C.; Cheuk, Adam T. C.; Khan, Javed] NCI, Oncogen Sect, Pediat Oncol Branch, Adv Technol Ctr, Bethesda, MD 20892 USA. [Wen, Xinyu] NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD 21701 USA. [Marshall, Jean-Claude; Steeg, Patricia S.] NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Diez, Jose P. Vaque; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Cell Growth Regulat Sect, Bethesda, MD USA. [Yu, Yanlin] NCI, Canc Modeling Sect, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wei, JS (reprint author), NCI, Oncogen Sect, Pediat Oncol Branch, Adv Technol Ctr, Bethesda, MD 20892 USA. EM weij@mail.nih.gov; khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014; Johansson, Peter/K-1053-2014; Vaque, Jose/H-8413-2015 OI Khan, Javed/0000-0002-5858-0488; Johansson, Peter/0000-0001-7015-5452; Vaque, Jose/0000-0002-3913-2495 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 6 Z9 7 U1 2 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 OCT 16 PY 2013 VL 8 IS 10 AR UNSP e77731 DI 10.1371/journal.pone.0077731 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 239JR UT WOS:000326019400129 PM 24147068 ER PT J AU Devor, A Bandettini, PA Boas, DA Bower, JM Buxton, RB Cohen, LB Dale, AM Einevoll, GT Fox, PT Franceschini, MA Friston, KJ Fujimoto, JG Geyer, MA Greenberg, JH Halgren, E Hamalainen, MS Helmchen, F Hyman, BT Jasanoff, A Jernigan, TL Judd, LL Kim, SG Kleinfeld, D Kopell, NJ Kutas, M Kwong, KK Larkum, ME Lo, EH Magistretti, PJ Mandeville, JB Masliah, E Mitra, PP Mobley, WC Moskowitz, MA Nimmerjahn, A Reynolds, JH Rosen, BR Salzberg, BM Schaffer, CB Silva, GA So, PTC Spitzer, NC Toote, RB Van Essen, DC Vanduffel, W Vinogradov, SA Wald, LL Wang, LV Weber, B Yodh, AG AF Devor, Anna Bandettini, Peter A. Boas, David A. Bower, James M. Buxton, Richard B. Cohen, Lawrence B. Dale, Anders M. Einevoll, Gaute T. Fox, Peter T. Franceschini, Maria Angela Friston, Karl J. Fujimoto, James G. Geyer, Mark A. Greenberg, Joel H. Halgren, Eric Haemaelaeinen, Math S. Helmchen, Fritjof Hyman, Bradley T. Jasanoff, Alan Jernigan, Terry L. Judd, Lewis L. Kim, Seong-Gi Kleinfeld, David Kopell, Nancy J. Kutas, Marta Kwong, Kenneth K. Larkum, Matthew E. Lo, Eng H. Magistretti, Pierre J. Mandeville, Joseph B. Masliah, Eliezer Mitra, Partha P. Mobley, William C. Moskowitz, Michael A. Nimmerjahn, Axel Reynolds, John H. Rosen, Bruce R. Salzberg, Brian M. Schaffer, Chris B. Silva, Gabriel A. So, Peter T. C. Spitzer, Nicholas C. Toote, Roger B. Van Essen, David C. Vanduffel, Wim Vinogradov, Sergei A. Wald, Lawrence L. Wang, Lihong V. Weber, Bruno Yodh, Arjun G. TI The Challenge of Connecting the Dots in the BRAIN SO NEURON LA English DT Editorial Material AB The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts and discuss likely technological deliverables and neuroscience progress. C1 [Devor, Anna; Dale, Anders M.; Halgren, Eric; Kutas, Marta; Masliah, Eliezer; Mobley, William C.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Devor, Anna; Buxton, Richard B.; Dale, Anders M.; Halgren, Eric; Jernigan, Terry L.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Devor, Anna; Boas, David A.; Franceschini, Maria Angela; Haemaelaeinen, Math S.; Kwong, Kenneth K.; Mandeville, Joseph B.; Rosen, Bruce R.; Toote, Roger B.; Vanduffel, Wim; Wald, Lawrence L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Bandettini, Peter A.] NIH, Sect Funct Imaging Methods, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Bandettini, Peter A.] NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. [Bower, James M.] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Cohen, Lawrence B.] Korea Inst Sci & Technol, Ctr Funct Connect, Seoul 139791, South Korea. [Cohen, Lawrence B.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. [Einevoll, Gaute T.] Norwegian Univ Life Sci, Dept Math Sci & Technol, N-1432 As, Norway. [Fox, Peter T.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Fox, Peter T.] Audie L Murphy South Texas Vet Adm Med Ctr, San Antonio, TX 78229 USA. [Friston, Karl J.] Wellcome Trust Ctr Neuroimaging, London WC1N 3BG, England. [Fujimoto, James G.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Fujimoto, James G.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Geyer, Mark A.; Jernigan, Terry L.; Judd, Lewis L.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Greenberg, Joel H.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Helmchen, Fritjof] Univ Zurich, Brain Res Inst, CH-8057 Zurich, Switzerland. [Helmchen, Fritjof; Weber, Bruno] Univ Zurich, Neurosci Ctr Zurich, CH-8057 Zurich, Switzerland. [Helmchen, Fritjof; Weber, Bruno] ETH, CH-8092 Zurich, Switzerland. [Hyman, Bradley T.] Harvard Univ, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol,Alzheimers Dis Res Lab,Med Sch, Charlestown, MA 02129 USA. [Jasanoff, Alan] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Jasanoff, Alan] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Jasanoff, Alan] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Jasanoff, Alan] MIT, Dept Nucl Sci & Engn, Cambridge, MA 02139 USA. [Jernigan, Terry L.] Univ Calif San Diego, Ctr Human Dev, La Jolla, CA 92093 USA. [Jernigan, Terry L.; Kutas, Marta] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA. [Kim, Seong-Gi] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15203 USA. [Kim, Seong-Gi] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA 15203 USA. [Kleinfeld, David] Univ Calif San Diego, Dept Phys, La Jolla, CA 92093 USA. [Kleinfeld, David] Univ Calif San Diego, Neurobiol Sect, La Jolla, CA 92093 USA. [Kopell, Nancy J.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Kutas, Marta] Univ Calif San Diego, Ctr Res Language, La Jolla, CA 92093 USA. [Larkum, Matthew E.] Charite, Neurosci Res Ctr NWFZ, D-10117 Berlin, Germany. [Lo, Eng H.; Moskowitz, Michael A.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Neurosci Ctr,Med Sch, Boston, MA 02129 USA. [Lo, Eng H.; Moskowitz, Michael A.] Harvard Univ, Massachusetts Gen Hosp, Dept Neurol, Neurosci Ctr,Med Sch, Boston, MA 02129 USA. [Magistretti, Pierre J.] Ecole Polytech Fed Lausanne, Brain Mind Inst, Lab Neuroenerget & Cellular Dynam, CH-1015 Lausanne, Switzerland. [Magistretti, Pierre J.] Univ Lausanne, CH-1015 Lausanne, Switzerland. [Mitra, Partha P.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Nimmerjahn, Axel] Salk Inst Biol Studies, Waitt Adv Biophoton Ctr, La Jolla, CA 92037 USA. [Reynolds, John H.] Salk Inst Biol Studies, Syst Neurobiol Labs, La Jolla, CA 92037 USA. [Salzberg, Brian M.] Univ Penn, Perelman Sch Med, Dept Neurosci, Philadelphia, PA 19104 USA. [Salzberg, Brian M.] Univ Penn, Perelman Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. [Schaffer, Chris B.] Cornell Univ, Dept Biomed Engn, Ithaca, NY 14850 USA. [Silva, Gabriel A.] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Silva, Gabriel A.] Univ Calif San Diego, Dept Ophthalmol, La Jolla, CA 92093 USA. [So, Peter T. C.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [So, Peter T. C.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Spitzer, Nicholas C.] Univ Calif San Diego, Div Biol Sci, Kavli Inst Brain & Mind, Neurobiol Sect, La Jolla, CA 92093 USA. [Toote, Roger B.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Van Essen, David C.] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Vanduffel, Wim] Katholieke Univ Leuven, Sch Med, Lab Neuro & Psychofysiol, B-3000 Louvain, Belgium. [Vinogradov, Sergei A.] Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. [Wang, Lihong V.] Washington Univ, Dept Biomed Engn, St Louis, MO 63130 USA. [Weber, Bruno] Univ Zurich, Inst Pharmacol & Toxicol, CH-8057 Zurich, Switzerland. [Yodh, Arjun G.] Univ Penn, Dept Phys & Astron, Philadelphia, PA 19104 USA. RP Devor, A (reprint author), Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. EM adevor@ucsd.edu RI Hamalainen, Matti/C-8507-2013; Schaffer, Chris/A-7409-2008; Friston, Karl/D-9230-2011; Fox, Peter/B-4725-2010; Weber, Bruno/E-4400-2013; Wald, Lawrence/D-4151-2009 OI Schaffer, Chris/0000-0002-7800-9596; Friston, Karl/0000-0001-7984-8909; Fox, Peter/0000-0002-0465-2028; FU NEI NIH HHS [R01 EY022096]; NIBIB NIH HHS [P41 EB015871, R01 EB000790, R01 EB003832]; NICHD NIH HHS [R01 HD022614]; NIDA NIH HHS [R01 DA029706]; NIH HHS [DP1 OD006831]; NINDS NIH HHS [DP1 NS082097, R01 NS040966, R01 NS057198, R01 NS058668]; Wellcome Trust [091593, 088130] NR 1 TC 30 Z9 30 U1 4 U2 53 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 16 PY 2013 VL 80 IS 2 BP 270 EP 274 DI 10.1016/j.neuron.2013.09.008 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 241VI UT WOS:000326196400009 PM 24139032 ER PT J AU Donnelly, CJ Zhang, PW Pham, JT Heusler, AR Mistry, NA Vidensky, S Daley, EL Poth, EM Hoover, B Fines, DM Maragakis, N Tienari, PJ Petrucelli, L Traynor, BJ Wang, JO Rigo, F Bennett, CF Blackshaw, S Sattler, R Rothstein, JD AF Donnelly, Christopher J. Zhang, Ping-Wu Pham, Jacqueline T. Heusler, Aaron R. Mistry, Nipun A. Vidensky, Svetlana Daley, Elizabeth L. Poth, Erin M. Hoover, Benjamin Fines, Daniel M. Maragakis, Nicholas Tienari, Pentti J. Petrucelli, Leonard Traynor, Bryan J. Wang, Jiou Rigo, Frank Bennett, C. Frank Blackshaw, Seth Sattler, Rita Rothstein, Jeffrey D. TI RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention SO NEURON LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; MYOTONIC-DYSTROPHY; REPEAT EXPANSION; FRONTOTEMPORAL DEMENTIA; HEXANUCLEOTIDE REPEAT; MOTOR-NEURONS; GGGGCC REPEAT; GLUTAMATE TRANSPORTER; TIME-COURSE; IN-VIVO AB A hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72 gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The function of the C9ORF72 protein is unknown, as is the mechanism by which the repeat expansion could cause disease. Induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients revealed disease-specific (1) intranuclear GGGGCC(exp) RNA foci, (2) dysregulated gene expression, (3) sequestration of GGGGCCexp RNA binding protein ADARB2, and (4) susceptibility to excitotoxicity. These pathological and pathogenic characteristics were confirmed in ALS brain and were mitigated with antisense oligonucleotide (ASO) therapeutics to the C9ORF72 transcript or repeat expansion despite the presence of repeat-associated non-ATG translation (RAN) products. These data indicate a toxic RNA gain-of-function mechanism as a cause of C9ORF72 ALS and provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy. C1 [Donnelly, Christopher J.; Zhang, Ping-Wu; Mistry, Nipun A.; Vidensky, Svetlana; Daley, Elizabeth L.; Hoover, Benjamin; Fines, Daniel M.; Maragakis, Nicholas; Traynor, Bryan J.; Sattler, Rita; Rothstein, Jeffrey D.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21205 USA. [Poth, Erin M.; Wang, Jiou; Blackshaw, Seth; Rothstein, Jeffrey D.] Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA. [Pham, Jacqueline T.; Rothstein, Jeffrey D.] Johns Hopkins Univ, Dept Cellular & Mol Med, Baltimore, MD 21205 USA. [Heusler, Aaron R.; Wang, Jiou] Johns Hopkins Univ, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. [Donnelly, Christopher J.; Zhang, Ping-Wu; Mistry, Nipun A.; Vidensky, Svetlana; Daley, Elizabeth L.; Hoover, Benjamin; Fines, Daniel M.; Sattler, Rita; Rothstein, Jeffrey D.] Johns Hopkins Univ, Brain Sci Inst, Baltimore, MD 21205 USA. [Tienari, Pentti J.] Univ Helsinki, Biomedicum, Res Programs Unit, FIN-00290 Helsinki, Finland. [Tienari, Pentti J.] Univ Helsinki, Cent Hosp, Dept Neurol, FIN-00290 Helsinki, Finland. [Petrucelli, Leonard] Mayo Clin, Dept Mol Neurosci, Jacksonville, FL 32224 USA. [Traynor, Bryan J.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Rigo, Frank; Bennett, C. Frank] ISIS Pharmaceut, Carlsbad, CA 92010 USA. RP Sattler, R (reprint author), Johns Hopkins Univ, Dept Neurol, 855 N Wolfe St,Rangos 2-270, Baltimore, MD 21205 USA. EM rsattle1@jhmi.edu; jrothstein@jhmi.edu RI Traynor, Bryan/G-5690-2010; Tienari, Pentti/A-4893-2012; OI Donnelly, Christopher/0000-0002-2383-9015 FU NIH; P2ALS; Muscular Dystrophy Association; Judith and Jean Pape Adams Charitable Foundation; ALS Association; Johns Hopkins Brain Science Institute; Ansari ALS Center for Cell Therapy and Regeneration Research at Johns Hopkins; Alzheimer Drug Discovery Foundation; Association for Frontotemporal Degeneration; Finnish Academy; Sigrid Juselius Foundation; Helsinki University Central Hospital; Robert Packard Center for ALS Research; Maryland Stem Cell Research Fund; Intramural Research Programs of the US National Institutes of Health (NIH); National Institute on Aging FX This work was funded by grants from NIH (J.D.R.), P2ALS (J.D.R.), Muscular Dystrophy Association (J.D.R.), The Judith and Jean Pape Adams Charitable Foundation (R.S.), ALS Association (R.S.), the Johns Hopkins Brain Science Institute, The Ansari ALS Center for Cell Therapy and Regeneration Research at Johns Hopkins, The Alzheimer Drug Discovery Foundation and the Association for Frontotemporal Degeneration, The Finnish Academy, The Sigrid Juselius Foundation, the Helsinki University Central Hospital, Robert Packard Center for ALS Research, Maryland Stem Cell Research Fund (C.J.D.), Intramural Research Programs of the US National Institutes of Health (NIH) (B.T.), and National Institute on Aging (B.T.). We would like to thank the Johns Hopkins Deep Sequencing and Microarray Core for the valuable insight on high-throughput experimental design and analysis. Dr. Phillip Wong provided data analysis and interpretation. Dr. Lyle Ostrow provided human tissue demographics. Additional technical and reagent support was graciously provided by Meredith Davitt, Uma Balasubramanian, Conover Talbot Jr., Dr. Tania Gendron, and Dr. Jean-Phillipe Richard. J.D.R, R.S., C.J.D., F.R., and C.F.B. have patents pending on antisense therapeutics and associated genetic bio-markers. B.T. has patents pending for the diagnostic and therapeutic uses of the C9ORF72 hexanucleotide repeat expansion. The remaining authors have no competing financial interests. NR 49 TC 231 Z9 235 U1 6 U2 49 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 16 PY 2013 VL 80 IS 2 BP 415 EP 428 DI 10.1016/j.neuron.2013.10.015 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 241VI UT WOS:000326196400022 PM 24139042 ER PT J AU Takahashi, YK Chang, CY Lucantonio, F Haney, RZ Berg, BA Yau, HJ Bonci, A Schoenbaum, G AF Takahashi, Yuji K. Chang, Chun Yun Lucantonio, Federica Haney, Richard Z. Berg, Benjamin A. Yau, Hau-Jie Bonci, Antonello Schoenbaum, Geoffrey TI Neural Estimates of Imagined Outcomes in the Orbitofrontal Cortex Drive Behavior and Learning SO NEURON LA English DT Article ID DORSOLATERAL PREFRONTAL CORTEX; REINFORCER DEVALUATION; RHESUS-MONKEYS; BASOLATERAL AMYGDALA; ECONOMIC VALUE; DECISION-MAKING; REWARD VALUE; LESIONS; REPRESENTATION; REVERSAL AB Imagination, defined as the ability to interpret reality in ways that diverge from past experience, is fundamental to adaptive behavior. This can be seen at a simple level in our capacity to predict novel outcomes in new situations. The ability to anticipate outcomes never before received can also influence learning if those imagined outcomes are not received. The orbitofrontal cortex is a key candidate for where the process of imagining likely outcomes occurs; however, its precise role in generating these estimates and applying them to learning remain open questions. Here we address these questions by showing that single-unit activity in the orbitofrontal cortex reflects novel outcome estimates. The strength of these neural correlates predicted both behavior and learning, learning that was abolished by temporally specific inhibition of orbitofrontal neurons. These results are consistent with the proposal that the orbitofrontal cortex is critical for integrating information to imagine future outcomes. C1 [Takahashi, Yuji K.; Chang, Chun Yun; Berg, Benjamin A.; Yau, Hau-Jie; Bonci, Antonello; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Cellular Neurobiol Res Branch, Behav Neurophysiol Res Sect, Baltimore, MD 21224 USA. [Lucantonio, Federica; Haney, Richard Z.; Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Bonci, Antonello; Schoenbaum, Geoffrey] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21287 USA. [Bonci, Antonello] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD 21287 USA. RP Takahashi, YK (reprint author), NIDA, Intramural Res Program, Cellular Neurobiol Res Branch, Behav Neurophysiol Res Sect, Baltimore, MD 21224 USA. EM yuji.takahashi@nih.gov; geoffrey.schoenbaum@nih.gov OI YAU, HAU-JIE/0000-0001-7454-7971 FU Intramural Research Program at the National Institute on Drug Abuse; [K99MH83940]; [R01MH080865] FX This work was supported by grant numbers K99MH83940 and R01MH080865 and by the Intramural Research Program at the National Institute on Drug Abuse. The authors would like to thank Dr. Karl Deisseroth and the Gene Therapy Center at the University of North Carolina at Chapel Hill core for providing viral reagents, and Dr. Garret Stuber for technical advice on their use. The opinions expressed in this article are the authors' own and do not reflect the views of the NIH/DHHS. NR 51 TC 24 Z9 25 U1 3 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 16 PY 2013 VL 80 IS 2 BP 507 EP 518 DI 10.1016/j.neuron.2013.08.008 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 241VI UT WOS:000326196400029 PM 24139047 ER PT J AU Ha, JH Eo, Y Grishaev, A Guo, M Smith, JAI Sintim, HO Kim, EH Cheong, HK Bentley, WE Ryu, KS AF Ha, Jung-Hye Eo, Yumi Grishaev, Alexander Guo, Min Smith, Jacqueline A. I. Sintim, Herman O. Kim, Eun-Hee Cheong, Hae-Kap Bentley, William E. Ryu, Kyoung-Seok TI Crystal Structures of the LsrR Proteins Complexed with Phospho-Al-2 and Two Signal-Interrupting Analogues Reveal Distinct Mechanisms for Ligand Recognition SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID QUORUM-SENSING SIGNAL; ESCHERICHIA-COLI; AI-2 ANALOGS; CELL COMMUNICATION; HYDROGEN-BONDS; REGULATOR LSRR; BINDING; IDENTIFICATION; REPRESSOR; BACTERIA AB Quorum sensing (QS) is a cell-to-cell communication system responsible for a variety of bacterial phenotypes including virulence and biofilm formation. QS is mediated by small molecules, autoinducers (AIs), including AI-2 that is secreted by both Gram-positive and -negative microbes. LsrR is a key transcription regulator that governs the varied downstream processes by perceiving AI-2 signal, but its activation via autoinducer-binding remains poorly understood. Here, we provide detailed regulatory mechanism of LsrR from the crystal structures in complexes with the native signal (phospho-AI-2, D5P) and two quorum quenching antagonists (ribose-5-phosphate, R5P; phospho-isobutyl-AI-2, D8P). Interestingly, the bound D5P and D8P molecules are not the diketone forms but rather hydrated, and the hydrated moiety forms important H-bonds with the carboxylate of D243. The D5P-binding flipped out F124 of the binding pocket, and resulted in the disruption of the dimeric interface-1 by unfolding the alpha 7 segment. However, the same movement of F124 by the D8P'-binding did not cause the unfolding of the alpha 7 segment. Although the LsrR-binding affinity of RSP (K-d, similar to 1 mM) is much lower than that of D5P and D8P (similar to 1.0 and similar to 0.5 mu M), the alpha-anomeric R5P molecule fits into the binding pocket without any structural perturbation, and thus stabilizes the LsrR tetramer. The binding of D5P, not D8P and R5P, disrupted the tetrameric structure and thus is able to activate LsrR. The detailed structural and mechanistic insights from this study could be useful for facilitating design of new antivirulence and antibiofilm agents based on LsrR. C1 [Ha, Jung-Hye; Eo, Yumi; Kim, Eun-Hee; Cheong, Hae-Kap; Ryu, Kyoung-Seok] Korea Basic Sci Inst, Div Magnet Resonance Res, Cheongwon Gun 363883, Chungcheongbuk, South Korea. [Ha, Jung-Hye; Eo, Yumi; Ryu, Kyoung-Seok] Univ Sci & Technol, Dept Bioanalyt Sci, Taejon 305333, South Korea. [Grishaev, Alexander] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Guo, Min; Smith, Jacqueline A. I.; Sintim, Herman O.] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Bentley, William E.] Univ Maryland, Grad Program Mol & Cell Biol, College Pk, MD 20742 USA. [Bentley, William E.] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA. RP Ryu, KS (reprint author), Korea Basic Sci Inst, Div Magnet Resonance Res, Yangcheong Ri 804-1, Cheongwon Gun 363883, Chungcheongbuk, South Korea. EM ksryu@kbsi.re.kr RI Sintim, Herman/B-4475-2009; Guo, Min/D-5989-2016 OI Sintim, Herman/0000-0002-2280-9359; Guo, Min/0000-0003-4632-7116 FU biointernational cooperative research program from Chungcheongbuk-Do province; high-field NMR research program from Korea Basic Science Institute (KBSI); KBSI grant [T33410]; Pohang Acceleratory Laboratory; Camille Dreyfus foundation; US Army DTRA [BO085PO008]; National Science Foundation [BES-0124401]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-ENG-38] FX This research was supported by biointernational cooperative research program from Chungcheongbuk-Do province and by high-field NMR research program from Korea Basic Science Institute (KBSI) to K.-S. Ryu, and was additionally supported by KBSI grant (T33410) to H. K. Cheong. We thank Photon Factory in Japan for using the X-ray beam-lines and appreciate that Pohang Acceleratory Laboratory supported a travel stipend to Photon Factory. We thank Dr. Yun, Sijung (NIH/NIDDK) for valuable discussions about the structural transition and the molecular dynamic simulation. We also thank Camille Dreyfus foundation for a grant to H. O Sintim, NSF CHE0746446 and a GANN fellowship to J. A. I. Smith and the support of US Army DTRA (BO085PO008) and the National Science Foundation (BES-0124401). We gratefully 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 Drs. Soenke Seifert and Xiaobing Zuo (Argonne National Laboratory) for their support of the SAXS experiments. 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 36 TC 5 Z9 5 U1 2 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 EI 1520-5126 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 16 PY 2013 VL 135 IS 41 BP 15526 EP 15535 DI 10.1021/ja407068v PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 240VG UT WOS:000326125200039 PM 24047255 ER PT J AU Belcher, AM Yen, CC Stepp, H Gu, H Lu, HB Yang, YH Silva, AC Stein, EA AF Belcher, Annabelle M. Yen, Cecil C. Stepp, Haley Gu, Hong Lu, Hanbing Yang, Yihong Silva, Afonso C. Stein, Elliot A. TI Large-Scale Brain Networks in the Awake, Truly Resting Marmoset Monkey SO JOURNAL OF NEUROSCIENCE LA English DT Article ID STATE FUNCTIONAL CONNECTIVITY; DEFAULT-MODE NETWORK; ORBITOFRONTAL CORTEX; MAGNETIC-RESONANCE; CALLITHRIX-JACCHUS; STRUCTURAL CONNECTIVITY; BIOMEDICAL-RESEARCH; PREFRONTAL CORTEX; ANIMAL-MODEL; ORGANIZATION AB Resting-state functional MRI is a powerful tool that is increasingly used as a noninvasive method for investigating whole-brain circuitry and holds great potential as a possible diagnostic for disease. Despite this potential, few resting-state studies have used animal models (of which nonhuman primates represent our best opportunity of understanding complex human neuropsychiatric disease), and no work has characterized networks in awake, truly resting animals. Here we present results from a small New World monkey that allows for the characterization of resting-state networks in the awake state. Six adult common marmosets (Callithrix jacchus) were acclimated to light, comfortable restraint using individualized helmets. Following behavioral training, resting BOLD data were acquired during eight consecutive 10 min scans for each conscious subject. Group independent component analysis revealed 12 brain networks that overlap substantially with known anatomically constrained circuits seen in the awake human. Specifically, we found eight sensory and "lower-order" networks (four visual, two somatomotor, one cerebellar, and one caudate-putamen network), and four "higher-order" association networks (one default mode-like network, one orbitofrontal, one frontopolar, and one network resembling the human salience network). In addition to their functional relevance, these network patterns bear great correspondence to those previously described in awake humans. This first-of-its-kind report in an awake New World nonhuman primate provides a platform for mechanistic neurobiological examination for existing disease models established in the marmoset. C1 [Belcher, Annabelle M.; Stepp, Haley; Gu, Hong; Lu, Hanbing; Yang, Yihong; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. [Yen, Cecil C.; Silva, Afonso C.] NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Belcher, AM (reprint author), NIDA, Neuroimaging Res Branch, NIDA IRP, NIH, BRC Bldg,Suite 200,251 Bayview Blvd, Baltimore, MD 21224 USA. EM belcher.mimi@gmail.com RI Yen, Cecil/C-2212-2009 OI Yen, Cecil/0000-0002-1519-9791 FU National Institute on Drug Abuse; National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Neurological Disorders and Stroke. We thank Julie B. Mackel (behavioral training and helmet manufacturing), Xianfeng Lisa Zhang (animal preparation), Dr. Hellmut Merkle (coil design and fabrication), Daniel C. Papoti (coil fabrication), and Lucia Notardonato, for their valuable contributions to this project. NR 73 TC 36 Z9 36 U1 1 U2 19 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 OCT 16 PY 2013 VL 33 IS 42 BP 16796 EP 16804 DI 10.1523/JNEUROSCI.3146-13.2013 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 236OY UT WOS:000325809800034 PM 24133280 ER PT J AU Rao, M AF Rao, Mahendra TI iPSC-Based Cell Therapy: An Important Step Forward SO STEM CELL REPORTS LA English DT Editorial Material AB Morizane et al. (2013) show that donor-matched differentiated derivatives of induced pluripotent stem cells (iPSC) do not cause an immune response after transplantation, whereas transplantation of HLA-mismatched iPSC derivatives to the same site clearly does. The importance of these results is discussed in this commentary as we assess how best to move forward with iPSC-based cell therapy. C1 NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Rao, M (reprint author), NIH, Ctr Regenerat Med, 50 South Dr, Bethesda, MD 20892 USA. EM mrao1234@verizon.net NR 8 TC 4 Z9 4 U1 2 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD OCT 15 PY 2013 VL 1 IS 4 BP 281 EP 282 DI 10.1016/j.stemcr.2013.10.002 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AI1SP UT WOS:000336633000001 PM 24319663 ER PT J AU Tilley, MK Justice, CM Swindle, K Marosy, B Wilson, AF Miller, NH AF Tilley, Mera K. Justice, Cristina M. Swindle, Kandice Marosy, Beth Wilson, Alexander F. Miller, Nancy H. TI CHD7 Gene Polymorphisms and Familial Idiopathic Scoliosis SO SPINE LA English DT Article DE familial idiopathic scoliosis; genetic linkage; association analysis; meta-analysis; chromosome 8q12; CHARGE syndrome; CHD7 ID CHARGE SYNDROME; ASSOCIATION; TWINS; SUSCEPTIBILITY; POPULATION; PREVALENCE; VARIANTS AB Study Design. Model-independent linkage analysis and tests of association were performed for 22 single nucleotide polymorphisms in the CHD7 gene in 244 families of European descent with familial idiopathic scoliosis (FIS). Objective. To replicate an association between FIS and the CHD7 gene on 8q12.2 in an independent sample of families of European descent. Summary of Background Data. The CHD7 gene on chromosome 8, responsible for the CHARGE syndrome, was previously associated with FIS in an independent study that included 52 families of European descent. Methods. Model-independent linkage analysis and intrafamilial tests of association were performed on the degree of lateral curvature considered as a qualitative trait (with thresholds of >= 10 degrees, >= 15 degrees, >= 20 degrees, and >= 30 degrees) and as a quantitative trait (degree of lateral curvature). Results from the tests of associations from this st Results. No significant results (P < 0.01) were found for linkage analysis or tests of association between genetic variants of the CHD7 and FIS in this study, failing to replicate the findings from the previous study. Furthermore, no significant results (P < 0.01) were found from meta-analysis of the results from the tests of association from this sample and from the previous sample. Conclusion. No association between the 22 genotyped single nucleotide polymorphisms in the CHD7 gene and FIS within this study sample was found, failing to replicate the earlier findings. Further investigation of the CHD7 gene and its potential association to FIS may be required. C1 [Tilley, Mera K.; Justice, Cristina M.; Wilson, Alexander F.] NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Swindle, Kandice; Miller, Nancy H.] Univ Colorado Denver, Dept Orthopaed Surg, Aurora, CO 80045 USA. [Marosy, Beth] Johns Hopkins Univ, Sch Med, Ctr Inherited Dis, Inst Med Genet, Baltimore, MD USA. RP Miller, NH (reprint author), Univ Colorado Denver, Dept Orthopaed Surg, Anschutz Med Campus,12800 E 19th Ave,MS8343, Aurora, CO 80045 USA. EM Nancy.Miller@childrenscolorado.org FU National Institutes of Health [N01-HG-65403 5R01AR048862-03]; National Center for Research Resources [1 P41 RR03655] FX Genotyping was performed at the Center for Inherited Disease Research (CIDR). CIDR is fully funded through federal contract N01-HG-65403 5R01AR048862-03 from the National Institutes of Health to the Johns Hopkins University. Some of the results were obtained with the program S. A. G. E., which is supported by grant 1 P41 RR03655 from the National Center for Research Resources. NR 35 TC 1 Z9 1 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD OCT 15 PY 2013 VL 38 IS 22 BP E1432 EP E1436 DI 10.1097/BRS.0b013e3182a51781 PG 5 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 299CM UT WOS:000330372600010 PM 23883829 ER PT J AU Cho, E Shamputa, IC Kwak, HK Lee, J Lee, M Hwang, S Jeon, D Kim, CT Cho, S Via, LE Barry, CE Lee, JS AF Cho, Eunjin Shamputa, Isdore Chola Kwak, Hyun-Kyung Lee, Jiim Lee, Myungsun Hwang, Soohee Jeon, Doosoo Kim, Cheon Tae Cho, Sangnae Via, Laura E. Barry, Clifton E., III Lee, Jong Seok TI Utility of the REBA MTB-rifa (R) assay for rapid detection of rifampicin resistant Mycobacterium Tuberculosis SO BMC INFECTIOUS DISEASES LA English DT Article DE Mycobacterium tuberculosis; Rifampicin resistance; REBA MTB-Rifa (R) assay; rpoB ID LINE PROBE ASSAY; XPERT MTB/RIF ASSAY; RPOB GENE; DRUG-RESISTANCE; ASIAN COUNTRIES; RISK-FACTORS; MUTATIONS; STRAINS; PERFORMANCE; POLYMERASE AB Background: Drug-resistant tuberculosis (TB), including resistance to both rifampicin (RIF) and isoniazid (INH) referred to as multidrug-resistant tuberculosis (MDR-TB), has become an increasing global threat in recent years. Effective management of patients infected with MDR-TB strains requires identifying such patients by performing conventional drug-susceptibility testing (DST) on bacteria isolated from sputum, a process that can take up to 2 months. This delay in diagnosis can result in worsening and continued transmission of MDR-TB. Molecular methods that rely upon nucleic acid amplification of specific alleles known to be associated with resistance to specific drugs have been helpful in shortening the time to detect drug resistant TB. Methods: We investigated the utility of the REBA MTB-Rifa (R), a commercially available line probe assay (LPA) for detecting rifampicin (RIF) resistance in the RIF resistance-determining region (RRDR) of the rpoB gene. Altogether, 492 Mycobacterium tuberculosis (M. tuberculosis) clinical isolates and additional 228 smear-and culture-positive sputum samples with confirmed M. tuberculosis were collected from subjects with suspected MDR-TB in South Korea. The results were compared with conventional phenotypic DST and sequencing of the rpoB gene. Results: A total of 215 of the 492 isolates were resistant to RIF by conventional DST, and of which 92.1% (198/215) were MDR-TB strains. The REBA MTB-Rifa (R) assay identified RIF resistance in 98.1% (211/215) of these isolates but failed to identify resistance in four phenotypically RIF resistant isolates. These four isolates lacked mutations in the RRDR but three were confirmed to be MDR-TB strains by sequencing. The sensitivity and specificity of this test for clinical isolates was thus 98.1% (211/215) and 100% (277/277), respectively. When applied directly to 228 smear positive sputum samples, the sensitivity and the specificity of REBA MTB-Rifa (R) assay was 100% (96/96, 132/132), respectively. Conclusions: These findings support the use of the REBA MTB-Rifa (R) assay for rapid detection of RIF resistance on clinical isolates and smear positive sputum samples. The results also suggest that RIF resistance is a good surrogate marker of MDR-TB in South Korea and the need to add more probes to other LPAs which can cover newly identified mutations relevant to RIF resistance. C1 [Cho, Eunjin; Kwak, Hyun-Kyung; Lee, Jiim; Lee, Myungsun; Cho, Sangnae; Lee, Jong Seok] Int TB Res Ctr, Sect Microbiol, Chang Won 4751, South Korea. [Cho, Sangnae] Yonsei Univ, Coll Med, Dept Microbiol, Seoul, South Korea. [Hwang, Soohee; Jeon, Doosoo; Kim, Cheon Tae] Masan Natl Hosp, Chang Won 4751, South Korea. [Shamputa, Isdore Chola; Via, Laura E.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Lee, JS (reprint author), Int TB Res Ctr, Sect Microbiol, Chang Won 4751, South Korea. EM cosmosljs@gmail.com RI Barry, III, Clifton/H-3839-2012; OI Via, Laura/0000-0001-6074-9521 FU Intramural Research Program of the NIAID, NIH, Bethesda, MD FX This work was supported (in part) by the Intramural Research Program of the NIAID, NIH, Bethesda, MD; and (in part) through continuing support from the Ministry for Health, Welfare and Family Affairs of the Republic of Korea. NR 32 TC 4 Z9 4 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD OCT 15 PY 2013 VL 13 AR 478 DI 10.1186/1471-2334-13-478 PG 8 WC Infectious Diseases SC Infectious Diseases GA 278PB UT WOS:000328901100001 PM 24128118 ER PT J AU Barros, MP Hollnagel, HC Glavina, AB Soares, CO Ganini, D Dagenais-Bellefeuille, S Morse, D Colepicolo, P AF Barros, M. P. Hollnagel, H. C. Glavina, A. B. Soares, C. O. Ganini, D. Dagenais-Bellefeuille, S. Morse, D. Colepicolo, P. TI Molybdate:sulfate ratio affects redox metabolism and viability of the dinoflagellate Lingulodinium polyedrum SO AQUATIC TOXICOLOGY LA English DT Article DE Molybdenum; Harmful algae; Oxidative stress; Gonyaulax; Peridinin; MoCo; Algal bloom ID SUPEROXIDE-DISMUTASE; NITRATE REDUCTASE; HYDROGEN-PEROXIDE; ASCORBATE PEROXIDASE; GONYAULAX-POLYEDRA; XANTHINE-OXIDASE; ALGA GONYAULAX; NO PRODUCTION; SALINE LAKES; MOLYBDENUM AB Molybdenum is a transition metal used primarily (90% or more) as an additive to steel and corrosion-resistant alloys in metallurgical industries and its release into the environment is a growing problem. As a catalytic center of some redox enzymes, molybdenum is an essential element for inorganic nitrogen assimilation/fixation, phytohormone synthesis, and free radical metabolism in photosynthesizing species. In oceanic and estuarine waters, microalgae absorb molybdenum as the water-soluble molybdate anion (MoO42-), although MoO42- uptake is thought to compete with uptake of the much more abundant sulfate anion (SO42-, approximately 25 mM in seawater). Thus, those aspects of microalgal biology impacted by molybdenum would be better explained by considering both MoO42- and SO42- concentrations in the aquatic milieu. This work examines toxicological, physiological and redox imbalances in the dinoflagellate Lingulodinium polyedrum that have been induced by changes in the molybdate:sulfate ratios. We prepared cultures of Lingulodinium polyedrum grown in artificial seawater containing eight different MoO42- concentrations (from 0 to 200 mu M) and three different SO42- concentrations (3.5 mM, 9.6 mM and 25 mM). We measured sulfur content in cells, the activities of the three major antioxidant enzymes (superoxide dismutase, catalase, and ascorbate peroxidase), indexes of oxidative modifications in proteins (carbonyl content) and lipids (thiobarbituric acid-reactive substances, TBARS), the activities of the molybdenum-dependent enzymes xanthine oxidase and nitrate reductase, expression of key protein components of dinoflagellate photosynthesis (peridinin-chlorophyll a protein and ribulose-1,5-biphosphate carboxylase/oxidase) and growth curves. We find evidence for Mo toxicity at relatively high [MoO42-]:[SO42-] ratios. We also find evidence for extensive redox adaptations at Mo levels well below lethal levels. (C) 2013 Elsevier B.V. All rights reserved. C1 [Barros, M. P.; Glavina, A. B.; Soares, C. O.; Ganini, D.] Univ Cruzeiro Sul, CBS, Postgrad Program Hlth Sci Environm Chem, BR-08060070 Sao Paulo, Brazil. [Hollnagel, H. C.] Fac Mario Schenberg, BR-06710500 Cotia, SP, Brazil. [Soares, C. O.; Colepicolo, P.] Univ Sao Paulo, Inst Quim, Dept Biochem, Sao Paulo, Brazil. [Ganini, D.] NIEHS, Free Rad Metab Grp, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Dagenais-Bellefeuille, S.; Morse, D.] Univ Montreal, Inst Rech Biol Vegetale, Dept Sci Biol, Montreal, PQ H1X 2B2, Canada. RP Barros, MP (reprint author), Univ Cruzeiro Sul, CBS, Av Ussiel Cirilo 225, BR-08060070 Sao Paulo, Brazil. EM marcelo.barros@cruzeirodosul.edu.br RI Colepicolo, Pio/C-1349-2013; Barros, Marcelo/K-1410-2013; CEPID, Redoxoma/J-2971-2015 OI Barros, Marcelo/0000-0003-3565-8331; FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Programa de Suporte a Posgraduacao de Instituicoes de Ensino Particulares, da Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (PROSUP/CAPES, Brazil); Projeto Redoxoma, "Red iberoamericana para el estudio de nuevos carotenoides bioactivos como ingredientes de alimentos" (IBERCAROT/CYTED) [112RT0445]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Bolsa Produtividade em Pesquisa, CNPq, Brazil) [307474/2012-7] FX This research was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Programa de Suporte a Posgraduacao de Instituicoes de Ensino Particulares, da Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (PROSUP/CAPES, Brazil), Projeto Redoxoma, "Red iberoamericana para el estudio de nuevos carotenoides bioactivos como ingredientes de alimentos" (112RT0445; IBERCAROT/CYTED), and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (Bolsa Produtividade em Pesquisa, Nivel 2, #307474/2012-7, CNPq, Brazil). NR 45 TC 0 Z9 0 U1 1 U2 33 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-445X EI 1879-1514 J9 AQUAT TOXICOL JI Aquat. Toxicol. PD OCT 15 PY 2013 VL 142 BP 195 EP 202 DI 10.1016/j.aquatox.2013.08.012 PG 8 WC Marine & Freshwater Biology; Toxicology SC Marine & Freshwater Biology; Toxicology GA 267JM UT WOS:000328093900019 PM 24036534 ER PT J AU Aggarwal, M Banerjee, T Sommers, JA Brosh, RM AF Aggarwal, Monika Banerjee, Taraswi Sommers, Joshua A. Brosh, Robert M., Jr. TI Targeting an Achilles' heel of cancer with a WRN helicase inhibitor SO CELL CYCLE LA English DT Article DE DNA repair; Fanconi anemia; Werner syndrome; anticancer therapy; helicase; small molecule; synthetic lethality ID WERNER-SYNDROME PROTEIN; CROSS-LINK REPAIR; FANCONI-ANEMIA PATHWAY; DNA-REPAIR; HOMOLOGOUS RECOMBINATION; SYNTHETIC LETHALITY; COMPLEX INTERACTS; REPLICATION; DEFICIENT; DAMAGE AB Our recently published work suggests that DNA helicases such as the Werner syndrome helicase (WRN) represent a novel class of proteins to target for anticancer therapy. Specifically, pharmacological inhibition of WRN helicase activity in human cells defective in the Fanconi anemia (FA) pathway of interstrand cross-link (ICL) repair are sensitized to the DNA cross-linking agent and chemotherapy drug mitomycin C (MMC) by the WRN helicase inhibitor NSC 617145.(1) The mechanistic basis for the synergistic interaction between NSC 617145 and MMC is discussed in this paper and extrapolated to potential implications for genetic or chemically induced synthetic lethality provoked by cellular exposure to the WRN helicase inhibitor under the context of relevant DNA repair deficiencies associated with cancers or induced by small-molecule inhibitors. Experimental data are presented showing that small-molecule inhibition of WRN helicase elevates sensitivity to MMC-induced stress in human cells that are deficient in both FANCD2 and DNA protein kinase catalytic subunit (DNA-PKcs). These findings suggest a model in which drug-mediated inhibition of WRN helicase activity exacerbates the deleterious effects of MMC-induced DNA damage when both the FA and NHEJ pathways are defective. We conclude with a perspective for the FA pathway and synthetic lethality and implications for DNA repair helicase inhibitors that can be developed for anticancer strategies. C1 [Aggarwal, Monika; Banerjee, Taraswi; Sommers, Joshua A.; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU Intramural Research program of the National Institutes of Health; National Institute on Aging; Fanconi Anemia Research Fund FX This work was supported by the Intramural Research program of the National Institutes of Health, National Institute on Aging, and the Fanconi Anemia Research Fund (RMB). NR 35 TC 18 Z9 18 U1 1 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD OCT 15 PY 2013 VL 12 IS 20 BP 3329 EP 3335 DI 10.4161/cc.26320 PG 7 WC Cell Biology SC Cell Biology GA 257KA UT WOS:000327381100015 PM 24036544 ER PT J AU Canepa, M Sorensen, LL Pozios, I Dimaano, VL Luo, HC Pinheiro, AC Strait, JB Brunelli, C Abraham, MR Ferrucci, L Abraham, TP AF Canepa, Marco Sorensen, Lars L. Pozios, Iraklis Dimaano, Veronica L. Luo, Hong-Chang Pinheiro, Aurelio C. Strait, James B. Brunelli, Claudio Abraham, M. Roselle Ferrucci, Luigi Abraham, Theodore P. TI Comparison of Clinical Presentation, Left Ventricular Morphology, Hemodynamics, and Exercise Tolerance in Obese Versus Nonobese Patients With Hypertrophic Cardiomyopathy SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID DIASTOLIC FUNCTION; OBSTRUCTIVE CARDIOMYOPATHY; PHYSICAL-ACTIVITY; BLOOD-PRESSURE; BODY-MASS; HYPERTENSION; ECHOCARDIOGRAPHY; IMPACT; INDEX; RECOMMENDATIONS AB Obesity is independently associated with left ventricular (LV) hypertrophy and thus may be an important modifier of the hypertrophic cardiomyopathy (HC) phenotype. We examined if obesity modifies the clinical presentation, LV morphology, outflow hemodynamics, and exercise tolerance in HC. In this cross-sectional study, 88 obese (body mass index [BMI] >= 30 kg/m(2)) and 154 nonobese (BMI <30 kg/m(2)) patients from the Johns Hopkins HC clinic were compared with respect to a variety of clinical and LV echocardiographic measurements. Obese patients (36.4%). were more likely to report exertional dyspnea (p = 0.04) and chest pain (p = 0.002) and had greater prevalence of hypertension (p = 0.008). LV posterior wall thickness (p = 0.01) but not the septal wall (p >= 0.21) was significantly greater in obese patients, resulting in an increased LV mass index (p = 0.003). No significant differences in LV systolic and diastolic functions were observed, but obesity was associated with higher LV stroke volume (p = 0.03), inducible LV outflow tract gradients (p = 0.045), and chance of developing LV outflow tract obstruction during stress (p = 0.035). In multivariate analysis, BMI was associated with increased posterior (but not septal) wall thickness (beta = 0.15, p = 0.02) and LV mass index (beta = 0.18, p = 0.005), particularly in those with hypertension. Obesity was also associated with reduced exercise time and functional capacity, and BMI independently correlated with reduced exercise tolerance. In conclusion, obesity is associated with larger LV mass, worse symptoms, lower exercise tolerance, and labile obstructive hemodynamics in HC. The association with increased outflow tract gradients has particular importance as contribution of obesity to the pressure gradients may influence clinical decisions in labile obstructive HC. (C) 2013 Elsevier Inc. All rights reserved. C1 [Canepa, Marco; Sorensen, Lars L.; Pozios, Iraklis; Dimaano, Veronica L.; Luo, Hong-Chang; Pinheiro, Aurelio C.; Abraham, M. Roselle; Abraham, Theodore P.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD 21218 USA. [Canepa, Marco; Strait, James B.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [Canepa, Marco; Brunelli, Claudio] Univ Genoa, Div Cardiol, Res Ctr Cardiovasc Biol, Genoa, Italy. [Luo, Hong-Chang] Huazhong Univ Sci & Technol, Dept Med Ultrasound, Tongji Med Coll, Wuhan, Peoples R China. RP Abraham, TP (reprint author), Johns Hopkins Univ, Div Cardiol, Baltimore, MD 21218 USA. EM tabraha3@jhmi.edu FU National Institutes of Health, Bethesda, Maryland [HL098046] FX This work was supported in part by grant HL098046 from the National Institutes of Health, Bethesda, Maryland. NR 30 TC 7 Z9 7 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD OCT 15 PY 2013 VL 112 IS 8 BP 1182 EP 1189 DI 10.1016/j.amjcard.2013.05.070 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 236XV UT WOS:000325833700021 PM 24079444 ER PT J AU Pinsky, P AF Pinsky, Paul TI Observation Versus Initial Treatment for Prostate Cancer SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Pinsky, P (reprint author), NCI, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 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 OCT 15 PY 2013 VL 159 IS 8 BP 574 EP 574 DI 10.7326/0003-4819-159-8-201310150-00014 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 249BH UT WOS:000326751200024 PM 24126652 ER PT J AU Pandya, AA Yakel, JL AF Pandya, Anshul A. Yakel, Jerrel L. TI Effects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies SO BIOCHEMICAL PHARMACOLOGY LA English DT Review DE Allosteric modulation; animal behavioral studies; cognition; nicotinic acetylcholine receptor; pain; positive allosteric modulators ID BRONCHIAL EPITHELIAL-CELLS; 4 BETA 2; ACH RECEPTOR; ALZHEIMERS-DISEASE; CA2+ PERMEABILITY; RAT HIPPOCAMPAL; TRANSMEMBRANE SITE; COGNITIVE FUNCTION; XENOPUS OOCYTES; PAIN MODELS AB Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation-conducting transmembrane channels from the cys-loop receptor superfamily. The neuronal subtypes of these receptors (e.g. the alpha 7 and alpha 4 beta 2 subtypes) are involved in neurobehavioral processes such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and a number of cognitive functions like learning and memory. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders, and behavioral studies in animals are useful models to assess the effects of compounds that act on these receptors. Allosteric modulators are ligands that bind to the receptors at sites other than the orthosteric site where acetylcholine, the endogenous agonist for the nAChRs, binds. While conventional ligands for the neuronal nAChRs have been studied for their behavioral effects in animals, allosteric modulators for these receptors have only recently gained attention, and research on their behavioral effects is growing rapidly. Here we will discuss the behavioral effects of allosteric modulators of the neuronal nAChRs. Published by Elsevier Inc. C1 [Pandya, Anshul A.] Univ Alaska Fairbanks, Coll Rural & Community Dev, Dept Biosci, Kotzebue, AK 99752 USA. [Yakel, Jerrel L.] Natl Inst Environm Hlth Sci, Neurobiol Lab, Natl Inst Hlth, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), Natl Inst Environm Hlth Sci, Neurobiol Lab, Natl Inst Hlth, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM aapandya@alaska.edu; yakel@niehs.nih.gov FU Intramural Research Program of the National Institute of Environmental Health Sciences, NIH FX We would like to thank and acknowledge the contributions of Drs. Christian Erxleben and Serena Dudek for their help in the review of the manuscript. Participants in this research review are supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH. NR 126 TC 30 Z9 30 U1 3 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD OCT 15 PY 2013 VL 86 IS 8 SI SI BP 1054 EP 1062 DI 10.1016/j.bcp.2013.05.018 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 239FC UT WOS:000326007000003 PM 23732296 ER PT J AU Yap, TL Gruschus, JM Velayati, A Sidransky, E Lee, JC AF Yap, Thai Leong Gruschus, James M. Velayati, Arash Sidransky, Ellen Lee, Jennifer C. TI Saposin C Protects Glucocerebrosidase against alpha-Synuclein Inhibition SO BIOCHEMISTRY LA English DT Article ID SPHINGOLIPID ACTIVATOR PROTEINS; NEURONOPATHIC GAUCHER-DISEASE; LYSOSOMAL STORAGE; BETA-GLUCOSIDASE; ENZYME-ACTIVITY; DEFICIENCY; MUTATIONS; GLUCOSYLCERAMIDE; RECONSTITUTION; ACCUMULATION AB Mutations in GBA1, the gene for glucocerebrosidase (GCase), are genetic risk factors for Parkinson disease (PD). alpha-Synuclein (alpha-Syn), a protein implicated in PD, interacts with GCase and efficiently inhibits enzyme activity. GCase deficiency causes the lysosomal storage disorder Gaucher disease (GD). We show that saposin C (Sap C), a protein vital for GCase activity in vivo, protects GCase against alpha-syn inhibition. Using nuclear magnetic resonance spectroscopy, site-specific fluorescence, and Forster energy transfer probes, Sap C was observed to displace alpha-syn from GCase in solution and on lipid vesicles. Our results suggest that Sap C might play a crucial role in GD-related PD. C1 [Yap, Thai Leong; Gruschus, James M.; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, Biochem & Biophys Ctr, Bethesda, MD 20892 USA. [Velayati, Arash; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov; leej4@mail.nih.gov RI Lee, Jennifer/E-9658-2015 OI Lee, Jennifer/0000-0003-0506-8349 FU Intramural Research Program at the National Institutes of Health; National Heart, Lung, and Blood Institute; National Human Genome Research Institute FX Supported by the Intramural Research Program at the National Institutes of Health, the National Heart, Lung, and Blood Institute, and the National Human Genome Research Institute. NR 32 TC 17 Z9 17 U1 1 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 EI 1943-295X J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 15 PY 2013 VL 52 IS 41 BP 7161 EP 7163 DI 10.1021/bi401191v PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 240UO UT WOS:000326123400001 PM 24070323 ER PT J AU Sim, HM Bhatnagar, J Chufan, EE Kapoor, K Ambudkar, SV AF Sim, Hong-May Bhatnagar, Jaya Chufan, Eduardo E. Kapoor, Khyati Ambudkar, Suresh V. TI Conserved Walker A Cysteines 431 and 1074 in Human P-Glycoprotein Are Accessible to Thiol-Specific Agents in the Apo and ADP-Vanadate Trapped Conformations SO BIOCHEMISTRY LA English DT Article ID NUCLEOTIDE-BINDING SITES; DISULFIDE CROSS-LINKING; STIMULATED ATPASE ACTIVITY; CATALYTIC CYCLE; ABC-TRANSPORTER; CRYSTAL-STRUCTURE; MAMMALIAN-CELLS; DRUG-BINDING; HYDROLYSIS; STATE AB P-Glycoprotein (P-gp) is an ATP-binding cassette efflux transporter involved in the development of multidrug resistance in cancer cells. Although the mechanism of P-gp efflux has been extensively studied, aspects of its catalytic and transport cycle are still unclear. In this study, we used conserved C431 and C1074 in the Walker A motif of nucleotide-binding domains (NBDs) as reporter sites to interrogate the interaction between the two NBDs during the catalytic cycle. Disulfide cross-linking of the C431 and C1074 residues in a Cys-less background can be observed in the presence of M14M and M17M cross-linkers, which have spacer arm lengths of 20 and 25 angstrom, respectively. However, cross-linking with both cross-linkers was prevented in the ADP-vanadate trapped (closed) conformation. Both C431 and C1074 alone or together (double mutant) in the apo and closed conformations were found to be accessible to fluorescein 5-maleimide (FM) and methanethiosulfonate derivatives of rhodamine and verapamil. In addition, C1074 showed 1.4- and 2-fold higher degrees of FM labeling than C431 in the apo and closed conformations, respectively, demonstrating that C1074 is more accessible than C431 in both conformations. In the presence of P-gp substrates, cross-linking with M17M is still observed, suggesting that binding of substrate in the transmembrane domains does not change the accessibility of the cysteines in the NBDs. In summary, the cysteines in the Walker A motifs of NBDs of human P-gp are differentially accessible to thiol-specific agents in the apo and closed conformations. C1 [Sim, Hong-May; Bhatnagar, Jaya; Chufan, Eduardo E.; Kapoor, Khyati; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ambudkar@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Department of Pharmacy, Faculty of Science, National University of Singapore FX This research is supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. H.-M.S. is supported in part by a NUS-OPF fellowship from the Department of Pharmacy, Faculty of Science, National University of Singapore. NR 30 TC 3 Z9 3 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 EI 1943-295X J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 15 PY 2013 VL 52 IS 41 BP 7327 EP 7338 DI 10.1021/bi4007786 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 240UO UT WOS:000326123400018 PM 24053441 ER PT J AU Hoppe, T AF Hoppe, Travis TI Singular Value Decomposition of the Radial Distribution Function for Hard Sphere and Square Well Potentials SO PLOS ONE LA English DT Article ID DISCRETE MOLECULAR-DYNAMICS; MONTE-CARLO-SIMULATION; INTEGRAL-EQUATION; PHASE COEXISTENCE; FLUIDS; SHOULDER; BEHAVIOR; PROTEIN; MODEL; EQUILIBRIA AB We compute the singular value decomposition of the radial distribution function g(r) for hard sphere, and square well solutions. We find that g(r) decomposes into a small set of basis vectors allowing for an extremely accurate representation at all interpolated densities and potential strengths. In addition, we find that the coefficient vectors describing the magnitude of each basis vector are well described by a low-order polynomial. We provide a program to calculate g(r) in this compact representation for the investigated parameter range. C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Hoppe, T (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM hoppeta@mail.nih.gov OI Hoppe, Travis/0000-0002-4694-3050 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney 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 29 TC 1 Z9 1 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 15 PY 2013 VL 8 IS 10 AR e75792 DI 10.1371/journal.pone.0075792 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 237TP UT WOS:000325894100009 PM 24143174 ER PT J AU Thomas, MA Song, R Demberg, T Vargas-Inchaustegui, DA Venzon, D Robert-Guroff, M AF Thomas, Michael A. Song, Rui Demberg, Thorsten Vargas-Inchaustegui, Diego A. Venzon, David Robert-Guroff, Marjorie TI Effects of the Deletion of Early Region 4 (E4) Open Reading Frame 1 (orf1), orf1-2, orf1-3 and orf1-4 on Virus-Host Cell Interaction, Transgene Expression, and Immunogenicity of Replicating Adenovirus HIV Vaccine Vectors SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIGEN PRESENTATION; CYCLIN-E; DNA-REPLICATION; RHESUS MACAQUES; DENDRITIC CELLS; T-LYMPHOCYTES; GENE-PRODUCTS; RANGE MUTANT; PROTECTION AB The global health burden engendered by human immunodeficiency virus (HIV)-induced acquired immunodeficiency syndrome (AIDS) is a sobering reminder of the pressing need for a preventative vaccine. In non-human primate models replicating adenovirus (Ad)-HIV/SIV recombinant vaccine vectors have been shown to stimulate potent immune responses culminating in protection against challenge exposures. Nonetheless, an increase in the transgene carrying capacity of these Ad vectors, currently limited to approximately 3000 base pairs, would greatly enhance their utility. Using a replicating, E3-deleted Ad type 5 host range mutant (Ad5 hr) encoding full-length single-chain HIV(BaL)gp120 linked to the D1 and D2 domains of rhesus macaque CD4 (rhFLSC) we systematically deleted the genes encoding early region 4 open reading frame 1 (E4orf1) through E4orf4. All the Ad-rhFLSC vectors produced similar levels of viral progeny. Cell cycle analysis of infected human and monkey cells revealed no differences in virus-host interaction. The parental and E4-deleted viruses expressed comparable levels of the transgene with kinetics similar to Ad late proteins. Similar levels of cellular immune responses and transgene-specific antibodies were elicited in vaccinated mice. However, differences in recognition of Ad proteins and induced antibody subtypes were observed, suggesting that the E4 gene products might modulate antibody responses by as yet unknown mechanisms. In short, we have improved the transgene carrying capacity by one thousand base pairs while preserving the replicability, levels of transgene expression, and immunogenicity critical to these vaccine vectors. This additional space allows for flexibility in vaccine design that could not be obtained with the current vector and as such should facilitate the goal of improving vaccine efficacy. To the best of our knowledge, this is the first report describing the effects of these E4 deletions on transgene expression and immunogenicity in a replicating Ad vector. C1 [Thomas, Michael A.; Song, Rui; Demberg, Thorsten; Vargas-Inchaustegui, Diego A.; Robert-Guroff, Marjorie] NCI, Sect Immune Biol Retroviral Infect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, Sect Immune Biol Retroviral Infect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU National Institutes of Health (NIH), National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 4 Z9 4 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 OCT 15 PY 2013 VL 8 IS 10 AR e76344 DI 10.1371/journal.pone.0076344 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 237TP UT WOS:000325894100022 PM 24143187 ER PT J AU Kent, EE Forsythe, LP Yabroff, KR Weaver, KE de Moor, JS Rodriguez, JL Rowland, JH AF Kent, Erin E. Forsythe, Laura P. Yabroff, K. Robin Weaver, Kathryn E. de Moor, Janet S. Rodriguez, Juan L. Rowland, Julia H. TI Are Survivors Who Report Cancer-Related Financial Problems More Likely to Forgo or Delay Medical Care? SO CANCER LA English DT Article DE cancer; health disparities; survivors; access to care; financial burden ID QUALITY-OF-LIFE; BREAST-CANCER; UNITED-STATES; LOW-INCOME; HEALTH; BURDEN; POPULATION; IMPACT; WOMEN; COST AB BACKGROUNDFinancial problems caused by cancer and its treatment can substantially affect survivors and their families and create barriers to seeking health care. METHODSThe authors identified cancer survivors diagnosed as adults (n=1556) from the nationally representative 2010 National Health Interview Survey. Using multivariable logistic regression analyses, the authors report sociodemographic, clinical, and treatment-related factors associated with perceived cancer-related financial problems and the association between financial problems and forgoing or delaying health care because of cost. Adjusted percentages using the predictive marginals method are presented. RESULTSCancer-related financial problems were reported by 31.8% (95% confidence interval, 29.3%-34.5%) of survivors. Factors found to be significantly associated with cancer-related financial problems in survivors included younger age at diagnosis, minority race/ethnicity, history of chemotherapy or radiation treatment, recurrence or multiple cancers, and shorter time from diagnosis. After adjustment for covariates, respondents who reported financial problems were more likely to report delaying (18.3% vs 7.4%) or forgoing overall medical care (13.8% vs 5.0%), prescription medications (14.2% vs 7.6%), dental care (19.8% vs 8.3%), eyeglasses (13.9% vs 5.8%), and mental health care (3.9% vs 1.6%) than their counterparts without financial problems (all P<.05). CONCLUSIONSCancer-related financial problems are not only disproportionately represented in survivors who are younger, members of a minority group, and have a higher treatment burden, but may also contribute to survivors forgoing or delaying medical care after cancer. Cancer 2013;119:3710-3717. (c) 2013 American Cancer Society. Approximately one-third of individuals with a history of cancer report cancer-related financial problems. Financial problems are disproportionately more common in survivors who are younger, members of a minority group, and report a higher treatment burden history. They are also associated with delaying or forgoing health care because of cost. C1 [Kent, Erin E.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Forsythe, Laura P.] Patient Ctr Outcomes Res Inst, Washington, DC USA. [Yabroff, K. Robin] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Weaver, Kathryn E.] Wake Forest Sch Med, Dept Social Sci & Hlth Policy, Div Publ Hlth Sci, Winston Salem, NC USA. [de Moor, Janet S.; Rowland, Julia H.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Rodriguez, Juan L.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. RP Kent, EE (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,MSC 9762, Bethesda, MD 20892 USA. EM Erin.Kent@nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 FU Intramural NIH HHS [Z99 CA999999] NR 42 TC 46 Z9 46 U1 4 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2013 VL 119 IS 20 BP 3710 EP 3717 DI 10.1002/cncr.28262 PG 8 WC Oncology SC Oncology GA 230WJ UT WOS:000325373700053 PM 23907958 ER PT J AU Bao, W Hu, FB Rong, S Rong, Y Bowers, K Schisterman, EF Liu, LG Zhang, CL AF Bao, Wei Hu, Frank B. Rong, Shuang Rong, Ying Bowers, Katherine Schisterman, Enrique F. Liu, Liegang Zhang, Cuilin TI Predicting Risk of Type 2 Diabetes Mellitus with Genetic Risk Models on the Basis of Established Genome-wide Association Markers: A Systematic Review SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE area under the curve; receiver operating characteristic curve; single nucleotide polymorphism; type 2 diabetes mellitus ID OPERATING CHARACTERISTIC CURVE; COMPLEX DISEASES; SUSCEPTIBILITY LOCI; CHINESE POPULATION; RANDOMIZED-TRIAL; LIFE-STYLE; VARIANTS; RECLASSIFICATION; POLYMORPHISMS; METAANALYSIS AB This study aimed to evaluate the predictive performance of genetic risk models based on risk loci identified and/or confirmed in genome-wide association studies for type 2 diabetes mellitus. A systematic literature search was conducted in the PubMed/MEDLINE and EMBASE databases through April 13, 2012, and published data relevant to the prediction of type 2 diabetes based on genome-wide association markerbased risk models (GRMs) were included. Of the 1,234 potentially relevant articles, 21 articles representing 23 studies were eligible for inclusion. The median area under the receiver operating characteristic curve (AUC) among eligible studies was 0.60 (range, 0.550.68), which did not differ appreciably by study design, sample size, participants race/ethnicity, or the number of genetic markers included in the GRMs. In addition, the AUCs for type 2 diabetes did not improve appreciably with the addition of genetic markers into conventional risk factorbased models (median AUC, 0.79 (range, 0.630.91) vs. median AUC, 0.78 (range, 0.630.90), respectively). A limited number of included studies used reclassification measures and yielded inconsistent results. In conclusion, GRMs showed a low predictive performance for risk of type 2 diabetes, irrespective of study design, participants race/ethnicity, and the number of genetic markers included. Moreover, the addition of genome-wide association markers into conventional risk models produced little improvement in predictive performance. C1 [Bao, Wei; Bowers, Katherine; Schisterman, Enrique F.; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Bao, Wei; Rong, Shuang; Rong, Ying; Liu, Liegang] Huazhong Univ Sci & Technol, Hubei Key Lab Food Nutr & Safety, Key Lab Environm & Hlth, Dept Nutr & Food Hyg,Minist Educ,Sch Publ Hlth,To, Wuhan 430074, Peoples R China. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM zhangcu@mail.nih.gov RI Bowers, Katherine/N-5226-2015; OI Schisterman, Enrique/0000-0003-3757-641X; Bao, Wei/0000-0002-7301-5786 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [DK58845]; China National High Technology Research and Development Program (863 program) [2009AA022704] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health (grant DK58845 to F. B. H.); and the China National High Technology Research and Development Program (863 program, grant 2009AA022704 to L.L.). NR 86 TC 23 Z9 23 U1 3 U2 21 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2013 VL 178 IS 8 BP 1197 EP 1207 DI 10.1093/aje/kwt123 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 235YK UT WOS:000325759000004 PM 24008910 ER PT J AU Harmon, QE Engel, SM Olshan, AF Moran, T Stuebe, AM Luo, JC Wu, MC Avery, CL AF Harmon, Quaker E. Engel, Stephanie M. Olshan, Andrew F. Moran, Thomas Stuebe, Alison M. Luo, Jingchun Wu, Michael C. Avery, Christy L. TI Association of Polymorphisms in Natural Killer Cell-Related Genes With Preterm Birth SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE African Americans; European Continental Ancestry Group; genetics; genetic association studies; inflammation; natural killer cells; premature birth ID TUMOR-NECROSIS-FACTOR; SINGLE-NUCLEOTIDE POLYMORPHISMS; RECEPTOR GENES; FACTOR-ALPHA; CYTOKINE POLYMORPHISMS; RECURRENT MISCARRIAGE; AFRICAN-AMERICAN; NORMAL-PREGNANCY; DELIVERY; WOMEN AB Inflammation is implicated in preterm birth, but genetic studies of inflammatory genes have yielded inconsistent results. Maternal DNA from 1,646 participants in the Pregnancy, Infection, and Nutrition Cohort, enrolled in Orange and Wake counties, North Carolina (19952005), were genotyped for 432 tag single-nucleotide polymorphisms (SNPs) in 30 candidate genes. Gene-level and SNP associations were modeled within strata of genetic ancestry. Six genes were associated with preterm birth among European Americans: interleukin 12A (IL12A); colony-stimulating factor 2 (CSF2); interferon receptor 2 (IFNGR2); killer cell immunoglobulinlike receptor, three domain, long cytoplasmic tail, 2 (KIR3DL2); interleukin 4 (IL4); and interleukin 13 (IL13). Of these, relatively strong single-SNP associations were seen in IFNGR2 and KIR3DL2. Among the 4 genes related to natural killer cell function, 2 (IL12A and CSF2) were consistently associated with reduced risk of prematurity for both European and African Americans. SNPs tagging a locus control region for IL4 and IL13 were associated with an increased risk of spontaneous preterm birth for European Americans (rs3091307; risk ratio 1.9; 95 confidence interval: 1.4, 2.5). Although gene-level associations were detected only in European Americans, single-SNP associations among European and African Americans were often similar in direction, though estimated with less precision among African Americans. In conclusion, we identified novel associations between variants in the natural killer cell immune pathway and prematurity in this biracial US population. C1 [Harmon, Quaker E.; Engel, Stephanie M.; Olshan, Andrew F.; Avery, Christy L.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Moran, Thomas] Mt Sinai Sch Med, Dept Microbiol, New York, NY USA. [Stuebe, Alison M.] Univ N Carolina, Sch Med, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Luo, Jingchun] Univ N Carolina, Sch Med, Dept Genet, Genom & Bioinformat Core,Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Wu, Michael C.] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. RP Harmon, QE (reprint author), NIEHS, POB 12233,MD A-305, Res Triangle Pk, NC 27709 USA. EM quaker.harmon@nih.gov OI Harmon, Quaker/0000-0002-5866-848X; Wu, Michael C./0000-0002-3357-6570 FU National Institute of Child Health and Development [R21 HD060207]; National Institute of Environmental Health Sciences [2-T32-ES07018, P30ES010126]; Mount Sinai Center for Children's Environmental Health; National Institutes of Health [HD28684, HD28684A, HD37584, HD39373, RR00046] FX This work was supported by the National Institute of Child Health and Development (R21 HD060207 to Stephanie M. Engel); National Institute of Environmental Health Sciences (2-T32-ES07018 and P30ES010126 to Andrew F. Olshan); and the Mount Sinai Center for Children's Environmental Health. The Pregnancy, Infection, and Nutrition Cohort was supported by the National Institutes of Health (HD28684, HD28684A, HD37584, HD39373, and RR00046). NR 57 TC 8 Z9 8 U1 0 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2013 VL 178 IS 8 BP 1208 EP 1218 DI 10.1093/aje/kwt108 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 235YK UT WOS:000325759000005 PM 23982189 ER PT J AU Tobias, DK Chavarro, JE Williams, MA Louis, GMB Hu, FB Rich-Edwards, J Missmer, SA Zhang, CL AF Tobias, Deirdre K. Chavarro, Jorge E. Williams, Michelle A. Louis, Germaine M. Buck Hu, Frank B. Rich-Edwards, Janet Missmer, Stacey A. Zhang, Cuilin TI History of Infertility and Risk of Gestational Diabetes Mellitus: A Prospective Analysis of 40,773 Pregnancies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; gestational diabetes mellitus; infertility ID BODY-MASS INDEX; OVULATORY DISORDER; PROSPECTIVE COHORT; PHYSICAL-ACTIVITY; LIFE; REPRODUCTION; METAANALYSIS; PREVALENCE; OUTCOMES; RATIOS AB Studies of delayed conception and risk of gestational diabetes (GDM) are sparse, although common underlying mechanisms are plausible, including insulin resistance and inflammation. The association between a history of infertility and GDM was assessed prospectively among 40,773 eligible pregnancies in the US Nurses Health Study II cohort (19892001). Biennial questionnaires provided updated information on infertility and several lifestyle and health-related characteristics. Multivariable log-binomial models with generalized estimating equations were used to compute risk ratios and 95 confidence intervals, adjusting for age, prepregnancy body mass index (weight (kg)/height (m)(2)), and additional potential confounders. GDM occurred among 1,405 (5.2) women. A prepregnancy history of infertility was reported by 5,497 (20.5) participants and was significantly associated with a 39 greater risk of GDM (risk ratio (RR) 1.39, 95 confidence interval (CI): 1.24, 1.57; P 0.001). Underlying reasons for infertility associated with GDM included ovulation disorders (RR 1.52, 95 CI: 1.23, 1.87; P 0.001) and tubal blockage (RR 1.83, 95 CI: 1.20, 2.77; P 0.005). The association of cervical mucus disorder with GDM was of borderline significance (RR 1.70, 95 CI: 0.88, 3.30; P 0.11). Endometriosis (RR 1.27, 95 CI: 0.70, 2.31; P 0.43) and male factor infertility (RR 1.12, 95 CI: 0.78, 1.61; P 0.55) were not associated with GDM risk. These novel findings suggest that infertility, particularly from ovulation disorders and tubal blockage, is associated with an increased GDM risk. Further research is needed to identify mechanisms or common underlying metabolic dysfunction explaining these observations. C1 [Tobias, Deirdre K.; Chavarro, Jorge E.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chavarro, Jorge E.; Williams, Michelle A.; Missmer, Stacey A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chavarro, Jorge E.; Hu, Frank B.; Rich-Edwards, Janet; Missmer, Stacey A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Chavarro, Jorge E.; Hu, Frank B.; Rich-Edwards, Janet; Missmer, Stacey A.] Harvard Univ, Sch Med, Boston, MA USA. [Louis, Germaine M. Buck; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Rich-Edwards, Janet] Brigham & Womens Hosp, Dept Med, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02115 USA. [Missmer, Stacey A.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Med, Boston, MA 02115 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM zhangcu@mail.nih.gov OI Buck Louis, Germaine/0000-0002-1774-4490 FU National Institutes of Health [DK58845, CA50385, P30 DK46200-18, HHSN275201000020C]; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; American Diabetes Association [7-12-MN-34] FX This work was supported by the National Institutes of Health (grants DK58845, CA50385, and P30 DK46200-18, and contract HHSN275201000020C); the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; and the American Diabetes Association (postdoctoral training award 7-12-MN-34 to D.K.T. and F.B.H.). NR 38 TC 12 Z9 13 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2013 VL 178 IS 8 BP 1219 EP 1225 DI 10.1093/aje/kwt110 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 235YK UT WOS:000325759000006 PM 23956097 ER PT J AU Abend, M Pfeiffer, RM Ruf, C Hatch, M Bogdanova, TI Tronko, MD Hartmann, J Meineke, V Mabuchi, K Brenner, AV AF Abend, M. Pfeiffer, R. M. Ruf, C. Hatch, M. Bogdanova, T. I. Tronko, M. D. Hartmann, J. Meineke, V. Mabuchi, K. Brenner, A. V. TI Iodine-131 dose-dependent gene expression: alterations in both normal and tumour thyroid tissues of post-Chernobyl thyroid cancers SO BRITISH JOURNAL OF CANCER LA English DT Article DE Chernobyl; ionising radiation; iodine-131; gene expression; whole-genome microarray; thyroid cancer ID EPIGENETIC MECHANISMS; PAPILLARY CARCINOMAS; RADIATION; ACCIDENT; SIGNATURE; EXPOSURE; UKRAINE; REARRANGEMENTS; IRRADIATION; GENOME AB Background: A strong, consistent association between childhood irradiation and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis. Methods: We evaluated gene expression in 63 paired RNA specimens from frozen normal and tumour thyroid tissues with individual iodine-131 (I-131) doses (0.008-8.6 Gy, no unirradiated controls) received from Chernobyl fallout during childhood (Ukrainian-American cohort). Approximately half of these randomly selected samples (32 tumour/normal tissue RNA specimens) were hybridised on 64 whole-genome microarrays (Agilent, 4 x 44 K). Associations between I-131 dose and gene expression were assessed separately in normal and tumour tissues using Kruskal - Wallis and linear trend tests. Of 155 genes significantly associated with I-131 after Bonferroni correction and with >= 2-fold increase per dose category, we selected 95 genes. On the remaining 31 RNA samples these genes were used for validation purposes using qRT-PCR. Results: Expression of eight genes (ABCC3, C1orf9, C6orf62, FGFR1OP2, HEY2, NDOR1, STAT3, and UCP3) in normal tissue and six genes (ANKRD46, CD47, HNRNPH1, NDOR1, SCEL, and SERPINA1) in tumour tissue was significantly associated with I-131. PANTHER/DAVID pathway analyses demonstrated significant over-representation of genes coding for nucleic acid binding in normal and tumour tissues, and for p53, EGF, and FGF signalling pathways in tumour tissue. Conclusion: The multistep process of radiation carcinogenesis begins in histologically normal thyroid tissue and may involve dose-dependent gene expression changes. C1 [Abend, M.; Ruf, C.; Hartmann, J.; Meineke, V.] Bundeswehr Inst Radiobiol, D-80937 Munich, Germany. [Pfeiffer, R. M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hatch, M.; Mabuchi, K.; Brenner, A. V.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bogdanova, T. I.; Tronko, M. D.] Ukraine Acad Med Sci, State Inst VP Komissarenko Inst Endocrinol & Meta, UA-254114 Kiev, Ukraine. RP Abend, M (reprint author), Bundeswehr Inst Radiobiol, Neuherbergstr 11, D-80937 Munich, Germany. EM michaelabend@bundeswehr.org FU German Ministry of Defense; Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH FX This work was primarily supported by the German Ministry of Defense. Additional funds were contributed by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. We are very thankful for the different dosimetry teams including Ilya Aronovich Likhtarev, Lina Kovgan, and Andre Bouville. We appreciate the careful and very accurate technical assistance by Sven Senf in generation of qRT - PCR data. We are grateful to Dr Geraldine Thomas (Imperial College, London, UK) for her valuable assistance and support of the study. NR 33 TC 9 Z9 11 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 15 PY 2013 VL 109 IS 8 BP 2286 EP 2294 DI 10.1038/bjc.2013.574 PG 9 WC Oncology SC Oncology GA 236KN UT WOS:000325795000029 PM 24045656 ER PT J AU Zhao, H Jin, GX Cui, KM Ren, D Liu, T Chen, PK Wong, SM Li, FH Fan, YB Rodriguez, A Chang, J Wong, STC AF Zhao, Hong Jin, Guangxu Cui, Kemi Ren, Ding Liu, Timothy Chen, Peikai Wong, Solomon Li, Fuhai Fan, Yubo Rodriguez, Angel Chang, Jenny Wong, Stephen T. C. TI Novel Modeling of Cancer Cell Signaling Pathways Enables Systematic Drug Repositioning for Distinct Breast Cancer Metastases SO CANCER RESEARCH LA English DT Article ID TEMOZOLOMIDE PLUS THALIDOMIDE; PHASE-II; IN-VITRO; BRAIN; NETWORKS; GENES; DASATINIB; MELANOMA; LEUKEMIA; DISEASES AB A new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed specific CSBs for each metastasis that satisfy (i) CSB proteins are activated by the maximal number of enriched signaling pathways specific to a given metastasis, and (ii) CSB proteins are involved in the most differential expressed coding genes specific to each breast cancer metastasis. The identified signaling networks for the three types of breast cancer metastases contain 31, 15, and 18 proteins and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases. We conducted both in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Of special note, we found that the Food and Drug Administration-approved drugs, sunitinib and dasatinib, prohibit brain metastases derived from breast cancer, addressing one particularly challenging aspect of this disease. Cancer Res; 73(20); 6149-63. (C) 2013 AACR. C1 [Zhao, Hong; Jin, Guangxu; Cui, Kemi; Ren, Ding; Liu, Timothy; Chen, Peikai; Li, Fuhai; Fan, Yubo; Wong, Stephen T. C.] Methodist Hosp, Dept Syst Med & Bioengn, Houston, TX 77030 USA. [Zhao, Hong; Jin, Guangxu; Li, Fuhai; Chang, Jenny; Wong, Stephen T. C.] Methodist Hosp, Weill Cornell Med Coll, Res Inst, NCI Ctr Modeling Canc Dev, Houston, TX 77030 USA. [Rodriguez, Angel; Chang, Jenny; Wong, Stephen T. C.] Methodist Hosp, Methodist Canc Ctr, Houston, TX USA. [Wong, Stephen T. C.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Wong, Solomon] Univ Texas Austin, Austin, TX 78712 USA. RP Wong, STC (reprint author), 6670 Bertner Ave,R6-211, Houston, TX 77030 USA. EM stwong@tmhs.org FU NIH [U54 CA149196, NIH R01 CA139976, NIH R01 CA121225]; John S. Dunn Research Foundation; Texas Advanced Computing Center (TACC) at The University of Texas in Austin and BlueBioU [TG-MCB110130]; Texas Advanced Computing Center (TACC) at Rice University FX This work is funded by NIH grants U54 CA149196, NIH R01 CA139976, and NIH R01 CA121225, a John S. Dunn Research Foundation grant (S.T.C. Wong), and an NIH U54 CA149196 pilot project grant (H. Zhao). The authors acknowledge the computational time funding support from the Texas Advanced Computing Center (TACC; Project ID: TG-MCB110130) at The University of Texas in Austin and BlueBioU (IBM POWER 7 Bioscience Computing Core) at Rice University to access their powerful super-computing resources. NR 48 TC 9 Z9 9 U1 1 U2 18 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2013 VL 73 IS 20 BP 6149 EP 6163 DI 10.1158/0008-5472.CAN-12-4617 PG 15 WC Oncology SC Oncology GA 236KV UT WOS:000325796100008 PM 24097821 ER PT J AU Markant, SL Esparza, LA Sun, J Barton, KL McCoig, LM Grant, GA Crawford, JR Levy, ML Northcott, PA Shih, D Remke, M Taylor, MD Wechsler-Reya, RJ AF Markant, Shirley L. Esparza, Lourdes Adriana Sun, Jesse Barton, Kelly L. McCoig, Lisa M. Grant, Gerald A. Crawford, John R. Levy, Michael L. Northcott, Paul A. Shih, David Remke, Marc Taylor, Michael D. Wechsler-Reya, Robert J. TI Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases SO CANCER RESEARCH LA English DT Article ID CANCER STEM-CELLS; ADVANCED SOLID TUMORS; GROWTH IN-VIVO; BREAST-CANCER; SMOOTHENED ANTAGONISTS; NEURONAL PRECURSORS; PATHWAY INHIBITOR; CYCLE PROGRESSION; GENE-EXPRESSION; BRAIN-TUMORS AB Medulloblastoma is the most common malignant brain tumor in children. Although aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated medulloblastomas do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated medulloblastoma. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPC). We previously identified a population of TPCs in tumors frompatched mutant mice, a model for SHH-dependent medulloblastoma. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G(2)-M phases of the cell cycle. Here, we show that CD15(+) cells progress more rapidly through the cell cycle than CD15(-) cells and contain an increased proportion of cells in G(2)-M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora kinase (Aurk) and Polo-like kinases (Plk), key regulators of G(2)-M, induces cell-cycle arrest, apoptosis, and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived medulloblastoma xenografts are also sensitive to Aurk and Plk inhibitors. Our findings suggest that targeting G(2)-M regulators may represent a novel approach for treatment of human medulloblastoma. Cancer Res; 73(20); 6310-22. (C) 2013 AACR. C1 [Markant, Shirley L.; Esparza, Lourdes Adriana; Wechsler-Reya, Robert J.] NCI, Tumor Initiat & Maintenance Program, Designated Canc Ctr, Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA. [Markant, Shirley L.; Esparza, Lourdes Adriana; Wechsler-Reya, Robert J.] Sanford Consortium Regenerat Med, La Jolla, CA USA. [Crawford, John R.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Crawford, John R.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Levy, Michael L.] Univ Calif San Diego, Dept Neurosurg, La Jolla, CA 92093 USA. [Crawford, John R.; Levy, Michael L.] Rady Childrens Hosp, San Diego, CA USA. [Markant, Shirley L.; Sun, Jesse; Barton, Kelly L.; McCoig, Lisa M.; Wechsler-Reya, Robert J.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA. [Sun, Jesse] Duke Univ, Med Ctr, Dept Med, Div Pulm Allergy & Crit Care, Durham, NC 27710 USA. [Barton, Kelly L.; Grant, Gerald A.] Duke Univ, Med Ctr, Dept Pediat, Div Pediat Hematol Oncol, Durham, NC 27710 USA. [Grant, Gerald A.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Northcott, Paul A.] German Canc Res Ctr, Heidelberg, Germany. [Northcott, Paul A.; Shih, David; Remke, Marc; Taylor, Michael D.] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. RP Wechsler-Reya, RJ (reprint author), NCI, Tumor Initiat & Maintenance Program, Designated Canc Ctr, Sanford Burnham Med Res Inst, 2880 Torrey Pines Scen Dr, La Jolla, CA 92037 USA. EM rwreya@sanfordburnham.org RI Shih, David/H-3186-2011; OI Shih, David/0000-0002-9802-4937; Remke, Marc/0000-0002-9404-9993 FU National Cancer Institute (NCI) [R01-CA122759]; National Institute of Neurological Diseases and Stroke [R01 NS052323]; Golfers Against Cancer; Pediatric Brain Tumor Foundation Institute at Duke University; California Institute for Regenerative Medicine (San Francisco, CA) [CIRM LA1-01747] FX These studies were supported by R01-CA122759 from the National Cancer Institute (NCI) and R01 NS052323 from the National Institute of Neurological Diseases and Stroke as well as pilot funds from Golfers Against Cancer and the Pediatric Brain Tumor Foundation Institute at Duke University. R.J. Wechsler-Reya is the recipient of a Leadership Award (CIRM LA1-01747) from the California Institute for Regenerative Medicine (San Francisco, CA). NR 54 TC 18 Z9 18 U1 0 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2013 VL 73 IS 20 BP 6310 EP 6322 DI 10.1158/0008-5472.CAN-12-4258 PG 13 WC Oncology SC Oncology GA 236KV UT WOS:000325796100022 PM 24067506 ER PT J AU Warren, RS Atreya, CE Niedzwiecki, D Weinberg, VK Donner, DB Mayer, RJ Goldberg, RM Compton, CC Zuraek, MB Ye, C Saltz, LB Bertagnolli, MM AF Warren, Robert S. Atreya, Chloe E. Niedzwiecki, Donna Weinberg, Vivian K. Donner, David B. Mayer, Robert J. Goldberg, Richard M. Compton, Carolyn C. Zuraek, Marlene B. Ye, Cynthia Saltz, Leonard B. Bertagnolli, Monica M. TI Association of TP53 Mutational Status and Gender with Survival after Adjuvant Treatment for Stage III Colon Cancer: Results of CALGB 89803 SO CLINICAL CANCER RESEARCH LA English DT Article ID ZINC-BINDING DOMAIN; LONG-TERM SURVIVAL; COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; POOR SURVIVAL; P53 MUTATIONS; BREAST-CANCER; TUMOR SITE; FLUOROURACIL; LEUCOVORIN AB Purpose: The TP53 tumor suppressor is frequently mutated in colon cancer, but the influence of such mutations on survival remains controversial. We investigated whether mutations in the DNA-binding domain of TP53 are associated with survival in stage III colon cancer. Experimental Design: The impact of TP53 genotype was prospectively evaluated in Cancer and Leukemia Group B 89803, a trial that randomized stage III colon cancer patients to receive adjuvant 5-fluorouracil/leucovorin (5FU/LV) or 5FU/LV with irinotecan (IFL). Results: TP53 mutations were identified in 274 of 607 cases. The presence of any TP53 mutation did not predict disease-free survival (DFS) or overall survival with either adjuvant regimen when men and women were considered together or as separate groups. However, outcome differences among women became apparent when tumor TP53 genotype was stratified as wild-type versus zinc-or non-zinc-binding mutations in the TP53 DNA-binding domain. DFS at 5 years was 0.59, 0.52, and 0.78 for women with TP53 wild-type tumors, and tumors with zinc-or non-zinc-binding mutations, respectively. Survival at 5 years for these same women was 0.72, 0.59, and 0.90, respectively. No differences in survival by TP53 genotype were observed in men. Conclusions: The presence of any TP53 mutation within the DNA-binding domain did not predict survival in stage III colon cancer. However, TP53 genotype was predictive of survival in women following adjuvant therapy. Future colon cancer therapeutic trials, with inclusion of correlative molecular markers, should be designed to permit evaluation of survival and/or response to treatment in women separately from men. (C) 2013 AACR. C1 [Warren, Robert S.; Atreya, Chloe E.; Weinberg, Vivian K.; Donner, David B.; Zuraek, Marlene B.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94115 USA. [Niedzwiecki, Donna; Ye, Cynthia] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Alliance Stat & Data Ctr, Durham, NC USA. [Mayer, Robert J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bertagnolli, Monica M.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Goldberg, Richard M.] Ohio State Univ, Columbus, OH 43210 USA. [Compton, Carolyn C.] NCI, Bethesda, MD 20892 USA. [Saltz, Leonard B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Warren, RS (reprint author), Univ Calif San Francisco, Dept Surg, Helen Diller Family Comprehens Canc Ctr, 1600 Divisadero St, San Francisco, CA 94115 USA. EM robert.warren@ucsfmedctr.org RI Goldberg , Richard/M-1311-2013; OI Saltz, Leonard/0000-0001-8353-4670 FU NIH [RO184018]; American Cancer Society [11-183-01-TBG]; American Society of Clinical Oncology; Edmund Wattis Littlefield Foundation; Cancer and Leukemia Group B Foundation; Conquer Cancer Foundation of the American Society of Clinical Oncology FX This work is supported by NIH, The American Cancer Society, The American Society of Clinical Oncology, the Edmund Wattis Littlefield Foundation, and the Cancer and Leukemia Group B Foundation. R.S. Warren was supported by a grant from the NIH (RO184018) and by the Edmund Wattis Littlefield Foundation. C.E. Atreya is supported by Postdoctoral Fellowship 11-183-01-TBG from the American Cancer Society and Young Investigator Awards from the Conquer Cancer Foundation of the American Society of Clinical Oncology and the Alliance for Clinical Trials in Oncology. NR 39 TC 10 Z9 10 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2013 VL 19 IS 20 BP 5777 EP 5787 DI 10.1158/1078-0432.CCR-13-0351 PG 11 WC Oncology SC Oncology GA 236LH UT WOS:000325797600026 PM 23983256 ER PT J AU Johnston, JJ Biesecker, LG AF Johnston, Jennifer J. Biesecker, Leslie G. TI Databases of genomic variation and phenotypes: existing resources and future needs SO HUMAN MOLECULAR GENETICS LA English DT Review ID AMINO-ACID SUBSTITUTIONS; GENETIC-VARIATION; MAP AB Massively parallel sequencing (MPS) has become an important tool for identifying medically significant variants in both research and the clinic. Accurate variation and genotypephenotype databases are critical in our ability to make sense of the vast amount of information that MPS generates. The purpose of this review is to summarize the state of the art of variation and genotypephenotype databases, how they can be used, and opportunities to improve these resources. Our working assumption is that the objective of the clinical genomicist is to identify highly penetrant variants that could explain existing disease or predict disease risk for individual patients or research participants. We have detailed how current databases contribute to this goal providing frequency data, literature reviews and predictions of causation for individual variants. For variant annotation, databases vary greatly in their ease of use, the use of standard mutation nomenclature, the comprehensiveness of the variant cataloging and the degree of expert opinion. Ultimately, we need a dynamic and comprehensive reference database of medically important variants that is easily cross referenced to exome and genome sequence data and allows for an accumulation of expert opinion. C1 [Johnston, Jennifer J.; Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Johnston, JJ (reprint author), Bldg 49,Room 4C60, Bethesda, MD 20892 USA. EM jjohnsto@mail.nih.gov FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX The authors are supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 7 TC 18 Z9 19 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2013 VL 22 SI 1 BP R27 EP R31 DI 10.1093/hmg/ddt384 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 230LH UT WOS:000325340500005 PM 23962721 ER PT J AU Brzostowski, JA Sawai, S Rozov, O Liao, XH Imoto, D Parent, CA Kimmel, AR AF Brzostowski, Joseph A. Sawai, Satoshi Rozov, Orr Liao, Xin-hua Imoto, Daisuke Parent, Carole A. Kimmel, Alan R. TI Phosphorylation of chemoattractant receptors regulates chemotaxis, actin reorganization and signal relay SO JOURNAL OF CELL SCIENCE LA English DT Article DE GPCR; cAMP; PI3K; TORC2; AKT; Oscillations; Heterotrimeric G proteins; ERK2 ID LIGAND-INDUCED PHOSPHORYLATION; DICTYOSTELIUM-DISCOIDEUM; BETA-ARRESTIN; MEDIATED ACTIVATION; CAMP RECEPTOR; CYCLIC-AMP; ADENYLATE-CYCLASE; TERMINAL DOMAIN; LIVING CELLS; SPATIOTEMPORAL DYNAMICS AB Migratory cells, including mammalian leukocytes and Dictyostelium, use G-protein-coupled receptor (GPCR) signaling to regulate MAPK/ERK, PI3K, TORC2/AKT, adenylyl cyclase and actin polymerization, which collectively direct chemotaxis. Upon ligand binding, mammalian GPCRs are phosphorylated at cytoplasmic residues, uncoupling G-protein pathways, but activating other pathways. However, connections between GPCR phosphorylation and chemotaxis are unclear. In developing Dictyostelium, secreted cAMP serves as a chemoattractant, with extracellular cAMP propagated as oscillating waves to ensure directional migratory signals. cAMP oscillations derive from transient excitatory responses of adenylyl cyclase, which then rapidly adapts. We have studied chemotactic signaling in Dictyostelium that express non-phosphorylatable cAMP receptors and show through chemotaxis modeling, single-cell FRET imaging, pure and chimeric population wavelet quantification, biochemical analyses and TIRF microscopy, that receptor phosphorylation is required to regulate adenylyl cyclase adaptation, long-range oscillatory cAMP wave production and cytoskeletal actin response. Phosphorylation defects thus promote hyperactive actin polymerization at the cell periphery, misdirected pseudopodia and the loss of directional chemotaxis. Our data indicate that chemoattractant receptor phosphorylation is required to co-regulate essential pathways for migratory cell polarization and chemotaxis. Our results significantly extend the understanding of the function of GPCR phosphorylation, providing strong evidence that this evolutionarily conserved mechanism is required in a signal attenuation pathway that is necessary to maintain persistent directional movement of Dictyostelium, neutrophils and other migratory cells. C1 [Brzostowski, Joseph A.; Rozov, Orr] NIAID, Lab Immunogenet Imaging Facil, NIH, Rockville, MD 20852 USA. [Sawai, Satoshi] Univ Tokyo, Grad Sch Arts & Sci, Tokyo 1538902, Japan. [Sawai, Satoshi] JST, PRESTO, Tokyo 1538902, Japan. [Liao, Xin-hua; Kimmel, Alan R.] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Imoto, Daisuke] Univ Tokyo, Grad Sch Arts & Sci, Tokyo 1538902, Japan. [Parent, Carole A.] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Brzostowski, JA (reprint author), NIAID, Lab Immunogenet Imaging Facil, NIH, Rockville, MD 20852 USA. EM jb363a@nih.gov; alank@helix.nih.gov FU National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and infectious Diseases; National Cancer Institute; Japan Society for the Promotion of Science (JSPS) [23111506, 25111704]; JSPS [22680024, 25710022]; Precursory Research for Embryonic Science and Technology (PRESTO); Japan Science and Technology Agency; Platform for Dynamic Approaches to Living System from the Ministry of Education, Culture, Sports, Science and Technology, Japan FX This research was supported by the Intramural Research Program of the National Institutes of Health; the National Institute of Diabetes and Digestive and Kidney Diseases to A. R. K.; the National Institute of Allergy and infectious Diseases to J.A.B.; and the National Cancer Institute to C. A. P.; Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research on Innovative Areas [grant numbers 23111506 and 25111704]; a JSPS Grant-in-Aid for Young Scientists (A) [grant numbers 22680024 and 25710022]; Precursory Research for Embryonic Science and Technology (PRESTO); Japan Science and Technology Agency, and Platform for Dynamic Approaches to Living System from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Deposited in PMC for immediate release. NR 74 TC 8 Z9 8 U1 1 U2 15 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD OCT 15 PY 2013 VL 126 IS 20 BP 4614 EP 4626 DI 10.1242/jcs.122952 PG 13 WC Cell Biology SC Cell Biology GA 236NC UT WOS:000325803200008 PM 23902692 ER PT J AU Thomas, LM Peterson, ME Long, EO AF Thomas, L. Michael Peterson, Mary E. Long, Eric O. TI Cutting Edge: NK Cell Licensing Modulates Adhesion to Target Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; MHC CLASS-I; INHIBITORY RECEPTORS; SELF-MHC; EDUCATION; RESPONSIVENESS; CYTOTOXICITY; ENVIRONMENT; ACTIVATION; MOLECULES AB Binding of NK cell inhibitory receptors to MHC class I (MHC-I) confers increased responsiveness to NK cells by a process known as NK cell licensing/education. Reduced MHC-I expression or a lack of inhibitory receptors for MHC-I results in diminished NK cell responsiveness. In this study, we evaluated the effect of human and mouse NK cell licensing on early stages of natural cytotoxicity. Unlicensed NK cells did not form as many stable conjugates with target cells. The reduction of NK cell conjugation to target cells was not attributed to altered beta(2) integrin LFA-1 properties but was instead due to reduced inside-out signaling to LFA-1 by activating receptors. For those unlicensed NK cells that did form conjugates, LFA-1-dependent granule polarization was similar to that in licensed NK cells. Thus, licensing controls signals as proximal as inside-out signaling by activating receptors but not integrin outside-in signaling for granule polarization. C1 [Thomas, L. Michael; Peterson, Mary E.; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM eLong@nih.gov RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 FU National Institutes of Health, National Institute of Allergy and Infectious Disease FX This work was supported by the Intramural Research Program at the National Institutes of Health, National Institute of Allergy and Infectious Disease (to L. M. T., M. E. P., and E.O.L.). NR 23 TC 19 Z9 19 U1 0 U2 6 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 OCT 15 PY 2013 VL 191 IS 8 BP 3981 EP 3985 DI 10.4049/jimmunol.1301159 PG 5 WC Immunology SC Immunology GA 232IT UT WOS:000325487700002 PM 24038086 ER PT J AU Lee-Chang, C Bodogai, M Martin-Montalvo, A Wejksza, K Sanghvi, M Moaddel, R de Cabo, R Biragyn, A AF Lee-Chang, Catalina Bodogai, Monica Martin-Montalvo, Alejandro Wejksza, Katarzyna Sanghvi, Mitesh Moaddel, Ruin de Cabo, Rafael Biragyn, Arya TI Inhibition of Breast Cancer Metastasis by Resveratrol-Mediated Inactivation of Tumor-Evoked Regulatory B Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELLS; SUPPRESSOR-CELLS; MULTIPLE-MYELOMA; PROSTATE-CANCER; BEARING MICE; INDUCTION; EXPRESSION; TOLERANCE; IMMUNITY; SURVIVAL AB We reported previously that tumor-evoked regulatory B cells (tBregs) play an essential role in breast cancer lung metastasis by inducing TGF-beta-dependent conversion of metastasis-promoting Foxp3(+) regulatory T cells (Tregs). In this article, we show that resveratrol (RSV), a plant-derived polyphenol, at low and noncytotoxic doses for immune cells, can efficiently inhibit lung metastasis in mice. The mechanism of this process is that RSV inactivates Stat3, preventing the generation and function of tBregs, including expression of TGF-beta. As a result, it frees antitumor effector immune responses by disabling tBreg-induced conversion of Foxp3(+) Tregs. We propose that low doses of RSV may also benefit humans by controlling cancer escape-promoting tBregs/Tregs without nonspecific inactivation of effector immune cells. C1 [Lee-Chang, Catalina; Bodogai, Monica; Wejksza, Katarzyna; Biragyn, Arya] NIA, Immunoregulat Sect, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Martin-Montalvo, Alejandro; de Cabo, Rafael] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. [Sanghvi, Mitesh; Moaddel, Ruin] NIA, Lab Clin Invest, Baltimore, MD 21224 USA. RP Biragyn, A (reprint author), NIA, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM biragyna@mail.nih.gov RI de Cabo, Rafael/J-5230-2016; Martin-Montalvo, Alejandro/C-2031-2017; Lee-Chang, Catalina/A-5580-2015 OI de Cabo, Rafael/0000-0002-3354-2442; Martin-Montalvo, Alejandro/0000-0002-3886-5355; , rafael/0000-0003-2830-5693; Lee-Chang, Catalina/0000-0002-7675-2124 FU National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 53 TC 26 Z9 28 U1 0 U2 14 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 OCT 15 PY 2013 VL 191 IS 8 BP 4141 EP 4151 DI 10.4049/jimmunol.1300606 PG 11 WC Immunology SC Immunology GA 232IT UT WOS:000325487700021 PM 24043896 ER PT J AU Arai, AE AF Arai, Andrew E. TI Computed Tomography Perfusion to Assess Physiological Significance of Coronary Stenosis in the Post-FAME Era (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE computed tomography; coronary angiography; coronary vessels; diagnostic accuracy; stents ID INTERVENTION C1 [Arai, Andrew E.] NHLBI, Cardiovasc & Pulm Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, NIH, Bldg 10,Room B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [ZIA HL006137-03, ZIA HL006138-03] NR 7 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 15 PY 2013 VL 62 IS 16 BP 1486 EP 1487 DI 10.1016/j.jacc.2013.05.056 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 231NZ UT WOS:000325425100016 PM 23773869 ER PT J AU Clausen, AR Murray, MS Passer, AR Pedersen, LC Kunkel, TA AF Clausen, Anders R. Murray, Michael S. Passer, Andrew R. Pedersen, Lars C. Kunkel, Thomas A. TI Structure-function analysis of ribonucleotide bypass by B family DNA replicases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE translesion synthesis; replication stalling; DNA replication ID LEADING-STRAND DNA; POLYMERASE-EPSILON; MISMATCH REPAIR; BASE SELECTIVITY; GENOME INTEGRITY; RNA; FIDELITY; INSTABILITY; DYNAMICS; REMOVAL AB Ribonucleotides are frequently incorporated into DNA during replication, they are normally removed, and failure to remove them results in replication stress. This stress correlates with DNA polymerase (Pol) stalling during bypass of ribonucleotides in DNA templates. Here we demonstrate that stalling by yeast replicative Pols delta and epsilon increases as the number of consecutive template ribonucleotides increases from one to four. The homologous bacteriophage RB69 Pol also stalls during ribonucleotide bypass, with a pattern most similar to that of Pol epsilon. Crystal structures of an exonuclease-deficient variant of RB69 Pol corresponding to multiple steps in single ribonucleotide bypass reveal that increased stalling is associated with displacement of Tyr391 and an unpreferred C2'-endo conformation for the ribose. Even less efficient bypass of two consecutive ribonucleotides in DNA correlates with similar movements of Tyr391 and displacement of one of the ribonucleotides along with the primer-strand DNA backbone. These structure-function studies have implications for cellular signaling by ribonucleotides, and they may be relevant to replication stress in cells defective in ribonucleotide excision repair, including humans suffering from autoimmune disease associated with RNase H2 defects. C1 [Clausen, Anders R.; Murray, Michael S.; Passer, Andrew R.; Pedersen, Lars C.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Clausen, Anders R.; Murray, Michael S.; Passer, Andrew R.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov OI Clausen, Anders Ranegaard/0000-0002-5069-0930 FU Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health (NIH) [ES065070, ES102645]; NIH; US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX We thank Katarzyna Bebenek and William Beard for thoughtful comments on the manuscript. This work was supported by Project ES065070 (T. A. K.) and Project ES102645 (L. C. P.), both from the Division of Intramural Research of the National Institute of Environmental Health Sciences, National Institutes of Health (NIH). The NIH provided funding for the open access charge. Crystallographic data were collected at the Southeast Regional Collaborative Access Team 22-ID beam line 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 US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. NR 47 TC 20 Z9 21 U1 1 U2 17 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 OCT 15 PY 2013 VL 110 IS 42 BP 16802 EP 16807 DI 10.1073/pnas.1309119110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 234HT UT WOS:000325634200033 PM 24082122 ER PT J AU Ibrahim, MA Na, M Oh, J Schinazi, RF McBrayer, TR Whitaker, T Doerksen, RJ Newman, DJ Zachos, LG Hamann, MT AF Ibrahim, Mohamed Ali Na, MinKyun Oh, Joonseok Schinazi, Raymond F. McBrayer, Tami R. Whitaker, Tony Doerksen, Robert J. Newman, David J. Zachos, Louis G. Hamann, Mark T. TI Significance of endangered and threatened plant natural products in the control of human disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE endangered plants; hepatitis C virus; diabetes mellitus ID TYROSINE-PHOSPHATASE 1B; HEPATITIS-C VIRUS; INHIBITION; EXTINCTION; DIVERSITY; OBESITY; DRUGS; MICE AB One in five of the world's plant species is threatened with extinction according to the 2010 first global analysis of extinction risk. Tilman et al. predicted a massive ecological change to terrestrial plants within the next 50-100 y, accompanied by an increase in the number of global plant species facing extinction [Tilman D, et al. (2001) Proc Natl Acad Sci USA 98(10): 5433-5440]. Most of the drug-producing plant families contain endangered species never previously studied for their utility to human health, which strongly validates the need to prioritize protection and assessment of these fragile and endangered groups [Zhu F, et al. (2011) Proc Natl Acad Sci USA 108(31): 12943-12948]. With little prior attention given to endangered and rare plant species, this report provides strong justification for conservation of the rare plant Diplostephium rhododendroides Hieron., as well as other potential drug-producing endangered species in this and other groups. C1 [Ibrahim, Mohamed Ali; Oh, Joonseok; Hamann, Mark T.] Univ Mississippi, Sch Pharm, Dept Pharmacognosy, University, MS 38677 USA. [Doerksen, Robert J.] Univ Mississippi, Sch Pharm, Dept Med Chem, University, MS 38677 USA. [Zachos, Louis G.] Univ Mississippi, Sch Pharm, Dept Geol & Geol Engn, University, MS 38677 USA. [Ibrahim, Mohamed Ali; Doerksen, Robert J.] Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA. [Hamann, Mark T.] Univ Mississippi, Sch Pharm, Dept Pharmacol, University, MS 38677 USA. [Hamann, Mark T.] Univ Mississippi, Sch Pharm, Dept Chem, University, MS 38677 USA. [Hamann, Mark T.] Univ Mississippi, Sch Pharm, Dept Biochem, University, MS 38677 USA. [Ibrahim, Mohamed Ali] Natl Res Ctr, Dept Chem Nat Cpds, Cairo 12622, Egypt. [Na, MinKyun] Chungnam Natl Univ, Coll Pharm, Taejon 305764, South Korea. [Schinazi, Raymond F.] Emory Univ, Dept Pediat, Ctr AIDS Res, Atlanta, GA 30322 USA. [Schinazi, Raymond F.] Vet Affairs Med Ctr, Decatur, GA 30033 USA. [McBrayer, Tami R.; Whitaker, Tony] RFS Pharma LLC, Tucker, GA 30084 USA. [Newman, David J.] US Natl Canc Inst, Nat Prod Branch, NIH, Bethesda, MD 21702 USA. RP Hamann, MT (reprint author), Univ Mississippi, Sch Pharm, Dept Pharmacognosy, University, MS 38677 USA. EM mthamann@olemiss.edu RI Schinazi, Raymond/B-6777-2017; OI Ibrahim, Mohamed Ali/0000-0003-0257-860X FU National Institutes of Health (NIH); National Center for Complementary and Alternative Medicine (NCCAM) [R01-AT-007318]; National Center for Research Resources (NCRR) [CO6-RR-145503]; Kraft Foods Group, Inc.; Ministry of Higher Education and Scientific Research-Egypt; Department of Veterans Affairs; NIH Centers for AIDS Research (CFAR) [2P30-AI-050409]; National Research Foundation of Korea (NRF) [NRF-C1ABA001-2010-0020484] FX The authors thank Ms. Christina Marrongelli and Dr. John S. Williamson for help with purification of the metabolites; Mr. Khaled Elokely for help with generation of the 3D minimized structure; and the Complex Carbohydrate Research Center (The University of Georgia) for carbohydrate analysis. The authors also acknowledge National Institutes of Health (NIH), National Center for Complementary and Alternative Medicine (NCCAM) Grant R01-AT-007318, National Center for Research Resources (NCRR) Award CO6-RR-145503 and a grant from Kraft Foods Group, Inc.; fellowship support provided through the Ministry of Higher Education and Scientific Research-Egypt (to M. A. I.); the Department of Veterans Affairs and NIH Centers for AIDS Research (CFAR) Grant 2P30-AI-050409 (to R. F. S.); and National Research Foundation of Korea (NRF) NRF-C1ABA001-2010-0020484 (to M.N.). NR 40 TC 14 Z9 14 U1 4 U2 23 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 15 PY 2013 VL 110 IS 42 BP 16832 EP 16837 DI 10.1073/pnas.1311528110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 234HT UT WOS:000325634200038 PM 24082148 ER PT J AU Zhou, ZF Karlsson, C Liang, TB Xiong, W Kimura, M Tapocik, JD Yuan, QP Barbier, E Feng, A Flanigan, M Augier, E Enoch, MA Hodgkinson, CA Shen, PH Lovinger, DM Edenberg, HJ Heilig, M Goldman, D AF Zhou, Zhifeng Karlsson, Camilla Liang, Tiebing Xiong, Wei Kimura, Mitsuru Tapocik, Jenica D. Yuan, Qiaoping Barbier, Estelle Feng, Austin Flanigan, Meghan Augier, Eric Enoch, Mary-Anne Hodgkinson, Colin A. Shen, Pei-Hong Lovinger, David M. Edenberg, Howard J. Heilig, Markus Goldman, David TI Loss of metabotropic glutamate receptor 2 escalates alcohol consumption SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene identification; selectively bred lines ID GENOME-WIDE ASSOCIATION; PREFERRING P RATS; GENE-EXPRESSION; DEPENDENCE; SEEKING; HIPPOCAMPUS; PREFERENCE; COCAINE; ANXIETY; MGLUR2 AB Identification of genes influencing complex traits is hampered by genetic heterogeneity, the modest effect size of many alleles, and the likely involvement of rare and uncommon alleles. Etiologic complexity can be simplified in model organisms. By genomic sequencing, linkage analysis, and functional validation, we identified that genetic variation of Grm2, which encodes metabotropic glutamate receptor 2 (mGluR2), alters alcohol preference in animal models. Selectively bred alcohol-preferring (P) rats are homozygous for a Grm2 stop codon (Grm2 *407) that leads to largely uncompensated loss of mGluR2. mGluR2 receptor expression was absent, synaptic glutamate transmission was impaired, and expression of genes involved in synaptic function was altered. Grm2 *407 was linked to increased alcohol consumption and preference in F2 rats generated by intercrossing inbred P and nonpreferring rats. Pharmacologic blockade of mGluR2 escalated alcohol self-administration in Wistar rats, the parental strain of P and nonpreferring rats. The causal role of mGluR2 in altered alcohol preference was further supported by elevated alcohol consumption in Grm2(-/-) mice. Together, these data point to mGluR2 as an origin of alcohol preference and a potential therapeutic target. C1 [Zhou, Zhifeng; Kimura, Mitsuru; Yuan, Qiaoping; Enoch, Mary-Anne; Hodgkinson, Colin A.; Shen, Pei-Hong; Goldman, David] NIAAA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Karlsson, Camilla; Tapocik, Jenica D.; Barbier, Estelle; Flanigan, Meghan; Augier, Eric; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Xiong, Wei; Feng, Austin; Lovinger, David M.] NIAAA, Sect Synapt Pharmacol, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. [Liang, Tiebing] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Edenberg, Howard J.] Indiana Univ Sch Med, Dept Biochem & Mol Biol & Med & Mol Genet, Indianapolis, IN 46202 USA. RP Goldman, D (reprint author), NIAAA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. EM davidgoldman@mail.nih.gov RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Edenberg, Howard/0000-0003-0344-9690; Flanigan, Meghan/0000-0002-3185-7459 FU Indiana Alcohol Research Center [P60-AA007611] FX We thank Dr. William J. McBride and Dr. Lawrence Lumeng for their contributions to the derivation of the P/NP rats. We thank Dr. Lucinda Carr for her contribution to the F2 rat drinking data. We thank Dr. Tatiana Foroud for assistance with statistical genetics. We thank Cheryl Marietta and Longina Akhtar for assistance with data generation, Basel Baghal for assistance with data analysis, and Elisa Moore for assistance with bioinformatics. This work was supported by Indiana Alcohol Research Center Grant P60-AA007611. NR 31 TC 30 Z9 30 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 OCT 15 PY 2013 VL 110 IS 42 BP 16963 EP 16968 DI 10.1073/pnas.1309839110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 234HT UT WOS:000325634200060 PM 24082084 ER PT J AU Oakley, RH Ren, RQ Cruz-Topete, D Bird, GS Myers, PH Boyle, MC Schneider, MD Willis, MS Cidlowski, JA AF Oakley, Robert H. Ren, Rongqin Cruz-Topete, Diana Bird, Gary S. Myers, Page H. Boyle, Michael C. Schneider, Michael D. Willis, Monte S. Cidlowski, John A. TI Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GLUCOCORTICOID-RECEPTOR GENE; CARDIAC RYANODINE RECEPTORS; CARDIOVASCULAR-DISEASE; ADDISONS-DISEASE; SKELETAL-MUSCLE; HYPERTROPHY; INFLAMMATION; EXPRESSION; FAILURE AB Heart failure is a leading cause of death in humans, and stress is increasingly associated with adverse cardiac outcomes. Glucocorticoids are primary stress hormones, but their direct role in cardiovascular health and disease is poorly understood. To determine the in vivo function of glucocorticoid signaling in the heart, we generated mice with cardiomyocyte-specific deletion of the glucocorticoid receptor (GR). These mice are born at the expected Mendelian ratio, but die prematurely from spontaneous cardiovascular disease. By 3 mo of age, mice deficient in cardiomyocyte GR display a marked reduction in left ventricular systolic function, as evidenced by decreases in ejection fraction and fractional shortening. Heart weight and left ventricular mass are elevated, and histology revealed cardiac hypertrophy without fibrosis. Removal of endogenous glucocorticoids and mineralocorticoids neither augmented nor lessened the hypertrophic response. Global gene expression analysis of knockout hearts before pathology onset revealed aberrant regulation of a large cohort of genes associated with cardiovascular disease as well as unique disease genes associated with inflammatory processes. Genes important for maintaining cardiac contractility, repressing cardiac hypertrophy, promoting cardiomyocyte survival, and inhibiting inflammation had decreased expression in the GR-deficient hearts. These findings demonstrate that a deficiency in cardiomyocyte glucocorticoid signaling leads to spontaneous cardiac hypertrophy, heart failure, and death, revealing an obligate role for GR in maintaining normal cardiovascular function. Moreover, our findings suggest that selective activation of cardiomyocyte GR may represent an approach for the prevention of heart disease. C1 [Oakley, Robert H.; Ren, Rongqin; Cruz-Topete, Diana; Bird, Gary S.; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Myers, Page H.] NIEHS, Comparat Med Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Boyle, Michael C.] NIEHS, Cellular & Mol Pathol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Schneider, Michael D.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW7 2AZ, England. [Willis, Monte S.] Univ N Carolina, McAllister Heart Inst, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov OI Willis, Monte/0000-0002-0769-5816 FU NIEHS, NIH FX This research was supported by the Intramural Research Program of the NIEHS, NIH. NR 22 TC 24 Z9 24 U1 1 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 OCT 15 PY 2013 VL 110 IS 42 BP 17035 EP 17040 DI 10.1073/pnas.1302546110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 234HT UT WOS:000325634200072 PM 24082121 ER PT J AU Cox, MA Schmid, MC Peters, AJ Saunders, RC Leopold, DA Maier, A AF Cox, Michele A. Schmid, Michael C. Peters, Andrew J. Saunders, Richard C. Leopold, David A. Maier, Alexander TI Receptive field focus of visual area V4 neurons determines responses to illusory surfaces SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE visual perception; illusory contours; modal completion; nonhuman primate; visual cortex ID FIGURE-GROUND SEGREGATION; COMPETITIVE INTERACTIONS; PERCEPTUAL COMPLETION; INFEROTEMPORAL CORTEX; MACAQUE V4; CONTOURS; ORGANIZATION; REAL; V1; REPRESENTATION AB Illusory figures demonstrate the visual system's ability to infer surfaces under conditions of fragmented sensory input. To investigate the role of midlevel visual area V4 in visual surface completion, we used multielectrode arrays to measure spiking responses to two types of visual stimuli: Kanizsa patterns that induce the perception of an illusory surface and physically similar control stimuli that do not. Neurons in V4 exhibited stronger and sometimes rhythmic spiking responses for the illusion-promoting configurations compared with controls. Moreover, this elevated response depended on the precise alignment of the neuron's peak visual field sensitivity (receptive field focus) with the illusory surface itself. Neurons whose receptive field focus was over adjacent inducing elements, less than 1.5 degrees away, did not show response enhancement to the illusion. Neither receptive field sizes nor fixational eye movements could account for this effect, which was present in both single-unit signals and multiunit activity. These results suggest that the active perceptual completion of surfaces and shapes, which is a fundamental problem in natural visual experience, draws upon the selective enhancement of activity within a distinct subpopulation of neurons in cortical area V4. C1 [Cox, Michele A.; Schmid, Michael C.; Peters, Andrew J.; Saunders, Richard C.; Leopold, David A.; Maier, Alexander] NIMH, Sect Cognit Neurophysiol & Imaging, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Saunders, Richard C.] NIMH, Neuropsychol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Cox, Michele A.; Maier, Alexander] Vanderbilt Univ, Dept Psychol, Coll Arts & Sci, Nashville, TN 37203 USA. [Schmid, Michael C.] Max Planck Gesell, Ernst Strungmann Inst Neurosci, DE-60528 Frankfurt, Germany. [Peters, Andrew J.] Univ Calif San Diego, Neurosci Grad Program, La Jolla, CA 92093 USA. [Leopold, David A.] NEI, Neurophysiol Imaging Facil, NIMH, NINDS,NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Leopold, DA (reprint author), NIMH, Sect Cognit Neurophysiol & Imaging, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM LeopoldD@mail.nih.gov RI Maier, Alexander/B-7489-2009; Schmid, Michael/G-1867-2010; OI Maier, Alexander/0000-0002-7250-502X; Schmid, Michael/0000-0003-1424-130X; Cox, Michele/0000-0002-6822-6503; Peters, Andrew/0000-0001-9351-1456; Leopold, David/0000-0002-1345-6360 FU Intramural Research Programs of the National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Eye Institute; National Science Foundation [DGE-0909667]; Whitehall Foundation; Alfred P. Sloan Foundation; Deutsche Forschungsgemeinschaft Emmy Noether grant; [P30-EY08126] FX We thank Dr. A. Mitz, G. Dold, D. Ide, T. Talbot, and A. Pugh, as well as N. Phipps, K. Smith, and J. Yu for technical assistance, and Drs. A. Roe, B. Tamber-Rosenau, and A. Tomarken for comments on an earlier version of the manuscript. The Intramural Research Programs of the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Eye Institute supported this work. M. A. C. is supported by a National Science Foundation Graduate Research Fellowship (DGE-0909667). A. M. is supported by P30-EY08126, a Whitehall Foundation research grant, and an Alfred P. Sloan Foundation Fellowship. M. C. S. is supported by a Deutsche Forschungsgemeinschaft Emmy Noether grant. NR 40 TC 11 Z9 11 U1 1 U2 18 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 15 PY 2013 VL 110 IS 42 BP 17095 EP 17100 DI 10.1073/pnas.1310806110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 234HT UT WOS:000325634200082 PM 24085849 ER PT J AU Loo, CS Chen, CW Wang, PJ Chen, PY Lin, SY Khoo, KH Fenton, RA Knepper, MA Yu, MJ AF Loo, Chin-San Chen, Cheng-Wei Wang, Po-Jen Chen, Pei-Yu Lin, Shu-Yu Khoo, Kay-Hooi Fenton, Robert A. Knepper, Mark A. Yu, Ming-Jiun TI Quantitative apical membrane proteomics reveals vasopressin-induced actin dynamics in collecting duct cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE SILAC; LC-MS/MS; proteome; dDAVP; AQP2 ID LC-MS/MS ANALYSIS; WATER CHANNEL AQUAPORIN-2; KIDNEY EPITHELIAL-CELLS; NONMUSCLE MYOSIN-II; F-ACTIN; SURFACE EXPRESSION; PLASMA-MEMBRANE; GENE-EXPRESSION; PROTEIN; RAT AB In kidney collecting duct cells, filamentous actin (F-actin) depolymerization is a critical step in vasopressin-induced trafficking of aquaporin-2 to the apical plasma membrane. However, the molecular components of this response are largely unknown. Using stable isotope-based quantitative protein mass spectrometry and surface biotinylation, we identified 100 proteins that showed significant abundance changes in the apical plasma membrane of mouse cortical collecting duct cells in response to vasopressin. Fourteen of these proteins are involved in actin cytoskeleton regulation, including actin itself, 10 actin-associated proteins, and 3 regulatory proteins. Identified were two integral membrane proteins (Clmn, Nckap1) and one actin-binding protein (Mpp5) that link F-actin to the plasma membrane, five F-actin end-binding proteins (Arpc2, Arpc4, Gsn, Scin, and Capzb) involved in F-actin reorganization, and two actin adaptor proteins (Dbn1, Lasp1) that regulate actin cytoskeleton organization. There were also protease (Capn1), protein kinase (Cdc42bpb), and Rho guanine nucleotide exchange factor 2 (Arhgef2) that mediate signal-induced F-actin changes. Based on these findings, we devised a live-cell imaging method to observe vasopressin-induced F-actin dynamics in polarized mouse cortical collecting duct cells. In response to vasopressin, F-actin gradually disappeared near the center of the apical plasma membrane while consolidating laterally near the tight junction. This F-actin peripheralization was blocked by calcium ion chelation. Vasopressin-induced apical aquaporin-2 trafficking and forskolin-induced water permeability increase were blocked by F-actin disruption. In conclusion, we identified a vasopressin-regulated actin network potentially responsible for vasopressin-induced apical F-actin dynamics that could explain regulation of apical aquaporin-2 trafficking and water permeability increase. C1 [Loo, Chin-San; Chen, Cheng-Wei; Wang, Po-Jen; Chen, Pei-Yu; Yu, Ming-Jiun] Natl Taiwan Univ, Coll Med, Inst Biochem & Mol Biol, Taipei 10051, Taiwan. [Lin, Shu-Yu; Khoo, Kay-Hooi] Acad Sinica, Inst Biol Chem, Taipei 11529, Taiwan. [Fenton, Robert A.] Aarhus Univ, Dept Biomed, InterPrET Ctr, DK-8000 Aarhus, Denmark. [Knepper, Mark A.] NHLBI, Syst Biol Ctr, Bethesda, MD 20892 USA. RP Yu, MJ (reprint author), Natl Taiwan Univ, Coll Med, Inst Biochem & Mol Biol, Taipei 10051, Taiwan. EM mjyu@ntu.edu.tw OI YU, MING-JIUN/0000-0003-0393-4696 FU National Science Council, Taiwan [100-2320-B-002-002-, 100-2320-B-002-097-, 101-2320-B-002-038-MY3]; Intramural Budget of the NHLBI [Z01-HL001285]; Danish Medical Research Council; Lundbeck Foundation FX We thank Suh-Yuen Liang (Core Facilities for Protein Structural Analysis, Academia Sinica) for assistance with protein MS. We thank Cheng-Yen Huang and Hua-Man Hsu (First Core Facility, National Taiwan University College of Medicine) for assistance with confocal and live-cell imaging. We thank Mathew Daniels and Patricia Connelly [Electron Microscope Core Facility, National Heart, Lung, and Blood Institute (NHLBI)] for advice with immunoelectron microscopy. M.-J.Y. is supported by National Science Council, Taiwan Grants 100-2320-B-002-002-, 100-2320-B-002-097-, and 101-2320-B-002-038-MY3. M. A. K. is supported by the Intramural Budget of the NHLBI (Grant Z01-HL001285). R. A. F. is supported by the Danish Medical Research Council and the Lundbeck Foundation. NR 57 TC 16 Z9 17 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 OCT 15 PY 2013 VL 110 IS 42 BP 17119 EP 17124 DI 10.1073/pnas.1309219110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 234HT UT WOS:000325634200086 PM 24085853 ER PT J AU Heymann, G Dai, J Li, MF Silberberg, SD Zhou, HX Swartz, KJ AF Heymann, Gabriel Dai, Jian Li, Mufeng Silberberg, Shai D. Zhou, Huan-Xiang Swartz, Kenton J. TI Inter- and intrasubunit interactions between transmembrane helices in the open state of P2X receptor channels SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pore-opening mechanism; transmembrane intersubunit crevices ID MOLECULAR-DYNAMICS SIMULATIONS; ATP-BINDING SITES; ION-CHANNEL; CRYSTAL-STRUCTURE; FORCE-FIELD; K+ CHANNEL; PORE; ACTIVATION; ACCESS; REARRANGEMENTS AB P2X receptor channels open in response to the binding of extracellular ATP, a property that is essential for purinergic sensory signaling. Apo and ATP-bound X-ray structures of the detergent-solubilized zebrafish P2X4 receptor provide a blueprint for receptor mechanisms but unexpectedly showed large crevices between subunits within the transmembrane (TM) domain of the ATP-bound structure. Here we investigate both intersubunit and intrasubunit interactions between TM helices of P2X receptors in membranes using both computational and functional approaches. Our results suggest that intersubunit crevices found in the TM domain of the ATP-bound crystal structure are not present in membrane-embedded receptors but substantiate helix interactions within individual subunits and identify a hot spot at the internal end of the pore where both the gating and permeation properties of P2X receptors can be tuned. We propose a model for the structure of the open state that has stabilizing intersubunit interactions and that is compatible with available structural constraints from functional channels in membrane environments. C1 [Heymann, Gabriel; Li, Mufeng; Silberberg, Shai D.; Swartz, Kenton J.] NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Dai, Jian; Zhou, Huan-Xiang] Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. [Dai, Jian; Zhou, Huan-Xiang] Florida State Univ, Dept Phys, Tallahassee, FL 32306 USA. RP Swartz, KJ (reprint author), NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM Kenton.Swartz@nih.gov RI Dai, Jian/C-2348-2014; Zhou, Huan-Xiang/M-5170-2016 OI Dai, Jian/0000-0002-1185-5165; Zhou, Huan-Xiang/0000-0001-9020-0302 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH); NIH [NS070954, GM058187, GM 088187] FX We thank Andres Jara-Oseguera, Mark Mayer, Miguel Holmgren, Dmitriy Krepkiy, Jeet Kalia, Gilman Toombes, and other members of the K.J.S. laboratory for helpful discussions. This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH) (K.J.S.), NIH Pathway to Independence Award NS070954 (to M. L.), and NIH Grants GM058187 and GM 088187(to H.-X.Z.). NR 38 TC 21 Z9 21 U1 2 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 15 PY 2013 VL 110 IS 42 BP E4045 EP E4054 DI 10.1073/pnas.1311071110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 234HT UT WOS:000325634200012 PM 24082111 ER PT J AU Curtis, DS Phillips, AR Callister, SJ Conlan, S McCue, LA AF Curtis, Darren S. Phillips, Aaron R. Callister, Stephen J. Conlan, Sean McCue, Lee Ann TI SPOCS: software for predicting and visualizing orthology/paralogy relationships among genomes SO BIOINFORMATICS LA English DT Article AB At the rate that prokaryotic genomes can now be generated, comparative genomics studies require a flexible method for quickly and accurately predicting orthologs among the rapidly changing set of genomes available. SPOCS implements a graph-based ortholog prediction method to generate a simple tab-delimited table of orthologs and in addition, html files that provide a visualization of the predicted ortholog/paralog relationships to which gene/protein expression metadata may be overlaid. C1 [Curtis, Darren S.; Phillips, Aaron R.] Pacific NW Natl Lab, Computat & Stat Analyt Div, Richland, WA 99352 USA. [Callister, Stephen J.] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Conlan, Sean] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [McCue, Lee Ann] Pacific NW Natl Lab, Computat Sci & Math Div, Richland, WA 99352 USA. RP McCue, LA (reprint author), Pacific NW Natl Lab, Computat Sci & Math Div, Richland, WA 99352 USA. EM leeann.mccue@pnnl.gov RI Conlan, Sean/B-4401-2008; OI Conlan, Sean/0000-0001-6848-3465; Curtis, Darren/0000-0002-4907-4575; McCue, Lee Ann/0000-0003-4456-517X FU U.S. Department of Energy, Office of Biological and Environmental Research (DOE-BER) Genome Science Program; DOE [DE-AC06-76RL01830] FX This work was supported by U.S. Department of Energy, Office of Biological and Environmental Research (DOE-BER) Genome Science Program, and performed at the Pacific Northwest National Laboratory, a multiprogram national laboratory operated by Battelle for the DOE under Contract DE-AC06-76RL01830. NR 7 TC 5 Z9 5 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD OCT 15 PY 2013 VL 29 IS 20 BP 2641 EP 2642 DI 10.1093/bioinformatics/btt454 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 232ID UT WOS:000325485800017 PM 23956303 ER PT J AU Kim, S Chen, MH Ibrahim, JG Shah, AK Lin, JX AF Kim, Sungduk Chen, Ming-Hui Ibrahim, Joseph G. Shah, Arvind K. Lin, Jianxin TI Bayesian inference for multivariate meta-analysis Box-Cox transformation models for individual patient data with applications to evaluation of cholesterol-lowering drugs SO STATISTICS IN MEDICINE LA English DT Article DE heterogeneity; individual patient data; Markov chain Monte Carlo; multiple trials; random effects ID HETEROGENEITY; OUTCOMES AB In this paper, we propose a class of Box-Cox transformation regression models with multidimensional random effects for analyzing multivariate responses for individual patient data in meta-analysis. Our modeling formulation uses a multivariate normal response meta-analysis model with multivariate random effects, in which each response is allowed to have its own Box-Cox transformation. Prior distributions are specified for the Box-Cox transformation parameters as well as the regression coefficients in this complex model, and the deviance information criterion is used to select the best transformation model. Because the model is quite complex, we develop a novel Monte Carlo Markov chain sampling scheme to sample from the joint posterior of the parameters. This model is motivated by a very rich dataset comprising 26 clinical trials involving cholesterol-lowering drugs where the goal is to jointly model the three-dimensional response consisting of low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG) (LDL-C, HDL-C, TG). Because the joint distribution of (LDL-C, HDL-C, TG) is not multivariate normal and in fact quite skewed, a Box-Cox transformation is needed to achieve normality. In the clinical literature, these three variables are usually analyzed univariately; however, a multivariate approach would be more appropriate because these variables are correlated with each other. We carry out a detailed analysis of these data by using the proposed methodology. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Kim, Sungduk] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Ibrahim, Joseph G.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Shah, Arvind K.; Lin, Jianxin] Merck Res Labs, Rahway, NJ USA. RP Ibrahim, JG (reprint author), Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. EM ibrahim@bios.unc.edu FU Intramural Research Program of National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH [GM 70335, CA 74015] FX We would like to thank the Editor, an Associate Editor, and two referees for their very helpful comments and suggestions, which have led to an improved version of the paper. Dr. Kim's research was partially supported by the Intramural Research Program of National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Chen and Dr. Ibrahim's research was partially supported by NIH grants GM 70335 and CA 74015. The conclusions in this paper are entirely those of the authors and do not necessarily represent the views of the National Institutes of Health and Merck & Co., Inc. NR 21 TC 0 Z9 0 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD OCT 15 PY 2013 VL 32 IS 23 BP 3972 EP 3990 DI 10.1002/sim.5814 PG 19 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 226AI UT WOS:000325006100002 PM 23580436 ER PT J AU Raznahan, A Wallace, GL Antezana, L Greenstein, D Lenroot, R Thurm, A Gozzi, M Spence, S Martin, A Swedo, SE Giedd, JN AF Raznahan, Armin Wallace, Gregory L. Antezana, Ligia Greenstein, Dede Lenroot, Rhoshel Thurm, Audrey Gozzi, Marta Spence, Sarah Martin, Alex Swedo, Susan E. Giedd, Jay N. TI Compared to What? Early Brain Overgrowth in Autism and the Perils of Population Norms SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Autism; bias; CDC; head circumference; systematic review; WHO ID HEAD CIRCUMFERENCE GROWTH; PERVASIVE DEVELOPMENTAL DISORDERS; AGE 2 YEARS; SPECTRUM DISORDERS; 1ST YEAR; BIRTH COHORT; CHILDREN; LIFE; INFANTS; SIZE AB Background: Early brain overgrowth (EBO) in autism spectrum disorder (ASD) is among the best replicated biological associations in psychiatry. Most positive reports have compared head circumference (HC) in ASD (an excellent proxy for early brain size) with well-known reference norms. We sought to reappraise evidence for the EBO hypothesis given 1) the recent proliferation of longitudinal HC studies in ASD, and 2) emerging reports that several of the reference norms used to define EBO in ASD may be biased toward detecting HC overgrowth in contemporary samples of healthy children. Methods: Systematic review of all published HC studies in children with ASD. Comparison of 330 longitudinally gathered HC measures between birth and 18 months from male children with autism (n = 35) and typically developing control subjects (n = 22). Results: In systematic review, comparisons with locally recruited control subjects were significantly less likely to identify EBO in ASD than norm-based studies (p < .001). Through systematic review and analysis of new data, we replicate seminal reports of EBO in ASD relative to classical HC norms but show that this overgrowth relative to norms is mimicked by patterns of HC growth age in a large contemporary community-based sample of US children (n similar to 75,000). Controlling for known HC norm biases leaves inconsistent support for a subtle, later emerging and subgroup specific pattern of EBO in clinically ascertained ASD versus community control subjects. Conclusions: The best-replicated aspects of EBO reflect generalizable HC norm biases rather than disease-specific biomarkers. The potential HC norm biases we detail are not specific to ASD research but apply throughout clinical and academic medicine. C1 [Raznahan, Armin; Greenstein, Dede; Giedd, Jay N.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Wallace, Gregory L.; Antezana, Ligia; Martin, Alex] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Lenroot, Rhoshel] Univ New S Wales, Dept Psychiat, Sydney, NSW, Australia. [Thurm, Audrey; Gozzi, Marta; Swedo, Susan E.] NIMH, Pediat Dev Neurosci Branch, NIH, Bethesda, MD 20892 USA. [Spence, Sarah] Harvard Univ, Sch Med, Dept Neurol, Childrens Hosp Boston, Boston, MA 02115 USA. RP Raznahan, A (reprint author), NIMH, NIH, Child Psychiat Branch, Room 4C108,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM raznahana@mail.nih.gov RI Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Wallace, Gregory/0000-0003-0329-5054 FU National Institutes of Health Intramural Research Program FX Financial support for this work was provided by the National Institutes of Health Intramural Research Program. NR 81 TC 47 Z9 47 U1 0 U2 24 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2013 VL 74 IS 8 BP 563 EP 575 DI 10.1016/j.biopsych.2013.03.022 PG 13 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 223OH UT WOS:000324814900003 PM 23706681 ER PT J AU Shaw, P Malek, M Watson, B Greenstein, D de Rossi, P Sharp, W AF Shaw, Philip Malek, Meaghan Watson, Bethany Greenstein, Deanna de Rossi, Pietro Sharp, Wendy TI Trajectories of Cerebral Cortical Development in Childhood and Adolescence and Adult Attention-Deficit/Hyperactivity Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Attention; cerebral cortex; cognition; development; neuroimaging; recovery ID DEFICIT-HYPERACTIVITY DISORDER; FOLLOW-UP; CONDUCT DISORDER; MENTAL-HEALTH; MRI DATA; ADHD; CHILDREN; THICKNESS; AGE; METAANALYSIS AB Background: Childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood in around half of those affected, constituting a major public health challenge. No known demographic, clinical, or neuropsychological factors robustly explain the clinical course, directing our focus to the brain. Herein, we link the trajectories of cerebral cortical development during childhood and adolescence with the severity of adult ADHD. Methods: Using a longitudinal study design, 92 participants with ADHD had childhood (mean 10.7 years, SD 3.3) and adult clinical assessments (mean 23.8 years, SD 4.3) with repeated neuroanatomic magnetic resonance imaging. Contrast was made against 184 matched typically developing volunteers. Results: Attention-deficit/hyperactivity disorder persisted in 37 (40%) subjects and adult symptom severity was linked to cortical trajectories. Specifically, as the number of adult symptoms increased, particularly inattentive symptoms, so did the rate of cortical thinning in the medial and dorsolateral prefrontal cortex. For each increase of one symptom of adult ADHD, the rate of cortical thinning increased by .0018 mm (SE = .0004, t = 4.2, p < .0001), representing a 5.6% change over the mean rate of thinning for the entire group. These differing trajectories resulted in a convergence toward typical dimensions among those who remitted and a fixed, nonprogressive deficit in persistent ADHD. Notably, cortical thickening or minimal thinning (greater than -.007 mm/year) was found exclusively among individuals who remitted. Conclusions: Adult ADHD status is linked with the developmental trajectories of cortical components of networks supporting attention, cognitive control, and the default mode network. This informs our understanding of the developmental pathways to adult ADHD. C1 [Shaw, Philip; Malek, Meaghan; Watson, Bethany; Greenstein, Deanna; de Rossi, Pietro] NHGRI, Social & Behav Res Branch, Sect Neurobehav Clin Res, Bethesda, MD 20892 USA. [Shaw, Philip; Sharp, Wendy] NIMH, Intramural Program, Bethesda, MD 20892 USA. [de Rossi, Pietro] Univ Roma La Sapienza, Neurosci Mental Hlth & Sensory Funct Dept, Sch Med & Psychol, St Andrea Hosp, I-00185 Rome, Italy. RP Shaw, P (reprint author), NHGRI, Social & Behav Res Branch, Sect Neurobehav Clin Res, Bldg 31,B1 B37,Room 3N 202, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov FU Intramural Programs of the National Human Genome Research Institute; National Institute of Mental Health FX This study was funded by the Intramural Programs of the National Human Genome Research Institute and the National Institute of Mental Health. NR 57 TC 66 Z9 67 U1 2 U2 38 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2013 VL 74 IS 8 BP 599 EP 606 DI 10.1016/j.biopsych.2013.04.007 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 223OH UT WOS:000324814900007 PM 23726514 ER PT J AU Janes, H Friedrich, DP Krambrink, A Smith, RJ Kallas, EG Horton, H Casimiro, DR Carrington, M Geraghty, DE Gilbert, PB McElrath, MJ Frahm, N AF Janes, Holly Friedrich, David P. Krambrink, Amy Smith, Rebecca J. Kallas, Esper G. Horton, Helen Casimiro, Danilo R. Carrington, Mary Geraghty, Daniel E. Gilbert, Peter B. McElrath, M. Juliana Frahm, Nicole TI Vaccine-Induced Gag-Specific T Cells Are Associated With Reduced Viremia After HIV-1 Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV-1 vaccine; Step study; Gag-specific T cells; HLA class I alleles ID IMMUNODEFICIENCY-VIRUS TYPE-1; VIRAL LOAD; DISCORDANT ASSOCIATIONS; GENETIC-DETERMINANTS; LYMPHOCYTE RESPONSE; MEDIATED-IMMUNITY; CONTROLLED-TRIAL; RHESUS-MONKEYS; STEP TRIAL; ESCAPE AB The contribution of host T-cell immunity and HLA class I alleles to the control of human immunodeficiency virus (HIV-1) replication in natural infection is widely recognized. We assessed whether vaccine-induced T-cell immunity, or expression of certain HLA alleles, impacted HIV-1 control after infection in the Step MRKAd5/HIV-1 gag/pol/nef study. Vaccine-induced T cells were associated with reduced plasma viremia, with subjects targeting >= 3 gag peptides presenting with half-log lower mean viral loads than subjects without Gag responses. This effect was stronger in participants infected proximal to vaccination and was independent of our observed association of HLA-B(star)27, -B(star)57 and -B(star)58:01 alleles with lower HIV-1 viremia. These findings support the ability of vaccine-induced T-cell responses to influence postinfection outcome and provide a rationale for the generation of T-cell responses by vaccination to reduce viremia if protection from acquisition is not achieved. Clinical trials identifier: NCT00095576. C1 [Janes, Holly; Friedrich, David P.; Krambrink, Amy; Smith, Rebecca J.; Geraghty, Daniel E.; Gilbert, Peter B.; McElrath, M. Juliana; Frahm, Nicole] Fred Hutchinson Canc Res Ctr, VIDD, Seattle, WA 98109 USA. [Janes, Holly; Friedrich, David P.; Krambrink, Amy; Smith, Rebecca J.; Geraghty, Daniel E.; Gilbert, Peter B.; McElrath, M. Juliana; Frahm, Nicole] Fred Hutchinson Canc Res Ctr, HIV Vaccine Trials Network, Seattle, WA 98109 USA. [Janes, Holly; Gilbert, Peter B.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [McElrath, M. Juliana; Frahm, Nicole] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [McElrath, M. Juliana] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [McElrath, M. Juliana] Univ Washington, Dept Med, Seattle, WA USA. [Horton, Helen] Seattle Biomed Res Inst, Washington, DC USA. [Kallas, Esper G.] Univ Sao Paulo, Div Clin Immunol & Allergy, Sch Med, BR-05508 Sao Paulo, Brazil. [Casimiro, Danilo R.] Merck Res Labs, Upper Gwynedd, PA USA. [Carrington, Mary] Frederick Natl Lab Canc Res, Canc & Inflammat Program, SAIC Frederick, Frederick, MD USA. [Carrington, Mary] Ragon Inst MGH MIT & Harvard, Boston, MA USA. RP Frahm, N (reprint author), Fred Hutchinson Canc Res Ctr, VIDD, 1100 Fairview Ave N,E4-200, Seattle, WA 98109 USA. EM nfrahm@fhcrc.org FU National Institutes of Health Public Health Service [UM1 AI068618, AI068635]; Frederick National Laboratory for Cancer Research [HHSN261200800001E] FX This work was supported by the National Institutes of Health Public Health Service (grants UM1 AI068618 and AI068635) and the Frederick National Laboratory for Cancer Research (contract HHSN261200800001E). NR 49 TC 26 Z9 27 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2013 VL 208 IS 8 BP 1231 EP 1239 DI 10.1093/infdis/jit322 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 223TJ UT WOS:000324832800006 PM 23878319 ER PT J AU Weinberger, DM Harboe, ZB Viboud, C Krause, TG Miller, M Molbak, K Konradsen, HB AF Weinberger, Daniel M. Harboe, Zitta B. Viboud, Cecile Krause, Tyra G. Miller, Mark Molbak, Kare Konradsen, Helle B. TI Serotype-Specific Effect of Influenza on Adult Invasive Pneumococcal Pneumonia SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE pneumococcus; influenza; coinfection; comorbidity; interaction; regression ID STREPTOCOCCUS-PNEUMONIAE; CAPSULAR TYPES; DISEASE; CHILDREN; VIRUS; MORTALITY; VIRULENCE; DENMARK; IMPACT; DEATH AB Background. Influenza affects host susceptibility to pneumococcus. We sought to evaluate whether this relationship varies by pneumococcal serotype using a large epidemiological database covering 3 decades. Methods. Weekly rates of invasive pneumococcal pneumonia (IPP) were obtained from the Danish National Laboratory Surveillance System, and influenza-like illness (ILI) data were collected from Danish sentinel surveillance, Statens Serum Institut, 1977-2007. We fit Poisson regression models for each age and comorbidity group, with predictors for seasonality and secular changes, ILI activity, and serotype. Results. Among individuals with low levels of comorbidities, influenza had the largest impact on IPP incidence among low-invasiveness serotypes (influenza attributable percent: 17.9%, 95% confidence interval [CI], 13.6-21.9) as compared with high-invasiveness serotypes (6.7%, 95% CI, 3.8%-11.7%). Among those with higher levels of comorbidities, the effect of influenza was smaller, but high-invasiveness serotypes increased more than low-invasiveness serotypes (8.9% [95% CI, 6.6-11.8] vs 1.3% [95% CI, -1.6-5.4]. Conclusions. Influenza was associated with the greatest increases in the incidence of disease caused by serotypes with lower invasive potential and among individuals with low levels of comorbid conditions. The importance of influenza for adult IPP varies by serotype and host comorbidity. C1 [Weinberger, Daniel M.; Viboud, Cecile; Miller, Mark] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Harboe, Zitta B.; Konradsen, Helle B.] Statens Serum Inst, Neisseria & Streptococcus Reference Ctr, Dept Microbiol & Infect Control, DK-2300 Copenhagen, Denmark. [Krause, Tyra G.; Molbak, Kare] Statens Serum Inst, Dept Epidemiol, DK-2300 Copenhagen, Denmark. [Weinberger, Daniel M.] Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT USA. RP Harboe, ZB (reprint author), Statens Serum Inst, Neisseria & Streptococcus Reference Ctr, Dept Microbiol Surveillance & Res, Orestads Blvd 5, DK-2300 S Copenhagen, Denmark. EM zit@ssi.dk OI Weinberger, Daniel/0000-0003-1178-8086 FU Office of Global Health Affairs' International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services FX This work is conducted in the context of the Multinational Influenza Seasonal Mortality Study (MISMS), with funding from the Office of Global Health Affairs' International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services. NR 43 TC 10 Z9 10 U1 1 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2013 VL 208 IS 8 BP 1274 EP 1280 DI 10.1093/infdis/jit375 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 223TJ UT WOS:000324832800011 PM 23901093 ER PT J AU Rosenthal, AS Dexheimer, TS Gileadi, O Nguyen, GH Chu, WK Hickson, ID Jadhav, A Simeonov, A Maloney, DJ AF Rosenthal, Andrew S. Dexheimer, Thomas S. Gileadi, Opher Nguyen, Giang H. Chu, Wai Kit Hickson, Ian D. Jadhav, Ajit Simeonov, Anton Maloney, David J. TI Synthesis and SAR studies of 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine derivatives as potent inhibitors of Bloom helicase SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Bloom helicase; Small molecule; Inhibitor ID BLM HELICASE; RECQ HELICASES; DNA; RECOMBINATION; MAINTENANCE; INSTABILITY; CELLS AB Human cells utilize a variety of complex DNA repair mechanisms in order to combat constant mutagenic and cytotoxic threats from both exogenous and endogenous sources. The RecQ family of DNA helicases, which includes Bloom helicase (BLM), plays an important function in DNA repair by unwinding complementary strands of duplex DNA as well as atypical DNA structures such as Holliday junctions. Mutations of the BLM gene can result in Bloom syndrome, an autosomal recessive disorder associated with cancer predisposition. BLM-deficient cells exhibit increased sensitivity to DNA damaging agents indicating that a selective BLM inhibitor could be useful in potentiating the anticancer activity of these agents. In this work, we describe the medicinal chemistry optimization of the hit molecule following a quantitative high-throughput screen of >355,000 compounds. These efforts lead to the identification of ML216 and related analogs, which possess potent BLM inhibition and exhibit selectivity over related helicases. Moreover, these compounds demonstrated cellular activity by inducing sister chromatid exchanges, a hallmark of Bloom syndrome. Published by Elsevier Ltd. C1 [Rosenthal, Andrew S.; Dexheimer, Thomas S.; Jadhav, Ajit; Simeonov, Anton; Maloney, David J.] Natl Ctr Adv Translat Sci, NIH, Rockville, MD 20850 USA. [Gileadi, Opher] Univ Oxford, Struct Genom Consortium, Oxford OX3 7DQ, England. [Nguyen, Giang H.; Hickson, Ian D.] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Dept Med Oncol, Oxford OX3 9DS, England. [Nguyen, Giang H.] NCI, NIH, Ctr Canc Res, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Chu, Wai Kit; Hickson, Ian D.] Univ Copenhagen, Nordea Ctr Healthy Aging, Dept Cellular & Mol Med, DK-2200 Copenhagen N, Denmark. RP Maloney, DJ (reprint author), Natl Ctr Adv Translat Sci, NIH, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM maloneyd@mail.nih.gov RI Chu, Wai Kit/F-9405-2016; OI Gileadi, Opher/0000-0001-6886-898X FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research [U54MH084681, R03MH087284]; National Institutes of Health Intramural Research Programs of the National Center for Advancing Translational Sciences; Cancer Research UK; Nordea Foundation (Denmark); NIH-Oxford Graduate Partnership Program; National Institute of Mental Health [R03MH087284]; AbbVie; Boehringer Ingelheim; Canada Foundation for Innovation; Canadian Institutes for Health Research; Genome Canada; GlaxoSmithKline; Janssen; Lilly Canada; Novartis Research Foundation; Ontario Ministry of Economic Development and Innovation; Pfizer; Takeda; Wellcome Trust [092809/Z/10/Z] FX This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research (grant U54MH084681 and R03MH087284), and the National Institutes of Health Intramural Research Programs of the National Center for Advancing Translational Sciences. I. D. H. was funded by Cancer Research UK and the Nordea Foundation (Denmark). G.H.N. was funded by the NIH-Oxford Graduate Partnership Program. The authors wish to thank Sam Michael and Richard Jones for automation support; Paul Shinn and Danielle van Leer for the assistance with compound management; William Leister, Heather Baker, Christopher Leclair and Elizabeth Fernandez for analytical chemistry and compound purification support. This research was supported in part by award No. R03MH087284 from the National Institute of Mental Health (to O.G.). The SGC is a registered charity (No. 1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda, and the Wellcome Trust [092809/Z/10/Z]. NR 25 TC 8 Z9 8 U1 0 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD OCT 15 PY 2013 VL 23 IS 20 BP 5660 EP 5666 DI 10.1016/j.bmcl.2013.08.025 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 216SJ UT WOS:000324304000037 PM 24012121 ER PT J AU Ranjan, N Kumar, S Watkins, D Wang, D Appella, DH Arya, DP AF Ranjan, Nihar Kumar, Sunil Watkins, Derrick Wang, Deyun Appella, Daniel H. Arya, Dev P. TI Recognition of HIV-TAR RNA using neomycin-benzimidazole conjugates SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE TAR; Neomycin; Aminoglycosides; tat-TAR inhibition; Benzimidazole ID NUCLEIC-ACID BINDING; CIRCULAR-DICHROISM; MAJOR GROOVE; B-DNA; INHIBITORS; AFFINITY; DIMERS; HOECHST-33258; DERIVATIVES; MOLECULES AB Synthesis of a novel class of compounds and their biophysical studies with TAR-RNA are presented. The synthesis of these compounds was achieved by conjugating neomycin, an aminoglycoside, with benzimidazoles modeled from a B-DNA minor groove binder, Hoechst 33258. The neomycin-benzimidazole conjugates have varying linkers that connect the benzimidazole and neomycin units. The linkers of varying length (5-23 atoms) in these conjugates contain one to three triazole units. The UV thermal denaturation experiments showed that the conjugates resulted in greater stabilization of the TAR-RNA than either neomycin or benzimidazole used in the synthesis of conjugates. These results were corroborated by the FID displacement and tat-TAR inhibition assays. The binding of ligands to the TAR-RNA is affected by the length and composition of the linker. Our results show that increasing the number of triazole groups and the linker length in these compounds have diminishing effect on the binding to TAR-RNA. Compounds that have shorter linker length and fewer triazole units in the linker displayed increased affinity towards the TAR RNA. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Ranjan, Nihar; Kumar, Sunil; Arya, Dev P.] Clemson Univ, Dept Chem, Med Chem Lab, Clemson, SC 29634 USA. [Watkins, Derrick; Arya, Dev P.] NUBAD LLC, Greenville, SC 29630 USA. [Wang, Deyun; Appella, Daniel H.] NIDDK, NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Arya, DP (reprint author), Clemson Univ, Dept Chem, Med Chem Lab, Clemson, SC 29634 USA. EM dparya@clemson.edu FU National Institutes of Health [R15CA125724, 1R41GM100607] FX Financial support to this work was provided by National Institutes of Health grants (R15CA125724 and 1R41GM100607). NR 48 TC 15 Z9 15 U1 2 U2 31 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD OCT 15 PY 2013 VL 23 IS 20 BP 5689 EP 5693 DI 10.1016/j.bmcl.2013.08.014 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 216SJ UT WOS:000324304000043 PM 24012122 ER PT J AU Trabert, B Zugna, D Richiardi, L McGlynn, KA Akre, O AF Trabert, Britton Zugna, Daniela Richiardi, Lorenzo McGlynn, Katherine A. Akre, Olof TI Congenital malformations and testicular germ cell tumors SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE congenital malformations; testicular germ cell tumors; hypospadias; cryptorchidism ID DYSGENESIS SYNDROME; CANCER; CRYPTORCHIDISM; RISK AB Cryptorchidism is one of the few known risk factors for testicular germ cell tumors (TGCT). It has been postulated that other congenital malformations, in particular hypospadias, are also associated with increased risk; however, associations with birth defects have not been extensively studied. Using Swedish population-based registries we evaluated the relationship between birth defects and risk of TGCT. TGCT cases (n = 6,593) diagnosed between 15 and 65 years of age were identified from the Swedish Cancer Registry between 1964 and 2008. Five controls per case were randomly selected from the population register and matched on birth year and birth county. Congenital malformations were identified via linkage with the Hospital Discharge Register. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each group of malformations and TGCT were estimated using conditional logistic regression. In addition to the expected association between cryptorchidism and TGCT risk [OR (95% CI): 3.18 (2.50-4.04)], hypospadias [2.41 (1.27-4.57)], inguinal hernia [1.37 (1.11-1.68)] and other genital malformations [2.19 (1.17-4.10)] were associated with an increased risk of TGCT. Mutual adjustment for cryptorchidism, hypospadias, inguinal hernia and other genital malformations did not appreciably change the associations (ORs: 3.16, 2.25, 1.30 and 1.90, respectively). The other (nongenital) malformations evaluated were not associated with TGCT. These data suggest that developmental urogenital abnormalities, specifically cryptorchidism, hypospadias and inguinal hernia, are associated with an increased risk of TGCT, further supporting the hypothesis that prenatal exposure(s) related to proper genital development are related to this tumor. What's new? While cryptorchidism is a known risk factor for testicular germ cell tumors (TGCT), few studies have evaluated the association between other birth defects and risk of TGCT. Using large, population-based registries in Sweden, the authors evaluated this important question and demonstrate that hypospadias, inguinal hernia, and other genital malformations are associated with an increased risk of TGCT. The findings highlight the importance of prenatal exposures related to proper genital development in the etiology of TGCT. C1 [Trabert, Britton; McGlynn, Katherine A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Zugna, Daniela; Richiardi, Lorenzo; Akre, Olof] Univ Turin, Dept Med Sci, Canc Epidemiol Unit, Turin, Italy. [Akre, Olof] Karolinska Inst, Clin Epidemiol Unit, Stockholm, Sweden. RP Trabert, B (reprint author), 6120 Execut Blvd, Rockville, MD 20852 USA. EM britton.trabert@nih.gov RI Trabert, Britton/F-8051-2015; OI richiardi, lorenzo/0000-0003-0316-9402 FU Swedish Cancer Society [4952-B04-01XAA]; Compagnia SanPaolo Foundation; Intramural Research Program on the National Cancer Institute FX Grant sponsor: Swedish Cancer Society; Grant number: 4952-B04-01XAA; Grant sponsor: the Compagnia SanPaolo Foundation; Grant sponsor: The Intramural Research Program on the National Cancer Institute NR 13 TC 16 Z9 16 U1 0 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2013 VL 133 IS 8 BP 1900 EP 1904 DI 10.1002/ijc.28207 PG 5 WC Oncology SC Oncology GA 198FW UT WOS:000322908600016 PM 23580254 ER PT J AU Barch, DM Burgess, GC Harms, MP Petersen, SE Schlaggar, BL Corbetta, M Glasser, MF Curtiss, S Dixit, S Feldt, C Nolan, D Bryant, E Hartley, T Footer, O Bjork, JM Poldrack, R Smith, S Johansen-Berg, H Snyder, AZ Van Essen, DC AF Barch, Deanna M. Burgess, Gregory C. Harms, Michael P. Petersen, Steven E. Schlaggar, Bradley L. Corbetta, Maurizio Glasser, Matthew F. Curtiss, Sandra Dixit, Sachin Feldt, Cindy Nolan, Dan Bryant, Edward Hartley, Tucker Footer, Owen Bjork, James M. Poldrack, Russ Smith, Steve Johansen-Berg, Heidi Snyder, Abraham Z. Van Essen, David C. CA WU-Minn HCP Consortium TI Function in the human connectome: Task-fMRI and individual differences in behavior SO NEUROIMAGE LA English DT Article DE Cognitive; Emotion; Sensory and motor function; Individual differences; Task-fMRI; Personality; Connectivity ID ROSTROLATERAL PREFRONTAL CORTEX; CONTRAST SENSITIVITY TEST; MAJOR DEPRESSIVE DISORDER; PROGRESSIVE MATRICES TEST; WORKING-MEMORY SPAN; MINI-MENTAL-STATE; NICOTINE DEPENDENCE; COMPUTERIZED METHOD; FLUID INTELLIGENCE; MULTIPLE-SCLEROSIS AB The primary goal of the Human Connectome Project (HCP) is to delineate the typical patterns of structural and functional connectivity in the healthy adult human brain. However, we know that there are important individual differences in such patterns of connectivity, with evidence that this variability is associated with alterations in important cognitive and behavioral variables that affect real world function. The HCP data will be a critical stepping-off point for future studies that will examine how variation in human structural and functional connectivity play a role in adult and pediatric neurological and psychiatric disorders that account for a huge amount of public health resources. Thus, the HCP is collecting behavioral measures of a range of motor, sensory, cognitive and emotional processes that will delineate a core set of functions relevant to understanding the relationship between brain connectivity and human behavior. In addition, the HCP is using task-fMRI (tfMRI) to help delineate the relationships between individual differences in the neurobiological substrates of mental processing and both functional and structural connectivity, as well as to help characterize and validate the connectivity analyses to be conducted on the structural and functional connectivity data. This paper describes the logic and rationale behind the development of the behavioral, individual difference, and tfMRI batteries and provides preliminary data on the patterns of activation associated with each of the fMRI tasks, at both group and individual levels. (C) 2013 Published by Elsevier Inc. C1 [Barch, Deanna M.; Petersen, Steven E.] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Barch, Deanna M.; Harms, Michael P.; Dixit, Sachin; Feldt, Cindy; Nolan, Dan; Bryant, Edward; Hartley, Tucker; Footer, Owen] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63130 USA. [Barch, Deanna M.; Petersen, Steven E.; Schlaggar, Bradley L.; Corbetta, Maurizio; Snyder, Abraham Z.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63130 USA. [Burgess, Gregory C.; Petersen, Steven E.; Schlaggar, Bradley L.; Corbetta, Maurizio; Glasser, Matthew F.; Curtiss, Sandra; Van Essen, David C.] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63130 USA. [Petersen, Steven E.; Schlaggar, Bradley L.; Corbetta, Maurizio] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63130 USA. [Schlaggar, Bradley L.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63130 USA. [Bjork, James M.] NIDA, Div Clin Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. [Poldrack, Russ] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA. [Poldrack, Russ] Univ Texas Austin, Dept Neurosci, Austin, TX 78712 USA. [Poldrack, Russ] Univ Texas Austin, Imaging Res Ctr, Austin, TX 78712 USA. [Smith, Steve; Johansen-Berg, Heidi] Univ Oxford, Ctr Funct MRI Brain FMRIB, Oxford, England. RP Barch, DM (reprint author), Washington Univ, Dept Psychol, Box 1125,1 Brookings Dr, St Louis, MO 63130 USA. EM dbarch@artsci.wustl.edu RI Barch, Deanna/G-8638-2013; OI Bjork, James/0000-0003-0593-3291; Harms, Michael/0000-0001-7945-036X; Johansen-Berg, Heidi/0000-0002-4134-9730 FU NIMH NIH HHS [F30 MH097312, U54 MH091657]; Wellcome Trust [090955, 098369] NR 153 TC 75 Z9 76 U1 5 U2 106 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 OCT 15 PY 2013 VL 80 BP 169 EP 189 DI 10.1016/j.neuroimage.2013.05.033 PG 21 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 191MB UT WOS:000322416000014 PM 23684877 ER PT J AU Scholvinck, ML Leopold, DA Brookes, MJ Khader, PH AF Schoelvinck, Marieke L. Leopold, David A. Brookes, Matthew J. Khader, Patrick H. TI The contribution of electrophysiology to functional connectivity mapping SO NEUROIMAGE LA English DT Article ID PRIMARY VISUAL-CORTEX; RESTING-STATE FMRI; SPONTANEOUS BRAIN ACTIVITY; SLOW CORTICAL POTENTIALS; INDEPENDENT COMPONENT ANALYSIS; ONGOING ACTIVITY FLUCTUATIONS; BOLD HEMODYNAMIC-RESPONSES; DEFAULT-MODE NETWORK; NEURAL ACTIVITY; STRUCTURAL CONNECTIVITY AB A powerful way to probe brain function is to assess the relationship between simultaneous changes in activity across different parts of the brain. In recent years, the temporal activity correlation between brain areas has frequently been taken as a measure of their functional connections. Evaluating 'functional connectivity' in this way is particularly popular in the fMRI community, but has also drawn interest among electrophysiologists. Like hemodynamic fluctuations observed with fMRI, electrophysiological signals display significant temporal fluctuations, even in the absence of a stimulus. These neural fluctuations exhibit a correlational structure over a wide range of spatial and temporal scales. Initial evidence suggests that certain aspects of this correlational structure bear a high correspondence to so-called functional networks defined using fMRI. The growing family of methods to study activity covariation, combined with the diverse neural mechanisms that contribute to the spontaneous fluctuations, has somewhat blurred the operational concept of functional connectivity. What is clear is that spontaneous activity is a conspicuous, energy-consuming feature of the brain. Given its prominence and its practical applications for the functional connectivity mapping of brain networks, it is of increasing importance that we understand its neural origins as well as its contribution to normal brain function. (C) 2013 Elsevier Inc. All rights reserved. C1 [Schoelvinck, Marieke L.] Max Planck Gesell, Ernst Strungmann Inst ESI Neurosci, D-60528 Frankfurt, Germany. [Leopold, David A.] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Leopold, David A.] NEI, Neurophysiol Imaging Facil, NIMH, NINDS,NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Brookes, Matthew J.] Univ Nottingham, Sch Phys & Astron, Sir Peter Mansfield Magnet Resonance Ctr, Nottingham NG7 2RD, England. [Khader, Patrick H.] Univ Munich, Dept Psychol, D-80802 Munich, Germany. RP Scholvinck, ML (reprint author), Max Planck Gesell, Ernst Strungmann Inst ESI Neurosci, Deutschordenstr 46, D-60528 Frankfurt, Germany. EM marieke.scholvinck@esi-frankfurt.de OI Leopold, David/0000-0002-1345-6360; Brookes, Matthew/0000-0002-8687-8185 FU Intramural Research Program of the National Institute of Mental Health; German Research Foundation [KH 235/1-1]; Human Frontiers Long-Term Fellowship; Leverhulme Trust Early Career Fellowship FX This research was supported in part by the Intramural Research Program of the National Institute of Mental Health (DAL) and by the German Research Foundation, grant KH 235/1-1 (PHK). MLS is supported by a Human Frontiers Long-Term Fellowship; MJB is supported by a Leverhulme Trust Early Career Fellowship. NR 149 TC 33 Z9 33 U1 2 U2 38 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 OCT 15 PY 2013 VL 80 BP 297 EP 306 DI 10.1016/j.neuroimage.2013.04.010 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 191MB UT WOS:000322416000024 PM 23587686 ER PT J AU Murphy, K Birn, RM Bandettini, PA AF Murphy, Kevin Birn, Rasmus M. Bandettini, Peter A. TI Resting-state fMRI confounds and cleanup SO NEUROIMAGE LA English DT Article DE Functional magnetic resonance imaging (fMRI); Resting-state; Functional connectivity; Noise correction; Physiological noise ID CEREBRAL-BLOOD-FLOW; END-TIDAL CO2; INDEPENDENT COMPONENT ANALYSIS; FUNCTIONAL CONNECTIVITY MRI; LOW-FREQUENCY OSCILLATIONS; GLOBAL SIGNAL REGRESSION; HUMAN BRAIN-FUNCTION; HUMAN MOTOR CORTEX; ECHO-PLANAR MRI; PHYSIOLOGICAL NOISE AB The goal of resting-state functional magnetic resonance imaging (fMRI) is to investigate the brain's functional connections by using the temporal similarity between blood oxygenation level dependent (BOLD) signals in different regions of the brain "at rest" as an indicator of synchronous neural activity. Since this measure relies on the temporal correlation of fMRI signal changes between different parts of the brain, any non-neural activity-related process that affects the signals will influence the measure of functional connectivity, yielding spurious results. To understand the sources of these resting-state fMRI confounds, this article describes the origins of the BOLD signal in terms of MR physics and cerebral physiology. Potential confounds arising from motion, cardiac and respiratory cycles, arterial CO2 concentration, blood pressure/cerebral autoregulation, and vasomotion are discussed. Two classes of techniques to remove confounds from resting-state BOLD time series are reviewed: 1) those utilising external recordings of physiology and 2) data-based cleanup methods that only use the resting-state fMRI data itself. Further methods that remove noise from functional connectivity measures at a group level are also discussed. For successful interpretation of resting-state fMRI comparisons and results, noise cleanup is an often over-looked but essential step in the analysis pipeline. (C) 2013 Elsevier Inc. All rights reserved. C1 [Murphy, Kevin] Cardiff Univ, Sch Psychol, Cardiff Univ Brain Res Imaging Ctr, Cardiff CF10 3AT, S Glam, Wales. [Birn, Rasmus M.] Univ Wisconsin, Dept Psychiat, Madison, WI 53719 USA. [Bandettini, Peter A.] NIH, Sect Funct Imaging Methods, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Bandettini, Peter A.] NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. RP Murphy, K (reprint author), Cardiff Univ, Sch Psychol, Cardiff Univ Brain Res Imaging Ctr, Cardiff CF10 3AT, S Glam, Wales. EM murphyk2@cardiff.ac.uk RI Murphy, Kevin/A-1581-2010 OI Murphy, Kevin/0000-0002-6516-313X FU Wellcome Trust Research Career Development Fellowship; NIH [RC1MH090912]; Health Emotions Research Institute; National Institute of Mental Health Intramural Research Program FX Kevin Murphy is supported by a Wellcome Trust Research Career Development Fellowship. Rasmus Birn is funded in part by NIH grant RC1MH090912 and by the Health Emotions Research Institute. Peter Bandettini is funded by the National Institute of Mental Health Intramural Research Program. NR 126 TC 118 Z9 118 U1 6 U2 56 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 OCT 15 PY 2013 VL 80 BP 349 EP 359 DI 10.1016/j.neuroimage.2013.04.001 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 191MB UT WOS:000322416000029 PM 23571418 ER PT J AU Hutchison, RM Womelsdorf, T Allen, EA Bandettini, PA Calhoun, VD Corbetta, M Penna, S Duyn, JH Glover, GH Gonzalez-Castillo, J Handwerker, DA Keilholz, S Kiviniemi, V Leopold, DA Pasquale, F Sporns, O Walter, M Chang, C AF Hutchison, R. Matthew Womelsdorf, Thilo Allen, Elena A. Bandettini, Peter A. Calhoun, Vince D. Corbetta, Maurizio Della Penna, Stefania Duyn, Jeff H. Glover, Gary H. Gonzalez-Castillo, Javier Handwerker, Daniel A. Keilholz, Sheila Kiviniemi, Vesa Leopold, David A. de Pasquale, Francesco Sporns, Olaf Walter, Martin Chang, Catie TI Dynamic functional connectivity: Promise, issues, and interpretations SO NEUROIMAGE LA English DT Article DE Functional connectivity; Resting state; Dynamics; Spontaneous activity; Functional MRI (fMRI); Fluctuations ID RESTING-STATE NETWORKS; DEFAULT-MODE NETWORK; SPONTANEOUS BRAIN ACTIVITY; HEART-RATE-VARIABILITY; INDEPENDENT COMPONENT ANALYSIS; FREQUENCY BOLD FLUCTUATIONS; FMRI SIGNAL FLUCTUATIONS; VISUAL WORKING-MEMORY; PROPOFOL-INDUCED LOSS; MAGNETIC-RESONANCE AB The brain must dynamically integrate, coordinate, and respond to internal and external stimuli across multiple time scales. Non-invasive measurements of brain activity with fMRI have greatly advanced our understanding of the large-scale functional organization supporting these fundamental features of brain function. Conclusions from previous resting-state fMRI investigations were based upon static descriptions of functional connectivity (FC), and only recently studies have begun to capitalize on the wealth of information contained within the temporal features of spontaneous BOLD FC. Emerging evidence suggests that dynamic FC metrics may index changes in macroscopic neural activity patterns underlying critical aspects of cognition and behavior, though limitations with regard to analysis and interpretation remain. Here, we review recent findings, methodological considerations, neural and behavioral correlates, and future directions in the emerging field of dynamic FC investigations. (C) 2013 Elsevier Inc. All rights reserved. C1 [Hutchison, R. Matthew] Univ Western Ontario, Robarts Res Inst, London, ON N6A 5K8, Canada. [Womelsdorf, Thilo] York Univ, Dept Biol, Ctr Vis Res, Toronto, ON M3J 2R7, Canada. [Allen, Elena A.] Univ Bergen, KG Jebsen Ctr Res Neuropsychiat Disorders, N-5020 Bergen, Norway. [Allen, Elena A.; Calhoun, Vince D.] Mind Res Network, Albuquerque, NM USA. [Bandettini, Peter A.; Gonzalez-Castillo, Javier; Handwerker, Daniel A.] NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Calhoun, Vince D.] Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA. [Corbetta, Maurizio; Della Penna, Stefania; de Pasquale, Francesco] Univ G DAnnunzio, Dept Neurosci & Imaging, Chieti, Italy. [Corbetta, Maurizio; Della Penna, Stefania; de Pasquale, Francesco] Univ G DAnnunzio, Inst Adv Biomed Technol, Chieti, Italy. [Corbetta, Maurizio] Washington Univ, Dept Radiol, St Louis, MO USA. [Duyn, Jeff H.; Chang, Catie] NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Glover, Gary H.] Stanford Univ, Dept Radiol, Stanford, CA USA. [Keilholz, Sheila] Emory Univ, Dept Biomed Engn, Georgia Inst Technol, Atlanta, GA 30322 USA. [Kiviniemi, Vesa] Oulu Univ Hosp, Dept Diagnost Radiol, Oulu, Finland. [Leopold, David A.] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Sporns, Olaf] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA. [Walter, Martin] Otto Von Guericke Univ, Clin Affect Neuroimaging Lab, Magdeburg, Germany. [Walter, Martin] Ctr Behav & Brain Sci, Leibniz Inst Neurobiol, Magdeburg, Germany. RP Hutchison, RM (reprint author), Univ Western Ontario, Robarts Res Inst, Cuddy Wing,Room 1256,100 Perth Dr, London, ON N6A 5K8, Canada. EM rhutchis@uwo.ca; catie.chang@nih.gov RI Sporns, Olaf/A-1667-2010; OI Leopold, David/0000-0002-1345-6360; Gonzalez-Castillo, Javier/0000-0002-6520-5125; Womelsdorf, Thilo/0000-0001-6921-4187; Sporns, Olaf/0000-0001-7265-4036; Della Penna, Stefania/0000-0001-5067-4327 FU Canadian Institute of Health Research postdoctoral fellowship; Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health FX The theme for this review was inspired from discussions and proceedings at the Neuro Bureau's BrainHack (Leipzig, Germany) the Biennial Resting-State Conference (Magdeburg, Germany). R.M.H. was supported by a Canadian Institute of Health Research postdoctoral fellowship, and C.C. was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. We thank Steve Smith and four anonymous reviewers for helpful suggestions. NR 245 TC 325 Z9 330 U1 16 U2 128 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 OCT 15 PY 2013 VL 80 BP 360 EP 378 DI 10.1016/j.neuroimage.2013.05.079 PG 19 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 191MB UT WOS:000322416000030 PM 23707587 ER PT J AU Picchioni, D Duyn, JH Horovitz, SG AF Picchioni, Dante Duyn, Jeff H. Horovitz, Silvina G. TI Sleep and the functional connectome SO NEUROIMAGE LA English DT Article DE Sleep; Connectivity; Memory; Arousal; Consciousness ID EYE-MOVEMENT SLEEP; SLOW-WAVE SLEEP; DEFAULT MODE NETWORK; DECLARATIVE MEMORY CONSOLIDATION; POSITRON-EMISSION-TOMOGRAPHY; PROPOFOL-INDUCED LOSS; CEREBRAL-BLOOD-FLOW; BRAIN ACTIVITY; K-COMPLEX; REM-SLEEP AB Sleep and the functional connectome are research areas with considerable overlap. Neuroimaging studies of sleep based on EEG-PET and EEG-fMRI are revealing the brain networks that support sleep, as well as networks that may support the roles and processes attributed to sleep. For example, phenomena such as arousal and consciousness are substantially modulated during sleep, and one would expect this modulation to be reflected in altered network activity. In addition, recent work suggests that sleep also has a number of adaptive functions that support waking activity. Thus the study of sleep may elucidate the circuits and processes that support waking function and complement information obtained from fMRI during waking conditions. In this review, we will discuss examples of this for memory, arousal, and consciousness after providing a brief background on sleep and on studying it with fMRI. Published by Elsevier Inc. C1 [Picchioni, Dante] Walter Reed Army Inst Res, Dept Behav Biol, Silver Spring, MD USA. [Duyn, Jeff H.] NINDS, Adv MRI, LFMI, NIH, Bethesda, MD 20892 USA. [Horovitz, Silvina G.] NINDS, Human Motor Control Sect, MNB, NIH, Bethesda, MD 20892 USA. RP Horovitz, SG (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, 10 Ctr Dr,Bldg 10-7D37, Bethesda, MD 20892 USA. EM silvina.horovitz@nih.gov FU NIH National Institute of Neurological Disorders and Stroke; Walter Reed Army Institute of Research FX This work was supported by the Intramural Research Program of the NIH National Institute of Neurological Disorders and Stroke, and Walter Reed Army Institute of Research. NR 143 TC 27 Z9 28 U1 3 U2 54 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 OCT 15 PY 2013 VL 80 BP 387 EP 396 DI 10.1016/j.neuroimage.2013.05.067 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 191MB UT WOS:000322416000032 PM 23707592 ER PT J AU Andrews, KW Pehrsson, PR Betz, JM AF Andrews, Karen W. Pehrsson, Pamela R. Betz, Joseph M. TI Variability in Vitamin D Content Among Products for Multivitamin and Mineral Supplements SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Andrews, Karen W.; Pehrsson, Pamela R.] USDA, Beltsville, MD 20705 USA. [Betz, Joseph M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Andrews, KW (reprint author), USDA, Nutrient Data Lab, 10300 Baltimore Ave,Bldg 005,Room 112, Beltsville, MD 20705 USA. EM karen.andrews@ars.usda.gov NR 5 TC 1 Z9 1 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD OCT 14 PY 2013 VL 173 IS 18 BP 1752 EP 1753 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 268TO UT WOS:000328193600025 PM 24126772 ER PT J AU Prasad, V Rho, J Cifu, A AF Prasad, Vinay Rho, Jason Cifu, Adam TI The Inferior Vena Cava Filter Reply SO JAMA INTERNAL MEDICINE LA English DT Letter ID EFFICACY C1 [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Rho, Jason] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Cifu, Adam] Univ Chicago, Dept Med, Chicago, IL 60637 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr,10-12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD OCT 14 PY 2013 VL 173 IS 18 BP 1754 EP 1755 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 268TO UT WOS:000328193600029 PM 24126777 ER PT J AU McDonald, CJ AF McDonald, Clement J. TI Toward Electronic Medical Record Alerts That Consume Less Physician Time SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [McDonald, Clement J.] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, US Dept HHS, Bethesda, MD 20894 USA. RP McDonald, CJ (reprint author), NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, HHS, 8600 Rockville Pike,MSC 3828,38A-7N707, Bethesda, MD 20894 USA. EM ClemMcDonald@mail.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD OCT 14 PY 2013 VL 173 IS 18 BP 1755 EP 1756 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 268TO UT WOS:000328193600030 PM 24126778 ER PT J AU Moon, JC Messroghli, DR Kellman, P Piechnik, SK Robson, MD Ugander, M Gatehouse, PD Arai, AE Friedrich, MG Neubauer, S Schulz-Menger, J Schelbert, EB AF Moon, James C. Messroghli, Daniel R. Kellman, Peter Piechnik, Stefan K. Robson, Matthew D. Ugander, Martin Gatehouse, Peter D. Arai, Andrew E. Friedrich, Matthias G. Neubauer, Stefan Schulz-Menger, Jeanette Schelbert, Erik B. TI Myocardial T1 mapping and extracellular volume quantification: a Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus statement SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article ID IDIOPATHIC DILATED CARDIOMYOPATHY; TRANSCYTOLEMMAL WATER-EXCHANGE; HYPERTENSIVE HEART-DISEASE; INVERSION-RECOVERY MOLLI; CONTRAST T1; DIABETIC CARDIOMYOPATHY; DIAGNOSTIC-ACCURACY; RELAXATION-TIMES; MATRIX EXPANSION; SKELETAL-MUSCLE AB Rapid innovations in cardiovascular magnetic resonance (CMR) now permit the routine acquisition of quantitative measures of myocardial and blood T1 which are key tissue characteristics. These capabilities introduce a new frontier in cardiology, enabling the practitioner/investigator to quantify biologically important myocardial properties that otherwise can be difficult to ascertain clinically. CMR may be able to track biologically important changes in the myocardium by: a) native T1 that reflects myocardial disease involving the myocyte and interstitium without use of gadolinium based contrast agents (GBCA), or b) the extracellular volume fraction (ECV)-a direct GBCA-based measurement of the size of the extracellular space, reflecting interstitial disease. The latter technique attempts to dichotomize the myocardium into its cellular and interstitial components with estimates expressed as volume fractions. This document provides recommendations for clinical and research T1 and ECV measurement, based on published evidence when available and expert consensus when not. We address site preparation, scan type, scan planning and acquisition, quality control, visualisation and analysis, technical development. We also address controversies in the field. While ECV and native T1 mapping appear destined to affect clinical decision making, they lack multi-centre application and face significant challenges, which demand a community-wide approach among stakeholders. At present, ECV and native T1 mapping appear sufficiently robust for many diseases; yet more research is required before a large-scale application for clinical decision-making can be recommended. C1 [Moon, James C.] Heart Hosp, London, England. [Moon, James C.] UCL, Inst Cardiovasc Sci, London, England. [Messroghli, Daniel R.] Deutsch Herzzentrum Berlin, Dept Congenital Heart Dis & Pediat Cardiol, Berlin, Germany. [Kellman, Peter; Arai, Andrew E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Piechnik, Stefan K.; Robson, Matthew D.; Neubauer, Stefan] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford Ctr Clin Magnet Resonance Res, Oxford, England. [Ugander, Martin] Karolinska Inst, Dept Clin Physiol, S-10401 Stockholm, Sweden. [Ugander, Martin] Karolinska Univ Hosp, Stockholm, Sweden. [Gatehouse, Peter D.] Royal Brompton Hosp, NIHR Cardiovasc BRU, London SW3 6LY, England. [Gatehouse, Peter D.] Univ London Imperial Coll Sci Technol & Med, London, England. [Friedrich, Matthias G.] Univ Montreal, Dept Cardiol, Montreal Heart Inst, Montreal, PQ, Canada. [Friedrich, Matthias G.] Univ Montreal, Dept Radiol, Montreal Heart Inst, Montreal, PQ, Canada. [Schulz-Menger, Jeanette] Humboldt Univ, Dept Cardiol & Nephrol, Working Grp Cardiac MRI, D-10099 Berlin, Germany. [Schulz-Menger, Jeanette] HELIOS Klinikum Berlin Buch, Charite Campus Buch Expt & Clin Res Ctr, Berlin, Germany. [Schelbert, Erik B.] Univ Pittsburgh, Sch Med, Dept Med, UPMC Cardiovasc Magnet Resonance Ctr, Pittsburgh, PA 15213 USA. RP Moon, JC (reprint author), Heart Hosp, London, England. EM J.Moon@ucl.ac.uk RI Moon, James/F-1031-2014; OI Moon, James/0000-0001-8071-1491; Gatehouse, Peter/0000-0002-0260-4719; Piechnik, Stefan K./0000-0002-0268-5221; Schelbert, Erik/0000-0003-0356-4437; Ugander, Martin/0000-0003-3665-2038 FU National Institute for Health Research Biomedical Research Centres funding scheme; National Institute for Health Research; National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS [HL004607-14CPB]; German Research Foundation (DFG); National Institute for Health Research Oxford Biomedical Research Centre Programme; Swedish Research Council; Swedish Heart and Lung Foundation; Stockholm County Council; Karolinska Institutet FX James C. Moon acknowledges support from the National Institute for Health Research Biomedical Research Centres funding scheme.; Peter D. Gatehouse. Biomedical Research Unit funding from the National Institute for Health Research. Research agreement with Siemens.; Peter Kellman acknowledges support from the National Heart, Lung and Blood Institute, National Institutes of Health by the Division of Intramural Research, NHLBI, NIH, DHHS (HL004607-14CPB).; Daniel R. Messroghli acknowledges support from the German Research Foundation (DFG) Stefan Neubauer acknowledges support from the National Institute for Health Research Oxford Biomedical Research Centre Programme. Stefan K. Piechnik acknowledges support from the National Institute for Health Research Oxford Biomedical Research Centre Programme.; Martin Ugander acknowledges minor compensation as a speaker for Covidien, and major funding support from the Swedish Research Council, Swedish Heart and Lung Foundation, Stockholm County Council and Karolinska Institutet. NR 87 TC 208 Z9 220 U1 5 U2 36 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD OCT 14 PY 2013 VL 15 AR 92 DI 10.1186/1532-429X-15-92 PG 12 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 245MZ UT WOS:000326469100001 PM 24124732 ER PT J AU Tesfaye, A Stift, J Maric, D Cui, QW Dienes, HP Feinstone, SM AF Tesfaye, Abeba Stift, Judith Maric, Dragan Cui, Qingwen Dienes, Hans-Peter Feinstone, Stephen M. TI Chimeric Mouse Model for the Infection of Hepatitis B and C Viruses SO PLOS ONE LA English DT Article ID LIVER-CANCER; GAMMA-CHAIN; GENOTYPE 1; MICE; HEPATOCYTES; REPLICATION; CHIMPANZEES; TRANSPLANTATION; REPOPULATION; DYSFUNCTION AB While the chimpanzee remains the only animal that closely models human hepatitis C virus (HCV) infection, transgenic and immunodeficient mice in which human liver can be engrafted serve as a partial solution to the need for a small animal model for HCV infection. The established system that was based on mice carrying a transgene for urokinase-type plasminogen activator (uPA) gene under the control of the human albumin promoter has proved to be useful for studies of virus infectivity and for testing antiviral drug agents. However, the current Alb-uPA transgenic model with a humanized liver has practical limitations due to the inability to maintain non-engrafted mice as dizygotes for the transgene, poor engraftment of hemizygotes, high neonatal and experimental death rates of dizygous mice and a very short time window for hepatocyte engraftment. To improve the model, we crossed transgenic mice carrying the uPA gene driven by the major urinary protein promoter onto a SCID/Beige background (MUP-uPA SCID/Bg). These transgenic mice are healthy relative to Alb-uPA mice and provide a long window from about age 4 to 12 months for engraftment with human hepatocytes and infection with hepatitis C or hepatitis B (HBV) viruses. We have demonstrated engraftment of human hepatocytes by immunohistochemistry staining for human albumin (30-80% engraftment) and observed a correlation between the number of human hepatocytes inoculated and the level of the concentration of human albumin in the serum. We have shown that these mice support the replication of both HBV and all six major HCV genotypes. Using HBV and HCV inocula that had been previously tittered in chimpanzees, we showed that the mice had approximately the same sensitivity for infection as chimpanzees. These mice should be useful for isolating non-cell culture adapted viruses as well as testing of antiviral drugs, antibody neutralization studies and examination of phenotypic changes in viral mutants. C1 [Tesfaye, Abeba; Cui, Qingwen; Feinstone, Stephen M.] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. [Stift, Judith; Dienes, Hans-Peter] Med Univ Vienna, Inst Pathol, Vienna, Austria. [Maric, Dragan] NINDS, Div Intramural Res, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. RP Tesfaye, A (reprint author), US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. EM abeba.tesfaye@fda.hhs.gov FU Food and Drug Administration FX This work was supported by internal funding from the Food and Drug Administration. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 19 Z9 21 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 OCT 14 PY 2013 VL 8 IS 10 AR UNSP e77298 DI 10.1371/journal.pone.0077298 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 237RD UT WOS:000325887300073 PM 24155939 ER PT J AU Zong, NC Li, HM Li, H Lam, MPY Jimenez, RC Kim, CS Deng, N Kim, AK Choi, JH Zelaya, I Liem, D Meyer, D Odeberg, J Fang, CY Lu, HJ Xu, T Weiss, J Duan, HL Uhlen, M Yates, JR Apweiler, R Ge, JB Hermjakob, H Ping, PP AF Zong, Nobel C. Li, Haomin Li, Hua Lam, Maggie P. Y. Jimenez, Rafael C. Kim, Christina S. Deng, Ning Kim, Allen K. Choi, Jeong Ho Zelaya, Ivette Liem, David Meyer, David Odeberg, Jacob Fang, Caiyun Lu, Hao-jie Xu, Tao Weiss, James Duan, Huilong Uhlen, Mathias Yates, John R., III Apweiler, Rolf Ge, Junbo Hermjakob, Henning Ping, Peipei TI Integration of Cardiac Proteome Biology and Medicine by a Specialized Knowledgebase SO CIRCULATION RESEARCH LA English DT Article DE computational biology; COPaKB; mitochondria; Omics science; organelles; proteomics; translational medical research ID GENE-EXPRESSION ATLAS; MENDELIAN-INHERITANCE; PHOSPHORYLATION; IDENTIFICATION; INFORMATION; PEPTIDES; OMIM; TOOL AB Rationale: Omics sciences enable a systems-level perspective in characterizing cardiovascular biology. Integration of diverse proteomics data via a computational strategy will catalyze the assembly of contextualized knowledge, foster discoveries through multidisciplinary investigations, and minimize unnecessary redundancy in research efforts. Objective: The goal of this project is to develop a consolidated cardiac proteome knowledgebase with novel bioinformatics pipeline and Web portals, thereby serving as a new resource to advance cardiovascular biology and medicine. Methods and Results: We created Cardiac Organellar Protein Atlas Knowledgebase (COPaKB; www.HeartProteome.org), a centralized platform of high-quality cardiac proteomic data, bioinformatics tools, and relevant cardiovascular phenotypes. Currently, COPaKB features 8 organellar modules, comprising 4203 LC-MS/MS experiments from human, mouse, drosophila, and Caenorhabditis elegans, as well as expression images of 10 924 proteins in human myocardium. In addition, the Java-coded bioinformatics tools provided by COPaKB enable cardiovascular investigators in all disciplines to retrieve and analyze pertinent organellar protein properties of interest. Conclusions: COPaKB provides an innovative and interactive resource that connects research interests with the new biological discoveries in protein sciences. With an array of intuitive tools in this unified Web server, nonproteomics investigators can conveniently collaborate with proteomics specialists to dissect the molecular signatures of cardiovascular phenotypes. C1 [Zong, Nobel C.; Li, Haomin; Lam, Maggie P. Y.; Jimenez, Rafael C.; Kim, Christina S.; Deng, Ning; Kim, Allen K.; Choi, Jeong Ho; Zelaya, Ivette; Liem, David; Odeberg, Jacob; Xu, Tao; Weiss, James; Duan, Huilong; Uhlen, Mathias; Yates, John R., III; Apweiler, Rolf; Hermjakob, Henning; Ping, Peipei] Univ Calif Los Angeles, Sch Med, UCLA NHLBI Prote Program, NHLBI Prote Ctr, Los Angeles, CA 90095 USA. [Zong, Nobel C.; Li, Haomin; Li, Hua; Lam, Maggie P. Y.; Kim, Christina S.; Kim, Allen K.; Choi, Jeong Ho; Zelaya, Ivette; Liem, David; Meyer, David; Weiss, James; Ping, Peipei] Univ Calif Los Angeles, Sch Med, CVRL, Dept Physiol, Los Angeles, CA 90095 USA. [Zong, Nobel C.; Li, Haomin; Li, Hua; Lam, Maggie P. Y.; Kim, Christina S.; Kim, Allen K.; Choi, Jeong Ho; Zelaya, Ivette; Liem, David; Meyer, David; Weiss, James; Ping, Peipei] Univ Calif Los Angeles, Sch Med, CVRL, Dept Med, Los Angeles, CA 90095 USA. [Li, Haomin; Deng, Ning; Duan, Huilong; Ping, Peipei] Zhejiang Univ, Coll Biomed Engn & Instrumentat, Key Lab Biomed Engn, Minist Educ, Hangzhou 310003, Zhejiang, Peoples R China. [Li, Hua; Ge, Junbo; Ping, Peipei] Fudan Univ, Zhongshan Hosp, Shanghai Inst Cardiovasc Dis, Shanghai 200433, Peoples R China. [Jimenez, Rafael C.; Apweiler, Rolf; Hermjakob, Henning] EMBL Outstn European Bioinformat Inst, Cambridge, England. [Odeberg, Jacob; Uhlen, Mathias] Royal Inst Technol KTH, Sci Life Lab, Stockholm, Sweden. [Fang, Caiyun; Lu, Hao-jie] Fudan Univ, Dept Chem, Shanghai 200433, Peoples R China. [Xu, Tao; Yates, John R., III] Scripps Res Inst TSRI, Dept Physiol Chem, La Jolla, CA USA. RP Ping, PP (reprint author), Univ Calif Los Angeles, Sch Med, 675 Charles E Young Dr S,MRL Bldg Suite 1-609, Los Angeles, CA 90095 USA. EM czong@mednet.ucla.edu; pping@mednet.ucla.edu RI Odeberg, Jacob/I-8314-2016; OI Odeberg, Jacob/0000-0003-0996-1644; Apweiler, Rolf/0000-0001-7078-200X; Ping, Peipei/0000-0003-3583-3881 FU National Heart, Lung, and Blood Institute Proteomics Center [HHSN268201000035C]; NIH [R01 HL063901]; [R37HL063901]; [R37HHSN268201000035C] FX This work was supported, in part, by National Heart, Lung, and Blood Institute Proteomics Center Award HHSN268201000035C, NIH R01 HL063901, an endowment from Theodore C. Laubisch to P.P.; R37HL063901 diversity supplement award to D.M.; and R37HHSN268201000035C diversity supplement award to I.Z. NR 28 TC 20 Z9 20 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD OCT 12 PY 2013 VL 113 IS 9 BP 1043 EP 1053 DI 10.1161/CIRCRESAHA.113.301151 PG 11 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 286QM UT WOS:000329483800008 PM 23965338 ER PT J AU Tao, RY Xiong, XW DePinho, RA Deng, CX Dong, XC AF Tao, Rongya Xiong, Xiwen DePinho, Ronald A. Deng, Chu-Xia Dong, X. Charlie TI FoxO3 Transcription Factor and Sirt6 Deacetylase Regulate Low Density Lipoprotein (LDL)-cholesterol Homeostasis via Control of the Proprotein Convertase Subtilisin/Kexin Type 9 (Pcsk9) Gene Expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA; MONOCLONAL-ANTIBODY; HUMAN LONGEVITY; CHOLESTEROL-BIOSYNTHESIS; RECEPTOR EXPRESSION; RANDOMIZED-TRIAL; LDL CHOLESTEROL; HEPATIC PCSK9; DOUBLE-BLIND; HEPG2 CELLS AB Elevated LDL-cholesterol is a risk factor for the development of cardiovascular disease. Thus, proper control of LDL-cholesterol homeostasis is critical for organismal health. Genetic analysis has identified PCSK9 (proprotein convertase subtilisin/kexin type 9) as a crucial gene in the regulation of LDL-cholesterol via control of LDL receptor degradation. Although biochemical characteristics and clinical implications of PCSK9 have been extensively investigated, epigenetic regulation of this gene is largely unknown. In this work we have discovered that Sirt6, an NAD(+)-dependent histone deacetylase, plays a critical role in the regulation of the Pcsk9 gene expression in mice. Hepatic Sirt6 deficiency leads to elevated Pcsk9 gene expression and LDL-cholesterol as well. Mechanistically, we have demonstrated that Sirt6 can be recruited by forkhead transcription factor FoxO3 to the proximal promoter region of the Pcsk9 gene and deacetylates histone H3 at lysines 9 and 56, thereby suppressing the gene expression. Also remarkably, overexpression of Sirt6 in high fat diet-fed mice lowers LDL-cholesterol. Overall, our data suggest that FoxO3 and Sirt6, two longevity genes, can reduce LDL-cholesterol levels through regulation of the Pcsk9 gene. C1 [Tao, Rongya; Xiong, Xiwen; Dong, X. Charlie] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [DePinho, Ronald A.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Dong, XC (reprint author), Indiana Univ Sch Med, Dept Biochem & Mol Biol, 635 Barnhill Dr,MS1021D, Indianapolis, IN 46202 USA. EM xcdong@iu.edu RI tao, rongya/B-8042-2014; deng, chuxia/N-6713-2016 OI tao, rongya/0000-0002-3316-5587; FU National Institutes of Health (NIDDK) [R00DK077505, R01DK091592] FX This work was supported, in whole or in part, by National Institutes of Health Grants R00DK077505 and R01DK091592 (NIDDK; to X.C.D.). NR 59 TC 22 Z9 25 U1 0 U2 11 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 OCT 11 PY 2013 VL 288 IS 41 BP 29252 EP 29259 DI 10.1074/jbc.M113.481473 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302OT UT WOS:000330615300005 PM 23974119 ER PT J AU McElwee, MK Ho, LA Chou, JW Smith, MV Freedman, JH AF McElwee, Matthew K. Ho, Lindsey A. Chou, Jeff W. Smith, Marjolein V. Freedman, Jonathan H. TI Comparative toxicogenomic responses of mercuric and methyl-mercury SO BMC GENOMICS LA English DT Article DE C. elegans; Inorganic mercury; Organic mercury; Methylmercury; Transcriptome; Metal toxicity ID NEMATODE CAENORHABDITIS-ELEGANS; GENE-EXPRESSION; METHYLMERCURY EXPOSURE; OXIDATIVE STRESS; DIETARY METHYLMERCURY; ASTROCYTE CULTURES; MINAMATA DISEASE; DANIO-RERIO; FATTY-ACIDS; RAT-BRAIN AB Background: Mercury is a ubiquitous environmental toxicant that exists in multiple chemical forms. A paucity of information exists regarding the differences or similarities by which different mercurials act at the molecular level. Results: Transcriptomes of mixed-stage C. elegans following equitoxic sub-, low- and high-toxicity exposures to inorganic mercuric chloride (HgCl2) and organic methylmercury chloride (MeHgCl) were analyzed. In C. elegans, the mercurials had highly different effects on transcription, with MeHgCl affecting the expression of significantly more genes than HgCl2. Bioinformatics analysis indicated that inorganic and organic mercurials affected different biological processes. RNAi identified 18 genes that were important in C. elegans response to mercurial exposure, although only two of these genes responded to both mercurials. To determine if the responses observed in C. elegans were evolutionarily conserved, the two mercurials were investigated in human neuroblastoma (SK-N-SH), hepatocellular carcinoma (HepG2) and embryonic kidney (HEK293) cells. The human homologs of the affected C. elegans genes were then used to test the effects on gene expression and cell viability after using siRNA during HgCl2 and MeHgCl exposure. As was observed with C. elegans, exposure to the HgCl2 and MeHgCl had different effects on gene expression, and different genes were important in the cellular response to the two mercurials. Conclusions: These results suggest that, contrary to previous reports, inorganic and organic mercurials have different mechanisms of toxicity. The two mercurials induced disparate effects on gene expression, and different genes were important in protecting the organism from mercurial toxicity. C1 [McElwee, Matthew K.; Freedman, Jonathan H.] NIEHS, Lab Toxicol & Pharmacol, NIH, Durham, NC 27709 USA. [Ho, Lindsey A.; Smith, Marjolein V.] SRA Int Inc, Durham, NC USA. [Chou, Jeff W.] NIEHS, Microarray & Genome Informat Grp, NIH, Durham, NC 27709 USA. RP Freedman, JH (reprint author), NIEHS, Lab Toxicol & Pharmacol, NIH, 111 TW Alexander Dr,POB 12233, Durham, NC 27709 USA. EM freedma1@niehs.nih.gov FU National Center for Research Resources; National Institute of Environmental Health Sciences, National Institutes of Health [Z01ES102045] FX The authors would like to acknowledge the support of Julie Rice and Paul Dunlap for technical assistance, Dr. Pierre Bushel for helpful discussions of data and bioinformatics analyses, and Dr. Changwon Lim for statistical determination of equimolar concentrations of the mercurials. All nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the National Center for Research Resources. Microarray data has been submitted to the NCBI Gene Expression Omnibus, and is accessible through GEO accession number GSE28915. This work was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (Z01ES102045). NR 70 TC 8 Z9 8 U1 2 U2 29 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 OCT 11 PY 2013 VL 14 AR 698 DI 10.1186/1471-2164-14-698 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 274UH UT WOS:000328631200002 PM 24118919 ER PT J AU Wang, XB Wang, G Li, WW Zhao, BX Xing, B Leng, YK Dou, HJ Sun, K Shen, LS Yuan, XL Li, JY Sun, K Han, JS Xiao, HS Li, Y Huang, P Chen, XY AF Wang, Xiebing Wang, Gang Li, Wanwan Zhao, Bingxia Xing, Bin Leng, Yuankui Dou, Hongjing Sun, Kang Shen, Lisong Yuan, Xiangliang Li, Jiyu Sun, Kun Han, Junsong Xiao, Huasheng Li, Yue Huang, Peng Chen, Xiaoyuan TI NIR-Emitting Quantum Dot-Encoded Microbeads through Membrane Emulsification for Multiplexed Immunoassays SO SMALL LA English DT Article DE quantum dots; microbeads; SPG membrane emulsification; multiplexed detection; immunoassays ID CORE-SHELL NANOCRYSTALS; ONE-POT SYNTHESIS; SEMICONDUCTOR NANOCRYSTALS; INAS NANOCRYSTALS; CDTE NANOCRYSTALS; FLOW-CYTOMETRY; POLYMER BEADS; MICROSPHERES; EFFICIENT; PROTEIN AB NIR-emitting CdSeTe/CdS/ZnS core/shell/shell QD-encoded microbeads are combined with common flow cytometry with one laser for multiplexed detection of hepatitis B virus (HBV). A facile one-pot synthetic route is developed to prepare CdSeTe/CdS/ZnS core/shell/shell QDs with high photoluminescence quantum yield and excellent stability in liquid paraffin, and a Shirasu porous glass (SPG) membrane emulsification technique is applied to incorporate the QDs into polystyrene-maleic anhydride (PSMA) microbeads to obtain highly fluorescent QD-encoded microbeads. The relatively wide NIR photoluminescence full width half maximum of the CdSeTe/CdS/ZnS QDs is used to develop a single wavelength' encoding method to obtain different optical codes by changing the wavelengh and emission intensity of the QDs incorporated into the microbeads. Moreover, a detection platform combining NIR-emitting CdSeTe/CdS/ZnS QD-encoded microbeads and Beckman Coulter FC 500 flow cytometry with one laser of 488 nm is successfully used to conduct a 2-plex hybridization assay for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and a 3-plex hybridization assay for hepatitis B surface antibody (HBsAb), hepatitis B e antibody (HBeAb), and hepatitis B core antibody (HBcAb), which suggests the promising application of NIR QD-encoded microbeads for multiplex immunoassays. C1 [Wang, Xiebing; Wang, Gang; Li, Wanwan; Zhao, Bingxia; Xing, Bin; Leng, Yuankui; Dou, Hongjing; Sun, Kang] Shanghai Jiao Tong Univ, State Key Lab Met Matrix Composites, Shanghai 200240, Peoples R China. [Shen, Lisong; Yuan, Xiangliang; Li, Jiyu; Sun, Kun] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Clin Lab, Shanghai 200092, Peoples R China. [Han, Junsong; Xiao, Huasheng; Li, Yue] Shanghai Biochip Co Ltd, Shanghai 201203, Peoples R China. [Han, Junsong; Xiao, Huasheng; Li, Yue] Natl Engn Ctr Biochip Shanghai, Shanghai 201203, Peoples R China. [Li, Yue; Huang, Peng; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. RP Li, WW (reprint author), Shanghai Jiao Tong Univ, State Key Lab Met Matrix Composites, 800 Dongchuan Rd, Shanghai 200240, Peoples R China. EM wwli@sjtu.edu.cn; ksun@sjtu.edu.cn RI Huang, Peng/H-9985-2013; Huang, Peng/R-2480-2016; dou, hongjing/S-8970-2016 OI Huang, Peng/0000-0003-3651-7813; dou, hongjing/0000-0001-5850-9174 FU National Basic Research Program of China (973 program) [2013CB733802]; National Natural Science Foundation of China [50902093, 81028009]; Science and Technology Committee of Shanghai [08ZR1415700, 10520706500]; PhD Programs Foundation of Ministry of Education of China [200802481131] FX X. Wang and G. Wang contributed equally to this work. This work was financially supported by the National Basic Research Program of China (973 program, 2013CB733802), the National Natural Science Foundation of China (Project No. 50902093, 81028009), Science and Technology Committee of Shanghai (Project No. 08ZR1415700, 10520706500) and a grant to Prof. Wanwan Li from the PhD Programs Foundation of Ministry of Education of China (Project No. 200802481131). We thank Instrumental Analysis Center of SJTU for the assistance with TEM and XRD characterizations. NR 45 TC 21 Z9 21 U1 15 U2 90 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1613-6810 EI 1613-6829 J9 SMALL JI Small PD OCT 11 PY 2013 VL 9 IS 19 BP 3327 EP 3335 DI 10.1002/smll.201203156 PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 264SD UT WOS:000327899900021 PM 23463727 ER PT J AU Garcia, J Espejo, V Nelson, M Sovero, M Villaran, MV Gomez, J Barrantes, M Sanchez, F Comach, G Arango, AE Aguayo, N de Rivera, IL Chicaiza, W Jimenez, M Aleman, W Rodriguez, F Gonzales, MS Kochel, TJ Halsey, ES AF Garcia, Josefina Espejo, Victoria Nelson, Martha Sovero, Merly Villaran, Manuel V. Gomez, Jorge Barrantes, Melvin Sanchez, Felix Comach, Guillermo Arango, Ana E. Aguayo, Nicolas de Rivera, Ivette L. Chicaiza, Wilson Jimenez, Mirna Aleman, Washington Rodriguez, Francisco Gonzales, Marina S. Kochel, Tadeusz J. Halsey, Eric S. TI Human rhinoviruses and enteroviruses in influenza-like illness in Latin America SO VIROLOGY JOURNAL LA English DT Article ID RESPIRATORY-TRACT INFECTIONS; HUMAN METAPNEUMOVIRUS; SEQUENCE ALIGNMENT; CLINICAL-FEATURES; YOUNG-CHILDREN; SPECIES C; HRV-C; RECOMBINATION; GENOTYPE; SURVEILLANCE AB Background: Human rhinoviruses (HRVs) belong to the Picornaviridae family with high similarity to human enteroviruses (HEVs). Limited data is available from Latin America regarding the clinical presentation and strains of these viruses in respiratory disease. Methods: We collected nasopharyngeal swabs at clinics located in eight Latin American countries from 3,375 subjects aged 25 years or younger who presented with influenza-like illness. Results: Our subjects had a median age of 3 years and a 1.2:1.0 male: female ratio. HRV was identified in 16% and HEV was identified in 3%. HRVs accounted for a higher frequency of isolates in those of younger age, in particular children < 1 years old. HRV-C accounted for 38% of all HRVs detected. Phylogenetic analysis revealed a high proportion of recombinant strains between HRV-A/HRV-C and between HEV-A/HEV-B. In addition, both EV-D68 and EV-A71 were identified. Conclusions: In Latin America as in other regions, HRVs and HEVs account for a substantial proportion of respiratory viruses identified in young people with ILI, a finding that provides additional support for the development of pharmaceuticals and vaccines targeting these pathogens. C1 [Garcia, Josefina; Espejo, Victoria; Sovero, Merly; Villaran, Manuel V.; Halsey, Eric S.] US Naval Med Res Unit 6, Lima, Peru. [Garcia, Josefina; Nelson, Martha] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Gomez, Jorge] Minist Salud, Direcc Gen Epidemiol, Lima, Peru. [Barrantes, Melvin] Hosp Solano, Buenos Aires, DF, Argentina. [Sanchez, Felix] Hosp Infantil Manuel de Jesus Rivera, Managua, Nicaragua. [Comach, Guillermo] LARDIDEV Biomed UC, Maracay, Venezuela. [Arango, Ana E.] Univ Antioquia, Medellin, Colombia. [Aguayo, Nicolas] ONG Rayos de Sol, Asuncion, Paraguay. [de Rivera, Ivette L.] Univ Nacl Autonoma Honduras, Tegucigalpa, Honduras. [Chicaiza, Wilson] Hosp Vozandes & Univ Amer, Quito, Ecuador. [Jimenez, Mirna] Hosp Nacl Metapan, Metapan, El Salvador. [Aleman, Washington] Clin Alcivar & Hosp Vernaza, Guayaquil, Ecuador. [Rodriguez, Francisco] Hosp Dept Humberto Alvarado de Masaya, Managua, Nicaragua. [Gonzales, Marina S.] Secretaria Secc Salud Meta, Dept Lab, Villavicencio, Colombia. [Kochel, Tadeusz J.] US Naval Med Res Ctr, Silver Spring, MD USA. RP Garcia, J (reprint author), US Naval Med Res Unit 6, Lima, Peru. EM jgarcian66@yahoo.com OI Chicaiza-Ayala, Wilson/0000-0001-8639-698X FU United States Department of Defense Global Emerging Infections Systems Research Program FX This study was funded by the United States Department of Defense Global Emerging Infections Systems Research Program, WORK UNIT NUMBER: 847705.82000.25GB.B0016. NR 54 TC 9 Z9 9 U1 4 U2 11 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 OCT 11 PY 2013 VL 10 AR 305 DI 10.1186/1743-422X-10-305 PG 12 WC Virology SC Virology GA 264KE UT WOS:000327875000001 PM 24119298 ER PT J AU Ratnapriya, R Swaroop, A AF Ratnapriya, Rinki Swaroop, Anand TI Genetic architecture of retinal and macular degenerative diseases: the promise and challenges of next-generation sequencing SO GENOME MEDICINE LA English DT Review ID LEBER CONGENITAL AMAUROSIS; LINKED RETINITIS-PIGMENTOSA; STATIONARY NIGHT BLINDNESS; INHERITED PHOTORECEPTOR DEGENERATIONS; RARE VARIANTS; EXOME CAPTURE; HUMAN GENOME; IDENTIFIES MUTATIONS; STRUCTURAL VARIATION; COMPLEX DISEASES AB Inherited retinal degenerative diseases (RDDs) display wide variation in their mode of inheritance, underlying genetic defects, age of onset, and phenotypic severity. Molecular mechanisms have not been delineated for many retinal diseases, and treatment options are limited. In most instances, genotype-phenotype correlations have not been elucidated because of extensive clinical and genetic heterogeneity. Next-generation sequencing (NGS) methods, including exome, genome, transcriptome and epigenome sequencing, provide novel avenues towards achieving comprehensive understanding of the genetic architecture of RDDs. Whole-exome sequencing (WES) has already revealed several new RDD genes, whereas RNA-Seq and ChIP-Seq analyses are expected to uncover novel aspects of gene regulation and biological networks that are involved in retinal development, aging and disease. In this review, we focus on the genetic characterization of retinal and macular degeneration using NGS technology and discuss the basic framework for further investigations. We also examine the challenges of NGS application in clinical diagnosis and management. C1 [Ratnapriya, Rinki; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. RP Ratnapriya, R (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. EM rinki.ratnapriya@nih.gov; swaroopa@nei.nih.gov OI Swaroop, Anand/0000-0002-1975-1141 FU Intramural Research Program of the National Eye Institute FX We thank Dr Emily Chew (National Eye Institute, National Institutes of Health, Bethesda, MD) for providing the fundus photograph of the human retina. This work is supported by the Intramural Research Program of the National Eye Institute. NR 131 TC 11 Z9 11 U1 1 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD OCT 11 PY 2013 VL 5 AR 84 DI 10.1186/gm488 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 246OQ UT WOS:000326548700001 PM 24112618 ER PT J AU Banerjee, A Abdelmegeed, MA Jang, S Song, BJ AF Banerjee, Atrayee Abdelmegeed, Mohamed A. Jang, Sehwan Song, Byoung-Joon TI Zidovudine (AZT) and Hepatic Lipid Accumulation: Implication of Inflammation, Oxidative and Endoplasmic Reticulum Stress Mediators SO PLOS ONE LA English DT Article ID INDUCED NONALCOHOLIC STEATOHEPATITIS; HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVATED PROTEIN-KINASE; ALCOHOLIC FATTY LIVER; HIV-INFECTED PATIENTS; NF-KAPPA-B; ANTIRETROVIRAL THERAPY; MITOCHONDRIAL PROTEINS; LACTIC-ACIDOSIS; MOUSE-LIVER AB The clinical effectiveness of Zidovudine (AZT) is constrained due to its side-effects including hepatic steatosis and toxicity. However, the mechanism(s) of hepatic lipid accumulation in AZT-treated individuals is unknown. We hypothesized that AZT-mediated oxidative and endoplasmic reticulum (ER) stress may play a role in the AZT-induced hepatic lipid accumulation. AZT treatment of C57BL/6J female mice (400 mg/day/kg body weight, i.p.) for 10 consecutive days significantly increased hepatic triglyceride levels and inflammation. Markers of oxidative stress such as protein oxidation, nitration, glycation and lipid peroxidation were significantly higher in the AZT-treated mice compared to vehicle controls. Further, the levels of ER stress marker proteins like GRP78, p-PERK, and p-eIF2 alpha were significantly elevated in AZT-treated mice. The level of nuclear SREBP-1c, a transcription factor involved in fat synthesis, was increased while significantly decreased protein levels of phospho-acetyl-CoA carboxylase, phospho-AMP kinase and PPAR alpha as well as inactivation of 3-keto-acyl-CoA thiolase in the mitochondrial fatty acid beta-oxidation pathway were observed in AZT-exposed mice compared to those in control animals. Collectively, these data suggest that elevated oxidative and ER stress plays a key role, at least partially, in lipid accumulation, inflammation and hepatotoxicity in AZT-treated mice. C1 [Banerjee, Atrayee; Abdelmegeed, Mohamed A.; Jang, Sehwan; Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD USA. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD USA. EM bj.song@nih.gov FU Intramural Program of National Institute on Alcohol Abuse and Alcoholism FX The research was supported by the Intramural Program of National Institute on Alcohol Abuse and Alcoholism. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 10 Z9 13 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 OCT 11 PY 2013 VL 8 IS 10 AR UNSP e76850 DI 10.1371/journal.pone.0076850 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 236SL UT WOS:000325819400086 PM 24146933 ER PT J AU Lu, X Wetter, E Bharti, N Tatem, AJ Bengtsson, L AF Lu, Xin Wetter, Erik Bharti, Nita Tatem, Andrew J. Bengtsson, Linus TI Approaching the Limit of Predictability in Human Mobility SO SCIENTIFIC REPORTS LA English DT Article AB In this study we analyze the travel patterns of 500,000 individuals in Cote d'Ivoire using mobile phone call data records. By measuring the uncertainties of movements using entropy, considering both the frequencies and temporal correlations of individual trajectories, we find that the theoretical maximum predictability is as high as 88%. To verify whether such a theoretical limit can be approached, we implement a series of Markov chain (MC) based models to predict the actual locations visited by each user. Results show that MC models can produce a prediction accuracy of 87% for stationary trajectories and 95% for non-stationary trajectories. Our findings indicate that human mobility is highly dependent on historical behaviors, and that the maximum predictability is not only a fundamental theoretical limit for potential predictive power, but also an approachable target for actual prediction accuracy. C1 [Lu, Xin] Natl Univ Def Technol, Coll Informat Syst & Management, Changsha 410073, Peoples R China. [Lu, Xin; Wetter, Erik; Bengtsson, Linus] Flowminder Fdn, S-17177 Stockholm, Sweden. [Lu, Xin; Bengtsson, Linus] Karolinska Inst, Dept Publ Hlth Sci, S-17177 Stockholm, Sweden. [Lu, Xin] Stockholm Univ, Dept Sociol, S-17177 Stockholm, Sweden. [Wetter, Erik] Stockholm Sch Econ, Dept Management & Org, S-11383 Stockholm, Sweden. [Bharti, Nita] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16801 USA. [Bharti, Nita] Penn State Univ, Huck Inst Life Sci, University Pk, PA 16801 USA. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Tatem, Andrew J.] Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Lu, X (reprint author), Natl Univ Def Technol, Coll Informat Syst & Management, Changsha 410073, Peoples R China. EM xin.lu@flowminder.org RI lu, xin/C-1940-2009 OI lu, xin/0000-0002-3547-6493 FU RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NIH/NIAID [U19AI089674]; Bill and Melinda Gates Foundation [49446, 1032350]; Branco Weiss - Society in Science FX The authors would like to thank the operator France Telecom-Orange and the "Data for Development'' committee for sharing the mobile phone dataset and organizing the D4D challenge. This paper forms part of the output of the Human Mobility Mapping Project (www.thummp.org) and the AfriPop population mapping project (www.afripop.org). AJT acknowledges funding support from the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and is also supported by grants from NIH/NIAID (U19AI089674) and the Bill and Melinda Gates Foundation (#49446 and #1032350). NB acknowledges funding from the Branco Weiss - Society in Science. NR 26 TC 31 Z9 31 U1 0 U2 36 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 OCT 11 PY 2013 VL 3 AR 2923 DI 10.1038/srep02923 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 233AN UT WOS:000325536600002 PM 24113276 ER PT J AU Shi, Q Andre, T Grothey, A Yothers, G Hamilton, SR Bot, BM Haller, DG Van Cutsem, E Twelves, C Benedetti, JK O'Connell, MJ Sargent, DJ AF Shi, Qian Andre, Thierry Grothey, Axel Yothers, Greg Hamilton, Stanley R. Bot, Brian M. Haller, Daniel G. Van Cutsem, Eric Twelves, Chris Benedetti, Jacqueline K. O'Connell, Michael J. Sargent, Daniel J. TI Comparison of Outcomes After Fluorouracil-Based Adjuvant Therapy for Stages II and III Colon Cancer Between 1978 to 1995 and 1996 to 2007: Evidence of Stage Migration From the ACCENT Database SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 46th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY JUN 04-08, 2010 CL Chicago, IL SP Amer Soc Clin Oncol ID METASTATIC COLORECTAL-CANCER; DISEASE-FREE SURVIVAL; PHASE-III; 1ST-LINE TREATMENT; RANDOMIZED-TRIAL; LEUCOVORIN; LEVAMISOLE; IRINOTECAN; CARCINOMA; CHEMOTHERAPY AB Purpose With improved patient care, better diagnosis, and more treatment options after tumor recurrence, outcomes after fluorouracil (FU) -based treatment are expected to have improved over time in early-stage colon cancer. Data from 18,449 patients enrolled onto 21 phase III trials conducted from 1978 to 2002 were evaluated for potential differences in time to recurrence (TTR), time from recurrence to death (TRD), and overall survival (OS) with regard to FU-based adjuvant regimens. Methods Trials were predefined as old versus newer era using initial accrual before or after 1995. Outcomes were compared between patients enrolled onto old-or newer-era trials, stratified by stage. Results Within the first 3 years, recurrence rates were lower in newer-versus old-era trials for patients with stage II disease, with no differences among those with stage III disease. Both TRD and OS were significantly longer in newer-era trials overall and within each stage. The lymph node (LN) ratio (ie, number of positive nodes divided by total nodes harvested) in those with stage III disease declined over time. TTR improved slightly, with larger number of LNs examined in both stages. Conclusion Improved TRD in newer trials supports the premise that more aggressive intervention (oxaliplatin- and irinotecan-based chemotherapy and/or surgery for recurrent disease) improves OS for patients previously treated in the adjuvant setting. Lower recurrence rates with identical treatments in those with stage II disease enrolled onto newer-era trials reflect stage migration over time, calling into question historical data related to the benefit of FU-based adjuvant therapy in such patients. C1 [Shi, Qian; Grothey, Axel; Bot, Brian M.; Sargent, Daniel J.] Mayo Clin, North Cent Canc Treatment Grp, Rochester, MN USA. [Andre, Thierry] Hop St Antoine, F-75571 Paris, France. [Yothers, Greg; O'Connell, Michael J.] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Haller, Daniel G.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Hamilton, Stanley R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Bot, Brian M.] Sage Bionetworks, Seattle, WA USA. [Benedetti, Jacqueline K.] SW Oncol Grp, Ctr Stat, Seattle, WA USA. [Van Cutsem, Eric] Univ Hosp Gasthuisberg, Gasthuisberg, Belgium. [Twelves, Chris] St James Univ Hosp, Leeds, W Yorkshire, England. RP Sargent, DJ (reprint author), 200 First St SW, Rochester, MN 55905 USA. EM sargent.daniel@mayo.edu OI Bot, Brian/0000-0002-2412-6826; Sargent, Daniel/0000-0002-2684-4741; Yothers, Greg/0000-0002-7965-7333 FU NCI NIH HHS [P30 CA015083, CA25224, U10 CA021115, U10 CA025224] NR 25 TC 12 Z9 12 U1 0 U2 1 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 OCT 10 PY 2013 VL 31 IS 29 BP 3656 EP + DI 10.1200/JCO.2013.49.4344 PG 11 WC Oncology SC Oncology GA 301NT UT WOS:000330539700013 PM 23980089 ER PT J AU Hirschberg, I Seidel, G Strech, D Bastian, H Dierks, ML AF Hirschberg, Irene Seidel, Gabriele Strech, Daniel Bastian, Hilda Dierks, Marie-Luise TI Evidence-based health information from the users' perspective - a qualitative analysis SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID WORLD-WIDE-WEB; DECISION AIDS; FOCUS GROUPS; STRATEGIES; LITERACY; WEBSITE AB Background: Evidence-based information is a precondition for informed decision-making and participation in health. There are several recommendations and definitions available on the generation and assessment of so called evidence-based health information for patients and consumers (EBHI). They stress the importance of objectively informing people about benefits and harms and any uncertainties in health-related procedures. There are also studies on the comprehensibility, relevance and user-friendliness of these informational materials. But to date there has been little research on the perceptions and cognitive reactions of users or lay people towards EBHI. The aim of our study is to define the spectrum of consumers' reaction patterns to written EBHI in order to gain a deeper understanding of their comprehension and assumptions, as well as their informational needs and expectations. Methods: This study is based on an external user evaluation of EBHI produced by the German Institute for Quality and Efficiency in Health Care (IQWiG), commissioned by the IQWiG. The EBHI were examined within guided group discussions, carried out with lay people. The test readers' first impressions and their appraisal of the informational content, presentation, structure, comprehensibility and effect were gathered. Then a qualitative text analysis of 25 discussion transcripts involving 94 test readers was performed. Results: Based on the qualitative text analysis a framework for reaction patterns was developed, comprising eight main categories: (i) interest, (ii) satisfaction, (iii) reassurance and trust, (iv) activation, (v) disinterest, (vi) dissatisfaction and disappointment, (vii) anxiety and worry, (viii) doubt. Conclusions: Many lay people are unfamiliar with core characteristics of this special information type. Two particularly critical issues are the description of insufficient evidence and the attendant absence of clear-cut recommendations. Further research is needed to examine strategies to explain the specific character of EBHI so as to minimize unintended or adverse reaction patterns. The presented framework describes the spectrum of users' reaction patterns to EBHI. It may support existing best practice models for editing EBHI. C1 [Hirschberg, Irene; Strech, Daniel] Hannover Med Sch, Inst Hist Eth & Philosophy Med, CELLS, D-30625 Hannover, Germany. [Seidel, Gabriele; Dierks, Marie-Luise] Hannover Med Sch, Inst Epidemiol Social Med & Hlth Syst Res, D-30625 Hannover, Germany. [Bastian, Hilda] NIH, US Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Hirschberg, I (reprint author), Hannover Med Sch, Inst Hist Eth & Philosophy Med, CELLS, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM hirschberg.irene@mh-hannover.de OI Bastian, Hilda/0000-0001-8544-7386; Strech, Daniel/0000-0002-9153-079X FU IQWiG FX The external user evaluation was commissioned by the IQWiG and partly financed by them. NR 39 TC 5 Z9 5 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD OCT 10 PY 2013 VL 13 AR 405 DI 10.1186/1472-6963-13-405 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 267RZ UT WOS:000328116700002 PM 24112403 ER PT J AU Goldberg, L Tijssen, MR Birger, Y Hannah, RL Kinston, SJ Schutte, J Beck, D Knezeyic, K Schiby, G Jacob-Hirsch, J Biran, A Kloog, Y Marcucci, G Bloomfield, CD Aplan, PD Pimanda, JE Gottgens, B Izraeli, S AF Goldberg, Liat Tijssen, Marloes R. Birger, Yehudit Hannah, Rebecca L. Kinston, Sarah J. Schuette, Judith Beck, Dominik Knezeyic, Kathy Schiby, Ginette Jacob-Hirsch, Jasmine Biran, Anat Kloog, Yoel Marcucci, Guido Bloomfield, Clara D. Aplan, Peter D. Pimanda, John E. Goettgens, Berthold Izraeli, Shai TI Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia SO BLOOD LA English DT Article ID PIM SERINE/THREONINE KINASES; ACUTE LYMPHOBLASTIC-LEUKEMIA; STEM-CELL ENHANCER; PROSTATE-CANCER; REGULATORY CIRCUIT; PANCREATIC-CANCER; PROGENITOR CELLS; GENE; INHIBITOR; RAS AB The ETS transcription factor ERG plays a central role in definitive hematopoiesis, and its overexpression in acute myeloid leukemia (AML) is associated with a stem cell signature and poor prognosis. Yet how ERG causes leukemia is unclear. Here we show that pan-hematopoietic ERG expression induces an early progenitor myeloid leukemia in transgenic mice. Integrated genome-scale analysis of gene expression and ERG binding profiles revealed that ERG activates a transcriptional program similar to human AML stem/progenitor cells and to human AML with high ERG expression. This transcriptional program was associated with activation of RAS that was required for leukemia cells growth in vitro and in vivo. We further show that ERG induces expression of the Pim1 kinase oncogene through a novel hematopoietic enhancer validated in transgenic mice and human CD34(+) normal and leukemic cells. Pim1 inhibition disrupts growth and induces apoptosis of ERG-expressing leukemic cells. The importance of the ERG/PIM1 axis is further underscored by the poorer prognosis of AML highly expressing ERG and PIM1. Thus, integrative genomic analysis demonstrates that ERG causes myeloid progenitor leukemia characterized by an induction of leukemia stem cell transcriptional programs. Pim1 and the RAS pathway are potential therapeutic targets of these high-risk leukemias. C1 [Goldberg, Liat; Birger, Yehudit; Jacob-Hirsch, Jasmine; Izraeli, Shai] Chaim Sheba Med Ctr, Canc Res Ctr, IL-52621 Ramat Gan, Israel. [Goldberg, Liat; Izraeli, Shai] Tel Aviv Univ, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. [Tijssen, Marloes R.; Hannah, Rebecca L.; Kinston, Sarah J.; Schuette, Judith; Goettgens, Berthold] Univ Cambridge, Dept Hematol, Cambridge Inst Med Res, Cambridge, England. [Tijssen, Marloes R.; Hannah, Rebecca L.; Kinston, Sarah J.; Schuette, Judith; Goettgens, Berthold] Univ Cambridge, Wellcome Trust, Cambridge, England. [Tijssen, Marloes R.; Hannah, Rebecca L.; Kinston, Sarah J.; Schuette, Judith; Goettgens, Berthold] Univ Cambridge, MRC, Cambridge Stem Cell Inst, Cambridge, England. [Beck, Dominik; Knezeyic, Kathy; Pimanda, John E.] Univ New S Wales, Lowy Canc Res Ctr, Sydney, NSW, Australia. [Beck, Dominik; Knezeyic, Kathy; Pimanda, John E.] Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW, Australia. [Schiby, Ginette] Chaim Sheba Med Ctr, Dept Pathol, Tel Aviv, Israel. [Schiby, Ginette] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Biran, Anat; Kloog, Yoel] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiol, IL-69978 Tel Aviv, Israel. [Marcucci, Guido; Bloomfield, Clara D.] Ohio State Univ, Ctr Comprehens Canc, Div Hematol & Oncol, Dept Internal Med, Columbus, OH 43210 USA. [Aplan, Peter D.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Izraeli, S (reprint author), Chaim Sheba Med Ctr, Canc Res Ctr, IL-52621 Ramat Gan, Israel. EM bg200@cam.ac.uk; Shai.Izraeli@sheba.health.gov.il RI Aplan, Peter/K-9064-2016 FU Israel Science Foundation; Israel Centers of Research Excellence [41/11]; Children with Cancer UK; Waxman Foundation; Israel Cancer Research Foundation; Academy of Medical Sciences; The European Hematology Association; Marie Curie Intra-European Fellowship [237296]; Leukaemia and Lymphoma Research Studentship; Leukaemia and Lymphoma Research and Cancer Research UK; Wellcome Trust; Wellcome Trust-MRC Cambridge Stem Cell Institute; NCI [P50 CA 140158]; The Coleman Leukemia Research Foundation FX This work was supported in part by the Israel Science Foundation, Israel Centers of Research Excellence 41/11, Children with Cancer UK and the Waxman Foundation (S. I.), the Israel Cancer Research Foundation (L. G.), a Daniel Turnberg UK/Middle East Travel Fellowship from the Academy of Medical Sciences (L. G.), The European Hematology Association (Y.B.), Marie Curie Intra-European Fellowship 237296 (M. R. T.), a Leukaemia and Lymphoma Research Studentship (J.S.), programmatic funding from Leukaemia and Lymphoma Research and Cancer Research UK (B. G.), and core support grants by the Wellcome Trust to the Cambridge Institute for Medical Research and Wellcome Trust-MRC Cambridge Stem Cell Institute (B. G.). This work was also supported in part by Grant NCI P50 CA 140158 and The Coleman Leukemia Research Foundation (C.D.B.). NR 55 TC 20 Z9 20 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 10 PY 2013 VL 122 IS 15 BP 2694 EP 2703 DI 10.1182/blood-2013-01-477133 PG 10 WC Hematology SC Hematology GA 240FD UT WOS:000326079400028 PM 23974202 ER PT J AU Kabyemela, E Goncalves, BP Prevots, DR Morrison, R Harrington, W Gwamaka, M Kurtis, JD Fried, M Duffy, PE AF Kabyemela, Edward Goncalves, Bronner P. Prevots, D. Rebecca Morrison, Robert Harrington, Whitney Gwamaka, Moses Kurtis, Jonathan D. Fried, Michal Duffy, Patrick E. TI Cytokine Profiles at Birth Predict Malaria Severity during Infancy SO PLOS ONE LA English DT Article ID TUMOR-NECROSIS-FACTOR; PLASMODIUM-FALCIPARUM MALARIA; PLACENTAL MALARIA; FACTOR-ALPHA; IMMUNE-RESPONSES; GAMMA-INTERFERON; AFRICAN CHILDREN; CEREBRAL MALARIA; IN-VITRO; ANEMIA AB Background: Severe malaria risk varies between individuals, and most of this variation remains unexplained. Here, we examined the hypothesis that cytokine profiles at birth reflect inter-individual differences that persist and influence malaria parasite density and disease severity throughout early childhood. Methods and Findings: Cytokine levels (TNF-alpha, IFN-gamma, IL-1 beta, IL-4, IL-5, IL-6 and IL-10) were measured at birth (cord blood; N=783) and during subsequent routine follow-up visits (peripheral blood) for children enrolled between 2002 and 2006 into a birth cohort in Muheza, Tanzania. Children underwent blood smear and clinical assessments every 2-4 weeks, and at the time of any illness. Cord blood levels of all cytokines were positively correlated with each other (Spearman's rank correlation). Cord levels of IL-1 beta and TNF-alpha (but not other cytokines) correlated with levels of the same cytokine measured at routine visits during early life (P < 0.05). Higher cord levels of IL-1 beta but not TNF-alpha were associated with lower parasite densities during infancy (P=0.003; Generalized Estimating Equation (GEE) method), with an average similar to 40% reduction versus children with low cord IL-1 beta levels, and with decreased risk of severe malaria during follow-up (Cox regression): adjusted hazard ratio (95% CI) 0.60 (0.39-0.92), P = 0.02. Conclusion: IL-1 beta levels at birth are related to future IL-1 beta levels as well as the risk of severe malaria in early life. The effect on severe malaria risk may be due in part to the effect of inflammatory cytokines to control parasite density. C1 [Kabyemela, Edward; Morrison, Robert; Gwamaka, Moses; Fried, Michal; Duffy, Patrick E.] Seattle Biomed Res Inst, MOMS Project, Seattle, WA 98109 USA. [Kabyemela, Edward; Morrison, Robert; Gwamaka, Moses; Fried, Michal; Duffy, Patrick E.] Muheza Designated Dist Hosp, Muheza, Tanzania. [Goncalves, Bronner P.; Fried, Michal; Duffy, Patrick E.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Goncalves, Bronner P.; Prevots, D. Rebecca] NIAID, Lab Clin Infect Dis, Epidemiol Unit, NIH, Bethesda, MD 20892 USA. [Harrington, Whitney] Seattle Childrens Hosp, Seattle, WA USA. [Harrington, Whitney] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Kurtis, Jonathan D.] Rhode Isl Hosp, Ctr Int Hlth Res, Providence, RI USA. [Kurtis, Jonathan D.] Brown Univ, Sch Med, Dept Pathol & Lab Med, Providence, RI 02912 USA. RP Duffy, PE (reprint author), Seattle Biomed Res Inst, MOMS Project, 4 Nickerson St, Seattle, WA 98109 USA. EM patrick.duffy@nih.gov FU Division of Intramural Research (DIR) of NIAID, NIH; NIAID, NIH [R01AI52059]; Bill & Melinda Gates Foundation [29202]; Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative [1364]; US National Institutes of Health Fogarty International Center (FIC) [D43 TW005509] FX This work was supported by the Division of Intramural Research (DIR) and the extramural program (grant R01AI52059) of NIAID, NIH; the Bill & Melinda Gates Foundation (grant 29202); the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative (grant 1364); the US National Institutes of Health Fogarty International Center (FIC) (grant D43 TW005509). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 7 Z9 7 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 10 PY 2013 VL 8 IS 10 AR e77214 DI 10.1371/journal.pone.0077214 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 236QM UT WOS:000325814200069 PM 24130857 ER PT J AU Khattar, SK Nayak, B Kim, SH Xiao, S Samal, S Paldurai, A Buchholz, UJ Collins, PL Samal, SK AF Khattar, Sunil K. Nayak, Baibaswata Kim, Shin-Hee Xiao, Sa Samal, Sweety Paldurai, Anandan Buchholz, Ursula J. Collins, Peter L. Samal, Siba K. TI Evaluation of the Replication, Pathogenicity, and Immunogenicity of Avian Paramyxovirus (APMV) Serotypes 2, 3, 4, 5, 7, and 9 in Rhesus Macaques SO PLOS ONE LA English DT Article ID NEWCASTLE-DISEASE VIRUS; COMPLETE GENOME SEQUENCE; PROTEIN CLEAVAGE SITE; RESPIRATORY-TRACT; INFLUENZA-VIRUS; VACCINE VECTOR; FUSION PROTEIN; NEUTRALIZING ANTIBODIES; NEURAMINIDASE PROTEIN; PROTECTIVE IMMUNITY AB Avian paramyxoviruses (APMV) serotypes 1-9 are frequently isolated from domestic and wild birds worldwide. APMV-1 (also called Newcastle disease virus, NDV) is attenuated in non-human primates and is being developed as a candidate human vaccine vector. The vector potential of the other serotypes was unknown. In the present study, we evaluated nine different biologically-or recombinantly-derived APMV strains for the ability to replicate and cause disease in rhesus macaque model. Five of the viruses were: biologically-derived wild type (wt) APMV-2, -3, -5, -7 and -9. Another virus was a recombinant (r) version of wt APMV-4. The remaining three viruses were versions of wt rAPMV-2, -4 and -7 in which the F cleavage site had been modified to be multi-basic. Rhesus macaques were inoculated intranasally and intratracheally and monitored for clinical disease, virus shedding from the upper and lower respiratory tract, and seroconversion. Virus shedding was not detected for wt APMV-5. Very limited shedding was detected for wt rAPMV-4 and modified rAPMV-4, and only in a subset of animals. Shedding by the other viruses was detected in every infected animal, and usually from both the upper and lower respiratory tract. In particular, shedding over a number of days in every animal was observed for modified rAPMV-2, wt APMV-7, and modified rAPMV-7. Modification of the F protein cleavage site appeared to increase shedding by wt rAPMV-2 and marginally by wt rAPMV-4. All APMVs except wt APMV-5 induced a virus-specific serum antibody response in all infected animals. None of the animals exhibited any clinical disease signs. These results indicate that APMVs 2, 3, 4, 7, and 9 are competent to infect non-human primates, but are moderately-to-highly restricted, depending on the serotype. This suggests that they are not likely to significantly infect primates in nature, and represent promising attenuated candidates for vector development. C1 [Khattar, Sunil K.; Nayak, Baibaswata; Kim, Shin-Hee; Xiao, Sa; Samal, Sweety; Paldurai, Anandan; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Buchholz, Ursula J.; Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu RI Nayak, Baibaswata/L-6156-2016 FU National Institute of Allergy and Infectious Diseases (NIAID) [N01A060009]; NIAID, National Institutes of Health (NIH) Intramural Research Program; Intramural Research Program of the NIAID, NIH FX This research was supported by National Institute of Allergy and Infectious Diseases (NIAID) contract number N01A060009 (85% support) and NIAID, National Institutes of Health (NIH) Intramural Research Program (15% support). PLC and UJB were supported by the Intramural Research Program of the NIAID, NIH. The views expressed herein do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the United States Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 0 Z9 0 U1 2 U2 19 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 OCT 10 PY 2013 VL 8 IS 10 AR e75456 DI 10.1371/journal.pone.0075456 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 236QM UT WOS:000325814200013 PM 24130713 ER PT J AU Zeron-Medina, J Wang, XT Repapi, E Campbell, MR Su, D Castro-Giner, F Davies, B Peterse, EFP Sacilotto, N Walker, GJ Terzian, T Tomlinson, IP Box, NF Meinshausen, N De Val, S Bell, DA Bond, GL AF Zeron-Medina, Jorge Wang, Xuting Repapi, Emmanouela Campbell, Michelle R. Su, Dan Castro-Giner, Francesc Davies, Benjamin Peterse, Elisabeth F. P. Sacilotto, Natalia Walker, Graeme J. Terzian, Tamara Tomlinson, Ian P. Box, Neil F. Meinshausen, Nicolai De Val, Sarah Bell, Douglas A. Bond, Gareth L. TI A Polymorphic p53 Response Element in KIT Ligand Influences Cancer Risk and Has Undergone Natural Selection SO CELL LA English DT Article ID GERM-CELL CANCER; SINGLE-NUCLEOTIDE POLYMORPHISMS; TUMOR-SUPPRESSOR PATHWAY; FACTOR-BINDING-SITES; TESTICULAR CANCER; HUMAN GENOME; DNA-DAMAGE; TRANSCRIPTIONAL ACTIVATION; HAPLOTYPE STRUCTURE; GENETIC-VARIANTS AB The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans. C1 [Zeron-Medina, Jorge; Repapi, Emmanouela; Peterse, Elisabeth F. P.; Sacilotto, Natalia; De Val, Sarah; Bond, Gareth L.] Univ Oxford, Nuffield Dept Clin Med, Ludwig Inst Canc Res, Oxford OX3 7DQ, England. [Wang, Xuting; Campbell, Michelle R.; Su, Dan; Bell, Douglas A.] NIEHS, Environm Genom Grp, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Castro-Giner, Francesc; Tomlinson, Ian P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Mol & Populat Genet Lab, Oxford OX3 7BN, England. [Davies, Benjamin] Univ Oxford, Wellcome Trust Ctr Human Genet, Transgen Technol Res Grp, Oxford OX3 7BN, England. [Walker, Graeme J.] Queensland Inst Med Res, Skin Carcinogenesis Lab, Herston, Qld 4006, Australia. [Terzian, Tamara; Box, Neil F.] Univ Colorado Denver, Dept Dermatol, Aurora, CO 80045 USA. [Terzian, Tamara; Box, Neil F.] Univ Colorado Denver, Charles C Gates Ctr Regenerat Med & Stem Cell Bio, Aurora, CO 80045 USA. [Meinshausen, Nicolai] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. RP Bell, DA (reprint author), NIEHS, Environm Genom Grp, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM bell1@niehs.nih.gov; gareth.bond@ndm.ox.ac.uk RI Castro-Giner, Francesc/D-7992-2014; Zeron-Medina, Jorge/E-2480-2013; OI Castro-Giner, Francesc/0000-0001-6111-0754; Zeron-Medina, Jorge/0000-0001-5030-3219; Wang, Xuting/0000-0001-6781-8008 FU Ludwig Institute for Cancer Research; Development Fund-Oxford Cancer Research Centre-University of Oxford; Nuffield Department of Medicine; Clarendon Fund; Wellcome Trust [090532/Z/09/Z]; Oxford NIHR Comprehensive Biomedical Research Centre; Intramural Research Program of the National Institute of Environmental Health Sciences-National Institutes of Health [Z01ES100475, Z01ES046008]; Australian NHMRC; NIAMS [1P30AR057212, 5K01AR063203]; Cancer Council of Queensland FX This work was funded in part by the Ludwig Institute for Cancer Research, the Development Fund-Oxford Cancer Research Centre-University of Oxford, the Nuffield Department of Medicine, the Clarendon Fund, the Wellcome Trust (090532/Z/09/Z), the Oxford NIHR Comprehensive Biomedical Research Centre, the Intramural Research Program of the National Institute of Environmental Health Sciences-National Institutes of Health (projects: Z01ES100475 and Z01ES046008), the Australian NHMRC, Cancer Council of Queensland and the NIAMS (projects: 1P30AR057212 and 5K01AR063203). The authors would like to acknowledge Daniel Biggs and Nicole Hortin for assistance with ES cell culture; Shuangshuang Dai for Linux computing support; Colin Goding and Will Fairbrother for helpful discussions; and Suzanne Christen, Claire Beveridge, Elisabeth Bond, and Mark Shipman for help with the preparation of this manuscript. NR 65 TC 46 Z9 47 U1 1 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD OCT 10 PY 2013 VL 155 IS 2 BP 410 EP 422 DI 10.1016/j.cell.2013.09.017 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 235LH UT WOS:000325719800017 PM 24120139 ER PT J AU Lam, TTY Wang, J Shen, YY Zhou, BP Duan, L Cheung, CL Ma, C Lycett, SJ Leung, CYH Chen, XC Li, LF Hong, WS Chai, YJ Zhou, LL Liang, HY Ou, ZH Liu, YM Farooqui, A Kelvin, DJ Poon, LLM Smith, DK Pybus, OG Leung, GM Shu, YL Webster, RG Webby, RJ Peiris, JSM Rambaut, A Zhu, HC Guan, Y AF Lam, Tommy Tsan-Yuk Wang, Jia Shen, Yongyi Zhou, Boping Duan, Lian Cheung, Chung-Lam Ma, Chi Lycett, Samantha J. Leung, Connie Yin-Hung Chen, Xinchun Li, Lifeng Hong, Wenshan Chai, Yujuan Zhou, Linlin Liang, Huyi Ou, Zhihua Liu, Yongmei Farooqui, Amber Kelvin, David J. Poon, Leo L. M. Smith, David K. Pybus, Oliver G. Leung, Gabriel M. Shu, Yuelong Webster, Robert G. Webby, Richard J. Peiris, Joseph S. M. Rambaut, Andrew Zhu, Huachen Guan, Yi TI The genesis and source of the H7N9 influenza viruses causing human infections in China SO NATURE LA English DT Article ID PHYLOGENETIC ANALYSIS; RECEPTOR-BINDING; SOUTHERN CHINA; ESTABLISHMENT; TRANSMISSION; SEQUENCES; ACCURACY; MODELS; ORIGIN; DUCKS AB A novel H7N9 influenza A virus first detected in March 2013 has since caused more than 130 human infections in China, resulting in 40 deaths(1,2). Preliminary analyses suggest that the virus is a reassortant of H7, N9 and H9N2 avian influenza viruses, and carries some amino acids associated with mammalian receptor binding, raising concerns of a new pandemic(1,3,4). However, neither the source populations of the H7N9 outbreak lineage nor the conditions for its genesis are fully known(5). Using a combination of active surveillance, screening of virus archives, and evolutionary analyses, here we show that H7 viruses probably transferred from domestic duck to chicken populations in China on at least two independent occasions. We show that the H7 viruses subsequently reassorted with enzootic H9N2 viruses to generate the H7N9 outbreak lineage, and a related previously unrecognized H7N7 lineage. The H7N9 outbreak lineage has spread over a large geographic region and is prevalent in chickens at live poultry markets, which are thought to be the immediate source of human infections. Whether the H7N9 outbreak lineage has, or will, become enzootic in China and neighbouring regions requires further investigation. The discovery here of a related H7N7 influenza virus in chickens that has the ability to infect mammals experimentally, suggests that H7 viruses may pose threats beyond the current outbreak. The continuing prevalence of H7 viruses in poultry could lead to the generation of highly pathogenic variants and further sporadic human infections, with a continued risk of the virus acquiring human-to-human transmissibility. C1 [Lam, Tommy Tsan-Yuk; Wang, Jia; Shen, Yongyi; Ma, Chi; Li, Lifeng; Hong, Wenshan; Liang, Huyi; Ou, Zhihua; Liu, Yongmei; Smith, David K.; Leung, Gabriel M.; Zhu, Huachen; Guan, Yi] Shantou Univ, Coll Med, Joint Influenza Res Ctr SUMC HKU, Shantou 515041, Peoples R China. [Lam, Tommy Tsan-Yuk; Zhou, Boping; Duan, Lian; Chen, Xinchun; Li, Lifeng; Chai, Yujuan; Liang, Huyi; Ou, Zhihua; Poon, Leo L. M.; Peiris, Joseph S. M.; Zhu, Huachen; Guan, Yi] Shenzhen Third Peoples Hosp, HKU Shenzhen Branch, State Key Lab Emerging Infect Dis, Shenzhen 518112, Peoples R China. [Lam, Tommy Tsan-Yuk; Wang, Jia; Shen, Yongyi; Duan, Lian; Cheung, Chung-Lam; Ma, Chi; Leung, Connie Yin-Hung; Li, Lifeng; Chai, Yujuan; Zhou, Linlin; Liang, Huyi; Ou, Zhihua; Liu, Yongmei; Poon, Leo L. M.; Smith, David K.; Leung, Gabriel M.; Peiris, Joseph S. M.; Zhu, Huachen; Guan, Yi] Univ Hong Kong, Sch Publ Hlth, Influenza Res Ctr, State Key Lab Emerging Infect Dis, Hong Kong, Hong Kong, Peoples R China. [Shen, Yongyi] Xiamen Univ, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361102, Peoples R China. [Lycett, Samantha J.; Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3JT, Midlothian, Scotland. [Farooqui, Amber; Kelvin, David J.] Shantou Univ, Coll Med, Joint Vaccine Res Ctr SUMC UHN, Shantou 515041, Peoples R China. [Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Pybus, Oliver G.] Metabiota, San Francisco, CA 94104 USA. [Shu, Yuelong] Natl Hlth & Family Planning Commiss, Chinese Ctr Dis Control & Prevent, Natl Inst Viral Dis Control & Prevent, Key Lab Med Virol, Beijing 102206, Peoples R China. [Webster, Robert G.; Webby, Richard J.] St Jude Childrens Res Hosp, Dept Infect Dis, Div Virol, Memphis, TN 38105 USA. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Zhu, HC (reprint author), Shantou Univ, Coll Med, Joint Influenza Res Ctr SUMC HKU, Shantou 515041, Peoples R China. EM zhuhch@hku.hk; yguan@hku.hk RI Lam, Tommy Tsan-Yuk/D-4837-2012; Zhu, Huachen/A-8252-2017; OI Zhu, Huachen/0000-0003-2711-0501; Pybus, Oliver/0000-0002-8797-2667; Rambaut, Andrew/0000-0003-4337-3707; Lycett, Samantha/0000-0003-3159-596X FU National Institutes of Health (National Institute of Allergy and Infectious Diseases) [HSN266200700005C]; Li Ka Shing Foundation; University Grants Committee of the Hong Kong SAR [AoE/M-12/06]; Shenzhen Peacock Plan High-End Talents Program [KQTD201203]; University Development Fund (HKU); Innovation and Technology Commission of the Hong Kong Government; Newton International Fellowship of the Royal Society; US Agency for International Development (USAID) Emerging Pandemic Threats Program, PREDICT project [GHN-A-OO-09-00010-00]; European Union [278433-PREDEMICS]; ERC [260864]; Wellcome Trust [092807] FX We thank our colleagues from the Joint Influenza Research Centre (SUMC/HKU) and the State Key Laboratory of Emerging Infectious Diseases for their technical assistance. This study was supported by the National Institutes of Health (National Institute of Allergy and Infectious Diseases contract HSN266200700005C), Li Ka Shing Foundation, the Area of Excellence Scheme of the University Grants Committee of the Hong Kong SAR (grant AoE/M-12/06), Shenzhen Peacock Plan High-End Talents Program (KQTD201203), the University Development Fund (HKU) and the Innovation and Technology Commission of the Hong Kong Government. T.T.-Y.L. was supported in part by a Newton International Fellowship of the Royal Society. Metabiota's involvement was supported by the US Agency for International Development (USAID) Emerging Pandemic Threats Program, PREDICT project, under the terms of Cooperative Agreement Number GHN-A-OO-09-00010-00. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreement no. 278433-PREDEMICS, ERC Grant agreement no. 260864 and the Wellcome Trust (grant 092807) to A. R. and S.J.L. NR 28 TC 186 Z9 203 U1 18 U2 149 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 10 PY 2013 VL 502 IS 7470 BP 241 EP + DI 10.1038/nature12515 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 231RU UT WOS:000325436100052 PM 23965623 ER PT J AU Evangelista, AM Kohr, MJ Murphy, E AF Evangelista, Alicia M. Kohr, Mark J. Murphy, Elizabeth TI S-Nitrosylation: Specificity, Occupancy, and Interaction with Other Post-Translational Modifications SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID NITRIC-OXIDE SYNTHASE; ISCHEMIA-REPERFUSION INJURY; BIOTIN-SWITCH TECHNIQUE; ACTIVE-SITE CYSTEINE; NEURONAL CELL-DEATH; NMDA RECEPTOR; OXIDATIVE STRESS; HEART-FAILURE; IN-VIVO; MITOCHONDRIAL PROTEINS AB Significance:S-nitrosylation (SNO) has been identified throughout the body as an important signaling modification both in physiology and a variety of diseases. SNO is a multifaceted post-translational modification, in that it can either act as a signaling molecule itself or as an intermediate to other modifications. Recent Advances and Critical Issues: Through extensive SNO research, we have made progress toward understanding the importance of single cysteine-SNO sites; however, we are just beginning to explore the importance of specific SNO within the context of other SNO sites and post-translational modifications. Additionally, compartmentalization and SNO occupancy may play an important role in the consequences of the SNO modification. Future Directions: In this review, we will consider the context of SNO signaling and discuss how the transient nature of SNO, its role as an oxidative intermediate, and the pattern of SNO, should be considered when determining the impact of SNO signaling. Antioxid. Redox Signal. 19, 1209-1219. C1 [Evangelista, Alicia M.; Kohr, Mark J.; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Kohr, Mark J.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. RP Evangelista, AM (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10,Room 8N206,10 Ctr Dr, Bethesda, MD 20892 USA. EM alicia.evangelista@nih.gov OI Kohr, Mark/0000-0002-6034-5962 FU National Institutes of Health [Z01HL006059, Z01HL002066]; American Heart Association [12BGIA11780030] FX The authors acknowledge the support of the National Institutes of Health (Z01HL006059 and Z01HL002066, A.M.E., E.M.) and the American Heart Association (12BGIA11780030, M.J.K.). NR 119 TC 17 Z9 17 U1 5 U2 20 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD OCT 10 PY 2013 VL 19 IS 11 BP 1209 EP 1219 DI 10.1089/ars.2012.5056 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 224MO UT WOS:000324891000007 PM 23157187 ER PT J AU Berman, BD Horovitz, SG Hallett, M AF Berman, Brian D. Horovitz, Silvina G. Hallett, Mark TI Modulation of functionally localized right insular cortex activity using real-time fMRI-based neurofeedback SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE neural modulation; real-time fMRI; biofeedback; insular cortex; urges ID RESONANCE-IMAGING FMRI; LA-TOURETTE-SYNDROME; BRAIN ACTIVATION; MOTOR IMAGERY; ANOREXIA-NERVOSA; DEFAULT NETWORK; ANTERIOR INSULA; TIC GENERATION; SELF; DISORDERS AB The capacity for subjects to learn to volitionally control localized brain activity using neurofeedback is actively being investigated. We aimed to investigate the ability of healthy volunteers to quickly learn to use visual feedback during real-time functional MRI (rtfMRI) to modulate brain activity within their anterior right insular cortex (RIC) localized during a blink suppression task, an approach of possible interest in the use of rtfMRI to reduce urges. The RIC region of interest (RIC-ROI) was functionally localized using a blink suppression task, and blood-oxygen level dependent (BOLD) signal changes within RIC-ROI used to create a constantly updating display fed back to the subject in the scanner. Subjects were instructed to use emotional imagery to try and increase activity within RIC-ROI during four feedback training runs (FB1FB4). A "control" run (CNTRL) before training and a "transfer" run (XSFR) after training were performed without feedback to assess for baseline abilities and learning effects. Fourteen participants completed all neurofeedback training runs. At the group-level, increased BOLD activity was seen in the anterior RIC during all the FB runs, but a significant increase in the functionally defined RIC-ROI was only attained during FB2. In atlas-defined insular cortex ROIs, significant increases were seen bilaterally during the CNTRL, FB1, FB2, and FB4 runs. Increased activity within the insular cortices did not show lateralization. Training did, however, result in a significant increase in functional connectivity between the RIC-ROI and the medial frontal gyrus when comparing FB4 to FB1. Since neurofeedback training did not lead to an increase in BOLD signal across all feedback runs, we suggest that learning to control ones brain activity in this fashion may require longer or repeated rtfMRI training sessions. C1 [Berman, Brian D.] Univ Colorado, Dept Neurol, Aurora, CO 80045 USA. [Berman, Brian D.; Horovitz, Silvina G.; Hallett, Mark] NINDS, Human Motor Control Sect, Bethesda, MD 20892 USA. RP Berman, BD (reprint author), Univ Colorado, Dept Neurol, Anschutz Med Campus,12631 East 17th Ave,Mail Stop, Aurora, CO 80045 USA. EM brian.berman@ucdenver.edu FU National Institute of Neurological Disorders and Stroke FX We would like to thank Jerzy Bodurka, Ph.D., for his help in setting up the real-time fMRI at NIH. This work was funded by the Intramural Program of the National Institute of Neurological Disorders and Stroke. NR 73 TC 7 Z9 7 U1 2 U2 17 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD OCT 10 PY 2013 VL 7 AR 638 DI 10.3389/fnhum.2013.00638 PG 11 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 231ZW UT WOS:000325458200001 PM 24133436 ER PT J AU Censor, N AF Censor, N. TI GENERALIZATION OF PERCEPTUAL AND MOTOR LEARNING: A CAUSAL LINK WITH MEMORY ENCODING AND CONSOLIDATION? SO NEUROSCIENCE LA English DT Review DE learning; perceptual; motor; memory; generalization ID INTERMANUAL TRANSFER; TEXTURE-DISCRIMINATION; VISUOMOTOR ADAPTATION; REACHING MOVEMENTS; CORTEX PLASTICITY; BRAIN PLASTICITY; VISUAL-CORTEX; TIME-COURSE; SKILL; SLEEP AB In both perceptual and motor learning, numerous studies have shown specificity of learning to the trained eye or hand and to the physical features of the task. However, generalization of learning is possible in both perceptual and motor domains. Here, I review evidence for perceptual and motor learning generalization, suggesting that generalization patterns are affected by the way in which the original memory is encoded and consolidated. Generalization may be facilitated during fast learning, with possible engagement of higher-order brain areas recurrently interacting with the primary visual or motor cortices encoding the stimuli or movements' memories. Such generalization may be supported by sleep, involving functional interactions between low and higher-order brain areas. Repeated exposure to the task may alter generalization patterns of learning and overall offline learning. Development of unifying frameworks across learning modalities and better understanding of the conditions under which learning can generalize may enable to gain insight regarding the neural mechanisms underlying procedural learning and have useful clinical implications. (c) 2013 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Censor, N.] NINDS, Human Cort Physiol & Stroke Neurorehabilitat Sect, NIH, Bethesda, MD 20892 USA. RP Censor, N (reprint author), Bldg 10,Room 7D50,MSC 1428,10 Ctr Dr, Bethesda, MD 20892 USA. EM censorn@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS), US National Institutes of Health (NIH); NINDS Ruth L. Kirschstein National Research Service Award (NRSA) FX I thank the reviewers for their useful comments. This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS), US National Institutes of Health (NIH), and an NINDS Ruth L. Kirschstein National Research Service Award (NRSA). NR 68 TC 7 Z9 8 U1 5 U2 48 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD OCT 10 PY 2013 VL 250 BP 201 EP 207 DI 10.1016/j.neuroscience.2013.06.062 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 223YC UT WOS:000324847400019 PM 23850685 ER PT J AU Listwak, SJ Rathore, P Herkenham, M AF Listwak, S. J. Rathore, P. Herkenham, M. TI MINIMAL NF-kappa B ACTIVITY IN NEURONS SO NEUROSCIENCE LA English DT Article DE NF-kappa B; transcription factor; plasticity; neuroprotection; TNF ID CENTRAL-NERVOUS-SYSTEM; TUMOR-NECROSIS-FACTOR; TRANSCRIPTION FACTOR; GROWTH-FACTOR; HIPPOCAMPAL-NEURONS; MESSENGER-RNA; SYNAPTIC PLASTICITY; CELL PROLIFERATION; NEURITE OUTGROWTH; CORTICAL-NEURONS AB Nuclear factor-kappa B (NF-kappa B) is a ubiquitous transcription factor that regulates immune and cell-survival signaling pathways. NF-kappa B has been reported to be present in neurons wherein it reportedly responds to immune and toxic stimuli, glutamate, and synaptic activity. However, because the brain contains many cell types, assays specifically measuring neuronal NF-kappa B activity are difficult to perform and interpret. To address this, we compared NF-kappa B activity in cultures of primary neocortical neurons, mixed brain cells, and liver cells, employing Western blot of NF-kappa B subunits, electrophoretic mobility shift assay (EMSA) of nuclear kappa B DNA binding, reporter assay of kappa B DNA binding, immunofluorescence of the NF-kappa B subunit protein p65, quantitative real-time polymerase chain reaction (PCR) of NF-kappa B-regulated gene expression, and enzyme-linked immunosorbent assay (ELISA) of produced proteins. Assay of p65 showed its constitutive presence in cytoplasm and nucleus of neurons at levels significantly lower than in mixed brain or liver cells. EMSA and reporter assays showed that constitutive NF-kappa B activity was nearly absent in neurons. Induced activity was minimal-many fold lower than in other cell types, as measured by phosphorylation and degradation of the inhibitor I kappa B alpha, nuclear accumulation of p65, binding to kappa B DNA consensus sites, NF-kappa B reporting, or induction of NF-kappa B-responsive genes. The most efficacious activating stimuli for neurons were the pro-inflammatory cytokines tumor necrosis factor alpha (TNF alpha) and interleukin-beta (IL-beta). Neuronal NF-kappa B was not responsive to glutamate in most assays, and it was also unresponsive to hydrogen peroxide, lipopolysaccharide, norepinephrine, ATP, phorbol ester, and nerve growth factor. The chemokine gene transcripts CCL2, CXCL1, and CXCL10 were strongly induced via NF-kappa B activation by TNF alpha in neurons, but many candidate responsive genes were not, including the neuroprotective genes SOD2 and Bcl-xL. Importantly, the level of induced neuronal NF-kappa B activity in response to TNR alpha or any other stimulus was lower than the level of constitutive activity in non-neuronal cells, calling into question the functional significance of neuronal NF-kappa B activity. Published by Elsevier Ltd. on behalf of IBRO. C1 [Listwak, S. J.; Rathore, P.; Herkenham, M.] NIMH, NIH, Funct Neuroanat Sect, Bethesda, MD 20892 USA. RP Herkenham, M (reprint author), NIMH, Funct Neuroanat Sect, Bldg 35,Room 1C913,35 Convent Dr, Bethesda, MD 20892 USA. EM herkenh@mail.nih.gov OI Herkenham, Miles/0000-0003-2228-4238 FU Intramural NIH HHS [ZIA MH001090-35] NR 79 TC 23 Z9 24 U1 0 U2 23 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD OCT 10 PY 2013 VL 250 BP 282 EP 299 DI 10.1016/j.neuroscience.2013.07.013 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 223YC UT WOS:000324847400027 PM 23872390 ER PT J AU Larson, CL Samuelson, DR Eucker, TP O'Loughlin, JL Konkel, ME AF Larson, Charles L. Samuelson, Derrick R. Eucker, Tyson P. O'Loughlin, Jason L. Konkel, Michael E. TI The fibronectin-binding motif within FlpA facilitates Campylobacter jejuni adherence to host cell and activation of host cell signaling SO EMERGING MICROBES & INFECTIONS LA English DT Article DE adherence; adhesion; extracellular matrix; lipoprotein; membrane; MSCRAMM ID HUMAN EPITHELIAL-CELLS; INTEGRIN BETA1; C5A PEPTIDASE; RHO GTPASES; PROTEIN; INVASION; IDENTIFICATION; COLONIZATION; TRANSDUCTION; MICE AB Campylobacter jejuni is a gram-negative, curved and rod-shaped bacterium that causes human gastroenteritis. Acute disease is associated with C. jejuni invasion of the intestinal epithelium. Epithelial cells infected with C. jejuni strains containing mutations in the FlpA and CadF fibronectin (Fn)-binding proteins exhibit reduced invasion of host cells and a C. jejuni CadF FlpA double mutant is impaired in the activation of epidermal growth factor receptor (EGFR) and Rho GTPase Rac1. Although these observations establish a role for Fn-binding proteins during C. jejuni invasion, their mechanistic contributions to invasion-associated signaling are unclear. We examined FlpA, a C. jejuni Fn-binding protein composed of three FNIII-like repeats D1, D2 and D3, to identify the interactions required for cellular adherence on pathogen-induced host cell signaling. We report that FlpA binds the Fn gelatin-binding domain via a motif within the D2 repeat. Epithelial cells infected with a flpA mutant exhibited decreased Rac1 activation and reduced membrane ruffling that coincided with impaired delivery of the secreted Cia proteins and reduced cell association. Phosphorylation of the Erk1/2 kinase, a downstream effector of EGFR signaling, was specifically associated with FlpA-mediated activation of beta(1)-integrin and EGFR signaling. In vivo experiments revealed that FlpA is necessary for C. jejuni disease based on bacterial dissemination to the spleen of IL-10(-/-) germ-free mice. Thus, a novel Fn-binding motif within FlpA potentiates activation of Erk1/2 signaling via beta(1)-integrin during C. jejuni infection. C1 [Larson, Charles L.; Samuelson, Derrick R.; Eucker, Tyson P.; O'Loughlin, Jason L.; Konkel, Michael E.] Washington State Univ, Coll Vet Med, Sch Mol Biosci, Pullman, WA 99164 USA. RP Konkel, ME (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, Hamilton, MT 59840 USA. EM konkel@vetmed.wsu.edu OI Samuelson, Derrick/0000-0002-5356-1413 FU Agriculture and Food Research Initiative Competitive from the USDA National Institute of Food and Agriculture [2011-67015-30772]; National Institute of General Medical Sciences [T32GM083864, T32GM008336]; National Institutes of Health T32 Training program in Infectious Diseases and Microbial Immunology [5 T32 AI 7025 33] FX We thank Dr Jason M Neal-McKinney (School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, USA) for proofreading this manuscript. We would also like to thank Dr Magnus Hook (Professor of Biochemistry and Biophysics, of the IBT-Houston, Veterinary Anatomy and Public Health, Director, Center for Extracellular Matrix Biology) and Dr Laurent Vuillard (BioXtal, PX Unit, c/o AFMB, UMR 6098, Case 932, 163 Avenue de Luminy, 13288 Marseille CEDEX 09, France) for helpful discussions. Finally, we thank Dr Maureen Bower at the Gnotobiotic Core Facility of the Center for Gastrointestinal and Dr Sue Tonkonogy at the College of Veterinary Medicine, North Carolina State University (Raleigh, NC, USA). This project was supported by Agriculture and Food Research Initiative Competitive (Grant NO. 2011-67015-30772) from the USDA National Institute of Food and Agriculture awarded to Michael E Konkel. Derrick R Samuelson and Tyson P Eucker were supported by Award Numbers T32GM083864 and T32GM008336 from the National Institute of General Medical Sciences, respectively. Jason L O'Loughlin was supported by a National Institutes of Health T32 Training program in Infectious Diseases and Microbial Immunology (Award Number 5 T32 AI 7025 33). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIGMS or the National Institutes of Health. NR 42 TC 0 Z9 0 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2222-1751 J9 EMERG MICROBES INFEC JI Emerg. Microbes Infect. PD OCT 9 PY 2013 VL 2 AR e65 DI 10.1038/emi.2013.65 PG 12 WC Immunology; Microbiology SC Immunology; Microbiology GA AL5RT UT WOS:000339191600001 PM 26038437 ER PT J AU Xu, SW Liu, ZP Liu, PQ AF Xu, Suowen Liu, Zhiping Liu, Peiqing TI HDL cholesterol in cardiovascular diseases: The good, the bad, and the ugly? SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Editorial Material DE Atherosclerosis; Chronic kidney disease; Coronary artery disease; HDL; LOX-1; TLR-2 ID HIGH-DENSITY-LIPOPROTEIN; HUMAN ENDOTHELIAL-CELLS; ATHEROSCLEROSIS; PROTECTION; MECHANISMS; EXPRESSION; LOX-1 AB Atherosclerotic cardiovascular diseases are the leading cause of death in developed and developing countries. HDL-raising therapeutic modalities (such as cholesterol ester transferase protein (CETP) inhibitors) are being developed to combat these diseases. However, recent setback of two CETP inhibitors (Torcetrapib and Dalcetrapib) has highlighted the importance of measuring qualitative functionality of HDL particles, rather than focusing quantitatively on HDL cholesterol serum concentrations. It has been known that, HDL from patients with coronary artery disease (CAD) (i.e., HDLCAD) limits the anti-inflammatory and endothelial repair properties of normal HDL, due to the activation of lectin-like oxidized LDL receptor-1 (LOX-1), thereby causing failure in endothelial nitric oxide (NO) production. A more recent study (Immunity 2013; 38: 754-768) also demonstrates that HDL from patients with chronic kidney dysfunction (CKD) (i.e., HDLCKD), unlike its healthy counterpart (i.e., HDLHealthy), promotes superoxide production, reduces NO bioavailability and raises blood pressure via toll-like receptor-2 (TLR-2) activation. This study provides novel insights into understanding why HDL-raising agents failed to demonstrate beneficial effects on cardiovascular mortality in large clinical trials and why CKD accelerates the development of atherosclerosis in CAD patients. Further research is warranted to elucidate whether HDLCKD and HDLCAD participate in other cellular processes in atherosclerosis, such as foam cell formation, the proliferation and migration of smooth muscle cells, and most importantly, plaque destabilization. Published by Elsevier Ireland Ltd. C1 [Xu, Suowen; Liu, Zhiping; Liu, Peiqing] Sun Yat Sen Univ, Sch Pharmaceut Sci, Dept Pharmacol & Toxicol, Guangzhou 510006, Guangdong, Peoples R China. RP Xu, SW (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM suo-wen.xu@nih.gov; liupq@mail.sysu.edu.cn NR 16 TC 6 Z9 6 U1 0 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD OCT 9 PY 2013 VL 168 IS 4 BP 3157 EP 3159 DI 10.1016/j.ijcard.2013.07.210 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 242EG UT WOS:000326219600014 PM 23962777 ER PT J AU Harhay, MO Tracy, RP Bagiella, E Barr, RG Pinder, D Hundley, WG Bluemke, DA Kronmal, RA Lima, JAC Kawut, SM AF Harhay, Michael O. Tracy, Russell P. Bagiella, Emilia Barr, R. Graham Pinder, Diane Hundley, W. Gregory Bluemke, David A. Kronmal, Richard A. Lima, Joao A. C. Kawut, Steven M. TI Relationship of CRP, IL-6, and fibrinogen with right ventricular structure and function: The MESA-Right Ventricle Study SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Systemic inflammation; Right ventricle; Heart failure; Multi-Ethnic Study of Atherosclerosis ID C-REACTIVE PROTEIN; CORONARY-HEART-DISEASE; PULMONARY ARTERIAL-HYPERTENSION; INDIVIDUAL PARTICIPANT METAANALYSIS; GLOBAL CARDIOVASCULAR RISK; AORTIC ENDOTHELIAL-CELLS; MENDELIAN RANDOMIZATION; INTERLEUKIN-6 RECEPTOR; INFLAMMATORY CYTOKINES; ATHEROSCLEROSIS AB Background/objectives: Inflammation contributes to the pathogenesis of disease associated with the left ventricle (LV); yet, our understanding of the effect of inflammation on the right ventricle (RV) is quite limited. Methods and results: The relationships of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with RV morphology and function (from cardiac MRI) were examined in participants free of clinical cardiovascular disease (n = 4009) from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of CRP, IL-6 and fibrinogen with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF). Unadjusted and adjusted analyses revealed strong inverse associations between both CRP and IL-6 with RV mass, RVEDV, RVESV and RVSV (all p < 0.01); there were no associations with RVEF. These relationships remained significant after adjustment for the respective LV parameters and lung function. However, GAM models suggested that extreme values of CRP and IL-6 might have positive associations with RV parameters. Fibrinogen showed significant associations in unadjusted models, but no associations after adjustment or in sensitivity analyses. Conclusion: Levels of CRP and IL-6 are independently associated with RV morphology even after adjustment for the respective LV measure in this multi-ethnic population free of clinical cardiovascular disease. Systemic inflammation may contribute to RV structural changes independent of effects on the LV. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Harhay, Michael O.; Kawut, Steven M.] Univ Penn, Perelman Sch Med, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA. [Harhay, Michael O.; Pinder, Diane; Kawut, Steven M.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Harhay, Michael O.; Kawut, Steven M.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Bagiella, Emilia] Mt Sinai Sch Med, Ctr Biostat, Dept Hlth Evidence & Policy, New York, NY 10029 USA. [Barr, R. Graham] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY USA. [Hundley, W. Gregory] Wake Forest Univ, Bowman Gray Sch Med, Dept Biomed Engn, Winston Salem, NC USA. [Hundley, W. Gregory] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Cardiol Sect, Winston Salem, NC 27103 USA. [Hundley, W. Gregory] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol, Winston Salem, NC USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, Bethesda, MD USA. [Kronmal, Richard A.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Kawut, SM (reprint author), 718 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM kawut@upenn.edu OI Bluemke, David/0000-0002-8323-8086; Harhay, Michael/0000-0002-0553-674X FU National Institutes of Health [R01-HL086719, K24-HL103844, R01-HL077612, N01-HC95159, N01-HC95160, N01-HC95161, N01-HC95162, N01-HC95163, N01-HC95164, N01-HC95165, N01-HC95169] FX This research was supported by the National Institutes of Health (R01-HL086719, K24-HL103844, R01-HL077612, N01-HC95159 through HC95165, and N01-HC95169). NR 44 TC 10 Z9 10 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD OCT 9 PY 2013 VL 168 IS 4 BP 3818 EP 3824 DI 10.1016/j.ijcard.2013.06.028 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 242EG UT WOS:000326219600110 PM 23932860 ER PT J AU Bella, JN Cole, SA Laston, S Almasy, L Comuzzie, A Lee, ET Best, LG Fabsitz, RR Howard, BV MacCluer, JW Roman, MJ Devereux, RB Goring, HHH AF Bella, Jonathan N. Cole, Shelley A. Laston, Sandy Almasy, Laura Comuzzie, Anthony Lee, Elisa T. Best, Lyle G. Fabsitz, Richard R. Howard, Barbara V. MacCluer, Jean W. Roman, Mary J. Devereux, Richard B. Goering, Harald H. H. TI Genome-wide linkage analysis of carotid artery lumen diameter: The strong heart family study SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Genetics; Carotid artery; Ultrasonography; Linkage analysis; Variance components ID STRAIN-STRESS RELATION; AMERICAN-INDIANS; CARDIOVASCULAR-DISEASE; DILATING DIATHESIS; AORTIC-ANEURYSMS; WALL THICKNESS; HYPERTENSION; RISK; MAP; ASSOCIATION AB Background: A significant proportion of the variability in carotid artery lumen diameter is attributable to genetic factors. Methods: Carotid ultrasonography and genotyping were performed in the 3300 American Indian participants in the Strong Heart Family Study (SHFS) to identify chromosomal regions harboring novel genes associated with inter-individual variation in carotid artery lumen diameter. Genome-wide linkage analysis was conducted using standard variance component linkage methods, implemented in SOLAR, based on multipoint identity-by-descent matrices. Results: Genome-wide linkage analysis revealed a significant evidence for linkage for a locus for left carotid artery diastolic and systolic lumen diameters in Arizona SHFS participants on chromosome 7 at 120 cM (lod = 4.85 and 3.77, respectively, after sex and age adjustment, and lod = 3.12 and 2.72, respectively, after adjustment for sex, age, height, weight, systolic and diastolic blood pressure, diabetes mellitus and current smoking). Other regions with suggestive evidence of linkage for left carotid artery diastolic and systolic lumen diameter were found on chromosome 12 at 153 cM (lod = 2.20 and 2.60, respectively, after sex and age adjustment, and lod = 2.44 and 2.16, respectively, after full covariate adjustment) in Oklahoma SHFS participants; suggestive linkage for right carotid artery diastolic and systolic lumen diameter was found on chromosome 9 at 154 cM (lod = 2.72 and 3.19, respectively after sex and age adjustment, and lod = 2.36 and 2.21, respectively, after full covariate adjustment) in Oklahoma SHFS participants. Conclusion: We found significant evidence for loci influencing carotid artery lumen diameter on chromosome 7q and suggestive linkage on chromosomes 12q and 9q. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Bella, Jonathan N.] Bronx Lebanon Hosp Ctr, Bronx, NY 10457 USA. [Bella, Jonathan N.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Cole, Shelley A.; Laston, Sandy; Almasy, Laura; Comuzzie, Anthony; MacCluer, Jean W.; Goering, Harald H. H.] Texas Biomed Res Inst, San Antonio, TX USA. [Lee, Elisa T.] Univ Oklahoma, Sch Publ Hlth Serv, Oklahoma City, OK USA. [Best, Lyle G.] Missouri Breaks Ind Res Inc, Timber Lake, SD USA. [Fabsitz, Richard R.] NHLBI, Bethesda, MD 20892 USA. [Howard, Barbara V.] Medstar Hlth Res Inst, Hyattsville, MD USA. [Roman, Mary J.; Devereux, Richard B.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. RP Bella, JN (reprint author), Bronx Lebanon Hosp Ctr, Div Cardiol, 1650 Grand Concourse,12th Floor, Bronx, NY 10457 USA. EM jonnbella@earthlink.net FU National Institutes of Health, Bethesda, MD [U01-HL41642, HL41652, HL41654, HL65520, HL65521, M10RR0047-34]; [MH059490] FX Grant support: This study is supported by cooperative agreements U01-HL41642, HL41652, HL41654, HL65520, HL65521 and grant M10RR0047-34 (General Clinical Research Center) from the National Institutes of Health, Bethesda, MD. Development of SOLAR is supported by grant MH059490. NR 45 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD OCT 9 PY 2013 VL 168 IS 4 BP 3902 EP 3908 DI 10.1016/j.ijcard.2013.06.048 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 242EG UT WOS:000326219600122 PM 23871337 ER PT J AU Huang, J AF Huang, Jing TI Thematic series: Epigenetics in stem cells and cancer SO CELL AND BIOSCIENCE LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Huang, J (reprint author), NCI, Bethesda, MD 20892 USA. EM huangj3@mail.nih.gov RI Huang, Jing/A-2566-2009 OI Huang, Jing/0000-0002-7163-5156 NR 7 TC 3 Z9 3 U1 1 U2 5 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 OCT 9 PY 2013 VL 3 AR 38 DI 10.1186/2045-3701-3-38 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 243VK UT WOS:000326346200001 PM 24499563 ER PT J AU Shin, MH He, YL Huang, J AF Shin, Min Hwa He, Yunlong Huang, Jing TI Embryonic stem cells shed new light on the developmental roles of p53 SO CELL AND BIOSCIENCE LA English DT Review DE p53; Development; Embryonic stem cells; Cancer ID CELLULAR TUMOR-ANTIGEN; WILD-TYPE P53; DNA-DAMAGE; TGF-BETA; TRANSCRIPTIONAL REGULATION; P53-DEPENDENT APOPTOSIS; MATERNAL REPRODUCTION; SUPPRESSOR P53; BREAST CANCERS; GENOME-WIDE AB The viability and subtle developmental defects of p53 knockout mice suggest that p53 does not play major role in development. However, contradictory evidence also exists. This discrepancy mainly results from the lack of molecular and cellular mechanisms and the general fact that p53 activation requires stresses. Recent studies of p53 in mouse and human ES cells and induced pluripotent stem (iPS) cells shed new light on the mechanisms of the developmental roles of p53. This review summarizes these new studies that support the developmental roles of p53, highlights the possible underlying molecular mechanisms, and discusses the potential relationship between the developmental roles and the tumor suppressive function of p53. In summary, the molecular mechanisms underlying the developmental roles of p53 are emerging, and the developmental roles and tumor suppressive function of p53 may be closely related. C1 [Shin, Min Hwa; He, Yunlong; Huang, Jing] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20814 USA. RP Huang, J (reprint author), NCI, Lab Canc Biol & Genet, NIH, 37 Convent Dr,Room 3140A, Bethesda, MD 20814 USA. EM huangj3@mail.nih.gov RI Huang, Jing/A-2566-2009; He, Yunlong/D-1278-2017 OI Huang, Jing/0000-0002-7163-5156; FU [1ZIABC011158] FX We apologize to our colleagues whose work cannot be referenced in this review because of the page limit. We thank Mangmang Li, Nan Roche, and the reviewers for critically reading the manuscript. We also thank the NIH Fellows Editorial Board for their review of the manuscript. JH's laboratory was funded by the intramural fund, 1ZIABC011158. NR 81 TC 2 Z9 2 U1 2 U2 10 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 OCT 9 PY 2013 VL 3 AR 42 DI 10.1186/2045-3701-3-42 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 243VK UT WOS:000326346200005 PM 24171803 ER PT J AU Remy, KE Qiu, P Li, Y Cui, XZ Eichacker, PQ AF Remy, Kenneth E. Qiu, Ping Li, Yan Cui, Xizhong Eichacker, Peter Q. TI B. anthracis associated cardiovascular dysfunction and shock: the potential contribution of both non-toxin and toxin components SO BMC MEDICINE LA English DT Review DE Bacillus anthracis; Anthrax; Cell wall components; Lethal and edema toxins; Metalloproteases; Cardiovascular dysfunction; Shock ID LETHAL TOXIN; BACILLUS-ANTHRACIS; EDEMA TOXIN; CYCLASE ACTIVITY; KINASE PATHWAY; DRUG-USERS; MODEL; ACTIVATION; INFECTION; SEPSIS AB The development of cardiovascular dysfunction and shock in patients with invasive Bacillus anthracis infection has a particularly poor prognosis. Growing evidence indicates that several bacterial components likely play important pathogenic roles in this injury. As with other pathogenic Gram-positive bacteria, the B. anthracis cell wall and its peptidoglycan constituent produce a robust inflammatory response with its attendant tissue injury, disseminated intravascular coagulation and shock. However, B. anthracis also produces lethal and edema toxins that both contribute to shock. Growing evidence suggests that lethal toxin, a metalloprotease, can interfere with endothelial barrier function as well as produce myocardial dysfunction. Edema toxin has potent adenyl cyclase activity and may alter endothelial function, as well as produce direct arterial and venous relaxation. Furthermore, both toxins can weaken host defense and promote infection. Finally, B. anthracis produces non-toxin metalloproteases which new studies show can contribute to tissue injury, coagulopathy and shock. In the future, an understanding of the individual pathogenic effects of these different components and their interactions will be important for improving the management of B. anthracis infection and shock. C1 [Remy, Kenneth E.; Qiu, Ping; Li, Yan; Cui, Xizhong; Eichacker, Peter Q.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. EM peichacker@mail.cc.nih.gov OI Remy, Kenneth/0000-0001-5222-9884 FU NIH, Clinical Center, Critical Care Medicine Department FX This research was supported by the Intramural Program of the NIH, Clinical Center, Critical Care Medicine Department. NR 65 TC 7 Z9 7 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD OCT 9 PY 2013 VL 11 AR 217 DI 10.1186/1741-7015-11-217 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 241QB UT WOS:000326181000001 PM 24107194 ER PT J AU Castoria, G Giovannelli, P Di Donato, M Hayashi, R Arra, C Appella, E Auricchio, F Migliaccio, A AF Castoria, Gabriella Giovannelli, Pia Di Donato, Marzia Hayashi, Ryo Arra, Claudio Appella, Ettore Auricchio, Ferdinando Migliaccio, Antimo TI Targeting Androgen Receptor/Src Complex Impairs the Aggressive Phenotype of Human Fibrosarcoma Cells SO PLOS ONE LA English DT Article ID DEPENDENT NUCLEAR EXPORT; SOFT-TISSUE SARCOMAS; BREAST-CANCER CELLS; ESTRADIOL-RECEPTOR; MATRIX METALLOPROTEINASES; DNA-SYNTHESIS; STEROID-RECEPTORS; GROWTH; SRC; PEPTIDE AB Background: Hormones and growth factors influence the proliferation and invasiveness of human mesenchymal tumors. The highly aggressive human fibrosarcoma HT1080 cell line harbors classical androgen receptor (AR) that responds to androgens triggering cell migration in the absence of significant mitogenesis. As occurs in many human cancer cells, HT1080 cells also express epidermal growth factor receptor (EGFR). Experimental: Findings: We report that the pure anti-androgen Casodex inhibits the growth of HT1080 cell xenografts in immune-depressed mice, revealing a novel role of AR in fibrosarcoma progression. In HT1080 cultured cells EGF, but not androgens, robustly increases DNA synthesis. Casodex abolishes the EGF mitogenic effect, implying a crosstalk between EGFR and AR. The mechanism underlying this crosstalk has been analyzed using an AR-derived small peptide, S1, which prevents AR/Src tyrosine kinase association and androgen-dependent Src activation. Present findings show that in HT1080 cells EGF induces AR/Src Association, and the S1 peptide abolishes both the assembly of this complex and Src activation. The S1 peptide inhibits EGF-stimulated DNA synthesis, cell matrix metalloproteinase-9 (MMP-9) secretion and invasiveness of HT1080 cells. Both Casodex and S1 peptide also prevent DNA synthesis and migration triggered by EGF in various human cancer-derived cells (prostate, breast, colon and pancreas) that express AR. Conclusion: This study shows that targeting the AR domain involved in AR/ Src association impairs EGF signaling in human fibrosarcoma HT1080 cells. The EGF-elicited processes inhibited by the peptide (DNA synthesis, MMP-9 secretion and invasiveness) cooperate in increasing the aggressive phenotype of HT1080 cells. Therefore, AR represents a new potential therapeutic target in human fibrosarcoma, as supported by Casodex inhibition of HT1080 cell xenografts. The extension of these findings in various human cancer-derived cell lines highlights the conservation of this process across divergent cancer cells and identifies new potential targets in the therapeutic approach to human cancers. C1 [Castoria, Gabriella; Giovannelli, Pia; Di Donato, Marzia; Auricchio, Ferdinando; Migliaccio, Antimo] Univ Naples 2, Dept Biochem Biophys & Gen Pathol, Naples, Italy. [Arra, Claudio] Ist Diag & Cura Tumori Fdn G Pascale, Naples, Italy. [Hayashi, Ryo; Appella, Ettore] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Migliaccio, A (reprint author), Univ Naples 2, Dept Biochem Biophys & Gen Pathol, Naples, Italy. EM antimo.migliaccio@unina2.it OI Arra, Claudio/0000-0003-3162-2091; Di Donato, Marzia/0000-0001-7207-826X; Castoria, Gabriella/0000-0002-0576-4494; Migliaccio, Antimo/0000-0002-4197-2055 FU Italian Association for Cancer Research (A.I.R.C.) [IG 11520]; Italian Ministry for University and Scientific Research (P.R.I.N) [2010NFEB9L_002]; A.I.R.C. FX The Italian Association for Cancer Research (A.I.R.C.; grant number IG 11520 to AM), and the Italian Ministry for University and Scientific Research (P.R.I.N 2010-2011; grant number 2010NFEB9L_002 to GC) funded this work. Pia Giovannelli is supported by a fellowship from A.I.R.C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 9 Z9 9 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 OCT 9 PY 2013 VL 8 IS 10 AR e76899 DI 10.1371/journal.pone.0076899 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 236PJ UT WOS:000325810900100 PM 24130806 ER PT J AU Mattoo, AR Pastan, I FitzGerald, D AF Mattoo, Abid R. Pastan, Ira FitzGerald, David TI Combination Treatments with the PKC Inhibitor, Enzastaurin, Enhance the Cytotoxicity of the Anti-Mesothelin Immunotoxin, SS1P SO PLOS ONE LA English DT Article ID PROTEIN-KINASE-C; ACUTE LYMPHOBLASTIC-LEUKEMIA; LUNG-CANCER CELLS; PSEUDOMONAS EXOTOXIN; RECOMBINANT IMMUNOTOXIN; PHASE-I; HEMATOLOGIC MALIGNANCIES; MONOCLONAL-ANTIBODIES; THERAPEUTIC TARGET; IMMUNOGENICITY AB Activated protein kinase C (PKC) contributes to tumor survival and proliferation, provoking the development of inhibitory agents as potential cancer therapeutics. Immunotoxins are antibody-based recombinant proteins that employ antibody fragments for cancer targeting and bacterial toxins as the cytotoxic agent. Pseudomonas exotoxin-based immunotoxins act via the ADP-ribosylation of EF2 leading to the enzymatic inhibition of protein synthesis. Combining PKC inhibitors with the immunotoxin SS1P, targeted to surface mesothelin, was undertaken to explore possible therapeutic strategies. Enzastaurin but not two other PKC inhibitors combined with SS1P to produce synergistic cell death via apoptosis. Mechanistic insights of the synergistic killing centered on the complete loss of the prosurvival Bcl2 protein, Mcl-1, the loss of AKT and the activation of caspase 3/7. Synergy was most evident when cells exhibited resistance to the immunotoxin alone. Further, because PKC inhibition by itself was not sufficient to enhance SS1P action, enzastaurin must target other kinases that are involved in the immunotoxin pathway. C1 [Mattoo, Abid R.; Pastan, Ira; FitzGerald, David] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP FitzGerald, D (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM fitzgerd@helix.nih.gov OI MATTOO, ABID/0000-0002-4947-0113 FU National Cancer Institute, Center for Cancer Research at the National Institutes of Health, Department of Health and Human Services FX This research was supported by funding from the Intramural Research Program, National Cancer Institute, Center for Cancer Research at the National Institutes of Health, 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 39 TC 9 Z9 9 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 9 PY 2013 VL 8 IS 10 AR e75576 DI 10.1371/journal.pone.0075576 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 236PJ UT WOS:000325810900044 PM 24130723 ER PT J AU Poudyal, D Cui, XL Le, PM Hofseth, AB Windust, A Nagarkatti, M Nagarkatti, PS Schetter, AJ Harris, CC Hofseth, LJ AF Poudyal, Deepak Cui, Xiangli Le, Phuong Mai Hofseth, Anne B. Windust, Anthony Nagarkatti, Mitzi Nagarkatti, Prakash S. Schetter, Aaron J. Harris, Curtis C. Hofseth, Lorne J. TI A Key Role of microRNA-29b for the Suppression of Colon Cancer Cell Migration by American Ginseng SO PLOS ONE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MATRIX METALLOPROTEINASES; BREAST-CANCER; COLORECTAL-CANCER; PROSTATE-CANCER; GENE-EXPRESSION; LIVER METASTASIS; TUMOR INVASION; MOUSE COLITIS; LUNG-CANCER AB Metastasis of colon cancer cells increases the risk of colon cancer mortality. We have recently shown that American ginseng prevents colon cancer, and a Hexane extract of American Ginseng (HAG) has particularly potent anti-inflammatory and anticancer properties. Dysregulated microRNA (miR) expression has been observed in several disease conditions including colon cancer. Using global miR expression profiling, we observed increased miR-29b in colon cancer cells following exposure to HAG. Since miR-29b plays a role in regulating the migration of cancer cells, we hypothesized that HAG induces miR-29b expression to target matrix metalloproteinase-2 (MMP-2) thereby suppressing the migration of colon cancer cells. Results are consistent with this hypothesis. Our study supports the understanding that targeting MMP-2 by miR-29b is a mechanism by which HAG suppresses the migration of colon cancer cells. C1 [Poudyal, Deepak; Cui, Xiangli; Hofseth, Anne B.; Hofseth, Lorne J.] Univ S Carolina, Dept Drug Discovery & Biomed Sci, South Carolina Coll Pharm, Columbia, SC 29208 USA. [Cui, Xiangli] Shanxi Med Univ, Taiyuan, Shanxi, Peoples R China. [Le, Phuong Mai; Windust, Anthony] Natl Res Council Canada, Inst Natl Measurement Stand, Ottawa, ON K1A 0R6, Canada. [Nagarkatti, Mitzi; Nagarkatti, Prakash S.] Univ S Carolina, Sch Med, Columbia, SC USA. [Schetter, Aaron J.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hofseth, LJ (reprint author), Univ S Carolina, Dept Drug Discovery & Biomed Sci, South Carolina Coll Pharm, Columbia, SC 29208 USA. EM hofseth@cop.sc.edu OI Nagarkatti, Mitzi/0000-0002-5977-5615 FU Center for CAM Research on Autoimmune and Inflammatory Diseases, NIH [1P01AT003961-01A1]; COBRE [P20RR17698-01] FX This work was supported by the Center for CAM Research on Autoimmune and Inflammatory Diseases, NIH grant 1P01AT003961-01A1 (PN, LJH, MN), and the COBRE funded University of South Carolina Center for Colon Cancer Research, NIH grant P20RR17698-01 (Franklin Berger, Director). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 16 Z9 16 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 9 PY 2013 VL 8 IS 10 AR UNSP e75034 DI 10.1371/journal.pone.0075034 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 236PJ UT WOS:000325810900016 PM 24130681 ER PT J AU Tompkins, VS Han, SS Olivier, A Syrbu, S Bair, T Button, A Jacobus, L Wang, ZB Lifton, S Raychaudhuri, P Morse, HC Weiner, G Link, B Smith, BJ Janz, S AF Tompkins, Van S. Han, Seong-Su Olivier, Alicia Syrbu, Sergei Bair, Thomas Button, Anna Jacobus, Laura Wang, Zebin Lifton, Samuel Raychaudhuri, Pradip Morse, Herbert C., III Weiner, George Link, Brian Smith, Brian J. Janz, Siegfried TI Identification of Candidate B-Lymphoma Genes by Cross-Species Gene Expression Profiling SO PLOS ONE LA English DT Article ID TRANSCRIPTION FACTOR FOXM1; PLASMA-CELL NEOPLASMS; C-MYC; BURKITTS-LYMPHOMA; TUMOR-SUPPRESSOR; CANCER; TARGET; PROGRESSION; CYCLE; RESISTANCE AB Comparative genome-wide expression profiling of malignant tumor counterparts across the human-mouse species barrier has a successful track record as a gene discovery tool in liver, breast, lung, prostate and other cancers, but has been largely neglected in studies on neoplasms of mature B-lymphocytes such as diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We used global gene expression profiles of DLBCL-like tumors that arose spontaneously in Myc-transgenic C57BL/6 mice as a phylogenetically conserved filter for analyzing the human DLBCL transcriptome. The human and mouse lymphomas were found to have 60 concordantly deregulated genes in common, including 8 genes that Cox hazard regression analysis associated with overall survival in a published landmark dataset of DLBCL. Genetic network analysis of the 60 genes followed by biological validation studies indicate FOXM1 as a candidate DLBCL and BL gene, supporting a number of studies contending that FOXM1 is a therapeutic target in mature B cell tumors. Our findings demonstrate the value of the "mouse filter" for genomic studies of human B-lineage neoplasms for which a vast knowledge base already exists. C1 [Tompkins, Van S.; Han, Seong-Su; Olivier, Alicia; Syrbu, Sergei; Lifton, Samuel; Janz, Siegfried] Univ Iowa, Dept Pathol, Carver Coll Med, Iowa City, IA 52242 USA. [Bair, Thomas] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Button, Anna; Smith, Brian J.] Univ Iowa, Dept Biostat, Coll Publ Hlth, Iowa City, IA USA. [Jacobus, Laura; Weiner, George; Link, Brian] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. [Syrbu, Sergei; Jacobus, Laura; Weiner, George; Link, Brian; Smith, Brian J.; Janz, Siegfried] Univ Iowa, Holden Comprehens Canc Ctr, Carver Coll Med, Iowa City, IA 52242 USA. [Wang, Zebin; Raychaudhuri, Pradip] Univ Illinois, Coll Med, Dept Biochem & Mol Genet, Chicago, IL USA. [Lifton, Samuel] Univ Iowa, Dept Stat & Actuarial Sci, Coll Liberal Arts & Sci, Iowa City, IA 52242 USA. [Morse, Herbert C., III] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Janz, S (reprint author), Univ Iowa, Dept Pathol, Carver Coll Med, Iowa City, IA 52242 USA. EM siegfried-janz@uiowa.edu OI Button, Anna/0000-0002-8540-6047; Morse, Herbert/0000-0002-9331-3705; Tompkins, Van/0000-0003-1279-8075 FU UI/MC Lymphoma SPORE [5 P50 CA097274]; American Cancer Society [PF0818001L2B]; NIH [T32 HL07734]; Multiple Myeloma Research and International Waldenstrom's Macroglobulinemia Foundations; NCI [R01CA151354]; NIH, National institute of Allergy and Infectious Diseases (HCM) FX This work was supported in part by a Developmental Research Award of the UI/MC Lymphoma SPORE 5 P50 CA097274 to SJ. VST was supported by Postdoctoral Fellowship PF0818001L2B from the American Cancer Society and NIH T32 HL07734. This work was also supported, in part, by research awards from the Multiple Myeloma Research and International Waldenstrom's Macroglobulinemia Foundations (SJ) and R01CA151354 from the NCI (SJ), as well as the Intramural Research Program of the NIH, National institute of Allergy and Infectious Diseases (HCM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 3 Z9 3 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 9 PY 2013 VL 8 IS 10 AR e76889 DI 10.1371/journal.pone.0076889 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 236PJ UT WOS:000325810900097 PM 24130802 ER PT J AU Ferguson, D Koo, JW Feng, J Heller, E Rabkin, J Heshmati, M Renthal, W Neve, R Liu, XC Shao, NY Sartorelli, V Shen, L Nestler, EJ AF Ferguson, Deveroux Koo, Ja Wook Feng, Jian Heller, Elizabeth Rabkin, Jacqui Heshmati, Mitra Renthal, William Neve, Rachael Liu, Xiaochuan Shao, Ningyi Sartorelli, Vittorio Shen, Li Nestler, Eric J. TI Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DELTA-FOSB; GENE-EXPRESSION; EPIGENETIC MECHANISMS; STRUCTURAL PLASTICITY; ADDICTION; SIRTUINS; REWARD; RESPONSES; EXPOSURE; BEHAVIOR AB Sirtuins (SIRTs), class III histone deacetylases, are well characterized for their control of cellular physiology in peripheral tissues, but their influence in brain under normal and pathological conditions remains poorly understood. Here, we establish an essential role for SIRT1 and SIRT2 in regulating behavioral responses to cocaine and morphine through actions in the nucleus accumbens (NAc), a key brain reward region. We show that chronic cocaine administration increases SIRT1 and SIRT2 expression in the mouse NAc, while chronic morphine administration induces SIRT1 expression alone, with no regulation of all other sirtuin family members observed. Drug induction of SIRT1 and SIRT2 is mediated in part at the transcriptional level via the drug-induced transcription factor Delta FosB and is associated with robust histone modifications at the Sirt1 and Sirt2 genes. Viral-mediated overexpression of SIRT1 or SIRT2 in the NAc enhances the rewarding effects of both cocaine and morphine. In contrast, the local knockdown of SIRT1 from theNAcof floxed Sirt1 mice decreases drug reward. Such behavioral effects of SIRT1 occur in concert with its regulation of numerous synaptic proteins in NAc as well as with SIRT1-mediated induction of dendritic spines on NAc medium spiny neurons. These studies establish sirtuins as key mediators of the molecular and cellular plasticity induced by drugs of abuse in NAc, and of the associated behavioral adaptations, and point toward novel signaling pathways involved in drug action. C1 [Ferguson, Deveroux; Koo, Ja Wook; Feng, Jian; Heller, Elizabeth; Rabkin, Jacqui; Heshmati, Mitra; Liu, Xiaochuan; Shao, Ningyi; Shen, Li; Nestler, Eric J.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Ferguson, Deveroux; Koo, Ja Wook; Feng, Jian; Heller, Elizabeth; Rabkin, Jacqui; Heshmati, Mitra; Liu, Xiaochuan; Shao, Ningyi; Shen, Li; Nestler, Eric J.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Renthal, William] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 78229 USA. [Neve, Rachael] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, Bethesda, MD 20892 USA. RP Nestler, EJ (reprint author), Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. EM Eric.Nestler@mssm.edu RI Shen, Li/B-3562-2008; SHAO, Ning-Yi/N-4947-2015; OI Shen, Li/0000-0002-5190-2851; SHAO, Ning-Yi/0000-0003-4231-828X; Ferguson, Deveroux/0000-0001-9302-5992 FU National Institute on Drug Abuse; National Alliance for Research on Schizophrenia and Depression; UNCF/MERCK Science Initiative; Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institutes of Health FX This work was supported by grants from National Institute on Drug Abuse, National Alliance for Research on Schizophrenia and Depression, and the UNCF/MERCK Science Initiative; and in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 43 TC 28 Z9 29 U1 0 U2 8 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 OCT 9 PY 2013 VL 33 IS 41 BP 16088 EP 16098 DI 10.1523/JNEUROSCI.1284-13.2013 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 234LE UT WOS:000325644800005 PM 24107942 ER PT J AU Kokkinaki, M Abu-Asab, M Gunawardena, N Ahern, G Javidnia, M Young, J Golestaneh, N AF Kokkinaki, Maria Abu-Asab, Mones Gunawardena, Nishantha Ahern, Gerard Javidnia, Monica Young, John Golestaneh, Nady TI Klotho Regulates Retinal Pigment Epithelial Functions and Protects Against Oxidative Stress SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GROWTH-FACTOR SECRETION; HAMSTER MELANOMA-CELLS; MACULAR DEGENERATION; ENDOTHELIAL-CELLS; TRANSCRIPTION FACTOR; L-TYROSINE; OUTER SEGMENTS; HUMAN RPE; L-DOPA; BRUCHS MEMBRANE AB The retinal pigment epithelium (RPE) is a highly specialized CNS tissue that plays crucial roles in retinal homeostasis. Age-related morphological changes in the RPE have been associated with retinal degenerative disorders; our understanding of the underlying molecular mechanisms, however, remains incomplete. Here we report on a key role of Klotho (Kl), an aging-suppressor gene, in retinal health and RPE physiology. Kl(-/-) mice show RPE and photoreceptor degeneration, reduced pigment synthesis in the RPE, and impaired phagocytosis of the outer segment of the photoreceptors. Klotho protein (KL) is expressed in primary cultured human RPE, and regulates pigment synthesis by increasing the expression of MITF (microphthalmia transcription factor) and TYR (tyrosinase), two pivotal genes in melanogenesis. Importantly, KL increases phagocytosis in cultured RPE by inducing gene expression of MERTK/AXL/TYRO3. These effects of KL are mediated through cAMP-PKA-dependent phosphorylation of transcription factor CREB. In cultured human RPE, KL increases the L-3,4-dihydroxyphenylalanine synthesis and inhibits vascular endothelial growth factor (VEGF) secretion from basal membrane by inhibiting IGF-1 signaling and VEGF receptor 2 phosphorylation. KL also regulates the expression of stress-related genes in RPE, lowers the production of reactive oxygen species, and thereby, protects RPE from oxidative stress. Together, our results demonstrate a critical function for KL in mouse retinal health in vivo, and a protective role toward human RPE cells in vitro. We conclude that KL is an important regulator of RPE homeostasis, and propose that an age-dependent decline of KL expression may contribute to RPE degeneration and retinal pathology. C1 [Kokkinaki, Maria; Golestaneh, Nady] Georgetown Univ, Med Ctr, Dept Ophthalmol, Washington, DC 20057 USA. [Ahern, Gerard; Javidnia, Monica] Georgetown Univ, Med Ctr, Dept Physiol & Pharmacol, Washington, DC 20057 USA. [Golestaneh, Nady] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20057 USA. [Gunawardena, Nishantha; Golestaneh, Nady] Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, Washington, DC 20057 USA. [Young, John] Howard Univ, Coll Med, Dept Anat, Washington, DC 20059 USA. [Abu-Asab, Mones] NEI, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Golestaneh, N (reprint author), Georgetown Univ, Med Ctr, Dept Ophthalmol, 3900 Reservoir Rd NW,Med Dent Bldg,Room NE203, Washington, DC 20057 USA. EM ncg8@georgetown.edu OI Abu-Asab, Mones/0000-0002-4047-1232 NR 95 TC 17 Z9 18 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 9 PY 2013 VL 33 IS 41 BP 16346 EP 16359 DI 10.1523/JNEUROSCI.0402-13.2013 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 234LE UT WOS:000325644800028 PM 24107965 ER PT J AU Zhang, AX Schu, DJ Tjaden, BC Storz, G Gottesman, S AF Zhang, Aixia Schu, Daniel J. Tjaden, Brian C. Storz, Gisela Gottesman, Susan TI Mutations in Interaction Surfaces Differentially Impact E. coli Hfq Association with Small RNAs and Their mRNA Targets SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE DsrA; ArcZ; McaS; RyhB; ChiX ID SM-LIKE PROTEIN; SMALL REGULATORY RNA; BINDING SMALL RNAS; RYHB SMALL RNA; ESCHERICHIA-COLI; SOLUBLE-RNA; RPOS TRANSLATION; STRESS-RESPONSE; NONCODING RNAS; DSRA AB The RNA chaperone protein Hfq is required for the function of all small RNAs (sRNAs) that regulate mRNA stability or translation by limited base pairing in Escherichia coli. While there have been numerous in vitro studies to characterize Hfq activity and the importance of specific residues, there has been only limited characterization of Hfq mutants in vivo. Here, we use a set of reporters as well as co-immunoprecipitation to examine 14 Hfq mutants expressed from the E. coli chromosome. The majority of the proximal face residues, as expected, were important for the function of sRNAs. The failure of sRNAs to regulate target mRNAs in these mutants can be explained by reduced sRNA accumulation. Two of the proximal mutants, D9A and F39A, acted differently from the others in that they had mixed effects on different sRNA/mRNA pairs and, in the case of F39A, showed differential sRNA accumulation. Mutations of charged residues at the rim of Hfq interfered with positive regulation and gave mixed effects for negative regulation. Some, but not all, sRNAs accumulated to lower levels in rim mutants, suggesting qualitative differences in how individual sRNAs are affected by Hfq. The distal face mutants were expected to disrupt binding of ARN motifs found in mRNAs. They were more defective for positive regulation than negative regulation at low mRNA expression, but the defects could be suppressed by higher levels of mRNA expression. We discuss the implications of these observations for Hfq binding to RNA and mechanisms of action. Published by Elsevier Ltd. C1 [Zhang, Aixia; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. [Schu, Daniel J.; Gottesman, Susan] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. [Tjaden, Brian C.] Wellesley Coll, Dept Comp Sci, Wellesley, MA 02481 USA. RP Storz, G (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Bethesda, MD 20892 USA. EM storzg@mail.nih.gov; gottesms@helix.nih.gov OI Storz, Gisela/0000-0001-6698-1241 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Science Foundation [MCB0919808] FX We thank Nadim Majdalani and Nicholas De Lay for providing strains and technical advice. We also thank Joyce Fu and Daniel Fu for assistance in constructing some mutants and Sarah Woodson and colleagues for helpful discussions. We thank Taylor Updegrove, Sarah Woodson, Kumaran Ramamurthi, and Nadim Majdalani for their comments on the manuscript. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (SG), in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (GS), and by the National Science Foundation (grant MCB0919808 to BCT). NR 53 TC 42 Z9 44 U1 0 U2 17 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 OCT 9 PY 2013 VL 425 IS 19 BP 3678 EP 3697 DI 10.1016/j.jmb.2013.01.006 PG 20 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 226MP UT WOS:000325040800009 PM 23318956 ER PT J AU Yoon, JH Abdelmohsen, K Gorospe, M AF Yoon, Je-Hyun Abdelmohsen, Kotb. Gorospe, Myriam TI Posttranscriptional Gene Regulation by Long Noncoding RNA SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Review DE lncRNA; lincRNA; RNA-binding protein; mRNA turnover; translational regulation ID GLOBAL INSIGHTS; GENOME; TRANSCRIPTION; STABILITY; TRANSLATION; EXPRESSION; PRODUCT; DISEASE; MALAT1; CELLS AB Eukaryotic cells transcribe a vast number of noncoding RNA species. Among them, long noncoding RNAs (lncRNAs) have been widely implicated in the regulation of gene transcription. However, examples of posttranscriptional gene regulation by lncRNAs are emerging. Through extended base-pairing, lncRNAs can stabilize or promote the translation of target mRNAs, while partial base-pairing facilitates mRNA decay or inhibits target mRNA translation. In the absence of complementarity, lncRNAs can suppress precursor mRNA splicing and translation by acting as decoys of RNA-binding proteins or microRNAs and can compete for microRNA-mediated inhibition leading to increased expression of the mRNA. Through these regulatory mechanisms, lncRNAs can elicit differentiation, proliferation, and cytoprotective programs, underscoring the rising recognition of lncRNA roles in human disease. In this review, we summarize the mechanisms of posttranscriptional gene regulation by lncRNAs identified until now. Published by Elsevier Ltd. C1 [Yoon, Je-Hyun; Abdelmohsen, Kotb.; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov OI abdelmohsen, Kotb/0000-0001-6240-5810 FU National Institute on Aging-Intramural Research Program, National Institutes of Health FX J.H.Y., K.A., and M.G. were supported by the National Institute on Aging-Intramural Research Program, National Institutes of Health. NR 44 TC 111 Z9 119 U1 5 U2 94 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 OCT 9 PY 2013 VL 425 IS 19 BP 3723 EP 3730 DI 10.1016/j.jmb.2012.11.024 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 226MP UT WOS:000325040800012 PM 23178169 ER PT J AU Wallace, KB Kissling, GE Melnick, RL Blystone, CR AF Wallace, K. B. Kissling, G. E. Melnick, R. L. Blystone, C. R. TI Structure-activity relationships for perfluoroalkane-induced in vitro interference with rat liver mitochondrial respiration SO TOXICOLOGY LETTERS LA English DT Article DE Perfluoroalkyl acids (PFAA); Mitochondria; Structure-activity ID ACTIVATED-RECEPTOR-ALPHA; PERFLUOROOCTANOIC ACID; PPAR-ALPHA; PERMEABILITY TRANSITION; NUCLEAR RECEPTORS; MOUSE; SULFONAMIDE; GAMMA; BIOENERGETICS; CHEMICALS AB Perfluorinated alkyl acids (PFAAs) represent a broad class of commercial products designed primarily for the coatings industry. However, detection of residues globally in a variety of species led to the discontinuation of production in the U.S. Although PFAAs cause activation of the PPAR alpha and CAR nuclear receptors, interference with mitochondrial bioenergetics has been implicated as an alternative mechanism of cytotoxicity. Although the mechanisms by which the eight carbon chain PFAAs interfere with mitochondrialbioenergetics are fairly well described, the activities of the more highly substituted or shorter chain PFAAsare far less well characterized. The current investigation was designed to explore structure-activity relationships by which PFAAs interfere with mitochondrial respiration in vitro. Freshly isolated rat livermitochondria were incubated with one of 16 different PFAAs, including perfluorinated carboxylic, acetic, and sulfonic acids, sulfonamides and sulfamido acetates, and alcohols. The effect on mitochondrial respiration was measured at five concentrations and dose-response curves were generated to describe theeffects on state 3 and 4 respiration and respiratory control. With the exception of PFOS, all PFAAs at sufficiently high concentrations (>20 mu M) stimulated state 4 and inhibited state 3 respiration. Stimulation of state 4 respiration was most pronounced for the carboxylic acids and the sulfonamides, which supports prior evidence that the perfluorinated carboxylic and acetic acids induce the mitochondrial permeability transition, whereas the sulfonamides are protonophoric uncouplers of oxidative phosphorylation. In both cases, potency increased with increasing carbon number, with a prominent inflection point between the six and eight carbon congeners. The results provide a foundation for classifying PFAAs according to specific modes of mitochondrial activity and, in combination with toxicokinetic considerations, establishing structure-activity-based boundaries for initial estimates of risk for noncancer endpoints for PFAAs for which minimal in vivo toxicity testing currently exists. (C) 2013 The Authors. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Wallace, K. B.] Univ Minnesota, Sch Med, Dept Biochem & Mol Biol, Duluth, MN 55812 USA. [Kissling, G. E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Melnick, R. L.; Blystone, C. R.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Wallace, KB (reprint author), Univ Minnesota, Sch Med, Dept Biochem & Mol Biol, Duluth, MN 55812 USA. EM kwallace@d.umn.edu FU NIEHS NTP [HHSN27320062005C] FX The authors acknowledge the expert technical assistant by Mr. Josiah Ray in conducting the mitochondrial respiration experiments. This work was supported in-part by a contract from the NIEHS NTP (HHSN27320062005C). We would like to thank Drs. Michael DeVito and Kristen Ryan for their comments on the manuscript. NR 26 TC 5 Z9 5 U1 5 U2 24 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD OCT 9 PY 2013 VL 222 IS 3 BP 257 EP 264 DI 10.1016/j.toxlet.2013.07.025 PG 8 WC Toxicology SC Toxicology GA 228DW UT WOS:000325166700003 PM 23954199 ER PT J AU Peterlin, BL Rosso, AL Williams, MA Rosenberg, JR Haythornthwaite, JA Merikangas, KR Gottesman, RF Bond, DS He, JP Zonderman, AB AF Peterlin, B. Lee Rosso, Andrea L. Williams, Michelle A. Rosenberg, Jason R. Haythornthwaite, Jennifer A. Merikangas, Kathleen R. Gottesman, Rebecca F. Bond, Dale S. He, Jian-Ping Zonderman, Alan B. TI Episodic migraine and obesity and the influence of age, race, and sex SO NEUROLOGY LA English DT Article ID BODY-MASS INDEX; REPLICATION NCS-R; VISCERAL ADIPOSE-TISSUE; WEIGHT-GAIN; COMORBIDITY; EPIDEMIOLOGY; HEADACHE; POPULATION; WOMEN; ASSOCIATION AB Objective: To evaluate the episodic migraine (EM)-obesity association and the influence of age, race, and sex on this relationship. Methods: We examined the EM-obesity association and the influence of age, race, and sex in 3,862 adult participants of both black and white race interviewed in the National Comorbidity Survey Replication. EM diagnostic criteria were based on the International Classification of Headache Disorders. Body mass index was classified as underweight (<18.5 kg/m(2)), normal (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), or obese (>30 kg/m(2)). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for EM were estimated using logistic regression. Models were stratified by age (<50/>= 50 years), race (white/black), and sex (male/female). Results: A total of 188 participants fulfilled criteria for EM. In all participants, the adjusted odds of EM were 81% greater in individuals who were obese compared with those of normal weight (OR 1.81; 95% CI: 1.27-2.57; p = 0.001), with a significant trend of increasing odds of EM with increasing obesity status from normal weight to overweight to obese (p = 0.001). In addition, stratified analyses demonstrated that the odds of EM were greater in obese as compared with normal-weight individuals who were 1) younger than 50 years of age (OR 1.86; 95% CI: 1.20-2.89; p for trend = 0.008), 2) white (OR 2.06; 95% CI: 1.41-3.01; p for trend <= 0.001), or 3) female (OR 1.95; 95% CI: 1.38-2.76; p for trend <= 0.001). Conclusion: The odds of EM are increased in those with obesity, with the strongest relationships among those younger than 50 years, white individuals, and women. C1 [Peterlin, B. Lee; Rosenberg, Jason R.; Gottesman, Rebecca F.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21218 USA. [Haythornthwaite, Jennifer A.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Rosso, Andrea L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Williams, Michelle A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Merikangas, Kathleen R.; He, Jian-Ping] NIMH, Intramural Res Program, NIH, Dept Hlth & Human Serv,Genet Epidemiol Res Branch, Bethesda, MD 20892 USA. [Bond, Dale S.] Miriam Hosp, Brown Alpert Med Sch, Weight Control & Diabet Res Ctr, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Zonderman, Alan B.] Natl Inst Aging, Intramural Res Program, Biomed Res Ctr, NIH, Baltimore, MD USA. RP Peterlin, BL (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21218 USA. EM lpeterlin@jhmi.edu OI Rosso, Andrea/0000-0001-5890-9856; Zonderman, Alan B/0000-0002-6523-4778 FU [R01 (NIA G040282)]; [R01 (NS077925)]; [R03 (DK095740)]; [K01 (DK083483)] FX B. Lee Peterlin: investigator-initiated research support from GSK and Luitpold Pharmaceuticals for studies unrelated to current manuscript, receives royalties from Oxford University Press, funding by NIH/National Institute of Neurological Disorders and Stroke grant K23-NS078345, Landenberger Foundation grant for a study unrelated to the current manuscript, and serves as an associate editor for the journals Headache and BMC Neurology. A. Rosso, M. Williams, and J. Rosenberg report no disclosures. J. Haythornthwaite: speaker for the American Pain Society. K. Merikangas reports no disclosures. R. Gottesman: R01 (NIA G040282) grant support. D. Bond: R01 (NS077925), R03 (DK095740), and K01 (DK083483) grant support. J. He and A. Zonderman report no disclosures. Go to Neurology.org for full disclosures. NR 32 TC 40 Z9 41 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 8 PY 2013 VL 81 IS 15 BP 1314 EP 1321 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AA0EQ UT WOS:000330768600011 PM 24027060 ER PT J AU van Blitterswijk, M Baker, MC DeJesus-Hernandez, M Ghidoni, R Benussi, L Finger, E Hsiung, GYR Kelley, BJ Murray, ME Rutherford, NJ Brown, PE Ravenscroft, T Mullen, B Ash, PEA Bieniek, KF Hatanpaa, KJ Karydas, A Wood, EM Coppola, G Bigio, EH Lippa, C Strong, MJ Beach, TG Knopman, DS Huey, ED Mesulam, M Bird, T White, CL Kertesz, A Geschwind, DH Van Deerlin, VM Petersen, RC Binetti, G Miller, BL Petrucelli, L Wszolek, ZK Boylan, KB Graff-Radford, NR Mackenzie, IR Boeve, BF Dickson, DW Rademakers, R AF van Blitterswijk, Marka Baker, Matthew C. DeJesus-Hernandez, Mariely Ghidoni, Roberta Benussi, Luisa Finger, Elizabeth Hsiung, Ging-Yuek R. Kelley, Brendan J. Murray, Melissa E. Rutherford, Nicola J. Brown, Patricia E. Ravenscroft, Thomas Mullen, Bianca Ash, Peter E. A. Bieniek, Kevin F. Hatanpaa, Kimmo J. Karydas, Anna Wood, Elisabeth McCarty Coppola, Giovanni Bigio, Eileen H. Lippa, Carol Strong, Michael J. Beach, Thomas G. Knopman, David S. Huey, Edward D. Mesulam, Marsel Bird, Thomas White, Charles L., III Kertesz, Andrew Geschwind, Dan H. Van Deerlin, Vivianna M. Petersen, Ronald C. Binetti, Giuliano Miller, Bruce L. Petrucelli, Leonard Wszolek, Zbigniew K. Boylan, Kevin B. Graff-Radford, Neill R. Mackenzie, Ian R. Boeve, Bradley F. Dickson, Dennis W. Rademakers, Rosa TI C9ORF72 repeat expansions in cases with previously identified pathogenic mutations SO NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; GGGGCC-HEXANUCLEOTIDE REPEAT; CLINICAL CHARACTERISTICS; DEMENTIA; PROGRANULIN; PATHOLOGY; GENETICS; TAU; NEUROPATHOLOGY AB Objective: To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases. Methods: A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology. Results: We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (> 3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations. Conclusions: Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members. C1 [van Blitterswijk, Marka; Baker, Matthew C.; DeJesus-Hernandez, Mariely; Murray, Melissa E.; Rutherford, Nicola J.; Brown, Patricia E.; Ravenscroft, Thomas; Mullen, Bianca; Ash, Peter E. A.; Bieniek, Kevin F.; Petrucelli, Leonard; Dickson, Dennis W.; Rademakers, Rosa] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Wszolek, Zbigniew K.; Boylan, Kevin B.; Graff-Radford, Neill R.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Ghidoni, Roberta; Benussi, Luisa; Binetti, Giuliano] IRCCS, Ist Ctr San Giovanni Diofatebenefratelli, Prote Unit, Brescia, Italy. [Ghidoni, Roberta; Benussi, Luisa; Binetti, Giuliano] IRCCS, Ist Ctr San Giovanni Diofatebenefratelli, NeuroBioGen Lab, Memory Clin, Brescia, Italy. [Finger, Elizabeth; Strong, Michael J.] Univ Western Ontario, Dept Clin Neurol Sci, Schulich Sch Med, London, ON, Canada. [Hsiung, Ging-Yuek R.] Univ British Columbia, Div Neurol, Vancouver, BC V5Z 1M9, Canada. [Mackenzie, Ian R.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Kelley, Brendan J.; Knopman, David S.; Petersen, Ronald C.; Boeve, Bradley F.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Hatanpaa, Kimmo J.; White, Charles L., III] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Hatanpaa, Kimmo J.; White, Charles L., III] Univ Texas SW Med Ctr Dallas, Alzheimers Dis Ctr, Dallas, TX 75390 USA. [Karydas, Anna; Miller, Bruce L.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Wood, Elisabeth McCarty; Van Deerlin, Vivianna M.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA. [Coppola, Giovanni; Geschwind, Dan H.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Bigio, Eileen H.; Mesulam, Marsel] Northwestern Univ Feinberg, Sch Med, Cognit Neurol & Alzheimer Dis Ctr, Chicago, IL USA. [Lippa, Carol] Drexel Univ, Coll Med, Dept Neurol, Philadelphia, PA 19104 USA. [Strong, Michael J.] Robarts Res Inst, Mol Brain Res Grp, London, ON N6A 5C1, Canada. [Beach, Thomas G.] Banner Sun Hlth Res Inst, Sun City, AZ USA. [Huey, Edward D.] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Huey, Edward D.] Columbia Univ, Dept Psychiat, New York, NY USA. [Huey, Edward D.] Columbia Univ, Dept Neurol, New York, NY USA. [Bird, Thomas] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. RP Rademakers, R (reprint author), Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. EM Rademakers.Rosa@mayo.edu RI Finger, Elizabeth/B-6453-2015; van Blitterswijk, Marka/H-7274-2012; Murray, Melissa/C-2763-2015; BENUSSI, LUISA/K-4409-2016; Ghidoni, Roberta/K-4507-2016; Binetti, Giuliano/K-4519-2016; Strong, Michael/H-9689-2012; OI van Blitterswijk, Marka/0000-0002-3054-7053; Bieniek, Kevin/0000-0003-4922-864X; Murray, Melissa/0000-0001-7379-2545; BENUSSI, LUISA/0000-0003-2836-8141; Ghidoni, Roberta/0000-0002-7691-1957; Binetti, Giuliano/0000-0003-2759-5844; Dickson, Dennis W/0000-0001-7189-7917 FU NIH [R01 NS080882, R01 NS065782, R01 AG026251, P01 AG017586, P50 NS072187, P50 AG 016574, P30 AG13854, P30 AG12300, U01 AG006786]; ALS Therapy Alliance; Consortium for Frontotemporal Dementia Research; Ricerca Corrente Italian Ministry of Health FX This work was funded by NIH grants R01 NS080882, R01 NS065782, R01 AG026251, P01 AG017586, P50 NS072187, P50 AG 016574, P30 AG13854, P30 AG12300, and U01 AG006786, the ALS Therapy Alliance, the Consortium for Frontotemporal Dementia Research, and Ricerca Corrente Italian Ministry of Health. Dr. Kelley is the Bob and Sandy Heimann Endowed Chair for Alzheimer's Disease Education and Research at the University of Cincinnati. NR 34 TC 36 Z9 37 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 8 PY 2013 VL 81 IS 15 BP 1332 EP 1341 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA AA0EQ UT WOS:000330768600013 PM 24027057 ER PT J AU Salmon, CR Tomazela, DM Ruiz, KGS Foster, BL Leme, AFP Sallum, EA Somerman, MJ Nociti, FH AF Salmon, Cristiane R. Tomazela, Daniela M. Silverio Ruiz, Karina Gonzales Foster, Brian L. Paes Leme, Adriana Franco Sallum, Enilson Antonio Somerman, Martha J. Nociti, Francisco H., Jr. TI Proteomic analysis of human dental cementum and alveolar bone SO JOURNAL OF PROTEOMICS LA English DT Article DE Alveolar bone; Dental cementum; Proteomic analysis; Periodontal ligament; Dentin; Superoxide dismutase 3 ID EXTRACELLULAR-SUPEROXIDE DISMUTASE; NONCOLLAGENOUS MATRIX PROTEINS; CONGENITAL MUSCULAR-DYSTROPHY; PERIODONTAL-LIGAMENT; SUSCEPTIBILITY GENE; BIGLYCAN; COLLAGEN; FIBRONECTIN; OSTEOARTHRITIS; EXPRESSION AB Dental cementum (DC) is a bone-like tissue covering the tooth root and responsible for attaching the tooth to the alveolar bone (AB) via the periodontal ligament (PDL). Studies have unsuccessfully tried to identify factors specific to DC versus AB, in an effort to better understand DC development and regeneration. The present study aimed to use matched human DC and AB samples (n = 7) to generate their proteomes for comparative analysis. Bone samples were harvested from tooth extraction sites, whereas DC samples were obtained from the apical root portion of extracted third molars. Samples were denatured, followed by protein extraction reduction, alkylation and digestion for analysis by nanoAcquity HPLC system and LTQ-FT Ultra. Data analysis demonstrated that a total of 318 proteins were identified in AB and DC. In addition to shared proteins between these tissues, 105 and 83 proteins exclusive to AB or DC were identified, respectively. This is the first report analyzing the proteomic composition of human DC matrix and identifying putative unique and enriched proteins in comparison to alveolar bone. These findings may provide novel insights into developmental differences between DC and AB, and identify candidate biomarkers that may lead to more efficient and predictable therapies for periodontal regeneration. Biological significance Periodontal disease is a highly prevalent disease affecting the world population, which involves breakdown of the tooth supporting tissues, the periodontal ligament, alveolar bone, and dental cementum. The lack of knowledge on specific factors that differentiate alveolar bone and dental cementum limits the development of more efficient and predictable reconstructive therapies. In order to better understand cementum development and potentially identify factors to improve therapeutic outcomes, we took the unique approach of using matched patient samples of dental cementum and alveolar bone to generate and compare a proteome list for each tissue. A potential biomarker for dental cementum was identified, superoxide dismutase 3 (SOD3), which is found in cementum and cementum-associated cells in mouse, pig, and human tissues. These findings may provide novel insights into developmental differences between alveolar bone and dental cementum, and represent the basis for improved and more predictable therapies. (C) 2013 Published by Elsevier B.V. C1 [Salmon, Cristiane R.; Silverio Ruiz, Karina Gonzales; Sallum, Enilson Antonio; Nociti, Francisco H., Jr.] Univ Estadual Campinas, Dept Prosthodont & Periodont, Div Periodont, Sch Dent, Piracicaba, SP, Brazil. [Tomazela, Daniela M.] Merck Res Labs, Palo Alto, CA USA. [Foster, Brian L.; Somerman, Martha J.; Nociti, Francisco H., Jr.] NIAMSD, NIAMS, NIH, Bethesda, MD USA. [Paes Leme, Adriana Franco] Brazilian Biosci Natl Lab, Campinas, SP, Brazil. RP Nociti, FH (reprint author), Ave Limeira 901, BR-13414903 Piracicaba, SP, Brazil. EM nociti@fop.unicamp.br RI Silverio, Karina/E-9424-2013; Salmon, Cristiane/A-9772-2015; Nociti, Francisco/G-4907-2015; Foster, Brian/H-8375-2015; Sallum, Enilson/G-2097-2016; Paes Leme, Adriana/C-9679-2012 OI Salmon, Cristiane/0000-0003-3304-5064; Foster, Brian/0000-0003-3444-0576; Paes Leme, Adriana/0000-0001-7959-147X FU Research Supporting Foundation of the State of Sao Paulo (FAPESP), Brazil [2010-12486-7]; National Institute of Arthritis and the Musculoskeletal and Skin Diseases of the National Institutes of Health FX This work was supported by the Research Supporting Foundation of the State of Sao Paulo (FAPESP), Brazil (grant no. 2010-12486-7), and in part, by the Intramural Research Program of the National Institute of Arthritis and the Musculoskeletal and Skin Diseases of the National Institutes of Health. The authors thank Dr. Tracy Popowics (University of Washington, Seattle, WA) and Dr. Kuang-Dah Yeh (Hualien Armed Forces General Hospital, Hualien, Taiwan) for preparing and providing pig molar tooth sections for analysis. NR 62 TC 18 Z9 18 U1 0 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-3919 EI 1876-7737 J9 J PROTEOMICS JI J. Proteomics PD OCT 8 PY 2013 VL 91 BP 544 EP 555 DI 10.1016/j.jprot.2013.08.016 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 264UH UT WOS:000327906000043 PM 24007660 ER PT J AU Yao, YN Belcher, J Berger, AJ Mayer, ML Lau, AY AF Yao, Yongneng Belcher, John Berger, Anthony J. Mayer, Mark L. Lau, Albert Y. TI Conformational Analysis of NMDA Receptor GluN1, GluN2, and GluN3 Ligand-Binding Domains Reveals Subtype-Specific Characteristics SO STRUCTURE LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; HISTOGRAM ANALYSIS METHOD; FREE-ENERGY CALCULATIONS; GLUTAMATE-RECEPTOR; CRYSTAL-STRUCTURES; PROTEIN STRUCTURES; AMPA RECEPTORS; ACTIVATION; MECHANISMS; CORE AB The NMDA receptor family of glutamate receptor ion channels is formed by obligate heteromeric assemblies of GluN1, GluN2, and GluN3 subunits. GluN1 and GluN3 bind glycine, whereas GluN2 binds glutamate. Crystal structures of the GluN1 and GluN3A ligand-binding domains (LBDs) in their apo states unexpectedly reveal open- and closed-cleft conformations, respectively, with water molecules filling the binding pockets. Computed conformational free energy landscapes for GluN1, GluN2A, and GluN3A LBDs reveal that the apo-state LBDs sample closed-cleft conformations, suggesting that their agonists bind via a conformational selection mechanism. By contrast, free energy landscapes for the AMPA receptor GluA2 LBD suggest binding of glutamate via an induced-fit mechanism. Principal component analysis reveals a rich spectrum of hinge bending, rocking, twisting, and sweeping motions that are different for the GluN1, GluN2A, GluN3A, and GluA2 LBDs. This variation highlights the structural complexity of signaling by glutamate receptor ion channels. C1 [Yao, Yongneng; Berger, Anthony J.; Mayer, Mark L.] NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. [Belcher, John; Lau, Albert Y.] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. RP Lau, AY (reprint author), Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, 725 N Wolfe St, Baltimore, MD 21205 USA. EM alau@jhmi.edu FU Office of Basic Energy Sciences, Office of Science, U.S. Department of Energy [W-31-109-Eng-38]; National Science Foundation [OCI-1053575]; Intramural Research Program of the National Institute of Child Health and Human Development, NIH, Department of Health and Human Services; NIH [GM094495]; Barry Grant FX We thank Barry Grant for helpful discussions on using the Bio3D package. Data were collected at the Southeast Regional Collaborative Access Team 22-ID beam line at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the Office of Basic Energy Sciences, Office of Science, U.S. Department of Energy under contract no. W-31-109-Eng-38. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (NIH) and resources provided by the Extreme Science and Engineering Discovery Environment, which is supported by National Science Foundation grant no. OCI-1053575. This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, NIH, Department of Health and Human Services (to M.L.M.) and NIH grant no. GM094495 (to A.Y.L.). NR 48 TC 30 Z9 30 U1 2 U2 18 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 OCT 8 PY 2013 VL 21 IS 10 BP 1788 EP 1799 DI 10.1016/j.str.2013.07.011 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 244TQ UT WOS:000326413500010 PM 23972471 ER PT J AU Gibbons, GH Shurin, SB Mensah, GA Lauer, MS AF Gibbons, Gary H. Shurin, Susan B. Mensah, George A. Lauer, Michael S. TI Refocusing the Agenda on Cardiovascular Guidelines An Announcement From the National Heart, Lung, and Blood Institute SO CIRCULATION LA English DT Editorial Material DE clinical practice guidelines; NHLBI; systematic evidence review ID 2010 ACCF/AHA GUIDELINE; ASSOCIATION TASK-FORCE; AMERICAN-COLLEGE; ASYMPTOMATIC ADULTS; CLINICAL GUIDELINES; RISK; CANCER C1 [Gibbons, Gary H.; Shurin, Susan B.; Mensah, George A.] NHLBI, Off Director, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Lauer, Michael S.] NHLBI, Off Director, Div Cardiovasc Sci, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Gibbons, GH (reprint author), NHLBI, Off Director, 31 Ctr Dr,Room 5A48,MSC 2486, Bethesda, MD 20892 USA. EM Gary.Gibbons@nih.gov NR 16 TC 26 Z9 26 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 8 PY 2013 VL 128 IS 15 BP 1713 EP 1715 DI 10.1161/CIRCULATIONAHA.113.004587 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 230MU UT WOS:000325345700023 PM 23785001 ER PT J AU Gibbons, GH Harold, JG Jessup, M Robertson, RM Oetgen, WJ AF Gibbons, Gary H. Harold, John Gordon Jessup, Mariell Robertson, Rose Marie Oetgen, William J. TI The Next Steps in Developing Clinical Practice Guidelines for Prevention SO CIRCULATION LA English DT Editorial Material DE ACCF; AHA; clinical practice guidelines; NHLBI; cardiovascular disease; prevention; systematic evidence review C1 [Gibbons, Gary H.] NHLBI, Off Director, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Harold, John Gordon] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Harold, John Gordon; Oetgen, William J.] Amer Coll Cardiol Fdn, Washington, DC USA. [Jessup, Mariell] Univ Penn, Philadelphia, PA 19104 USA. [Jessup, Mariell; Robertson, Rose Marie] Amer Heart Assoc, Dallas, TX USA. RP Gibbons, GH (reprint author), NHLBI, Off Director, NIH, US Dept HHS, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 10 Z9 10 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 8 PY 2013 VL 128 IS 15 BP 1716 EP 1717 DI 10.1161/CIRCULATIONAHA.113.005548 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 230MU UT WOS:000325345700024 PM 23929910 ER PT J AU Hou, Y Mattson, MP Cheng, AW AF Hou, Yan Mattson, Mark P. Cheng, Aiwu TI Permeability Transition Pore-Mediated Mitochondrial Superoxide Flashes Regulate Cortical Neural Progenitor Differentiation SO PLOS ONE LA English DT Article ID STEM-CELLS; CYCLOSPORINE-A; NEURONAL DIFFERENTIATION; NEGATIVE REGULATOR; OXIDATIVE-STRESS; PROLIFERATION; NEUROGENESIS; PRECURSOR; BRAIN; FATE AB In the process of neurogenesis, neural progenitor cells (NPCs) cease dividing and differentiate into postmitotic neurons that grow dendrites and an axon, become excitable, and establish synapses with other neurons. Mitochondrial biogenesis and aerobic metabolism provide energy substrates required to support the differentiation, growth and synaptic activity of neurons. Mitochondria may also serve signaling functions and, in this regard, it was recently reported that mitochondria can generate rapid bursts of superoxide (superoxide flashes), the frequency of which changes in response to environmental conditions and signals including oxygen levels and Ca2+ fluxes. Here we show that the frequency of mitochondrial superoxide flashes increases as embryonic cerebral cortical neurons differentiate from NPCs, and provide evidence that the superoxide flashes serve a signaling function that is critical for the differentiation process. The superoxide flashes are mediated by mitochondrial permeability transition pore (mPTP) opening, and pharmacological inhibition of the mPTP suppresses neuronal differentiation. Moreover, superoxide flashes and neuronal differentiation are inhibited by scavenging of mitochondrial superoxide. Conversely, manipulations that increase superoxide flash frequency accelerate neuronal differentiation. Our findings reveal a regulatory role for mitochondrial superoxide flashes, mediated by mPTP opening, in neuronal differentiation. C1 [Hou, Yan; Mattson, Mark P.; Cheng, Aiwu] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov; chengai@mail.nih.gov FU National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institute on Aging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 14 Z9 14 U1 1 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 8 PY 2013 VL 8 IS 10 AR e76721 DI 10.1371/journal.pone.0076721 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 233FK UT WOS:000325552200063 PM 24116142 ER PT J AU Shi, M Kumar, SR Motajo, O Kretschmer, F Mu, XQ Badea, TC AF Shi, Melody Kumar, Sumit R. Motajo, Oluwaseyi Kretschmer, Friedrich Mu, Xiuqian Badea, Tudor C. TI Genetic Interactions between Brn3 Transcription Factors in Retinal Ganglion Cell Type Specification SO PLOS ONE LA English DT Article ID DOMAIN FACTOR BRN-3B; AMACRINE CELLS; MOUSE RETINA; SOMATOSENSORY NEURONS; MAMMALIAN RETINA; NERVOUS-SYSTEM; PRIMATE RETINA; VISUAL-SYSTEM; EXPRESSION; DIFFERENTIATION AB Background: Visual information is conveyed from the retina to the brain via 15-20 Retinal Ganglion Cell (RGC) types. The developmental mechanisms by which RGC types acquire their distinct molecular, morphological, physiological and circuit properties are essentially unknown, but may involve combinatorial transcriptional regulation. Brn3 transcription factors are expressed in RGCs from early developmental stages, and are restricted in adults to distinct, partially overlapping populations of RGC types. Previously, we described cell autonomous effects of Brn3b (Pou4f2) and Brn3a (Pou4f1) on RGC axon and dendrites development. Methods and Findings: We now have investigated genetic interactions between Brn3 transcription factors with respect to RGC development, by crossing conventional knock-out alleles of each Brn3 gene with conditional knock-in reporter alleles of a second Brn3 gene, and analyzing the effects of single or double Brn3 knockouts on RGC survival and morphology. We find that Brn3b loss results in axon defects and dendritic arbor area and lamination defects in Brn3a positive RGCs, and selectively affects survival and morphology of specific Brn3c (Pou4f3) positive RGC types. Brn3a and Brn3b interact synergistically to control RGC numbers. Melanopsin positive ipRGCs are resistant to combined Brn3 loss but are under the transcriptional control of Isl1, expanding the combinatorial code of RGC specification. Conclusions: Taken together these results complete our knowledge on the mechanisms of transcriptional control of RGC type specification. They demonstrate that Brn3b is required for the correct development of more RGC cell types than suggested by its expression pattern in the adult, but that several cell types, including some Brn3a, Brn3c or Melanopsin positive RGCs are Brn3b independent. C1 [Shi, Melody; Kumar, Sumit R.; Motajo, Oluwaseyi; Kretschmer, Friedrich; Badea, Tudor C.] NEI, NIH, Bethesda, MD 20892 USA. [Mu, Xiuqian] SUNY Buffalo, Dept Ophthalmol, Ross Eye Inst, Dev Genom Grp, Buffalo, NY 14260 USA. [Mu, Xiuqian] SUNY Buffalo, Ctr Excellence Bioinformat & Life Sci, Buffalo, NY 14260 USA. [Mu, Xiuqian] SUNY Eye Inst, Buffalo, NY USA. [Mu, Xiuqian] Roswell Pk Canc Inst, CCSG Genet Program, Buffalo, NY 14263 USA. RP Badea, TC (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM badeatc@mail.nih.gov RI Mu, Xiuqian/I-9146-2014 OI Mu, Xiuqian/0000-0002-8003-7529 FU National Eye Institute; NEI [EY020545]; Whitehall Foundation; Research to Prevent Blindness to the Department of Ophthalmology of University at Buffalo FX Funding for this work was provided by the Intramural Research Program of the National Eye Institute for M. S., S. R. K., O.M., F. K. and T. C. B. and NEI grant EY020545, the Whitehall Foundation and an unrestricted grant from the Research to Prevent Blindness to the Department of Ophthalmology of University at Buffalo to X. M. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 10 Z9 10 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 OCT 8 PY 2013 VL 8 IS 10 AR e76347 DI 10.1371/journal.pone.0076347 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 233FK UT WOS:000325552200051 PM 24116103 ER PT J AU Okazaki, K Hummer, G AF Okazaki, Kei-ichi Hummer, Gerhard TI Phosphate release coupled to rotary motion of F-1-ATPase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BOVINE HEART-MITOCHONDRIA; MOLECULAR-DYNAMICS SIMULATION; ATP SYNTHASE; ENERGY-TRANSFER; MECHANISM; HYDROLYSIS; CATALYSIS; ROTATION; RESOLUTION; SUBUNIT AB F-1-ATPase, the catalytic domain of ATP synthase, synthesizes most of the ATP in living organisms. Running in reverse powered by ATP hydrolysis, this hexameric ring-shaped molecular motor formed by three alpha beta-dimers creates torque on its central gamma-subunit. This reverse operation enables detailed explorations of the mechanochemical coupling mechanisms in experiment and simulation. Here, we use molecular dynamics simulations to construct a first atomistic conformation of the intermediate state following the 40 degrees substep of rotary motion, and to study the timing and molecular mechanism of inorganic phosphate ( Pi) release coupled to the rotation. In response to torque-driven rotation of the.-subunit in the hydrolysis direction, the nucleotide-free alpha beta(E) interface forming the "empty" E site loosens and singly charged Pi readily escapes to the P loop. By contrast, the interface stays closed with doubly charged P-i. The.-rotation tightens the ATP-bound alpha beta(TP) interface, as required for hydrolysis. The calculated rate for the outward release of doubly charged P-i from the alpha beta(E) interface 120 after ATP hydrolysis closely matches the similar to 1-ms functional timescale. Conversely, P-i release from the ADP-bound alpha beta(DP) interface postulated in earlier models would occur through a kinetically infeasible in-ward-directed pathway. Our simulations help reconcile conflicting interpretations of single-molecule experiments and crystallographic studies by clarifying the timing of P-i exit, its pathway and kinetics, associated changes in P-i protonation, and changes of the F-1-ATPase structure in the 40 substep. Important elements of the molecular mechanism of Pi release emerging from our simulations appear to be conserved in myosin despite the different functional motions. C1 [Okazaki, Kei-ichi; Hummer, Gerhard] Max Planck Inst Biophys, Dept Theoret Biophys, D-60438 Frankfurt, Germany. [Okazaki, Kei-ichi; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Okazaki, Kei-ichi] Waseda Univ, Dept Pure & Appl Phys, Tokyo 1698555, Japan. RP Hummer, G (reprint author), Max Planck Inst Biophys, Dept Theoret Biophys, D-60438 Frankfurt, Germany. EM gerhard.hummer@biophys.mpg.de RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Max Planck Society; Japan Society for the Promotion of Science FX We thank Drs. Kazuhiko Kinosita and Hiroyuki Noji for insightful discussions, and Drs. Edina Rosta, Fangqiang Zhu, Jurgen Kofinger, Pilar Cossio, and Ikuo Kurisaki for technical help. This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health and by the Max Planck Society. K.-i.O. is supported by research fellowship for young scientists and postdoctoral fellowship for research abroad of the Japan Society for the Promotion of Science. The research used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (http://biowulf.nih.gov). NR 61 TC 36 Z9 36 U1 4 U2 45 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 OCT 8 PY 2013 VL 110 IS 41 BP 16468 EP 16473 DI 10.1073/pnas.1305497110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 231ED UT WOS:000325395600049 PM 24062450 ER PT J AU de Wit, E Rasmussen, AL Falzarano, D Bushmaker, T Feldmann, F Brining, DL Fischer, ER Martellaro, C Okumura, A Chang, J Scott, D Benecke, AG Katze, MG Feldmann, H Munster, VJ AF de Wit, Emmie Rasmussen, Angela L. Falzarano, Darryl Bushmaker, Trenton Feldmann, Friederike Brining, Douglas L. Fischer, Elizabeth R. Martellaro, Cynthia Okumura, Atsushi Chang, Jean Scott, Dana Benecke, Arndt G. Katze, Michael G. Feldmann, Heinz Munster, Vincent J. TI Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE emerging infectious disease; DPP4 ID CLINICAL-FEATURES; SARS CORONAVIRUS; AFRICAN-GREEN; ANIMAL-MODEL; VIRUS; PNEUMONIA; MONKEYS; SYSTEM AB In 2012, a novel betacoronavirus, designated Middle East respiratory syndrome coronavirus or MERS-CoV and associated with severe respiratory disease in humans, emerged in the Arabian Peninsula. To date, 108 human cases have been reported, including cases of human-to-human transmission. The availability of an animal disease model is essential for understanding pathogenesis and developing effective countermeasures. Upon a combination of intratracheal, ocular, oral, and intranasal inoculation with 7 x 10(6) 50% tissue culture infectious dose of the MERS-CoV isolate HCoV-EMC/2012, rhesus macaques developed a transient lower respiratory tract infection. Clinical signs, virus shedding, virus replication in respiratory tissues, gene expression, and cytokine and chemokine profiles peaked early in infection and decreased over time. MERS-CoV caused a multifocal, mild to marked interstitial pneumonia, with virus replication occurring mainly in alveolar pneumocytes. This tropism of MERS-CoV for the lower respiratory tract may explain the severity of the disease observed in humans and the, up to now, limited human-to-human transmission. C1 [de Wit, Emmie; Falzarano, Darryl; Bushmaker, Trenton; Martellaro, Cynthia; Feldmann, Heinz; Munster, Vincent J.] NIAID, Lab Virol, NIH, Hamilton, MT 59840 USA. [Feldmann, Friederike; Brining, Douglas L.; Scott, Dana] NIAID, Rocky Mt Vet Branch, NIH, Hamilton, MT 59840 USA. [Fischer, Elizabeth R.] NIAID, Microscopy Unit, Res Technol Branch, Div Intramural Res,NIH, Hamilton, MT 59840 USA. [Rasmussen, Angela L.; Okumura, Atsushi; Chang, Jean; Benecke, Arndt G.; Katze, Michael G.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Benecke, Arndt G.] Univ Paris 06, Dept Biol, Ctr Natl Rech Sci, Unite Mixte Rech 7224, F-75005 Paris, France. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0J9, Canada. RP Feldmann, H (reprint author), NIAID, Lab Virol, NIH, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov; Vincent.Munster@nih.gov RI Okumura, Atsushi/E-8012-2015; OI Okumura, Atsushi/0000-0002-7779-3059; Rasmussen, Angela/0000-0001-9462-3169; de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institute of Allergy and Infectious Diseases Regional Centers of Excellence, National Institutes of Health/National Institute of Allergy and Infectious Diseases Contract [U54 AI081680, HHSN272200800060C]; National Institutes of Health (Washington National Primate Center) [P51OD010425] FX We thank Drs. Bart Haagmans and Ron Fouchier at the Erasmus Medical Center for providing Middle East respiratory coronavirus isolate HCoV-EMC/2012; Ralph Baric at the University of North Carolina at Chapel Hill for subgenomic RNA primer sequences; Laura Baseler, Tina Thomas, Dan Long, and Rebecca Rosenke for histopathology; the staff of the Rocky Mountain Veterinary Branch for assistance with the animal experiments; and Anita Mora for figure preparation. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; A.L.R., A.G.B., A.O., and M.G.K. are funded through Grant U54 AI081680, National Institute of Allergy and Infectious Diseases Regional Centers of Excellence, National Institutes of Health/National Institute of Allergy and Infectious Diseases Contract HHSN272200800060C, and National Institutes of Health Grant P51OD010425 (Washington National Primate Center). NR 30 TC 82 Z9 82 U1 0 U2 17 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 OCT 8 PY 2013 VL 110 IS 41 BP 16598 EP 16603 DI 10.1073/pnas.1310744110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 231ED UT WOS:000325395600071 PM 24062443 ER PT J AU Gibbons, GH Shurin, SB Mensah, GA Lauer, MS AF Gibbons, Gary H. Shurin, Susan B. Mensah, George A. Lauer, Michael S. TI Refocusing the Agenda on Cardiovascular Guidelines An Announcement From the National Heart, Lung, and Blood Institute SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE clinical practice guidelines; NHLBI; systematic evidence review ID 2010 ACCF/AHA GUIDELINE; ASSOCIATION TASK-FORCE; AMERICAN-COLLEGE; ASYMPTOMATIC ADULTS; CLINICAL GUIDELINES; RISK; CANCER C1 [Gibbons, Gary H.; Shurin, Susan B.; Mensah, George A.] NHLBI, Off Director, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Lauer, Michael S.] NHLBI, Off Director, Div Cardiovasc Sci, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Gibbons, GH (reprint author), NHLBI, Off Director, 31 Ctr Dr,Room 5A48,MSC 2486, Bethesda, MD 20892 USA. EM Gary.Gibbons@nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 16 TC 23 Z9 23 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 8 PY 2013 VL 62 IS 15 BP 1396 EP 1398 DI 10.1016/j.jacc.2013.08.003 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 225ZY UT WOS:000325005000018 PM 24091225 ER PT J AU Gibbons, GH Harold, JG Jessup, M Robertson, RM Oetgen, WJ AF Gibbons, Gary H. Harold, John Gordon Jessup, Mariell Robertson, Rose Marie Oetgen, William J. TI The Next Steps in Developing Clinical Practice Guidelines for Prevention SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE ACCF; AHA; clinical practice guidelines; NHLBI cardiovascular disease; prevention; systematic evidence review C1 [Gibbons, Gary H.] NHLBI, Off Director, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Harold, John Gordon] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Harold, John Gordon; Oetgen, William J.] Amer Coll Cardiol Fdn, Washington, DC USA. [Jessup, Mariell] Univ Penn, Philadelphia, PA 19104 USA. [Jessup, Mariell; Robertson, Rose Marie] Amer Heart Assoc, Dallas, TX USA. RP Gibbons, GH (reprint author), NHLBI, Off Director, NIH, US Dept HHS, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 19 Z9 19 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 8 PY 2013 VL 62 IS 15 BP 1399 EP 1400 DI 10.1016/j.jacc.2013.08.004 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 225ZY UT WOS:000325005000019 PM 24091226 ER PT J AU Haase, J Mishra, PK Stephens, A Haggerty, R Quammen, C Taylor, RM Yeh, E Basrai, MA Bloom, K AF Haase, Julian Mishra, Prashant K. Stephens, Andrew Haggerty, Rachel Quammen, Cory Taylor, Russell M., II Yeh, Elaine Basrai, Munira A. Bloom, Kerry TI A 3D Map of the Yeast Kinetochore Reveals the Presence of Core and Accessory Centromere-Specific Histone SO CURRENT BIOLOGY LA English DT Article ID MICROTUBULE-ATTACHMENT SITES; PERICENTRIC CHROMATIN; POINT CENTROMERES; NUCLEOSOMES; LOOP AB The budding yeast kinetochore is similar to 68 nm in length with a diameter slightly larger than a 25 nm microtubule [1]. The kinetochores from the 16 chromosomes are organized in a stereotypic cluster encircling central spindle microtubules. Quantitative analysis of the inner kinetochore cluster (Cse4, COMA) reveals structural features not apparent in singly attached kinetochores. The cluster of Cse4-containing kinetochores is physically larger perpendicular to the spindle axis relative to the cluster of Ndc80 molecules [2]. If there was a single Cse4 (molecule or nucleosome) at the kinetochore attached to each microtubule plus end, the cluster of Cse4 would appear geometrically identical to Ndc80. Thus, the structure of the inner kinetochore at the surface of the chromosomes remains unsolved. We have used point fluorescence microscopy and statistical probability maps [2] to deduce the two-dimensional mean position of representative components of the yeast kinetochore relative to the mitotic spindle in metaphase. Comparison of the experimental images to three-dimensional architectures from convolution of mathematical models reveals a pool of Cse4 radially displaced from Cse4 at the kinetochore and kinetochore microtubule plus ends. The pool of displaced Cse4 can be experimentally depleted in mRNA processing pat1 Delta or xrn1 Delta mutants. The peripheral Cse4 molecules do not template outer kinetochore components. This study suggests an inner kinetochore plate at the centromere-microtubule interface in budding yeast and yields information on the number of Ndc80 molecules at the microtubule attachment site. C1 [Haase, Julian; Stephens, Andrew; Haggerty, Rachel; Yeh, Elaine; Bloom, Kerry] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Quammen, Cory; Taylor, Russell M., II] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. [Mishra, Prashant K.; Basrai, Munira A.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Basrai, MA (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM basraim@mail.nih.gov; kerry_bloom@unc.edu OI Stephens, Andrew/0000-0001-5474-7845; Bloom, Kerry/0000-0002-3457-004X FU NIH [R37 GM32238, P41 EB002025]; National Cancer Institute, National Institutes of Health FX We thank the members of the Bloom laboratory as well as the centromere community for productive and open scientific discourse. This work was supported by NIH R37 GM32238 (to K.B.) and NIH P41 EB002025 (to R.M.T. II; Center for Computer Integrated Systems for Microscopy and Manipulation). Support for M.A.B. and P.K.M. was provided by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 23 TC 24 Z9 24 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD OCT 7 PY 2013 VL 23 IS 19 BP 1939 EP 1944 DI 10.1016/j.cub.2013.07.083 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 241WP UT WOS:000326199700032 PM 24076245 ER PT J AU Shiba, Y Kametaka, S Waguri, S Presley, JF Randazzo, PA AF Shiba, Yoko Kametaka, Satoshi Waguri, Satoshi Presley, John F. Randazzo, Paul Agostino TI ArfGAP3 Regulates the Transport of Cation-Independent Mannose 6-Phosphate Receptor in the Post-Golgi Compartment SO CURRENT BIOLOGY LA English DT Article ID COP; ENDOSOMES; BINDING; CELLS; COAT; MEMBRANE; VESICLES; FAMILY; DOMAIN; GGAS AB ArfGAPs are known to be involved in cargo sorting in COPI transport. However, the role of ArfGAPs in post-Golgi membrane traffic has not been defined. To determine the function of ArfGAPs in post-Golgi traffic, we used small interfering RNA to examine each of 25 ArfGAPs for effects on cation-independent mannose 6-phosphate receptor (CIMPR) localization. We found that downregulation of ArfGAP3 resulted in the peripheral localization of CIMPR. The effect was specific for ArfGAP3 and dependent on its GAP activity, because the phenotype was rescued by ArfGAP3 but not by ArfGAP1, ArfGAP2, or the GAP domain mutants of ArfGAP3. ArfGAP3 localized to the trans-Golgi network and early endosomes. In cells with reduced expression of ArfGAP3, Cathepsin D maturation was slowed and its secretion was accelerated. Also retrograde transport from the endosomes to the trans-Golgi network of endogenous CIMPR, but not truncated CIMPR lacking the luminal domain, was perturbed in cells with reduced expression of ArfGAP3. Furthermore the exit of epidermal growth factor receptor (EGFR) from the early endosomes and degradation of EGFR after EGF stimulation was slowed in cells with reduced expression of ArfGAP3. ArfGAP3 associates with Golgi-localized, gamma-ear-containing, ADP-ribosylation factor binding proteins (GGAs), and ArfGAP3 knockdown reduces membrane association of GGAs. A possible mechanism explaining our results is that ArfGAP3 regulates transport from early endosomes to late endosomes. We suggest a model in which ArfGAP3 regulates Golgi association of GGA clathrin adaptors. C1 [Shiba, Yoko; Randazzo, Paul Agostino] NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. [Kametaka, Satoshi; Waguri, Satoshi] Fukushima Med Univ, Dept Anat & Histol, Fukushima 9601295, Japan. [Presley, John F.] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ H3A 0C7, Canada. RP Randazzo, PA (reprint author), NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. EM randazzp@mail.nih.gov FU NIH [BC 007365]; National Cancer Institute, National Institutes of Health FX We thank Elizabeth Sztul for helpful discussions. The work was supported by NIH Intramural Program (Project BC 007365). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes 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 37 TC 5 Z9 5 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD OCT 7 PY 2013 VL 23 IS 19 BP 1945 EP 1951 DI 10.1016/j.cub.2013.07.087 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 241WP UT WOS:000326199700033 PM 24076238 ER PT J AU Buonaguro, FM Gueye, SN Wabinga, HR Ngoma, TA Vermorken, JB Mbulaiteye, SM AF Buonaguro, Franco M. Gueye, Serigne N. Wabinga, Henry R. Ngoma, Twalib A. Vermorken, Jan B. Mbulaiteye, Sam M. TI Clinical oncology in resource-limited settings SO INFECTIOUS AGENTS AND CANCER LA English DT Editorial Material ID KAPOSIS-SARCOMA; VIRUS-INFECTION; CANCER; DNA AB Infectious Agents and Cancer is introducing a new section of Clinical Oncology with the main objective of stimulating debate through articles published in the section. Infectious diseases have been the major causes of morbidity and mortality in human populations, and have dominated the medical approach to clinical and public health. Successful efforts to control mortality from acute infections have paved the way for chronic, mostly indolent, infections to become major causes of morbidity. Cancer, hitherto thought to be rare in resource-limited settings, is becoming a major contributor. The changes in mortality patterns are due, in part, to diseases linked to rapid changes in lifestyle, urbanization, and pollution. These diseases include many of the non-infection associated cancers. However, there is a dearth of information about the burden, pathogenesis, and therapeutic approaches about cancer in resource-limited countries. There are also substantial other challenges, including economic, infrastructure, technology, and personnel. The Journal advocates for interactive local-global (lo-bal) efforts to generate relevant knowledge about cancer burden, pathogenesis, and therapeutic approaches using a bottom-up approach to sharpen the focus on local and global relevance of research and clinical and public practice, particularly in resource-limited countries. The section on Clinical Oncology in Infectious Agents and Cancer will harness these "lo-bal" strategies to reduce substantially the time from concept, discovery, and development and implementation of locally and globally applicable diagnostic and therapeutic technologies. C1 [Buonaguro, Franco M.] Ist Nazl Tumori IRCCS Fond Pascale, Dept Expt Oncol, Div Mol Biol & Viral Oncol, Naples, Italy. [Gueye, Serigne N.] Univ Cheikh Anta DIOP, Grand Yoff Gen Hosp, Dept Urol Surg, Div Urol & Androl, Dakar, Senegal. [Wabinga, Henry R.] Makerere Univ, Coll Hlth Sci, Dept Pathol, Kampala, Uganda. [Ngoma, Twalib A.] Ocean Rd Canc Inst, Dar Es Salaam, Tanzania. [Vermorken, Jan B.] Univ Antwerp Hosp, Dept Med Oncol, Antwerp, Belgium. [Mbulaiteye, Sam M.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Mbulaiteye, SM (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 9609 Med Ctr Dr,Rm 6E118 MSC 9704, Bethesda, MD 20892 USA. EM mbulaits@mail.nih.gov NR 20 TC 2 Z9 2 U1 2 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-9378 J9 INFECT AGENTS CANCER JI Infect. Agents Cancer PD OCT 7 PY 2013 VL 8 AR UNSP 39 DI 10.1186/1750-9378-8-39 PG 4 WC Oncology; Immunology SC Oncology; Immunology GA 241LO UT WOS:000326168600002 PM 24099039 ER PT J AU Chun, JH Pike, VW AF Chun, Joong-Hyun Pike, Victor W. TI Single-step syntheses of no-carrier-added functionalized [F-18]fluoroarenes as labeling synthons from diaryliodonium salts SO ORGANIC & BIOMOLECULAR CHEMISTRY LA English DT Article ID NUCLEOPHILIC AROMATIC-SUBSTITUTION; HETEROAROMATIC IODONIUM SALTS; COUPLING REACTIONS; F-18 FLUORIDE; PET; RADIOFLUORINATION; SUCCINIMIDYL; RADIOSYNTHESIS; FLUORINATION; CONJUGATION AB Radiotracers labelled with short-lived fluorine-18 (t(1/2) = 109.7 min) are keenly sought for biomedical imaging with positron emission tomography (PET). The radiotracers are mostly required at high specific radioactivities, necessitating their radiosyntheses from cyclotron-produced no-carrier-added [F-18]fluoride ion. PET radiotracers encompass wide structural diversity and molecular weight. Hence, diverse F-18-labeling methodology is needed to accomplish the required radiosyntheses in a simple and rapid manner. A useful strategy is to introduce nucleophilic [F-18]fluoride ion first into a labeling synthon that may then be applied to label the target radiotracer. Here, we show that various functionalized [F-18]fluoroarenes may be rapidly synthesized as labeling synthons through single-step reactions of appropriate diaryliodonium salts with [F-18]fluoride ion. Decay-corrected radiochemical yields (RCYs) varied with position of functional group, choice of electron-rich aryl ring in the diaryliodonium salt, and choice of anion. Under best conditions, F-18-labeled fluorobenzaldehydes, fluorobenzyl halides, fluorobenzoic acid esters and fluorophenyl ketones were obtained selectively in 40-73%, 20-55%, 46-89% and 81-98% RCYs, respectively. This versatile straightforward methodology will enhance the scope for producing structurally complex, yet useful, PET radiotracers. 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 research was funded by the Intramural Research Program of the National Institutes of Health (NIMH). Authors are grateful to the NIH Clinical PET Department (Chief, Dr Peter Herscovitch) for the cyclotron production of fluorine-18. NR 52 TC 13 Z9 13 U1 1 U2 40 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1477-0520 EI 1477-0539 J9 ORG BIOMOL CHEM JI Org. Biomol. Chem. PD OCT 7 PY 2013 VL 11 IS 37 BP 6300 EP 6306 DI 10.1039/c3ob41353e PG 7 WC Chemistry, Organic SC Chemistry GA 219KZ UT WOS:000324507100011 PM 23942997 ER PT J AU Cantley, JL Hanlon, J Chell, E Lee, C Smith, WC Bolch, WE AF Cantley, Justin L. Hanlon, Justin Chell, Erik Lee, Choonsik Smith, W. Clay Bolch, Wesley E. TI Influence of eye size and beam entry angle on dose to non-targeted tissues of the eye during stereotactic x-ray radiosurgery of AMD SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID CHOROIDAL NEOVASCULARIZATION SECONDARY; PLAQUE RADIATION-THERAPY; MACULAR DEGENERATION; SUBRETINAL NEOVASCULARIZATION; RADIOTHERAPY; BRACHYTHERAPY; BEVACIZUMAB; SAFETY; RANIBIZUMAB; IRRADIATION AB Age-related macular degeneration is a leading cause of vision loss for the elderly population of industrialized nations. The IRay (R) Radiotherapy System, developed by Oraya (R) Therapeutics, Inc., is a stereotactic low-voltage irradiation system designed to treat the wet form of the disease. The IRay System uses three robotically positioned 100 kVp collimated photon beams to deliver an absorbed dose of up to 24 Gy to the macula. The present study uses the Monte Carlo radiation transport code MCNPX to assess absorbed dose to six non-targeted tissues within the eye-total lens, radiosensitive tissues of the lens, optic nerve, distal tip of the central retinal artery, non-targeted portion of the retina, and the ciliary body-all as a function of eye size and beam entry angle. The ocular axial length was ranged from 20 to 28 mm in 2 mm increments, with the polar entry angle of the delivery system varied from 18 degrees to 34 degrees in 2 degrees increments. The resulting data showed insignificant variations in dose for all eye sizes. Slight variations in the dose to the optic nerve and the distal tip of the central retinal artery were noted as the polar beam angle changed. An increase in non-targeted retinal dose was noted as the entry angle increased, while the dose to the lens, sensitive volume of the lens, and ciliary body decreased as the treatment polar angle increased. Polar angles of 26 degrees or greater resulted in no portion of the sensitive volume of the lens receiving an absorbed dose of 0.5 Gy or greater. All doses to non-targeted structures reported in this study were less than accepted thresholds for post-procedure complications. C1 [Cantley, Justin L.; Bolch, Wesley E.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA. [Hanlon, Justin; Chell, Erik] Oraya Therapeut Inc, Newark, CA 94560 USA. [Lee, Choonsik] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Smith, W. Clay] Univ Florida, Dept Ophthalmol, Gainesville, FL 32610 USA. RP Bolch, WE (reprint author), Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA. EM jlcantley@gmail.com; wbolch@ufl.edu RI Lee, Choonsik/C-9023-2015 OI Lee, Choonsik/0000-0003-4289-9870 FU Oraya Therapeutics, Inc. [Oraya-002-2010] FX This work was supported by grant Oraya-002-2010 from Oraya Therapeutics, Inc. to the University of Florida. NR 32 TC 2 Z9 4 U1 0 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 7 PY 2013 VL 58 IS 19 BP 6887 EP 6896 DI 10.1088/0031-9155/58/19/6887 PG 10 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 220HN UT WOS:000324573600017 PM 24025704 ER PT J AU Stead, CM Omsland, A Beare, PA Sandoz, KM Heinzen, RA AF Stead, Christopher M. Omsland, Anders Beare, Paul A. Sandoz, Kelsi M. Heinzen, Robert A. TI Sec-mediated secretion by Coxiella burnetii SO BMC MICROBIOLOGY LA English DT Article DE Coxiella; Secretion; Signal sequence; Outer membrane vesicles; Pili; Q fever; Sec-mediated ID HEAT-STABLE ENTEROTOXIN; LEGIONELLA-PNEUMOPHILA; IV PILI; Q-FEVER; PROTEIN SECRETION; ESCHERICHIA-COLI; OUTER-MEMBRANE; II SECRETION; HOST-CELL; FRANCISELLA-TULARENSIS AB Background: Coxiella burnetii is a Gram-negative intracellular bacterial pathogen that replicates within a phagolysosome-like parasitophorous vacuole (PV) of macrophages. PV formation requires delivery of effector proteins directly into the host cell cytoplasm by a type IVB secretion system. However, additional secretion systems are likely responsible for modification of the PV lumen microenvironment that promote pathogen replication. Results: To assess the potential of C. burnetii to secrete proteins into the PV, we analyzed the protein content of modified acidified citrate cysteine medium for the presence of C. burnetii proteins following axenic (host cell-free) growth. Mass spectrometry generated a list of 105 C. burnetii proteins that could be secreted. Based on bioinformatic analysis, 55 proteins were selected for further study by expressing them in C. burnetii with a C-terminal 3xFLAG-tag. Secretion of 27 proteins by C. burnetii transformants was confirmed by immunoblotting culture supernatants. Tagged proteins expressed by C. burnetii transformants were also found in the soluble fraction of infected Vero cells, indicating secretion occurs ex vivo. All secreted proteins contained a signal sequence, and deletion of this sequence from selected proteins abolished secretion. These data indicate protein secretion initially requires translocation across the inner-membrane into the periplasm via the activity of the Sec translocase. Conclusions: C. burnetii secretes multiple proteins, in vitro and ex vivo, in a Sec-dependent manner. Possible roles for secreted proteins and secretion mechanisms are discussed. C1 [Stead, Christopher M.; Beare, Paul A.; Sandoz, Kelsi M.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Omsland, Anders] NIAID, Host Parasite Interact Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Heinzen, RA (reprint author), NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov FU Intramural Research Program of the 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 64 TC 8 Z9 8 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD OCT 5 PY 2013 VL 13 AR 222 DI 10.1186/1471-2180-13-222 PG 10 WC Microbiology SC Microbiology GA 235CU UT WOS:000325693700001 PM 24093460 ER PT J AU Jia, ZW Mao, YR Zhang, FJ Ruan, YH Ma, Y Li, J Guo, W Liu, EW Dou, ZH Zhao, Y Wang, L Li, QQ Xie, PY Tang, HL Han, J Jin, X Xu, J Xiong, R Zhao, DC Li, P Wang, X Wang, LY Qing, QQ Ding, ZW Chen, RY Liu, ZF Shao, YM AF Jia, Zhongwei Mao, Yurong Zhang, Fujie Ruan, Yuhua Ma, Ye Li, Jian Guo, Wei Liu, Enwu Dou, Zhihui Zhao, Yan Wang, Lu Li, Qianqian Xie, Peiyan Tang, Houlin Han, Jing Jin, Xia Xu, Juan Xiong, Ran Zhao, Decai Li, Ping Wang, Xia Wang, Liyan Qing, Qianqian Ding, Zhengwei Chen, Ray Y. Liu, Zhongfu Shao, Yiming TI Antiretroviral therapy to prevent HIV transmission in serodiscordant couples in China (2003-11): a national observational cohort study SO LANCET LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HETEROSEXUAL TRANSMISSION; INFECTED INDIVIDUALS; SEXUAL TRANSMISSION; DISCORDANT COUPLES; DRUG-RESISTANCE; VIRAL LOAD; MORTALITY; SEROCONVERSION; METAANALYSIS AB Background On the basis of the results of the randomised clinical trial HPTN 052 and observational studies, WHO has recommended that antiretroviral therapy be off ered to all HIV-infected individuals with uninfected partners of the opposite sex (serodiscordant couples) to reduce the risk of transmission. Whether or not such a public health approach is feasible and the outcomes are sustainable at a large scale and in a developing country setting has not previously been assessed. Methods In this retrospective observational cohort study, we included treated and treatment-naive HIV-positive individuals with HIV-negative partners of the opposite sex who had been added to the national HIV epidemiology and treatment databases between Jan 1, 2003 and Dec 31, 2011. We analysed the annual rate of HIV infection in HIVnegative partners during follow-up, stratifi ed by treatment status of the index partner. Cox proportional hazards analyses were done to examine factors related to HIV transmission. Findings Based on data from 38 862 serodiscordant couples, with 101 295.1 person-years of follow-up for the seronegative partners, rates of HIV infection were 2.6 per 100 person-years (95% CI 2.4-2.8) among the 14 805 couples in the treatment-naive cohort (median baseline CD4 count for HIV-positive partners 441 cells per mu l [IQR 314-590]) and 1.3 per 100 person-years (1.2-1.3) among the 24 057 couples in the treated cohort (median baseline CD4 count for HIV-positive partners 168 cells per mu l [62-269]). We calculated a 26% relative reduction in HIV transmission (adjusted hazard ratio 0.74, 95% CI 0.65-0.84) in the treated cohort. The reduction in transmission was seen across almost all demographic subgroups and was signifi cant in the fi rst year (0.64, 0.54-0.76), and among couples in which the HIV-positive partner had been infected by blood or plasma transfusion (0.76, 0.59-0.99) or heterosexual intercourse (0.69, 0.56-0.84), but not among couples in which the HIV-positive partner was infected by injecting drugs (0.98, 0.71-1.36). Interpretation Antiretroviral therapy for HIV-positive individuals in serodiscordant couples reduced HIV transmission across China, which suggests that the treatment-as-prevention approach is a feasible public health prevention strategy on a national scale in a developing country context. The durability and generalisability of such protection, however, needs to be further studied. C1 [Jia, Zhongwei] Peking Univ, Natl Inst Drug Dependence, Beijing 100871, Peoples R China. [Mao, Yurong; Zhang, Fujie; Ruan, Yuhua; Ma, Ye; Li, Jian; Guo, Wei; Liu, Enwu; Dou, Zhihui; Zhao, Yan; Wang, Lu; Xie, Peiyan; Tang, Houlin; Han, Jing; Jin, Xia; Xu, Juan; Xiong, Ran; Zhao, Decai; Li, Ping; Wang, Xia; Qing, Qianqian; Ding, Zhengwei; Liu, Zhongfu; Shao, Yiming] Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent, Beijing 102206, Peoples R China. [Ruan, Yuhua; Xie, Peiyan; Li, Ping; Wang, Xia; Shao, Yiming] Chinese Ctr Dis Control & Prevent, State Key Lab Infect Dis Prevent & Control, Beijing 102206, Peoples R China. [Ruan, Yuhua; Wang, Xia; Shao, Yiming] Collaborat Innovat Ctr Infect Dis, Hangzhou, Zhejiang, Peoples R China. [Jia, Zhongwei] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Takemi Program Int Hlth, Boston, MA 02115 USA. [Li, Qianqian] China Ocean Univ, Coll Math Sci, Qingdao, Peoples R China. [Xie, Peiyan; Li, Ping] Guangxi Med Univ, Sch Publ Hlth, Nanning, Peoples R China. [Chen, Ray Y.] NIAID, NIH, Bethesda, MD 20892 USA. RP Shao, YM (reprint author), Chinese Ctr Dis Control & Prevent, State Key Lab Infect Dis Prevent & Control, Beijing 102206, Peoples R China. EM zhongfuliu@163.com; yshao08@gmail.com OI Chen, Ray/0000-0001-6344-1442; Liu, Enwu/0000-0003-2580-3523 FU Chinese Government's 12th Five-Year Plan; National Natural Science Foundation of China,; Canadian International Development Research Centre FX Chinese Government's 12th Five-Year Plan, the National Natural Science Foundation of China, and the Canadian International Development Research Centre. NR 31 TC 51 Z9 60 U1 3 U2 32 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 5 PY 2013 VL 382 IS 9899 BP 1195 EP 1203 DI 10.1016/S0140-6736(12)61898-4 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 228SL UT WOS:000325209100024 PM 23206835 ER PT J AU Hammer, JA Wagner, W AF Hammer, John A., III Wagner, Wolfgang TI Functions of Class V Myosins in Neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review DE Cell Polarity; Endoplasmic Reticulum (ER); Ionotropic Glutamate Receptors (AMPA; NMDA); mRNA; Myosin; Neurons; PTEN; Rab Proteins; Receptor Recycling; Synaptic Plasticity ID LONG-TERM DEPRESSION; RECYCLING ENDOSOMES; DENDRITIC SPINES; AMPA RECEPTORS; IN-VIVO; INTERACTING PROTEIN; GLUTAMATE-RECEPTOR; EPITHELIAL-CELLS; PURKINJE-CELLS; MOTOR COMPLEX AB This minireview focuses on recent studies implicating class V myosins in organelle and macromolecule transport within neurons. These studies reveal that class V myosins play important roles in a wide range of fundamental processes occurring within neurons, including the transport into dendritic spines of organelles that support synaptic plasticity, the establishment of neuronal shape, the specification of polarized cargo transport, and the subcellular localization of mRNA. C1 [Hammer, John A., III] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Wagner, Wolfgang] Univ Med Ctr Hamburg Eppendorf UKE, Dept Mol Neurogenet, Ctr Mol Neurobiol Hamburg ZMNH, D-20251 Hamburg, Germany. RP Hammer, JA (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov OI Hammer, John/0000-0002-2496-5179 FU Marie Curie FP7 Integration Grant within the Seventh European Union Framework Programme [GA-2012-321905] FX This work was supported by Marie Curie FP7 Integration Grant PCIG11-GA-2012-321905 within the Seventh European Union Framework Programme (to W. W.). NR 69 TC 7 Z9 7 U1 0 U2 18 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 OCT 4 PY 2013 VL 288 IS 40 BP 28428 EP 28434 DI 10.1074/jbc.R113.514497 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 298BL UT WOS:000330298800001 PM 23990471 ER PT J AU Humbard, MA Surkov, S De Donatis, GM Jenkins, LM Maurizi, MR AF Humbard, Matthew A. Surkov, Serhiy De Donatis, Gian Marco Jenkins, Lisa M. Maurizi, Michael R. TI The N-degradome of Escherichia coli LIMITED PROTEOLYSIS IN VIVO GENERATES A LARGE POOL OF PROTEINS BEARING N-DEGRONS SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Adaptor Proteins; ATP-dependent Protease; Protein Degradation; Protein Processing; Proteomics; Aat; ClpA; ClpS; END Site; N-end Rule ID END RULE SUBSTRATE; CLPAP PROTEASE; CLPXP PROTEASE; RECOGNITION; DEGRADATION; MACHINE; ADAPTER; PATHWAY; TRANSLOCATION; STABILITY AB The N-end rule is a conserved mechanism found in Gram-negative bacteria and eukaryotes for marking proteins to be degraded by ATP-dependent proteases. Specific N-terminal amino acids (N-degrons) are sufficient to target a protein to the degradation machinery. In Escherichia coli, the adaptor ClpS binds an N-degron and delivers the protein to ClpAP for degradation. As ClpS recognizes N-terminal Phe, Trp, Tyr, and Leu, which are not found at the N terminus of proteins translated and processed by the canonical pathway, proteins must be post-translationally modified to expose an N-degron. One modification is catalyzed by Aat, an enzyme that adds leucine or phenylalanine to proteins with N-terminal lysine or arginine; however, such proteins are also not generated by the canonical protein synthesis pathway. Thus, the mechanisms producing N-degrons in proteins and the frequency of their occurrence largely remain a mystery. To address these issues, we used a ClpS affinity column to isolate interacting proteins from E. coli cell lysates under non-denaturing conditions. We identified more than 100 proteins that differentially bound to a column charged with wild-type ClpS and eluted with a peptide bearing an N-degron. Thirty-two of 37 determined N-terminal peptides had N-degrons. Most of the proteins were N-terminally truncated by endoproteases or exopeptidases, and many were further modified by Aat. The identities of the proteins point to possible physiological roles for the N-end rule in cell division, translation, transcription, and DNA replication and reveal widespread proteolytic processing of cellular proteins to generate N-end rule substrates. C1 [Humbard, Matthew A.; Surkov, Serhiy; De Donatis, Gian Marco; Maurizi, Michael R.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Jenkins, Lisa M.] NCI, Collaborat Prot Technol Resource, Cell Biol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Maurizi, MR (reprint author), NCI, NIH, Bldg 37,Rm 2128,37 Convent Dr,MSC4256, Bethesda, MD 20892 USA. EM mmaurizi@helix.nih.gov FU National Institutes of Health Intramural Research Program of the Center for Cancer Research, NCI FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the Center for Cancer Research, NCI. NR 37 TC 13 Z9 14 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 4 PY 2013 VL 288 IS 40 BP 28913 EP 28924 DI 10.1074/jbc.M113.492108 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 298BL UT WOS:000330298800043 PM 23960079 ER PT J AU Cai, H Cong, WN Daimon, CM Wang, R Tschop, MH Sevigny, J Martin, B Maudsley, S AF Cai, Huan Cong, Wei-na Daimon, Caitlin M. Wang, Rui Tschoep, Matthias H. Sevigny, Jean Martin, Bronwen Maudsley, Stuart TI Altered Lipid and Salt Taste Responsivity in Ghrelin and GOAT Null Mice SO PLOS ONE LA English DT Article ID VASOACTIVE-INTESTINAL-PEPTIDE; EPITHELIAL NA+ CHANNEL; CHAIN FATTY-ACIDS; INSULIN SENSITIVITY; DIETARY LIPIDS; KNOCKOUT MICE; MOLECULAR-MECHANISMS; ALPHA-GUSTDUCIN; ENERGY-BALANCE; FOOD-INTAKE AB Taste perception plays an important role in regulating food preference, eating behavior and energy homeostasis. Taste perception is modulated by a variety of factors, including gastric hormones such as ghrelin. Ghrelin can regulate growth hormone release, food intake, adiposity, and energy metabolism. Octanoylation of ghrelin by ghrelin O-acyltransferase (GOAT) is a specific post-translational modification which is essential for many biological activities of ghrelin. Ghrelin and GOAT are both widely expressed in many organs including the gustatory system. In the current study, overall metabolic profiles were assessed in wild-type (WT), ghrelin knockout (ghrelin(-/-)), and GOAT knockout (GOAT(-/-)) mice. Ghrelin(-/-) mice exhibited decreased food intake, increased plasma triglycerides and increased ketone bodies compared to WT mice while demonstrating WT-like body weight, fat composition and glucose control. In contrast GOAT(-/-) mice exhibited reduced body weight, adiposity, resting glucose and insulin levels compared to WT mice. Brief access taste behavioral tests were performed to determine taste responsivity in WT, ghrelin(-/-) and GOAT(-/-) mice. Ghrelin and GOAT null mice possessed reduced lipid taste responsivity. Furthermore, we found that salty taste responsivity was attenuated in ghrelin(-/-) mice, yet potentiated in GOAT(-/-) mice compared to WT mice. Expression of the potential lipid taste regulators Cd36 and Gpr120 were reduced in the taste buds of ghrelin and GOAT null mice, while the salt-sensitive ENaC subunit was increased in GOAT(-/-) mice compared with WT mice. The altered expression of Cd36, Gpr120 and ENaC may be responsible for the altered lipid and salt taste perception in ghrelin(-/-) and GOAT(-/-) mice. The data presented in the current study potentially implicates ghrelin signaling activity in the modulation of both lipid and salt taste modalities. C1 [Cai, Huan; Cong, Wei-na; Daimon, Caitlin M.; Wang, Rui; Martin, Bronwen] NIA, Metab Unit, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Tschoep, Matthias H.] Helmholtz Ctr Munich, Inst Diabet & Obes, Munich, Germany. [Sevigny, Jean] Ctr Rech CHU Quebec, Ctr Rech Rhumatol & Immunol, Quebec City, PQ, Canada. [Sevigny, Jean] Univ Laval, Fac Med, Dept Microbiol Infectiol & Immunol, Quebec City, PQ G1K 7P4, Canada. [Maudsley, Stuart] NIA, Receptor Pharmacol Unit, Lab Neurosci, NIH, Baltimore, MD 21224 USA. RP Martin, B (reprint author), NIA, Metab Unit, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. EM martinbro@mail.nih.gov RI Sevigny, Jean/E-8039-2012; Tschoep, Matthias/I-5443-2014; Cai, Huan/B-6578-2016; OI Sevigny, Jean/0000-0003-2922-1600; Cai, Huan/0000-0001-7731-8891; Tschoep, Matthias/0000-0002-4744-371X FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work was supported entirely by the Intramural Research Program of the National Institute on Aging, 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 81 TC 13 Z9 13 U1 2 U2 15 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 OCT 4 PY 2013 VL 8 IS 10 AR e76553 DI 10.1371/journal.pone.0076553 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 232JF UT WOS:000325489100129 PM 24124572 ER PT J AU Dasgupta, N Xu, YH Oh, S Sun, Y Jia, L Keddache, M Grabowski, GA AF Dasgupta, Nupur Xu, You-Hai Oh, Sunghee Sun, Ying Jia, Li Keddache, Mehdi Grabowski, Gregory A. TI Gaucher Disease: Transcriptome Analyses Using Microarray or mRNA Sequencing in a Gba1 Mutant Mouse Model Treated with Velaglucerase alfa or Imiglucerase SO PLOS ONE LA English DT Article ID DIFFERENTIAL EXPRESSION ANALYSIS; LINKED SIDEROBLASTIC ANEMIA; ENZYME REPLACEMENT THERAPY; GLOBAL GENE-EXPRESSION; ACID-BETA-GLUCOSIDASE; MEGAKARYOCYTIC DIFFERENTIATION; MITOCHONDRIAL DYSFUNCTION; PARKINSONS-DISEASE; FACTOR GATA-1; GLUCOCEREBROSIDASE AB Gaucher disease type 1, an inherited lysosomal storage disorder, is caused by mutations in GBA1 leading to defective glucocerebrosidase (GCase) function and consequent excess accumulation of glucosylceramide/glucosylsphingosine in visceral organs. Enzyme replacement therapy (ERT) with the biosimilars, imiglucerase (imig) or velaglucerase alfa (vela) improves/reverses the visceral disease. Comparative transcriptomic effects (microarray and mRNA-Seq) of no ERT and ERT (imig or vela) were done with liver, lung, and spleen from mice having Gba1 mutant alleles, termed D409V/null. Disease-related molecular effects, dynamic ranges, and sensitivities were compared between mRNA-Seq and microarrays and their respective analytic tools, i.e. Mixed Model ANOVA (microarray), and DESeq and edgeR (mRNA-Seq). While similar gene expression patterns were observed with both platforms, mRNA-Seq identified more differentially expressed genes (DEGs) (similar to 3-fold) than the microarrays. Among the three analytic tools, DESeq identified the maximum number of DEGs for all tissues and treatments. DESeq and edgeR comparisons revealed differences in DEGs identified. In 9V/null liver, spleen and lung, post-therapy transcriptomes approximated WT, were partially reverted, and had little change, respectively, and were concordant with the corresponding histological and biochemical findings. DEG overlaps were only 8-20% between mRNA-Seq and microarray, but the biological pathways were similar. Cell growth and proliferation, cell cycle, heme metabolism, and mitochondrial dysfunction were most altered with the Gaucher disease process. Imig and vela differentially affected specific disease pathways. Differential molecular responses were observed in direct transcriptome comparisons from imig- and vela-treated tissues. These results provide cross-validation for the mRNA-Seq and microarray platforms, and show differences between the molecular effects of two highly structurally similar ERT biopharmaceuticals. C1 [Dasgupta, Nupur; Xu, You-Hai; Oh, Sunghee; Sun, Ying; Keddache, Mehdi; Grabowski, Gregory A.] Cincinnati Childrens Hosp Res Fdn, Div Human Genet, Cincinnati, OH USA. [Xu, You-Hai; Oh, Sunghee; Sun, Ying; Keddache, Mehdi; Grabowski, Gregory A.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. [Jia, Li] NIH, CCR Bioinformat Core, Adv Biomed Comp Ctr, Frederick Natl Lab Canc Res, Bethesda, MD 20892 USA. RP Grabowski, GA (reprint author), Cincinnati Childrens Hosp Res Fdn, Div Human Genet, Cincinnati, OH USA. EM greg.grabowski@cchmc.org FU National Institutes of Health [DK 36729] FX The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work is supported by a grant by from the National Institutes of Health (DK 36729). NR 84 TC 5 Z9 5 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 4 PY 2013 VL 8 IS 10 AR e74912 DI 10.1371/journal.pone.0074912 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 232JF UT WOS:000325489100018 PM 24124461 ER PT J AU Li, SQ Cheuk, AT Shern, JF Song, YK Hurd, L Liao, HL Wei, JS Khan, J AF Li, Samuel Q. Cheuk, Adam T. Shern, Jack F. Song, Young K. Hurd, Laura Liao, Hongling Wei, Jun S. Khan, Javed TI Targeting Wild-Type and Mutationally Activated FGFR4 in Rhabdomyosarcoma with the Inhibitor Ponatinib (AP24534) SO PLOS ONE LA English DT Article ID TYROSINE KINASE INHIBITOR; EMBRYONAL RHABDOMYOSARCOMA; IN-VIVO; ALVEOLAR RHABDOMYOSARCOMA; MYELOID-LEUKEMIA; CANCER MODELS; POTENT; IDENTIFICATION; GENE; NEUROBLASTOMA AB Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) is a cell surface tyrosine kinase receptor that is involved in normal myogenesis and muscle regeneration, but not commonly expressed in differentiated muscle tissues. Amplification and mutational activation of FGFR4 has been reported in RMS and promotes tumor progression. Therefore, FGFR4 is a tractable therapeutic target for patients with RMS. In this study, we used a chimeric Ba/F3 TEL-FGFR4 construct to test five tyrosine kinase inhibitors reported to specifically inhibit FGFRs in the nanomolar range. We found ponatinib (AP24534) to be the most potent FGFR4 inhibitor with an IC50 in the nanomolar range. Ponatinib inhibited the growth of RMS cells expressing wild-type or mutated FGFR4 through increased apoptosis. Phosphorylation of wild-type and mutated FGFR4 as well as its downstream target STAT3 was also suppressed by ponatinib. Finally, ponatinib treatment inhibited tumor growth in a RMS mouse model expressing mutated FGFR4. Therefore, our data suggests that ponatinib is a potentially effective therapeutic agent for RMS tumors that are driven by a dysregulated FGFR4 signaling pathway. C1 [Li, Samuel Q.; Cheuk, Adam T.; Shern, Jack F.; Song, Young K.; Hurd, Laura; Liao, Hongling; Wei, Jun S.; Khan, Javed] NCI, Oncogen Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Khan, J (reprint author), NCI, Oncogen Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 10 Z9 12 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 4 PY 2013 VL 8 IS 10 AR e76551 DI 10.1371/journal.pone.0076551 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 232JF UT WOS:000325489100128 PM 24124571 ER PT J AU Sun, ZJ Zhang, L Zhang, W Hall, B Bian, YS Kulkarni, AB AF Sun, Zhi-jun Zhang, Lu Zhang, Wei Hall, Bradford Bian, Yansong Kulkarni, Ashok B. TI Inhibition of mTOR Reduces Anal Carcinogenesis in Transgenic Mouse Model SO PLOS ONE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; TGF-BETA; CANCER; HEAD; NECK; GROWTH; PATHWAY; PTEN; INFLAMMATION; ACTIVATION AB The molecular mechanism of human anal squamous cell carcinoma (ASCC) is unclear, and the accumulating evidence indicate association of ASCC with the activation of the Akt/mTOR pathway. Here we describe a mouse model with spontaneous anal squamous cell cancer, wherein a combined deletion of Tgfbr1 and Pten in stratified squamous epithelia was induced using inducible K14-Cre. Histopathologic analyses confirmed that 33.3% of the mice showed increased susceptibility to ASCC and precancerous lesions. Biomarker analyses demonstrated that the activation of the Akt pathway in ASCC of the Tgfbr1 and Pten double knockout (2cKO) mouse was similar to that observed in human anal cancer. Chemopreventive experiments using mTOR inhibitor-rapamycin treatment significantly delayed the onset of the ASCC tumors and reduced the tumor burden in 2cKO mice by decreasing the phosphorylation of Akt and S6. This is the first conditional knockout mouse model used for investigating the contributions of viral and cellular factors in anal carcinogenesis without carcinogen-mediated induction, and it would provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer. C1 [Sun, Zhi-jun; Zhang, Lu; Zhang, Wei] Wuhan Univ, Sch & Hosp Stomatol, State Key Lab Breeding Base Basic Sci Stomatol, Wuhan 430072, Peoples R China. [Sun, Zhi-jun; Zhang, Lu; Zhang, Wei] Wuhan Univ, Sch & Hosp Stomatol, Minist Educ, Key Lab Oral Biomed, Wuhan 430072, Peoples R China. [Sun, Zhi-jun; Zhang, Lu; Hall, Bradford; Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. [Bian, Yansong] Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, NIH, Bethesda, MD USA. RP Sun, ZJ (reprint author), Wuhan Univ, Sch & Hosp Stomatol, State Key Lab Breeding Base Basic Sci Stomatol, Wuhan 430072, Peoples R China. EM zhijundejia@163.com; ak40m@nih.gov FU National Institute of Dental and Craniofacial Research, NIH [ZIA-DE-000698]; National Natural Science Foundation of China [81072203, 81272963, 81371106] FX This work was supported by Intramural Research Programs ZIA-DE-000698 (ABK) of the National Institute of Dental and Craniofacial Research, NIH, and National Natural Science Foundation of China 81072203, 81272963 (ZJS) and 81371106 (LZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 1 Z9 1 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 4 PY 2013 VL 8 IS 10 AR e74888 DI 10.1371/journal.pone.0074888 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 232JF UT WOS:000325489100017 PM 24124460 ER PT J AU Zeituni, AE Miura, K Diakite, M Doumbia, S Moretz, SE Diouf, A Tullo, G Lopera-Mesa, TM Bess, CD Mita-Mendoza, NK Anderson, JM Fairhurst, RM Long, CA AF Zeituni, Amir E. Miura, Kazutoyo Diakite, Mahamadou Doumbia, Saibou Moretz, Samuel E. Diouf, Ababacar Tullo, Gregory Lopera-Mesa, Tatiana M. Bess, Cameron D. Mita-Mendoza, Neida K. Anderson, Jennifer M. Fairhurst, Rick M. Long, Carole A. TI Effects of Age, Hemoglobin Type and Parasite Strain on IgG Recognition of Plasmodium falciparum-Infected Erythrocytes in Malian Children SO PLOS ONE LA English DT Article ID VARIANT SURFACE-ANTIGENS; SICKLE-CELL TRAIT; APICAL MEMBRANE ANTIGEN-1; ACQUIRED-IMMUNITY; HUMAN MALARIA; FLUORESCENT ANTIBODY; PROTECTIVE ANTIBODIES; SYSTEMATIC ANALYSIS; HEME OXYGENASE-1; SAIMIRI MONKEY AB Background: Naturally-acquired antibody responses to antigens on the surface of Plasmodium falciparum-infected red blood cells (iRBCs) have been implicated in antimalarial immunity. To profile the development of this immunity, we have been studying a cohort of Malian children living in an area with intense seasonal malaria transmission. Methodology/Principal Findings: We collected plasma from a sub-cohort of 176 Malian children aged 3-11 years, before (May) and after (December) the 2009 transmission season. To measure the effect of hemoglobin (Hb) type on antibody responses, we enrolled age-matched HbAA, HbAS and HbAC children. To quantify antibody recognition of iRBCs, we designed a high-throughput flow cytometry assay to rapidly test numerous plasma samples against multiple parasite strains. We evaluated antibody reactivity of each plasma sample to 3 laboratory-adapted parasite lines (FCR3, D10, PC26) and 4 short-term-cultured parasite isolates (2 Malian and 2 Cambodian). 97% of children recognized >= 1 parasite strain and the proportion of IgG responders increased significantly during the transmission season for most parasite strains. Both strain-specific and strain-transcending IgG responses were detected, and varied by age, Hb type and parasite strain. In addition, the breadth of IgG responses to parasite strains increased with age in HbAA, but not in HbAS or HbAC, children. Conclusions/Significance: Our assay detects both strain-specific and strain-transcending IgG responses to iRBCs. The magnitude and breadth of these responses varied not only by age, but also by Hb type and parasite strain used. These findings indicate that studies of acquired humoral immunity should account for Hb type and test large numbers of diverse parasite strains. C1 [Zeituni, Amir E.; Miura, Kazutoyo; Moretz, Samuel E.; Diouf, Ababacar; Tullo, Gregory; Lopera-Mesa, Tatiana M.; Bess, Cameron D.; Mita-Mendoza, Neida K.; Anderson, Jennifer M.; Fairhurst, Rick M.; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Diakite, Mahamadou; Doumbia, Saibou] Univ Bamako, Fac Med Pharm & Odontostomatol, Bamako, Mali. [Mita-Mendoza, Neida K.] Ctr Invest & Estudios Avanzados, Dept Biomed Mol, Mexico City, DF, Mexico. RP Long, CA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM clong@niaid.nih.gov NR 77 TC 2 Z9 3 U1 2 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 OCT 4 PY 2013 VL 8 IS 10 AR e76734 DI 10.1371/journal.pone.0076734 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 232JF UT WOS:000325489100148 PM 24124591 ER PT J AU Ainsworth, WB Hughes, BT Au, WC Sakelaris, S Kerscher, O Benton, MG Basrai, MA AF Ainsworth, William B. Hughes, Bridget Todd Au, Wei Chun Sakelaris, Sally Kerscher, Oliver Benton, Michael G. Basrai, Munira A. TI Cytoplasmic localization of Hug1p, a negative regulator of the MEC1 pathway, coincides with the compartmentalization of Rnr2p-Rnr4p SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Saccharomyces cerevisiae; HUG1; MEC1; RNR; HU arrest; DNA damage; Subcellular localization ID RIBONUCLEOTIDE REDUCTASE INHIBITOR; DAMAGE CHECKPOINT PATHWAYS; DNA-DAMAGE; SACCHAROMYCES-CEREVISIAE; SUBCELLULAR-LOCALIZATION; NUCLEAR IMPORT; DNTP POOLS; CELL-CYCLE; REPLICATION; YEAST AB The evolutionarily conserved MEC1 checkpoint pathway mediates cell cycle arrest and induction of genes including the RNR (Ribonucleotide reductase) genes and HUG1 (Hydroxyurea, ultraviolet, and gamma radiation) in response to DNA damage and replication arrest. Rnr complex activity is in part controlled by cytoplasmic localization of the Rnr2p-Rnr4p subunits and inactivation of negative regulators Sml1p and Dif1p upon DNA damage and hydroxyurea (HU) treatment. We previously showed that a deletion of HUG1 rescues lethality of mec1 Delta and suppresses dun1 Delta strains. In this study, multiple approaches demonstrate the regulatory response of Hug1p to DNA damage and HU treatment and support its role as a negative effector of the MEC1 pathway. Consistent with our hypothesis, wild-type cells are sensitive to DNA damage and HU when HUG1 is overexpressed. A Hug1 polyclonal antiserum reveals that HUG1 encodes a protein in budding yeast and its MEC1-dependent expression is delayed compared to the rapid induction of Rnr3p in response to HU treatment. Cell biology and subcellular fractionation experiments show localization of Hug1p-GFP to the cytoplasm upon HU treatment. The cytoplasmic localization of Hug1p-GFP is dependent on MEC1 pathway genes and coincides with the cytoplasmic localization of Rnr2p-Rnr4p. Taken together, the genetic interactions, gene expression, and localization studies support a novel role for Hug1p as a negative regulator of the MEC1 checkpoint response through its compartmentalization with Rnr2p-Rnr4p. Published by Elsevier Inc. C1 [Ainsworth, William B.; Benton, Michael G.] Louisiana State Univ, Cain Dept Chem Engn, Baton Rouge, LA 70803 USA. [Hughes, Bridget Todd; Au, Wei Chun; Sakelaris, Sally; Basrai, Munira A.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kerscher, Oliver] Coll William & Mary, Dept Biol, Williamsburg, VA 23185 USA. RP Benton, MG (reprint author), Louisiana State Univ, Cain Dept Chem Engn, 110 Chem Engn,S Stadium Rd, Baton Rouge, LA 70803 USA. EM benton@lsu.edu; basraim@mail.nih.gov FU Donald Clayton Assistantship; Longwell Family Foundation; Intramural Research Program of the National Cancer Institute, National Institutes of Health FX The authors gratefully acknowledge Sushma Sharma and Andrei Chabes for helpful discussions. W.B.A. was supported by a Donald Clayton Assistantship. M.G.B. was supported by a Ralph E. Powe Enhancement Award and a FIER grant from the Longwell Family Foundation. Support for M.A.B. was provided by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 25 TC 4 Z9 4 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 4 PY 2013 VL 439 IS 4 BP 443 EP 448 DI 10.1016/j.bbrc.2013.08.089 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 231AI UT WOS:000325385000005 PM 24012676 ER PT J AU Sohn, YI Lee, NJ Chung, A Saavedra, JM Turner, RS Pak, DTS Hoe, HS AF Sohn, Young In Lee, Nathanael J. Chung, Andrew Saavedra, Juan M. Turner, R. Scott Pak, Daniel T. S. Hoe, Hyang-Sook TI Antihypertensive drug Valsartan promotes dendritic spine density by altering AMPA receptor trafficking SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Valsartan; CaMKII alpha; AMPA receptor; Spinogenesis ID COGNITIVE DECLINE; ALZHEIMER-DISEASE; ANGIOTENSIN-II; BLOOD-PRESSURE; AMYLOID-BETA; HYPERTENSION; DEMENTIA; BRAIN; ACTIVATION; SYNAPTOGENESIS AB Recent studies demonstrated that the antihypertensive drug Valsartan improved spatial and episodic memory in mouse models of Alzheimer's Disease (AD) and human subjects with hypertension. However, the molecular mechanism by which Valsartan can regulate cognitive function is still unknown. Here, we investigated the effect of Valsartan on dendritic spine formation in primary hippocampal neurons, which is correlated with learning and memory. Interestingly, we found that Valsartan promotes spinogenesis in developing and mature neurons. In addition, we found that Valsartan increases the puncta number of PSD-95 and trends toward an increase in the puncta number of synaptophysin. Moreover, Valsartan increased the cell surface levels of AMPA receptors and selectively altered the levels of spinogenesis-related proteins, including CaMKII alpha and phospho-CDK5. These data suggest that Valsartan may promote spinogenesis by enhancing AMPA receptor trafficking and synaptic plasticity signaling. (c) 2013 Elsevier Inc. All rights reserved. C1 [Hoe, Hyang-Sook] KBRI, Taegu 700010, South Korea. [Sohn, Young In; Lee, Nathanael J.; Chung, Andrew; Hoe, Hyang-Sook] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20057 USA. [Turner, R. Scott; Hoe, Hyang-Sook] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20057 USA. [Pak, Daniel T. S.] Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20057 USA. [Saavedra, Juan M.] NIMH, Pharmacol Sect, DIRP, Bethesda, MD 20892 USA. RP Pak, DTS (reprint author), Georgetown Univ, Dept Pharmacol, 3900 Reservoir Rd NW, Washington, DC 20057 USA. EM dtp6@georgetown.edu; sookhoe72@kbri.re.kr RI Turner, Raymond/G-2263-2011 OI Turner, Raymond/0000-0001-7534-2935 FU NIH [AG039708]; Establishment and Operation of Korea Brain Research Institute (KBRI), Basic Research Program of the Ministry of Science, Ict & future Planning [2031-415] FX This work was supported by NIH AG039708 (HSH) and Establishment and Operation of Korea Brain Research Institute (KBRI), Basic Research Program of the Ministry of Science, Ict & future Planning (2031-415, HSH). The monoclonal antibodies PSD-95, GluN1, GluN2B were developed and obtained from UC Davis/NIH NeuroMab Facility. The authors declare no competing financial interests. NR 31 TC 5 Z9 6 U1 1 U2 6 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 OCT 4 PY 2013 VL 439 IS 4 BP 464 EP 470 DI 10.1016/j.bbrc.2013.08.091 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 231AI UT WOS:000325385000009 PM 24012668 ER PT J AU Turner, M Leslie, S Martin, NG Peschanski, M Rao, M Taylor, CJ Trounson, A Turner, D Yamanaka, S Wilmut, I AF Turner, Marc Leslie, Stephen Martin, Nicholas G. Peschanski, Marc Rao, Mahendra Taylor, Craig J. Trounson, Alan Turner, David Yamanaka, Shinya Wilmut, Ian TI Toward the Development of a Global Induced Pluripotent Stem Cell Library SO CELL STEM CELL LA English DT Editorial Material ID IPS CELLS; TRANSPLANTATION; BANKING AB The ability to preselect the donor genotype of iPSC lines provides important opportunities for immunematching in cell therapy. Here we propose that an international assessment should be made of how immune incompatibility can best be managed and how a network of GMP HLA homozygous haplobanks could be operated. C1 [Turner, Marc] SNBTS HeadQuarters, Edinburgh EH17 7QT, Midlothian, Scotland. [Leslie, Stephen] Univ Melbourne, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Leslie, Stephen] Univ Melbourne, Dept Math & Stat, Parkville, Vic 3052, Australia. [Martin, Nicholas G.] Queensland Inst Med Res, Brisbane, Qld Q4029, Australia. [Peschanski, Marc] INSERM UMR861, AFM, F-91030 Evry, France. [Peschanski, Marc] UEVE UMR861, F-91030 Evry, France. [Rao, Mahendra] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA. [Taylor, Craig J.] Addenbrookes Hosp, Cambridge Univ Hosp NHS Fdn Trust, Tissue Typing Lab, Cambridge CB2 0QQ, England. [Trounson, Alan] Calif Inst Regenerat Med, San Francisco, CA 94107 USA. [Turner, David] Royal Infirm Edinburgh NHS Trust, SNBTS, Edinburgh EH16 4SA, Midlothian, Scotland. [Yamanaka, Shinya] Kyoto Univ, Ctr IPS Cell Res & Applicat, Dept Reprogramming Sci, Kyoto 6068507, Japan. [Yamanaka, Shinya] Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA. [Wilmut, Ian] Univ Edinburgh, Edinburgh BioQuarter, Scottish Ctr Regenerat Med, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland. RP Wilmut, I (reprint author), Univ Edinburgh, Edinburgh BioQuarter, Scottish Ctr Regenerat Med, MRC Ctr Regenerat Med, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland. EM ian.wilmut@ed.ac.uk OI Martin, Nicholas/0000-0003-4069-8020 NR 10 TC 70 Z9 70 U1 2 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD OCT 3 PY 2013 VL 13 IS 4 BP 382 EP 384 DI 10.1016/j.stem.2013.08.003 PG 3 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 287VT UT WOS:000329571100006 PM 24094319 ER PT J AU Schiffman, SS Rother, KI AF Schiffman, Susan S. Rother, Kristina I. TI SUCRALOSE, A SYNTHETIC ORGANOCHLORINE SWEETENER: OVERVIEW OF BIOLOGICAL ISSUES SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART B-CRITICAL REVIEWS LA English DT Review ID HUMAN LIVER-MICROSOMES; ST-JOHNS-WORT; PREGNANE-X-RECEPTOR; HUMAN CYTOCHROME-P450 ISOFORMS; P-GLYCOPROTEIN TRANSPORT; RAT SMALL-INTESTINE; HIGH-INTENSITY SWEETENERS; BLOOD-BRAIN-BARRIER; 1,4-DIHYDROPYRIDINE CALCIUM-ANTAGONISTS; PERSISTENT ORGANIC POLLUTANTS AB Sucralose is a synthetic organochlorine sweetener (OC) that is a common ingredient in the world's food supply. Sucralose interacts with chemosensors in the alimentary tract that play a role in sweet taste sensation and hormone secretion. In rats, sucralose ingestion was shown to increase the expression of the efflux transporter P-glycoprotein (P-gp) and two cytochrome P-450 (CYP) isozymes in the intestine. P-gp and CYP are key components of the presystemic detoxification system involved in first-pass drug metabolism. The effect of sucralose on first-pass drug metabolism in humans, however, has not yet been determined. In rats, sucralose alters the microbial composition in the gastrointestinal tract (GIT), with relatively greater reduction in beneficial bacteria. Although early studies asserted that sucralose passes through the GIT unchanged, subsequent analysis suggested that some of the ingested sweetener is metabolized in the GIT, as indicated by multiple peaks found in thin-layer radiochromatographic profiles of methanolic fecal extracts after oral sucralose administration. The identity and safety profile of these putative sucralose metabolites are not known at this time. Sucralose and one of its hydrolysis products were found to be mutagenic at elevated concentrations in several testing methods. Cooking with sucralose at high temperatures was reported to generate chloropropanols, a potentially toxic class of compounds. Both human and rodent studies demonstrated that sucralose may alter glucose, insulin, and glucagon-like peptide 1 (GLP-1) levels. Taken together, these findings indicate that sucralose is not a biologically inert compound. C1 [Schiffman, Susan S.] N Carolina State Univ, Coll Engn, Dept Elect & Comp Engn, Raleigh, NC 27695 USA. [Rother, Kristina I.] NIDDK, Sect Pediat Diabet & Metab, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. RP Schiffman, SS (reprint author), N Carolina State Univ, Coll Engn, Dept Elect & Comp Engn, Raleigh, NC 27695 USA. EM sschiffman@nc.rr.com FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) FX This research was supported in part by the Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). NR 473 TC 20 Z9 23 U1 11 U2 79 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1093-7404 EI 1521-6950 J9 J TOXICOL ENV HEAL B JI J. Toxicol. Env. Health-Pt b-Crit. Rev. PD OCT 3 PY 2013 VL 16 IS 7 BP 399 EP 451 DI 10.1080/10937404.2013.842523 PG 53 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 249LU UT WOS:000326779500001 PM 24219506 ER PT J AU Li, HT Zhu, F Sun, YW Li, B Oi, NM Chen, HY Lubet, RA Bode, AM Dong, ZG AF Li, Haitao Zhu, Feng Sun, Yanwen Li, Bing Oi, Naomi Chen, Hanyong Lubet, Ronald A. Bode, Ann M. Dong, Zigang TI Select Dietary Phytochemicals Function as Inhibitors of COX-1 but Not COX-2 SO PLOS ONE LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; EPITHELIAL-CELLS; CYCLOOXYGENASE-2 TRANSCRIPTION; CARDIOVASCULAR-DISEASE; SOYBEAN ISOFLAVONES; CANCER PREVENTION; PHARMACOKINETICS; BIOAVAILABILITY; ASPIRIN; RATS AB Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors. Many active dietary factors are reported to suppress carcinogenesis by targeting COX-2. A major question was accordingly raised: why has the lifelong use of phytochemicals that likely inhibit COX-2 presumably not been associated with adverse cardiovascular side effects. To answer this question, we selected a library of dietary-derived phytochemicals and evaluated their potential cardiovascular toxicity in human umbilical vein endothelial cells. Our data indicated that the possibility of cardiovascular toxicity of these dietary phytochemicals was low. Further mechanistic studies revealed that the actions of these phytochemicals were similar to aspirin in that they mainly inhibited COX-1 rather than COX-2, especially at low doses. C1 [Li, Haitao; Zhu, Feng; Sun, Yanwen; Li, Bing; Oi, Naomi; Chen, Hanyong; Bode, Ann M.; Dong, Zigang] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [Lubet, Ronald A.] NCI, NIH, Bethesda, MD 20892 USA. RP Dong, ZG (reprint author), Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA. EM zgdong@hi.umn.edu FU Hormel Foundation and National Institutes of Health [R37 CA081064, ES016548]; NCI [HHSN-261200533001C-NO1-CN9 53301, N01-CN-43309-18018-01WA 13B] FX This work was supported by The Hormel Foundation and National Institutes of Health grants R37 CA081064 and ES016548 and NCI Contract Numbers HHSN-261200533001C-NO1-CN9 53301 and N01-CN-43309-18018-01WA 13B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 2 Z9 2 U1 1 U2 14 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 OCT 3 PY 2013 VL 8 IS 10 AR e76452 DI 10.1371/journal.pone.0076452 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 232HM UT WOS:000325483600055 PM 24098505 ER PT J AU Hsu, PF Chuang, SY Cheng, HM Sung, SH Ting, CT Lakatta, EG Yin, FCP Chou, P Chen, CH AF Hsu, Pai-Feng Chuang, Shao-Yuan Cheng, Hao-Min Sung, Shih-Hsien Ting, Chih-Tai Lakatta, Edward G. Yin, Frank C. P. Chou, Pesus Chen, Chen-Huan TI Associations of serum uric acid levels with arterial wave reflections and central systolic blood pressure SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Uric acid; Hypertension; Arterial stiffness; Wave reflection; c-Peptide ID ALL-CAUSE; CARDIOVASCULAR-DISEASE; ESSENTIAL-HYPERTENSION; METABOLIC SYNDROME; AORTIC STIFFNESS; MORTALITY; CHINESE; POPULATION; MEN; HYPERURICEMIA AB Background: Uric acid may be involved in the pathogenesis of hypertension. We investigated the roles of four major hemodynamic parameters of blood pressure, including arterial stiffness, wave reflections, cardiac output (CO), and total peripheral resistance (TPR), in the association between uric acid and central systolic blood pressure (SBP-c). Methods: A sample of 1303 normotensive and untreated hypertensive Taiwanese participants (595 women, aged 30-79 years) was drawn from a community-based survey. Study subjects' baseline characteristics, biochemical parameters, carotid-femoral pulse wave velocity (cf-PWV), amplitude of the backward pressure wave decomposed from a calibrated tonometry-derived carotid pressure waveform (Pb), CO, TPR, and SBP-c were analyzed. Results: In multi-variate analyses adjusted for age, waist circumference, body mass index, creatinine, total cholesterol, smoking, and heart rate, uric acid significantly correlated with Pb and cf-PWV in men, and Pb and TPR in women. The correlation between uric acid and Pb remained significant in men and women when cf-PWV was further adjusted. In the final multi-variate prediction model (model r(2)=0.839) for SBP-c, the significant independent variables included uric acid (partial r(2)=0.005), Pb (partial r(2)=0.651), cf-PWV (partial r(2)=0.005), CO (partial r(2)=0.062), TPR (partial r(2)=0.021), with adjustment for age, sex, waist circumference, body mass index, creatinine, total cholesterol, smoking, and heart rate. Conclusions: Uric acid was significantly independently associated with wave reflections, which is the dominant determinant of SBP-c. Uric acid was also significantly associated with SBP-c independently of the major hemodynamic parameters. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Hsu, Pai-Feng; Sung, Shih-Hsien] Taipei Vet Gen Hosp, Dept Med, Taipei, Taiwan. [Chuang, Shao-Yuan] Natl Hlth Res Inst, Inst Populat Hlth Sci, Miaoli, Taiwan. [Cheng, Hao-Min; Chen, Chen-Huan] Taipei Vet Gen Hosp, Dept Med Res & Educ, Taipei, Taiwan. [Ting, Chih-Tai] Taichung Vet Gen Hosp, Ctr Cardiovasc, Taichung, Taiwan. [Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Yin, Frank C. P.] Washington Univ, Dept Biomed Engn, St Louis, MO USA. [Hsu, Pai-Feng; Sung, Shih-Hsien; Chou, Pesus; Chen, Chen-Huan] Natl Yang Ming Univ, Inst Publ Hlth, Taipei 112, Taiwan. [Hsu, Pai-Feng; Cheng, Hao-Min; Sung, Shih-Hsien; Chen, Chen-Huan] Natl Yang Ming Univ, Cardiovasc Res Ctr, Taipei 112, Taiwan. RP Chen, CH (reprint author), Taipei Vet Gen Hosp, Dept Med Res & Educ, 201,Sec 2,Shih Pai Rd, Taipei, Taiwan. EM chench@vghtpe.gov.tw RI Chuang, Shao-Yuan/B-3478-2011 FU National Science Council [NSC 99-2314-B-010-034-MY3]; Taipei Veterans General Hospital, Taiwan, Republic of China [V97C1-101, V98C1-028, V99C1-091]; NIH, National Institute on Aging FX This work was supported by a grant from the National Science Council (NSC 99-2314-B-010-034-MY3) and intramural grants (V97C1-101, V98C1-028, and V99C1-091) from Taipei Veterans General Hospital, Taiwan, Republic of China, and was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 40 TC 9 Z9 10 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD OCT 3 PY 2013 VL 168 IS 3 BP 2057 EP 2063 DI 10.1016/j.ijcard.2013.01.164 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 241RF UT WOS:000326184400059 PM 23453449 ER PT J AU von Bonsdorff, MB Groffen, DAI Vidal, JS Rantanen, T Jonsson, PV Garcia, M Aspelund, T Eiriksdottir, G Siggeirsdottir, K Launer, L Gudnason, V Harris, TB AF von Bonsdorff, Mikaela B. Groffen, Danielle A. I. Vidal, Jean-Sebastien Rantanen, Taina Jonsson, Palmi V. Garcia, Melissa Aspelund, Thor Eiriksdottir, Gudny Siggeirsdottir, Kristin Launer, Lenore Gudnason, Vilmundur Harris, Tamara B. CA Age Gene Environm Susceptibility-R TI Coronary artery calcium and physical performance as determinants of mortality in older age: The AGES-Reykjavik Study SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Atherosclerosis; Coronary artery calcification; Cardiovascular disease risk factors; Aging; Mortality; Epidemiology ID BEAM COMPUTED-TOMOGRAPHY; WALKING SPEED; GAIT SPEED; SUBCLINICAL ATHEROSCLEROSIS; MYOCARDIAL-INFARCTION; PROGNOSTIC VALUE; RISK-FACTORS; TASK-FORCE; FOLLOW-UP; ADULTS AB Background: Coronary artery calcium (CAC) and physical performance have been shown to be associated with mortality, but it is not clear whether one of them modifies the association. We investigated the association between the extent of CAC and physical performance among older individuals and explored these individual and combined effects on cardiovascular disease (CVD) mortality and non-CVD mortality. Methods: We studied 4074 participants of the AGES-Reykjavik Study who were free from coronary heart disease, had a CAC score calculated from computed tomography scans and had data on mobility limitations and gait speed at baseline in 2002-2006 at a mean age of 76 years. Register-based mortality was available until 2009. Results: Odds for mobility limitation and slow gait increased according to the extent of CAC. Altogether 645 persons died during the follow-up. High CAC, mobility limitation and slow gait were independent predictors of CVD mortality and non-CVD mortality. The joint effect of CAC and gait speed on non-CVD mortality was synergistic, i.e. compared to having low CAC and normal gait, the joint effect of high CAC and slow gait exceeded the additive effect of these individual exposures on non-CVD mortality. For CVD mortality, the effect was additive i.e. the joint effect of high CAC and slow gait did not exceed the sum of the individual exposures. Conclusions: The extent of CAC and decreased physical performance were independent predictors of mortality and the joint presence of these risk factors increased the risk of non-CVD mortality above and beyond the individual effects. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [von Bonsdorff, Mikaela B.; Groffen, Danielle A. I.; Vidal, Jean-Sebastien; Garcia, Melissa; Launer, Lenore; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [von Bonsdorff, Mikaela B.; Rantanen, Taina] Univ Jyvaskyla, Gerontol Res Ctr, FIN-40014 Jyvaskyla, Finland. [von Bonsdorff, Mikaela B.; Rantanen, Taina] Univ Jyvaskyla, Dept Hlth Sci, FIN-40014 Jyvaskyla, Finland. [Groffen, Danielle A. I.] Maastricht Univ, CAPHRI Sch Publ Hlth & Primary Care, Dept Social Med, Maastricht, Netherlands. [Vidal, Jean-Sebastien] Hop Broca, AP HP, Serv Gerontol, Paris, France. [Jonsson, Palmi V.; Aspelund, Thor; Eiriksdottir, Gudny; Siggeirsdottir, Kristin; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. RP von Bonsdorff, MB (reprint author), Univ Jyvaskyla, Gerontol Res Ctr, POB 35, FIN-40014 Jyvaskyla, Finland. EM mikaela.vonbonsdorff@jyu.fi RI Aspelund, Thor/C-5983-2008; von Bonsdorff, Mikaela/A-5218-2015; Gudnason, Vilmundur/K-6885-2015; Vidal, Jean-Sebastien/D-1941-2016; Rantanen, Taina/O-6579-2016 OI Aspelund, Thor/0000-0002-7998-5433; von Bonsdorff, Mikaela/0000-0001-8530-5230; Gudnason, Vilmundur/0000-0001-5696-0084; Vidal, Jean-Sebastien/0000-0001-6770-0720; Rantanen, Taina/0000-0002-1604-1945 FU National Institutes of Health [N01-AG-1-2100]; National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Icelandic Heart Association; Academy of Finland; University of Jyvaskyla; Yrjo Jahnsson Foundation; Fulbright Center, the Finland-US Educational Exchange Commission FX The AGES-Reykjavik Study was supported by a grant from the National Institutes of Health (N01-AG-1-2100), the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Reykjavik Study was funded by the Icelandic Heart Association. MBvB was supported by grants from the Academy of Finland; University of Jyvaskyla; Yrjo Jahnsson Foundation and Fulbright Center, the Finland-US Educational Exchange Commission. NR 46 TC 6 Z9 6 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD OCT 3 PY 2013 VL 168 IS 3 BP 2094 EP 2099 DI 10.1016/j.ijcard.2013.01.067 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 241RF UT WOS:000326184400064 PM 23414742 ER PT J AU Zhang, XL Shu, XO Li, HL Yang, G Xiang, YB Cai, QY Ji, BT Gao, YT Zheng, W AF Zhang, Xianglan Shu, Xiao-Ou Li, Honglan Yang, Gong Xiang, Yong-Bing Cai, Qiuyin Ji, Bu-Tian Gao, Yu-Tang Zheng, Wei TI Visceral adiposity and risk of coronary heart disease in relatively lean Chinese adults SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Visceral adiposity; Heart disease; Chinese ID CARDIOVASCULAR-DISEASE; HYPERTRIGLYCERIDEMIC-WAIST; CARDIOMETABOLIC RISK; SCIENTIFIC STATEMENT; METABOLIC SYNDROME; ABDOMINAL OBESITY; WOMENS HEALTH; FAT; MEN; ASSOCIATION AB Background: The hypertriglyceridemic waist phenotype (defined using both elevated waist circumference and triglycerides) and visceral adiposity index (VAI, defined using waist circumference, body mass index, triglycerides, and high-density lipoprotein cholesterol) have been suggested to be inexpensive yet effective markers of visceral (intra-abdominal) obesity and related dysmetabolic state. These markers may be particularly useful to Asian populations who generally have a low body weight but are prone to visceral adiposity. Methods: We examined associations of the hypertriglyceridemic waist phenotype and VAI with risk of coronary heart disease (CHD) in a nested case-control study conducted within two prospective cohort studies of Chinese adults. We identified 355 incident cases of CHD and 697controls matched for sex, age, and date and time of baseline sample collection. Anthropometric and lipid measurements were performed and used to define the hypertriglyceridemic waist phenotype and VAI according to published methods. Conditional logistic regression was used to evaluate the associations. Results: Cases had a higher prevalence of the hypertriglyceridemic waist phenotype and higher VAI score than controls in both sexes. Adjusted odds ratios of CHD associated with hypertriglyceridemic waist were 5.18 (95% CI, 2.46-10.9) and 4.63 (2.03-10.5) for women and men, respectively. Adjusted odds ratios of CHD comparing the highest vs. lowest quartile of VAI were 4.44 (95% CI, 2.24-8.82) and 4.23 (1.99-9.00) for women and men, respectively. Conclusion: Our study demonstrates, for the first time, that the hypertriglyceridemic waist phenotype and high VAI score are associated with substantially elevated risk of CHD in Chinese men and women. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Zhang, Xianglan; Shu, Xiao-Ou; Yang, Gong; Cai, Qiuyin; Zheng, Wei] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37203 USA. [Li, Honglan; Xiang, Yong-Bing; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Zhang, XL (reprint author), Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, IMPH, 2525 West End Ave,Suite 600, Nashville, TN 37203 USA. EM xianglan.zhang@vanderbilt.edu FU US National Institutes of Health [R01HL079123, R37CA070867, R01CA082729] FX This work was supported by research grants R01HL079123, R37CA070867, and R01CA082729 from the US National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 22 TC 12 Z9 14 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD OCT 3 PY 2013 VL 168 IS 3 BP 2141 EP 2145 DI 10.1016/j.ijcard.2013.01.275 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 241RF UT WOS:000326184400070 PM 23453877 ER PT J AU Jang, H Arce, FT Ramachandran, S Kagan, BL Lal, R Nussinov, R AF Jang, Hyunbum Arce, Fernando Teran Ramachandran, Srinivasan Kagan, Bruce L. Lal, Ratnesh Nussinov, Ruth TI Familial Alzheimer's Disease Osaka Mutant (Delta E22) beta-Barrels Suggest an Explanation for the Different A beta(1-40/42) Preferred Conformational States Observed by Experiment SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID AMYLOID ION CHANNELS; ATOMIC-FORCE MICROSCOPY; ALL-D-ENANTIOMER; MOLECULAR-DYNAMICS; LIPID-MEMBRANES; FIBRILS; PEPTIDE; OLIGOMERS; PROTEIN; SUBSTITUTIONS AB An unusual Delta E693 mutation in the amyloid precursor protein (APP) producing a beta-amyloid (A beta) peptide lacking glutamic acid at position 22 (Glu22) was recently discovered, and dabbed the Osaka mutant (Delta E22). Previously, several point mutations in the A beta peptide involving Glu22 substitutions were identified and implicated in the early onset of familial Alzheimer's disease (FAD). Despite the absence of Glu22, the Osaka mutant is also associated with FAD, showing a recessive inheritance in families affected by the disease. To see whether this aggregation-prone A beta mutant could directly relate to the A beta ion channel-mediated mechanism as observed for the wild type (WT) Ail peptide in A beta pathology, we modeled Osaka mutant beta-barrels in a lipid bilayer. Using molecular dynamics (MD) simulations, two conformer Delta E22 barrels with the U-shaped monomer conformation derived from NMR-based WT A beta fibrils were simulated in explicit lipid environment. Here, we show that the Delta E22 barrels obtain the lipid-relaxed beta-sheet channel topology, indistinguishable from the WT A beta(1-42) barrels, as do the outer and pore dimensions of octadecameric (18-mer) Delta E22 barrels. Although the Delta E22 barrels lose the cationic binding site in the pore which is normally provided by the negatively charged Glu22 side chains, the mutant pores gain a new cationic binding site by Glu11 at the lower bilayer leaflet, and exhibit ion fluctuations similar to the WT barrels. Of particular interest, this deletion mutant suggests that toxic WT A beta(1-42) would preferentially adopt a less C-terminal turn similar to that observed for A beta(17-42), and explains why the solid state NMR data for A beta(1-40) point to a more C-terminal turn conformation. The observed Delta E22 barrels conformational preferences also suggest an explanation for the lower neurotoxicity in rat primary neurons as compared to WT A beta(1-42). C1 [Jang, Hyunbum; Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Arce, Fernando Teran; Ramachandran, Srinivasan; Lal, Ratnesh] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Arce, Fernando Teran; Ramachandran, Srinivasan; Lal, Ratnesh] Univ Calif San Diego, Dept Mech & Aerosp Engn, La Jolla, CA 92093 USA. [Arce, Fernando Teran; Ramachandran, Srinivasan; Lal, Ratnesh] Univ Calif San Diego, Mat Sci Program, La Jolla, CA 92093 USA. [Kagan, Bruce L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Sci Program, SAIC Frederick Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. EM nussinor@helix.nih.gov RI Ramachandran, Srinivasan/G-5300-2010 OI Ramachandran, Srinivasan/0000-0002-4912-0279 FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research; National Institutes of Health (National Institute on Aging) [AG028709] FX This project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. This research was supported [in part] by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. This research was supported by the National Institutes of Health (National Institute on Aging AG028709 to ILL.). All simulations had been performed using the high-performance computational facilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). NR 51 TC 11 Z9 12 U1 2 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 EI 1520-5207 J9 J PHYS CHEM B JI J. Phys. Chem. B PD OCT 3 PY 2013 VL 117 IS 39 BP 11518 EP 11529 DI 10.1021/jp405389n PG 12 WC Chemistry, Physical SC Chemistry GA 243EZ UT WOS:000326301000012 PM 24000923 ER PT J AU Gong, J Schumacher, F Lim, U Hindorff, LA Haessler, J Buyske, S Carlson, CS Rosse, S Buzkova, P Fornage, M Gross, M Pankratz, N Pankow, JS Schreiner, PJ Cooper, R Ehret, G Gu, CC Houston, D Irvin, MR Jackson, R Kuller, L Henderson, B Cheng, I Wilkens, L Leppert, M Lewis, CE Li, RL Nguyen, KDH Goodloe, R Farber-Eger, E Boston, J Dilks, HH Ritchie, MD Fowke, J Pooler, L Graff, M Fernandez-Rhodes, L Cochrane, B Boerwinkle, E Kooperberg, C Matise, TC Le Marchand, L Crawford, DC Haiman, CA North, KE Peters, U AF Gong, Jian Schumacher, Fredrick Lim, Unhee Hindorff, Lucia A. Haessler, Jeff Buyske, Steven Carlson, Christopher S. Rosse, Stephanie Buzkova, Petra Fornage, Myriam Gross, Myron Pankratz, Nathan Pankow, James S. Schreiner, Pamela J. Cooper, Richard Ehret, Georg Gu, C. Charles Houston, Denise Irvin, Marguerite R. Jackson, Rebecca Kuller, Lew Henderson, Brian Cheng, Iona Wilkens, Lynne Leppert, Mark Lewis, Cora E. Li, Rongling Nguyen, Khanh-Dung H. Goodloe, Robert Farber-Eger, Eric Boston, Jonathan Dilks, Holli H. Ritchie, Marylyn D. Fowke, Jay Pooler, Loreall Graff, Misa Fernandez-Rhodes, Lindsay Cochrane, Barbara Boerwinkle, Eric Kooperberg, Charles Matise, Tara C. Le Marchand, Loic Crawford, Dana C. Haiman, Christopher A. North, Kari E. Peters, Ulrike TI Fine Mapping and Identification of BMI Loci in African Americans SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; EPIDEMIOLOGY PAGE; OBESITY; RELEVANCE; VARIANTS; TRAITS; DESIGN; RISK AB Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 x 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 x 10(-8)) and DHX34 (rs4802349, p = 1.2 x 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci. C1 [Gong, Jian; Haessler, Jeff; Carlson, Christopher S.; Rosse, Stephanie; Kooperberg, Charles; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27514 USA. [Graff, Misa; Fernandez-Rhodes, Lindsay; North, Kari E.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Buyske, Steven; Matise, Tara C.] Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA. [Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ 08854 USA. [Jackson, Rebecca] Ohio State Med Ctr, Dept Internal Med, Columbus, OH 43210 USA. [Kuller, Lew] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. [Lim, Unhee; Wilkens, Lynne; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA. [Schumacher, Fredrick; Henderson, Brian; Pooler, Loreall; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90089 USA. [Hindorff, Lucia A.; Li, Rongling] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Ehret, Georg; Nguyen, Khanh-Dung H.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA. [Ehret, Georg] Univ Hosp Geneva, Div Cardiol, CH-44041 Geneva, OH, Switzerland. [Cooper, Richard] Loyola Univ, Chicago, IL 60153 USA. [Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Leppert, Mark] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. [Irvin, Marguerite R.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Gu, C. Charles] Washington Univ, Dept Biostat, St Louis, MO 63110 USA. [Houston, Denise] Wake Forest Univ, Sch Med, Winston Salem, NC 27157 USA. [Buzkova, Petra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Ritchie, Marylyn D.] Penn State Univ, State Coll, PA 16801 USA. [Fowke, Jay] Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Goodloe, Robert; Farber-Eger, Eric; Boston, Jonathan; Dilks, Holli H.; Fowke, Jay; Crawford, Dana C.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN 37203 USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Gross, Myron; Pankratz, Nathan] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Pankow, James S.; Schreiner, Pamela J.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Cochrane, Barbara] Baylor Coll Med, Houston, TX 77030 USA. [Cheng, Iona] Canc Prevent Inst Calif, Fremont, CA 94538 USA. RP Gong, J (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. EM jgong@fhcrc.org; upeters@fhcrc.org RI EHRET, Georg/A-9532-2009; OI EHRET, Georg/0000-0002-5730-0675; Buyske, Steven/0000-0001-8539-5416; Pankow, James/0000-0001-7076-483X FU NHGRI NIH HHS [U01 HG007416, U01 HG004790]; NICHD NIH HHS [R24 HD050924]; NIDDK NIH HHS [P30 DK092986] NR 30 TC 32 Z9 33 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 3 PY 2013 VL 93 IS 4 BP 661 EP 671 DI 10.1016/j.ajhg.2013.08.012 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 243GT UT WOS:000326305600008 PM 24094743 ER PT J AU Austin-Tse, C Halbritter, J Zariwala, MA Gilberti, RM Gee, HY Hellman, N Pathak, N Liu, Y Panizzi, JR Patel-King, RS Tritschler, D Bower, R O'Toole, E Porath, JD Hurd, TW Chaki, M Diaz, KA Kohl, S Lovric, S Hwang, DY Braun, DA Schueler, M Airik, R Otto, EA Leigh, MW Noone, PG Carson, JL Davis, SD Pittman, JE Ferkol, TW Atkinson, JJ Olivier, KN Sagel, SD Dell, SD Rosenfeld, M Milla, CE Loges, NT Omran, H Porter, ME King, SM Knowles, MR Drummond, IA Hildebrandt, F AF Austin-Tse, Christina Halbritter, Jan Zariwala, Maimoona A. Gilberti, Renee M. Gee, Heon Yung Hellman, Nathan Pathak, Narendra Liu, Yan Panizzi, Jennifer R. Patel-King, Ramila S. Tritschler, Douglas Bower, Raqual O'Toole, Eileen Porath, Jonathan D. Hurd, Toby W. Chaki, Moumita Diaz, Katrina A. Kohl, Stefan Lovric, Svjetlana Hwang, Daw-Yang Braun, Daniela A. Schueler, Markus Airik, Rannar Otto, Edgar A. Leigh, Margaret W. Noone, Peadar G. Carson, Johnny L. Davis, Stephanie D. Pittman, Jessica E. Ferkol, Thomas W. Atkinson, Jeffry J. Olivier, Kenneth N. Sagel, Scott D. Dell, Sharon D. Rosenfeld, Margaret Milla, Carlos E. Loges, Niki T. Omran, Heymut Porter, Mary E. King, Stephen M. Knowles, Michael R. Drummond, Iain A. Hildebrandt, Friedhelm TI Zebrafish Ciliopathy Screen Plus Human Mutational Analysis Identifies C21orf59 and CCDC65 Defects as Causing Primary Ciliary Dyskinesia SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DYNEIN REGULATORY COMPLEX; OUTER ARM DYNEIN; CHLAMYDOMONAS-REINHARDTII; PROTEOMIC ANALYSIS; MOTILE CILIA; SCHMIDTEA-MEDITERRANEA; KARTAGENER-SYNDROME; FLAGELLAR MOTILITY; SEQUENCE-ANALYSIS; DISEASE GENES AB Primary ciliary dyskinesia (PCD) is caused when defects of motile cilia lead to chronic airway infections, male infertility, and situs abnormalities. Multiple causative PCD mutations account for only 65% of cases, suggesting that many genes essential for cilia function remain to be discovered. By using zebrafish morpholino knockdown of PCD candidate genes as an in vivo screening platform, we identified c21orf59, ccdc65, and c15orf26 as critical for cilia motility. c21orf59 and c15orf26 knockdown in zebrafish and planaria blocked outer dynein arm assembly, and ccdc65 knockdown altered cilia beat pattern. Biochemical analysis in Chlamydomonas revealed that the C21orf59 ortholog FBB18 is a flagellar matrix protein that accumulates specifically when cilia motility is impaired. The Chlamydomonas ida6 mutant identifies CCDC65/FAP250 as an essential component of the nexin-dynein regulatory complex. Analysis of 295 individuals with PCD identified recessive truncating mutations of C21orf59 in four families and CCDC65 in two families. Similar to findings in zebrafish and planaria, mutations in C21orf59 caused loss of both outer and inner dynein arm components. Our results characterize two genes associated with PCD-causing mutations and elucidate two distinct mechanisms critical for motile cilia function: dynein arm assembly for C21orf59 and assembly of the nexin-dynein regulatory complex for CCDC65. C1 [Austin-Tse, Christina; Hellman, Nathan; Pathak, Narendra; Liu, Yan; Panizzi, Jennifer R.; Drummond, Iain A.] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA. [Austin-Tse, Christina; Drummond, Iain A.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Nephrol,Dept Genet, Boston, MA 02115 USA. [Halbritter, Jan; Gee, Heon Yung; Porath, Jonathan D.; Kohl, Stefan; Lovric, Svjetlana; Hwang, Daw-Yang; Braun, Daniela A.; Schueler, Markus; Airik, Rannar; Hildebrandt, Friedhelm] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Zariwala, Maimoona A.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Gilberti, Renee M.; Patel-King, Ramila S.; King, Stephen M.] Univ Connecticut, Ctr Hlth, Dept Mol Microbial & Struct Biol, Farmington, CT 06030 USA. [Tritschler, Douglas; Bower, Raqual; Porter, Mary E.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [O'Toole, Eileen] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder Lab Electron Microscopy Cells 3D, Boulder, CO 80309 USA. [Hurd, Toby W.; Chaki, Moumita; Diaz, Katrina A.; Otto, Edgar A.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Leigh, Margaret W.; Noone, Peadar G.; Carson, Johnny L.; Davis, Stephanie D.; Pittman, Jessica E.] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC 27599 USA. [Ferkol, Thomas W.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Atkinson, Jeffry J.] Washington Univ, Sch Med, Div Pulm & Crit Care, St Louis, MO 63110 USA. [Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Sagel, Scott D.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA. [Dell, Sharon D.] Univ Toronto, Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Rosenfeld, Margaret] Childrens Hosp, Seattle, WA 98105 USA. [Rosenfeld, Margaret] Univ Washington, Seattle, WA 98105 USA. [Milla, Carlos E.] Stanford Univ, Dept Pediat, Stanford, CA 94304 USA. [Loges, Niki T.; Omran, Heymut] Univ Childrens Hosp Muenster, Dept Gen Pediat, D-48149 Munster, Germany. [Knowles, Michael R.] Cyst Fibrosis Pulm Res & Treatment Ctr, Chapel Hill, NC 27599 USA. [Hildebrandt, Friedhelm] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Drummond, IA (reprint author), Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA. EM idrummond@partners.org; friedhelm.hildebrandt@childrens.harvard.edu OI Austin-Tse, Christina/0000-0001-6492-6716; Otto, Edgar/0000-0002-2387-9973 FU National Institutes of Health; Howard Hughes Medical Institute; Deutsche Forschungsgemeinschaft; IZKF Muenster; European Community FX We are grateful to all PCD subjects and family members for their participation and thank the US PCD Foundation and to the investigators and the coordinators of the "Genetic Disorders of Mucociliary Clearance Consortium." We are also grateful to the funding agencies that supported this work; these include the National Institutes of Health, the Howard Hughes Medical Institute, the Deutsche Forschungsgemeinschaft, the IZKF Muenster, and the European Community's Seventh Framework Programme. Detailed acknowledgements can be found in the Supplemental Data. NR 71 TC 47 Z9 54 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 3 PY 2013 VL 93 IS 4 BP 672 EP 686 DI 10.1016/j.ajhg.2013.08.015 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 243GT UT WOS:000326305600009 PM 24094744 ER PT J AU Knowles, MR Ostrowski, LE Loges, NT Hurd, T Leigh, MW Huang, L Wolf, WE Carson, JL Hazucha, MJ Yin, WN Davis, SD Dell, SD Ferkol, TW Sagel, SD Olivier, KN Jahnke, C Olbrich, H Werner, C Raidt, J Wallmeier, J Pennekamp, P Dougherty, GW Hjeij, R Gee, HY Otto, EA Halbritter, J Chaki, M Diaz, KA Braun, DA Porath, JD Schueler, M Baktai, G Griese, M Turner, EH Lewis, AP Bamshad, MJ Nickerson, DA Hildebrandt, F Shendure, J Omran, H Zariwala, MA AF Knowles, Michael R. Ostrowski, Lawrence E. Loges, Niki T. Hurd, Toby Leigh, Margaret W. Huang, Lu Wolf, Whitney E. Carson, Johnny L. Hazucha, Milan J. Yin, Weining Davis, Stephanie D. Dell, Sharon D. Ferkol, Thomas W. Sagel, Scott D. Olivier, Kenneth N. Jahnke, Charlotte Olbrich, Heike Werner, Claudius Raidt, Johanna Wallmeier, Julia Pennekamp, Petra Dougherty, Gerard W. Hjeij, Rim Gee, Heon Yung Otto, Edgar A. Halbritter, Jan Chaki, Moumita Diaz, Katrina A. Braun, Daniela A. Porath, Jonathan D. Schueler, Markus Baktai, Gyoergy Griese, Matthias Turner, Emily H. Lewis, Alexandra P. Bamshad, Michael J. Nickerson, Deborah A. Hildebrandt, Friedhelm Shendure, Jay Omran, Heymut Zariwala, Maimoona A. TI Mutations in SPAG1 Cause Primary Ciliary Dyskinesia Associated with Defective Outer and Inner Dynein Arms SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID OF-FUNCTION MUTATIONS; RETINITIS-PIGMENTOSA; TETRATRICOPEPTIDE REPEAT; CYSTIC KIDNEY; GENE; PROTEIN; DISEASE; CELLS; DNAH5; RPGR AB Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only similar to 65% of all PCDs. To identify mutations in additional genes that cause PCD, we performed exome sequencing on three unrelated probands with ciliary outer and inner dynein arm (ODA+IDA) defects. Mutations in SPAG1 were identified in one family with three affected siblings. Further screening of SPAG1 in 98 unrelated affected individuals (62 with ODA+IDA defects, 35 with ODA defects, 1 without available ciliary ultrastructure) revealed biallelic loss-of-function mutations in 11 additional individuals (including one sib-pair). All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities. Additionally, all individuals with mutations who had defined ciliary ultrastructure had ODA+IDA defects. SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms. Zebrafish morpholino studies of spag1 produced cilia-related phenotypes previously reported for PCD-causing mutations in genes encoding cytoplasmic proteins. Together, these results demonstrate that mutations in SPAG1 cause PCD with ciliary ODA+IDA defects and that exome sequencing is useful to identify genetic causes of heterogeneous recessive disorders. C1 [Knowles, Michael R.; Ostrowski, Lawrence E.; Huang, Lu; Wolf, Whitney E.; Hazucha, Milan J.; Yin, Weining] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA. [Loges, Niki T.; Jahnke, Charlotte; Olbrich, Heike; Werner, Claudius; Raidt, Johanna; Wallmeier, Julia; Pennekamp, Petra; Dougherty, Gerard W.; Hjeij, Rim] Univ Hosp Muenster, Dept Gen Pediat & Adolescent Med, D-48149 Munster, Germany. [Hurd, Toby; Gee, Heon Yung; Otto, Edgar A.; Chaki, Moumita; Diaz, Katrina A.; Braun, Daniela A.; Porath, Jonathan D.; Schueler, Markus; Hildebrandt, Friedhelm] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Leigh, Margaret W.; Carson, Johnny L.; Davis, Stephanie D.] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC 27599 USA. [Dell, Sharon D.] Univ Toronto, Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Ferkol, Thomas W.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Sagel, Scott D.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA. [Olivier, Kenneth N.] NIAID, NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Baktai, Gyoergy] Pediat Inst Svabhegy, Dept Bronchol, H-1535 Budapest, Hungary. [Griese, Matthias] Univ Munich, Hauner Childrens Hosp, Member German Ctr Lung Res, D-80337 Munich, Germany. [Turner, Emily H.; Lewis, Alexandra P.; Bamshad, Michael J.; Nickerson, Deborah A.; Shendure, Jay] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. [Bamshad, Michael J.] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Hildebrandt, Friedhelm] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Zariwala, Maimoona A.] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. RP Knowles, MR (reprint author), Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA. EM knowles@med.unc.edu; zariwala@med.unc.edu RI Huang, Lu/E-4250-2014; OI Otto, Edgar/0000-0002-2387-9973; Turner, Emily/0000-0001-9040-9229; Shendure, Jay/0000-0002-1516-1865 FU US NIH/ORDR/NHLBI [5U54HL096458-06]; NIH-NHLBI [5R01HL071798, 5R01HL094976, RC2 HL-102923]; NIH-NHGRI [5R21HG004749]; NIH-NIAID; RSG by NIH-NHLBI [HHSN268201100037C]; NIH-NCATS [UL1 TR000083, UL1 TR000154]; CF foundation [CFF R026-CR07]; DFG [Om6/4]; IZKF Muenster [Om2/009/12]; European Community FX Funding support for research was provided to M.R.K., M.W.L., J.L.C., M.J.H., S.D. Dell, S.D. Davis, T.W.F., S.D.S., K.N.O., and M.A.Z. by US NIH/ORDR/NHLBI grant 5U54HL096458-06; to M.R.K., L.E.O., and M.A.Z. by NIH-NHLBI grant 5R01HL071798; to J.S. and D.A.N. by NIH-NHLBI grant 5R01HL094976; to M.J.B. by NIH-NHLBI grant RC2 HL-102923; and to J.S. by NIH-NHGRI grant 5R21HG004749. K.N.O. is supported by the Intramural Research Program of NIH-NIAID. Resequencing was provided through RS&G by NIH-NHLBI contract # HHSN268201100037C. The work was supported by NIH-NCATS grants UL1 TR000083 to UNC-CH and UL1 TR000154 to Colorado CTSI and CF foundation grant CFF R026-CR07. H. Omran is supported by funding from DFG Om6/4, IZKF Muenster Om2/009/12, and BESTCILIA and SYSCILIA from the European Community. F.H. is an investigator of the Howard Hughes Medical Institute. NR 45 TC 38 Z9 41 U1 0 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT 3 PY 2013 VL 93 IS 4 BP 711 EP 720 DI 10.1016/j.ajhg.2013.07.025 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 243GT UT WOS:000326305600012 PM 24055112 ER PT J AU Fowler, DH AF Fowler, Daniel H. TI Doubling down on PKC benefits allogeneic BMT SO BLOOD LA English DT Editorial Material ID SOTRASTAURIN; RECIPIENTS; SURVIVAL; AEB071; CELLS C1 NIH, Bethesda, MD USA. RP Fowler, DH (reprint author), NIH, Bethesda, MD USA. NR 9 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 3 PY 2013 VL 122 IS 14 BP 2298 EP 2299 DI 10.1182/blood-2013-08-519900 PG 4 WC Hematology SC Hematology GA 240ER UT WOS:000326078200009 PM 24092926 ER PT J AU Tinsley, KW Hong, CW Luckey, MA Park, JY Kim, GY Yoon, HW Keller, HR Sacks, AJ Feigenbaum, L Park, JH AF Tinsley, Kevin W. Hong, Changwan Luckey, Megan A. Park, Joo-Young Kim, Grace Y. Yoon, Hee-won Keller, Hilary R. Sacks, Andrew J. Feigenbaum, Lionel Park, Jung-Hyun TI Ikaros is required to survive positive selection and to maintain clonal diversity during T-cell development in the thymus SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CUTTING EDGE IKAROS; THYMOCYTE DEVELOPMENT; TRANSCRIPTION FACTOR; NEGATIVE SELECTION; CYCLE PROGRESSION; TRANSGENIC MICE; GENE; DIFFERENTIATION; ACTIVATION AB The zinc-finger protein Ikaros is a key player in T-cell development and a potent tumor suppressor in thymocytes. To understand the molecular basis of its function, we disabled Ikaros activity in vivo using a dominant negative Ikaros transgene (DN-IkTg). In DN-IkTg mice, T-cell development was severely suppressed, and positively selected thymocytes clonally expanded, resulting in a small thymus with a heavily skewed T-cell receptor (TCR) repertoire. Notably, DN-IkTg induced vigorous proliferation concomitant to downregulation of antiapoptotic factor expression such as Bcl2. Ikaros activity was required during positive selection, and specifically at the CD4(+) CD8(lo) intermediate stage of thymocyte differentiation, where it prevented persistent TCR signals from inducing aberrant proliferation and expansion. In particular, DN-IkTg induced the accumulation of CD4 single-positive (SP) thymocytes with a developmentally transitional phenotype, and it imposed a developmental arrest accompanied by massive apoptosis. Thus, we identified an in vivo requirement for Ikaros function, which is to suppress the proliferative potential of persistent TCR signals and to promote the survival and differentiation of positively selected thymocytes. C1 [Tinsley, Kevin W.; Hong, Changwan; Luckey, Megan A.; Park, Joo-Young; Kim, Grace Y.; Yoon, Hee-won; Keller, Hilary R.; Sacks, Andrew J.; Park, Jung-Hyun] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Feigenbaum, Lionel] NCI, Sci Applicat Int Corp Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. RP Park, JH (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 5B17,10 Ctr Dr, Bethesda, MD 20892 USA. EM parkhy@mail.nih.gov RI Park, Jung Hyun /B-5712-2015; Davis, Megan/F-5339-2015 OI Park, Jung Hyun /0000-0002-9547-9055; FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 49 TC 3 Z9 3 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 3 PY 2013 VL 122 IS 14 BP 2358 EP 2368 DI 10.1182/blood-2012-12-472076 PG 11 WC Hematology SC Hematology GA 240ER UT WOS:000326078200019 PM 23908463 ER PT J AU Chang, BY Francesco, M De Rooij, MFM Magadala, P Steggerda, SM Huang, MM Kuil, A Herman, SEM Chang, S Pals, ST Wilson, W Wiestner, A Spaargaren, M Buggy, JJ Elias, L AF Chang, Betty Y. Francesco, Michelle De Rooij, Martin F. M. Magadala, Padmaja Steggerda, Susanne M. Huang, Min Mei Kuil, Annemieke Herman, Sarah E. M. Chang, Stella Pals, Steven T. Wilson, Wyndham Wiestner, Adrian Spaargaren, Marcel Buggy, Joseph J. Elias, Laurence TI Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELLS; CHEMOKINE RECEPTORS; STROMAL CELLS; THERAPEUTIC TARGET; EXPRESSION; PCI-32765; CXCR4; CD38; MICROENVIRONMENT AB Ibrutinib (PCI-32765) is a highly potent oral Bruton tyrosine kinase (BTK) inhibitor in clinical development for treating B-cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B-cell receptor (BCR) pathway. In a phase 1 study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). Here, we characterize the patterns and phenotypes of cells mobilized among patients with MCL and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38, and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40% to 60% after treatment. Mechanistically, ibrutinib inhibited BCR-and chemokine-mediated adhesion and chemotaxis of MCL cell lines and dose-dependently inhibited BCR, stromal cell, and CXCL12/CXCL13 stimulations of pBTK, pPLC gamma 2, pERK, or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in coculture. We propose that BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. C1 [Chang, Betty Y.; Francesco, Michelle; Magadala, Padmaja; Steggerda, Susanne M.; Huang, Min Mei; Chang, Stella; Buggy, Joseph J.; Elias, Laurence] Pharmacyclics Inc, Res Dept, Sunnyvale, CA 94085 USA. [De Rooij, Martin F. M.; Kuil, Annemieke; Pals, Steven T.; Buggy, Joseph J.] Univ Amsterdam, Acad Med Ctr, Dept Pathol, NL-1105 AZ Amsterdam, Netherlands. [Herman, Sarah E. M.; Wilson, Wyndham; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Chang, BY (reprint author), Pharmacyclics Inc, Res Dept, Div Immunol, 995 E Arques Ave, Sunnyvale, CA 94085 USA. EM bchang@pcyc.com OI Spaargaren, Marcel/0000-0002-3135-5109 FU intramural research program of the National Heart, Lung, and Blood Institute; National Cancer Institute FX This work was supported by the intramural research program of the National Heart, Lung, and Blood Institute (A.W.) and the National Cancer Institute (W.W.). NR 53 TC 70 Z9 73 U1 1 U2 15 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 3 PY 2013 VL 122 IS 14 BP 2412 EP 2424 DI 10.1182/blood-2013-02-482125 PG 13 WC Hematology SC Hematology GA 240ER UT WOS:000326078200024 PM 23940282 ER PT J AU Vlachos, A Farrar, JE Atsidaftos, E Muir, E Narla, A Markello, TC Singh, SA Landowski, M Gazda, HT Blanc, L Liu, JM Ellis, SR Arceci, RJ Ebert, BL Bodine, DM Lipton, JM AF Vlachos, Adrianna Farrar, Jason E. Atsidaftos, Eva Muir, Ellen Narla, Anupama Markello, Thomas C. Singh, Sharon A. Landowski, Michael Gazda, Hanna T. Blanc, Lionel Liu, Johnson M. Ellis, Steven R. Arceci, Robert J. Ebert, Benjamin L. Bodine, David M. Lipton, Jeffrey M. TI Diminutive somatic deletions in the 5q region lead to a phenotype atypical of classical 5q-syndrome SO BLOOD LA English DT Article ID DIAMOND-BLACKFAN ANEMIA; PROTEIN GENE DELETIONS; IDENTIFICATION; LENALIDOMIDE AB Classical 5q- syndrome is an acquired macrocytic anemia of the elderly. Similar to Diamond Blackfan anemia (DBA), an inherited red cell aplasia, the bone marrow is characterized by a paucity of erythroid precursors. RPS14 deletions in combination with other deletions in the region have been implicated as causative of the 5q- syndrome phenotype. We asked whether smaller, less easily detectable deletions could account for a syndrome with a modified phenotype. We employed single-nucleotide polymorphism array genotyping to identify small deletions in patients diagnosed with DBA and other anemias lacking molecular diagnoses. Diminutive mosaic deletions involving RPS14 were identified in a 5-year-old patient with nonclassical DBA and in a 17-year-old patient with myelodysplastic syndrome. Patients with nonclassical DBA and other hypoproliferative anemias may have somatically acquired 5q deletions with RPS14 haploinsufficiency not identified by fluorescence in situ hybridization or cytogenetic testing, thus refining the spectrum of disorders with 5q- deletions. C1 [Vlachos, Adrianna; Singh, Sharon A.; Blanc, Lionel; Liu, Johnson M.; Lipton, Jeffrey M.] Steven & Alexandra Cohen Childrens Med Ctr New Yo, New Hyde Pk, NY 11040 USA. [Vlachos, Adrianna; Atsidaftos, Eva; Muir, Ellen; Singh, Sharon A.; Blanc, Lionel; Liu, Johnson M.; Lipton, Jeffrey M.] Feinstein Inst Med Res, Manhasset, NY USA. [Farrar, Jason E.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Narla, Anupama; Ebert, Benjamin L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Narla, Anupama; Gazda, Hanna T.; Ebert, Benjamin L.] Harvard Univ, Sch Med, Boston, MA USA. [Narla, Anupama; Ebert, Benjamin L.] Brigham & Womens Hosp, Dept Hematol, Boston, MA 02115 USA. [Markello, Thomas C.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Landowski, Michael; Gazda, Hanna T.] Childrens Hosp Boston, Div Genet, Manton Ctr Orphan Dis Res, Boston, MA USA. [Landowski, Michael; Gazda, Hanna T.] Childrens Hosp Boston, Program Genom, Manton Ctr Orphan Dis Res, Boston, MA USA. [Ellis, Steven R.] Univ Louisville, Louisville, KY 40292 USA. [Arceci, Robert J.] Johns Hopkins Univ, Baltimore, MD USA. [Bodine, David M.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Vlachos, A (reprint author), Steven & Alexandra Cohen Childrens Med Ctr New Yo, 269-01 76th Ave, New Hyde Pk, NY 11040 USA. EM avlachos@nshs.edu OI Farrar, Jason/0000-0003-2148-5839; Blanc, Lionel/0000-0002-0185-6260 FU Diamond Blackfan Anemia Foundation; Pediatric Cancer Foundation; Arkansas Biosciences Institute; Feinstein Institute for Medical Research General Clinical Research Center [M01 RR018535]; Centers for Disease Control-sponsored Diamond Blackfan Anemia Surveillance and Awareness Program; National Institutes of Health [R01-HL079571, R01-HL107558, R109-MOHLKE, K02-HL111156, K08-HL092224]; National Human Genome Research Institute Intramural funds; St. Baldrick's Foundation Scholar Career Development Award; St. Baldrick's Consortium on Pediatric Myelodysplastic Syndrome FX This work was supported in part by grants from the Diamond Blackfan Anemia Foundation (H. T. G., D. M. B., A. V., E. M.), the Pediatric Cancer Foundation (J.M. Lipton), the Arkansas Biosciences Institute (J.E.F.), The Feinstein Institute for Medical Research General Clinical Research Center (M01 RR018535; A. V., J.M. Lipton), the Centers for Disease Control-sponsored Diamond Blackfan Anemia Surveillance and Awareness Program (A. V., E. M.), and the National Institutes of Health (R01-HL079571 [A. V., E. A., J.M. Lipton], R01-HL107558 [H. T. G.], R109-MOHLKE [A. V., E. A., J.M. Lipton], K02-HL111156 [H. T. G.], K08-HL092224 [J.E.F.], and National Human Genome Research Institute Intramural funds [D. M. B.]), St. Baldrick's Foundation Scholar Career Development Award (S. A. S.), and St. Baldrick's Consortium on Pediatric Myelodysplastic Syndrome (J.M. Liu). NR 16 TC 6 Z9 6 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 3 PY 2013 VL 122 IS 14 BP 2487 EP 2490 DI 10.1182/blood-2013-06-509935 PG 4 WC Hematology SC Hematology GA 240ER UT WOS:000326078200032 PM 23943650 ER PT J AU Pasha, O McClure, EM Wright, LL Saleem, S Goudar, SS Chomba, E Patel, A Esamai, F Garces, A Althabe, F Kodkany, B Mabeya, H Manasyan, A Carlo, WA Derman, RJ Hibberd, PL Liechty, EK Krebs, N Hambidge, KM Buekens, P Moore, J Jobe, AH Koso-Thomas, M Wallace, DD Stalls, S Goldenberg, RL AF Pasha, Omrana McClure, Elizabeth M. Wright, Linda L. Saleem, Sarah Goudar, Shivaprasad S. Chomba, Elwyn Patel, Archana Esamai, Fabian Garces, Ana Althabe, Fernando Kodkany, Bhala Mabeya, Hillary Manasyan, Albert Carlo, Waldemar A. Derman, Richard J. Hibberd, Patricia L. Liechty, Edward K. Krebs, Nancy Hambidge, K. Michael Buekens, Pierre Moore, Janet Jobe, Alan H. Koso-Thomas, Marion Wallace, Dennis D. Stalls, Suzanne Goldenberg, Robert L. CA EMONC Trial Investigators TI A combined community- and facility-based approach to improve pregnancy outcomes in low-resource settings: a Global Network cluster randomized trial SO BMC MEDICINE LA English DT Article DE Stillbirth; Neonatal mortality; Maternal mortality; Emergency obstetric care ID TRADITIONAL BIRTH ATTENDANTS; INTRAPARTUM-RELATED DEATHS; MATERNAL MORTALITY; OBSTETRIC CARE; DEVELOPING-COUNTRIES; PERINATAL-MORTALITY; LIFESAVING SKILLS; NEWBORN-CARE; INTERVENTION; STILLBIRTH AB Background: Fetal and neonatal mortality rates in low-income countries are at least 10-fold greater than in high-income countries. These differences have been related to poor access to and poor quality of obstetric and neonatal care. Methods: This trial tested the hypothesis that teams of health care providers, administrators and local residents can address the problem of limited access to quality obstetric and neonatal care and lead to a reduction in perinatal mortality in intervention compared to control locations. In seven geographic areas in five low-income and one middle-income country, most with high perinatal mortality rates and substantial numbers of home deliveries, we performed a cluster randomized non-masked trial of a package of interventions that included community mobilization focusing on birth planning and hospital transport, community birth attendant training in problem recognition, and facility staff training in the management of obstetric and neonatal emergencies. The primary outcome was perinatal mortality at >= 28 weeks gestation or birth weight >= 1000 g. Results: Despite extensive effort in all sites in each of the three intervention areas, no differences emerged in the primary or any secondary outcome between the intervention and control clusters. In both groups, the mean perinatal mortality was 40.1/1,000 births (P = 0.9996). Neither were there differences between the two groups in outcomes in the last six months of the project, in the year following intervention cessation, nor in the clusters that best implemented the intervention. Conclusions: This cluster randomized comprehensive, large-scale, multi-sector intervention did not result in detectable impact on the proposed outcomes. While this does not negate the importance of these interventions, we expect that achieving improvement in pregnancy outcomes in these settings will require substantially more obstetric and neonatal care infrastructure than was available at the sites during this trial, and without them provider training and community mobilization will not be sufficient. Our results highlight the critical importance of evaluating outcomes in randomized trials, as interventions that should be effective may not be. C1 [Pasha, Omrana; Saleem, Sarah] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [McClure, Elizabeth M.] Res Triangle Inst, Dept Social Stat & Environm Sci, Durham, NC USA. [Wright, Linda L.; Koso-Thomas, Marion] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Goudar, Shivaprasad S.; Kodkany, Bhala] KLE Univ, Jawaharlal Nehru Med Coll, Belgaum, India. [Chomba, Elwyn] Univ Teaching Hosp, Dept Pediat, Lusaka, Zambia. [Patel, Archana] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Esamai, Fabian; Mabeya, Hillary] Moi Univ, Sch Med, Eldoret, Kenya. [Garces, Ana] Francisco Marroquin Univ, Guatemala City, Guatemala. [Althabe, Fernando] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Manasyan, Albert] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Derman, Richard J.] Christiana Care Hlth Syst, Newark, DE USA. [Hibberd, Patricia L.] Massachusetts Gen Hosp Children, Boston, MA USA. [Liechty, Edward K.] Indiana Univ, Indianapolis, IN 46204 USA. [Krebs, Nancy; Hambidge, K. Michael] Univ Colorado, Denver, CO 80202 USA. [Buekens, Pierre] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA 70118 USA. [Moore, Janet; Wallace, Dennis D.] Res Triangle Inst, Durham, NC USA. [Jobe, Alan H.] Univ Cincinnati, Cincinnati, OH USA. [Stalls, Suzanne] Amer Coll Nurse Midw, Washington, DC USA. [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. RP Pasha, O (reprint author), Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. EM omrana.pasha@aku.edu OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research [U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636] FX This trial was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research (grants U01 HD058322, U01 HD040477, U01 HD043464, U01 HD040657, U01 HD042372, U01 HD040607, U01 HD058326, U01 HD040636). Other members of the Global Network EMONC trial include Agustina Mazzoni, MD; Marina Laski; Ariel Karolinski, MD, and Mabel Berrueta, MD, Argentina; Mabel; Christine Kaseba, MD, and Melody Miselo Kunda Chiwila University of Zambia, Lusaka, Zambia; Evelyn Morales, IMSALUD, Guatemala City, Guatemala; N.S. Mahantshetti, MD, N.V. Honnungar, MD, and Kamal Patil, and M.K. Swamy, MD, KLE JN Medical College, Belgaum, India; Sadiah Ahsan, MD, MRCOG, Khadim Hussain and Azra Ahsan, MD, MRCOG, FRCOG, Aga Khan University, Karachi, Pakistan; Manju Waikar, MD, Nivedita Kulkarni, MD, Sushama Thakre, MD, and Manoj Bhatnagar, MD, Indira Ghandi Medical School, Nagpur India; Betsy Rono, Peter Gisore, MD, and Hillary Mbeya, MD, Moi University, Eldoret, Kenya. NR 40 TC 14 Z9 14 U1 3 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD OCT 3 PY 2013 VL 11 AR UNSP 215 DI 10.1186/1741-7015-11-215 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 241PU UT WOS:000326180300001 PM 24090370 ER PT J AU Truog, RD Miller, FG Halpern, SD AF Truog, Robert D. Miller, Franklin G. Halpern, Scott D. TI The Dead-Donor Rule and the Future of Organ Donation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material AB The ethics of organ transplantation have been premised on the dead-donor rule: vital organs should be taken only from persons who are dead. But why shouldn't some living patients, such as those near death but on life support, be allowed to donate organs? The ethics of organ transplantation have been premised on the dead-donor rule (DDR), which states that vital organs should be taken only from persons who are dead. Yet it is not obvious why certain living patients, such as those who are near death but on life support, should not be allowed to donate their organs, if doing so would benefit others and be consistent with their own interests. This issue is not merely theoretical. In one recent case, the parents of a young girl wanted to donate her organs after an accident had left her with devastating brain damage. Plans ... C1 [Truog, Robert D.] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Truog, Robert D.] Harvard Univ, Sch Med, Global Heath & Social Med, Boston, MA 02115 USA. [Truog, Robert D.] Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. [Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Halpern, Scott D.] Univ Penn, Dept Med Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Halpern, Scott D.] Univ Penn, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. [Halpern, Scott D.] Univ Penn, FIELDS Program, Philadelphia, PA 19104 USA. RP Truog, RD (reprint author), Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. NR 5 TC 35 Z9 36 U1 0 U2 18 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 OCT 3 PY 2013 VL 369 IS 14 BP 1287 EP 1289 DI 10.1056/NEJMp1307220 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 227KI UT WOS:000325111200003 PM 24088088 ER PT J AU Gluck, ME Ziker, C Schwegler, M Thearle, M Votruba, SB Krakoff, J AF Gluck, Marci E. Ziker, Cindy Schwegler, Matthew Thearle, Marie Votruba, Susanne B. Krakoff, Jonathan TI Impaired glucose regulation is associated with poorer performance on the Stroop Task SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Executive function; Processing speed; Interference; Obesity; Cognitive performance; Insulin ID TYPE-2 DIABETES-MELLITUS; X-RAY ABSORPTIOMETRY; BODY-MASS INDEX; COGNITIVE FUNCTION; INSULIN-RESISTANCE; OLDER-ADULTS; MULTIPLE-SCLEROSIS; ELDERLY POPULATION; METABOLIC SYNDROME; OBESE INDIVIDUALS AB Background: Type 2 diabetes is a risk factor for development of cognitive dysfunction. Impairments in glucose regulation have been associated with poorer performance on tests of executive function and information processing speed. Methods: We administered the Stroop Color Word Task, where higher interference scores are indicative of decreased selective attention, to 98 non-diabetic volunteers (64 m; %fat = 37 +/- 12; age = 36 +/- 9 yrs, race = 41 NA/30 C/13 H/14 AA) on our inpatient unit. After 3d on a weight maintaining diet, % body fat was measured by DXA and a 75 g oral glucose tolerance test (OGTT) was administered. Impaired glucose regulation (IGR) was defined as: fasting plasma glucose >= 100 and <= 125 mg/dL and/or 2 h plasma glucose between >= 140 and <= 199 mg/dL (IGR; n = 48; NCR; n = 50). Total and incremental area under the curve (AUC) for insulin and glucose were calculated. Results: Stroop interference scores were not significantly associated with any measure of adiposity or insulin concentrations. Individuals with IGR had significantly higher interference scores than those with normal glucose regulation (NGR; p = 0.003). Higher interference scores were significantly correlated with fasting plasma glucose concentrations (r = 0.26, p = 0.007) and total glucose AUC (r = 0.30, p = 0.02) and only trending so for iAUC and 2 h plasma glucose (r = 0.18, p = 0.08; r = 0.17, p = 0.09 respectively). In separate multivariate linear models, fasting plasma glucose (p = 0.002) and total glucose AUC (p = 0.0005) remained significant predictors of Stroop interference scores, even after adjustment for age, sex, race, education and %fat. Conclusions: Individuals with IGR had decreased performance on a test of selective attention. Fasting plasma glucose was more strongly associated with lower performance scores than 2 h plasma glucose. Our results indicate that even mild hyperglycemia in the non-diabetic range is associated with attentional processing difficulties in a sample of younger adults. Whether these impairments precede or are induced by impaired glucose regulation is not clear. Published by Elsevier Inc. C1 [Gluck, Marci E.; Ziker, Cindy; Schwegler, Matthew; Thearle, Marie; Votruba, Susanne B.; Krakoff, Jonathan] NIDDK, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Gluck, ME (reprint author), NIDDK, NIH, ODCRS, 4212 North 16th St,Room 541, Phoenix, AZ 85016 USA. EM gmarci@niddk.nih.gov FU Intramural Research Program of the NIDDK FX The authors thank Ms. Carol Massengill and all of the nursing and laboratory staff of the NIH Clinical Unit and the staff of the Diabetes Epidemiology and Clinical Research Section, NIDDK. This study was supported by the Intramural Research Program of the NIDDK. Drs. Gluck, Ziker, Thearle, Votruba and Krakoff and Mr. Schwegler have no biomedical financial interests or potential conflicts of interest. Most of all, we thank the volunteers for their participation in the study. NR 60 TC 4 Z9 4 U1 3 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD OCT 2 PY 2013 VL 122 SI SI BP 113 EP 119 DI 10.1016/j.physbeh.2013.09.001 PG 7 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 287OS UT WOS:000329552700016 PM 24036382 ER PT J AU Chambers, DA Glasgow, RE Stange, KC AF Chambers, David A. Glasgow, Russell E. Stange, Kurt C. TI The dynamic sustainability framework: addressing the paradox of sustainment amid ongoing change SO IMPLEMENTATION SCIENCE LA English DT Article DE Sustainability; Maintenance; Adaptation; Dissemination; Implementation; Framework; Model ID IMPLEMENTATION SCIENCE; EFFECTIVENESS TRIALS; FUTURE-DIRECTIONS; HEALTH BEHAVIOR; CANCER CONTROL; PUBLIC-HEALTH; PROGRAMS; INTERVENTIONS; CARE; INNOVATIONS AB Background: Despite growth in implementation research, limited scientific attention has focused on understanding and improving sustainability of health interventions. Models of sustainability have been evolving to reflect challenges in the fit between intervention and context. Discussion: We examine the development of concepts of sustainability, and respond to two frequent assumptions - 'voltage drop,' whereby interventions are expected to yield lower benefits as they move from efficacy to effectiveness to implementation and sustainability, and 'program drift,' whereby deviation from manualized protocols is assumed to decrease benefit. We posit that these assumptions limit opportunities to improve care, and instead argue for understanding the changing context of healthcare to continuously refine and improve interventions as they are sustained. Sustainability has evolved from being considered as the endgame of a translational research process to a suggested 'adaptation phase' that integrates and institutionalizes interventions within local organizational and cultural contexts. These recent approaches locate sustainability in the implementation phase of knowledge transfer, but still do not address intervention improvement as a central theme. We propose a Dynamic Sustainability Framework that involves: continued learning and problem solving, ongoing adaptation of interventions with a primary focus on fit between interventions and multi-level contexts, and expectations for ongoing improvement as opposed to diminishing outcomes over time. Summary: A Dynamic Sustainability Framework provides a foundation for research, policy and practice that supports development and testing of falsifiable hypotheses and continued learning to advance the implementation, transportability and impact of health services research. C1 [Chambers, David A.] NIMH, Div Serv & Intervent Res, Rockville, MD 20857 USA. [Glasgow, Russell E.] Univ Colorado, Sch Med, Dept Family Med, Denver, CO USA. [Stange, Kurt C.] Case Western Reserve Univ, Dept Family Med, Cleveland, OH 44106 USA. RP Chambers, DA (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd, Rockville, MD 20857 USA. EM dchamber@mail.nih.gov NR 58 TC 97 Z9 97 U1 7 U2 29 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD OCT 2 PY 2013 VL 8 AR 117 DI 10.1186/1748-5908-8-117 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 260KN UT WOS:000327593900001 PM 24088228 ER PT J AU Mattson, MP AF Mattson, Mark P. TI Excitation BolsTORs Motor Neurons in ALS Mice SO NEURON LA English DT Editorial Material ID AMYOTROPHIC-LATERAL-SCLEROSIS; ENDOPLASMIC-RETICULUM STRESS; CALCIUM HOMEOSTASIS; OXIDATIVE STRESS; MOUSE MODEL; AUTOPHAGY; PROTEINOPATHIES; EXCITOTOXICITY; APOPTOSIS; RAPAMYCIN AB It is unclear why motor neurons selectively degenerate in amyotrophic lateral sclerosis (ALS). Saxena et al. (2013) demonstrate that excitation of motor neurons can prevent their demise in a mouse model of inherited ALS by a mechanism involving the mTOR pathway. C1 [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM mark.mattson@nih.gov FU Intramural NIH HHS NR 14 TC 2 Z9 2 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 2 PY 2013 VL 80 IS 1 BP 1 EP 3 DI 10.1016/j.neuron.2013.09.017 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 243GQ UT WOS:000326305300001 PM 24094096 ER PT J AU Jakkamsetti, V Tsai, NP Gross, C Molinaro, G Collins, KA Nicoletti, F Wang, KH Osten, P Bassell, GJ Gibson, JR Huber, KM AF Jakkamsetti, Vikram Tsai, Nien-Pei Gross, Christina Molinaro, Gemma Collins, Katie A. Nicoletti, Ferdinando Wang, Kuan H. Osten, Pavel Bassell, Gary J. Gibson, Jay R. Huber, Kimberly M. TI Experience-Induced Arc/Arg3.1 Primes CA1 Pyramidal Neurons for Metabotropic Glutamate Receptor-Dependent Long-Term Synaptic Depression SO NEURON LA English DT Article ID FRAGILE-X-SYNDROME; IMMEDIATE-EARLY GENE; MENTAL-RETARDATION; NOVELTY ACQUISITION; PROTEIN EXPRESSION; MOUSE MODEL; IN-VIVO; HIPPOCAMPAL; ARC; PLASTICITY AB A novel experience induces the Arc/Arg3.1 gene as well as plasticity of CA1 neural networks. To understand how these are linked, we briefly exposed GFP reporter mice of Arc transcription to a novel environment. Excitatory synaptic function of CA1 neurons with recent in vivo Arc induction (ArcGFP+) was similar to neighboring noninduced neurons. However, in response to group 1 metabotropic glutamate receptor (mGluR) activation, ArcGFP+ neurons preferentially displayed long-term synaptic depression (mGluR-LTD) and robust increases in dendritic Arc protein. mGluR-LTD in ArcGFP+ neurons required rapid protein synthesis and Arc, suggesting that dendritic translation of Arc underlies the priming of mGluR-LTD. In support of this idea, novelty exposure increased Arc messenger RNA in CA1 dendrites and promoted mGluR-induced translation of Arc in hippocannpal synaptoneurosomes. Repeated experience suppressed synaptic transmission onto ArcGFP+ neurons and occluded mGluR-LTD ex vivo. mGluR-LTD priming in neurons with similar Arc activation history may contribute to encoding a novel environment. C1 [Jakkamsetti, Vikram; Tsai, Nien-Pei; Molinaro, Gemma; Collins, Katie A.; Gibson, Jay R.; Huber, Kimberly M.] Univ Texas SW Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA. [Gross, Christina; Bassell, Gary J.] Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA 30322 USA. [Molinaro, Gemma; Nicoletti, Ferdinando] IRCCS Neuromed, I-80077 Pozzilli, Italy. [Nicoletti, Ferdinando] Univ Roma La Sapienza, Dept Physiol & Pharmacol, I-00185 Rome, Italy. [Wang, Kuan H.] NIMH, Bethesda, MD 20892 USA. [Osten, Pavel] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. RP Huber, KM (reprint author), Univ Texas SW Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA. EM kimberly.huber@utsouthwestern.edu RI Wang, Kuan Hong/J-1150-2016; Nicoletti, Ferdinando/K-4410-2016; OI Wang, Kuan Hong/0000-0002-2249-5417; Jakkamsetti, Vikram/0000-0001-6524-2893; NICOLETTI, Ferdinando/0000-0003-3366-7269 FU National Institutes of Health [NS045711, HD052731, HD056370, MH085617]; Emory Neuroscience NINDS [P30NS055077] FX This research was supported by the grants from the National Institutes of Health grants NS045711, HD052731 (to K.M.H.), HD056370 (to J.R.G.), and MH085617 (to G.J.B.) and Emory Neuroscience NINDS Core Facilities grant P30NS055077 (to G.J.B. and C.G.). We would like to thank Dr. John Isaac for discussions and sending us the ArcGFP-BAC mice; Darya Fakhretdinova, Lorea Ormazabal, and Nicole Cabalo for technical assistance; and members of the Huber lab for discussions and comments on the manuscript. We thank Dr. Darrin Brager and Dr. Daniel Johnston for technical assistance with whole-cell recordings in mice. NR 38 TC 25 Z9 26 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD OCT 2 PY 2013 VL 80 IS 1 BP 72 EP 79 DI 10.1016/j.neuron.2013.07.020 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 243GQ UT WOS:000326305300009 PM 24094104 ER PT J AU Chowell, G Simonsen, L Towers, S Miller, MA Viboud, C AF Chowell, Gerardo Simonsen, Lone Towers, Sherry Miller, Mark A. Viboud, Cecile TI Transmission potential of influenza A/H7N9, February to May 2013, China SO BMC MEDICINE LA English DT Article DE Influenza A/H7N9; Transmissibility; Reproduction number; Spillover; Animal reservoir; Emerging infection; Influenza A/H5N1; Swine influenza; Transmission potential; China; Real-time estimation ID A H7N9 VIRUS; PANDEMIC INFLUENZA; REPRODUCTION NUMBER; RESPIRATORY SYNDROME; BAYESIAN-ESTIMATION; HUMAN INFECTIONS; UNITED-STATES; NIPAH VIRUS; HONG-KONG; EPIDEMIC AB Background: On 31 March 2013, the first human infections with the novel influenza A/H7N9 virus were reported in Eastern China. The outbreak expanded rapidly in geographic scope and size, with a total of 132 laboratory-confirmed cases reported by 3 June 2013, in 10 Chinese provinces and Taiwan. The incidence of A/H7N9 cases has stalled in recent weeks, presumably as a consequence of live bird market closures in the most heavily affected areas. Here we compare the transmission potential of influenza A/H7N9 with that of other emerging pathogens and evaluate the impact of intervention measures in an effort to guide pandemic preparedness. Methods: We used a Bayesian approach combined with a SEIR (Susceptible-Exposed-Infectious-Removed) transmission model fitted to daily case data to assess the reproduction number (R) of A/H7N9 by province and to evaluate the impact of live bird market closures in April and May 2013. Simulation studies helped quantify the performance of our approach in the context of an emerging pathogen, where human-to-human transmission is limited and most cases arise from spillover events. We also used alternative approaches to estimate R based on individual-level information on prior exposure and compared the transmission potential of influenza A/H7N9 with that of other recent zoonoses. Results: Estimates of R for the A/H7N9 outbreak were below the epidemic threshold required for sustained human-to-human transmission and remained near 0.1 throughout the study period, with broad 95% credible intervals by the Bayesian method (0.01 to 0.49). The Bayesian estimation approach was dominated by the prior distribution, however, due to relatively little information contained in the case data. We observe a statistically significant deceleration in growth rate after 6 April 2013, which is consistent with a reduction in A/H7N9 transmission associated with the preemptive closure of live bird markets. Although confidence intervals are broad, the estimated transmission potential of A/H7N9 appears lower than that of recent zoonotic threats, including avian influenza A/H5N1, swine influenza H3N2sw and Nipah virus. Conclusion: Although uncertainty remains high in R estimates for H7N9 due to limited epidemiological information, all available evidence points to a low transmission potential. Continued monitoring of the transmission potential of A/H7N9 is critical in the coming months as intervention measures may be relaxed and seasonal factors could promote disease transmission in colder months. C1 [Chowell, Gerardo; Simonsen, Lone; Miller, Mark A.; Viboud, Cecile] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Chowell, Gerardo; Towers, Sherry] Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Tempe, AZ 85287 USA. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC 20037 USA. RP Chowell, G (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, 31 Ctr Dr,MSC 2220, Bethesda, MD 20892 USA. EM gchowell@asu.edu OI Simonsen, Lone/0000-0003-1535-8526 FU RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Office of Global Affairs' International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services FX This research was conducted in the context of the Multinational Influenza Seasonal Mortality Study (MISMS), an on-going international collaborative effort to understand influenza epidemiological and evolutionary patterns, led by the Fogarty International Center, National Institutes of Health (http://www.origem.info/misms/index.php). Funding for this project comes in part (LS) from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and from the Office of Global Affairs' International Influenza Unit in the Office of the Secretary of the Department of Health and Human Services. NR 52 TC 22 Z9 24 U1 2 U2 23 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD OCT 2 PY 2013 VL 11 AR 214 DI 10.1186/1741-7015-11-214 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 241PS UT WOS:000326180100001 PM 24083506 ER PT J AU Umhau, JC Zhou, WY Thada, S Demar, J Hussein, N Bhattacharjee, AK Ma, KZ Majchrzak-Hong, S Herscovitch, P Salem, N Urish, A Hibbeln, JR Cunnane, SC Rapoport, SI Hirvonen, J AF Umhau, John C. Zhou, Weiyin Thada, Shantalaxmi Demar, James Hussein, Nahed Bhattacharjee, Abesh K. Ma, Kaizong Majchrzak-Hong, Sharon Herscovitch, Peter Salem, Norman, Jr. Urish, Abigail Hibbeln, Joseph R. Cunnane, Stephen C. Rapoport, Stanley I. Hirvonen, Jussi TI Brain Docosahexaenoic Acid [DHA] Incorporation and Blood Flow Are Increased in Chronic Alcoholics: A Positron Emission Tomography Study Corrected for Cerebral Atrophy SO PLOS ONE LA English DT Article ID ALPHA-LINOLENIC ACID; RAT-BRAIN; FATTY-ACIDS; DOCOSAPENTAENOIC ACID; MAMMALIAN BRAIN; NERVOUS-SYSTEM; METABOLISM; CONSUMPTION; TURNOVER; PHOSPHOLIPIDS AB Objective: Chronic alcohol dependence has been associated with disturbed behavior, cerebral atrophy and a low plasma concentration of docosahexaenoic acid (DHA, 22:6n-3), particularly if liver disease is present. In animal models, excessive alcohol consumption is reported to reduce brain DHA concentration, suggesting disturbed brain DHA metabolism. We hypothesized that brain DHA metabolism also is abnormal in chronic alcoholics. Methods: We compared 15 non-smoking chronic alcoholics, studied within 7 days of their last drink, with 22 non-smoking healthy controls. Using published neuroimaging methods with positron emission tomography (PET), we measured regional coefficients (K*) and rates (J(in)) of DHA incorporation from plasma into the brain of each group using [1-C-11]DHA, and regional cerebral blood flow (rCBF) using [O-15]water. Data were partial volume error corrected for brain atrophy. Plasma unesterified DHA concentration also was quantified. Results: Mean K* for DHA was significantly and widely elevated by 10-20%, and rCBF was elevated by 7%-34%, in alcoholics compared with controls. Unesterified plasma DHA did not differ significantly between groups nor did whole brain J(in), the product of K* and unesterified plasma DHA concentration. Discussion: Significantly higher values of K* for DHA in alcoholics indicate increased brain avidity for DHA, thus a brain DHA metabolic deficit vis-a-vis plasma DHA availability. Higher rCBF in alcoholics suggests increased energy consumption. These changes may reflect a hypermetabolic state related to early alcohol withdrawal, or a general brain metabolic change in chronic alcoholics. C1 [Umhau, John C.; Zhou, Weiyin; Urish, Abigail] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. [Thada, Shantalaxmi; Herscovitch, Peter] NIH, PET Dept, Bethesda, MD 20892 USA. [Demar, James; Bhattacharjee, Abesh K.; Ma, Kaizong; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, Neurosci Lab, NIH, Bethesda, MD 20892 USA. [Demar, James; Hussein, Nahed; Majchrzak-Hong, Sharon; Salem, Norman, Jr.; Hibbeln, Joseph R.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Cunnane, Stephen C.] Univ Sherbrooke, Dept Med, Sherbrook, PQ, Canada. [Hirvonen, Jussi] Univ Turku, Dept Radiol, Turku, Finland. [Hirvonen, Jussi] Univ Turku, Turku PET Ctr, Turku, Finland. RP Umhau, JC (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. EM Umhau@nih.gov RI Majchrzak, Sharon/F-1830-2013 OI Majchrzak, Sharon/0000-0001-8934-7294 FU National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA); NIA FX This research was supported by the Intramural Research Programs of the National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), and NIA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 11 Z9 12 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 2 PY 2013 VL 8 IS 10 AR UNSP e75333 DI 10.1371/journal.pone.0075333 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 231RG UT WOS:000325434500026 PM 24098376 ER PT J AU Choi, S Thapa, N Hedman, AC Li, ZG Sacks, DB Anderson, RA AF Choi, Suyong Thapa, Narendra Hedman, Andrew C. Li, Zhigang Sacks, David B. Anderson, Richard A. TI IQGAP1 is a novel phosphatidylinositol 4,5 bisphosphate effector in regulation of directional cell migration SO EMBO JOURNAL LA English DT Article DE cell migration; IQGAP1; PIP2; PIPKI gamma; polybasic motif ID PHOSPHATE KINASE; PLASMA-MEMBRANE; LEADING-EDGE; PTDINS(4,5)P-2 SYNTHESIS; CAPTURE MICROTUBULES; ACTIN CYTOSKELETON; EXOCYST COMPLEX; BETA-CATENIN; N-WASP; CDC42 AB Phosphatidylinositol 4,5 bisphosphate (PIP2) is a key lipid messenger for regulation of cell migration. PIP2 modulates many effectors, but the specificity of PIP2 signalling can be defined by interactions of PIP2-generating enzymes with PIP2 effectors. Here, we show that type I gamma phosphatidylinositol 4-phosphate 5-kinase (PIPKI gamma) interacts with the cytoskeleton regulator, IQGAP1, and modulates IQGAP1 function in migration. We reveal that PIPKI gamma is required for IQGAP1 recruitment to the leading edge membrane in response to integrin or growth factor receptor activation. Moreover, IQGAP1 is a PIP2 effector that directly binds PIP2 through a polybasic motif and PIP2 binding activates IQGAP1, facilitating actin polymerization. IQGAP1 mutants that lack PIPKI gamma or PIP2 binding lose the ability to control directional cell migration. Collectively, these data reveal a synergy between PIPKI gamma and IQGAP1 in the control of cell migration. C1 [Choi, Suyong; Anderson, Richard A.] Univ Wisconsin, Sch Med & Publ Hlth, Cellular & Mol Biol Grad Program, Madison, WI 53706 USA. [Thapa, Narendra; Hedman, Andrew C.; Anderson, Richard A.] Univ Wisconsin, Sch Med & Publ Hlth, Mol & Cellular Pharmacol Program, Madison, WI 53706 USA. [Li, Zhigang; Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Anderson, RA (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, 3750 Med Sci Ctr,1300 Univ Ave, Madison, WI 53706 USA. EM raanders@wisc.edu OI Anderson, Richard/0000-0001-6265-8359; Sacks, David/0000-0003-3100-0735 FU NIH; Intramural Research Program of the National Institutes of Health; American Heart Association FX We are grateful to Ruth Kroschewski (ETH Zurich) for providing the IQGAP1-C1 and 2 constructs, to Wendell Lim (University of California, San Francisco) for the N-WASP constructs. We also thank Kurt Amann (University of Wisconsin-Madison) for technical advice for an actin polymerization assay. This work was supported by NIH grants to RAA, the Intramural Research Program of the National Institutes of Health to DBS and American Heart Association fellowships to SC, ACH and NT. NR 67 TC 16 Z9 17 U1 2 U2 16 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 OCT 2 PY 2013 VL 32 IS 19 BP 2617 EP 2630 DI 10.1038/emboj.2013.191 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 229ON UT WOS:000325276800009 PM 23982733 ER PT J AU Manson, JE Chlebowski, RT Stefanick, ML Aragaki, AK Rossouw, JE Prentice, RL Anderson, G Howard, BV Thomson, CA LaCroix, AZ Wactawski-Wende, J Jackson, RD Limacher, M Margolis, KL Wassertheil-Smoller, S Beresford, SA Cauley, JA Eaton, CB Gass, M Hsia, J Johnson, KC Kooperberg, C Kuller, LH Lewis, CE Liu, SM Martin, LW Ockene, JK O'Sullivan, MJ Powell, LH Simon, MS Van Horn, L Vitolins, MZ Wallace, RB AF Manson, JoAnn E. Chlebowski, Rowan T. Stefanick, Marcia L. Aragaki, Aaron K. Rossouw, Jacques E. Prentice, Ross L. Anderson, Garnet Howard, Barbara V. Thomson, Cynthia A. LaCroix, Andrea Z. Wactawski-Wende, Jean Jackson, Rebecca D. Limacher, Marian Margolis, Karen L. Wassertheil-Smoller, Sylvia Beresford, Shirley A. Cauley, Jane A. Eaton, Charles B. Gass, Margery Hsia, Judith Johnson, Karen C. Kooperberg, Charles Kuller, Lewis H. Lewis, Cora E. Liu, Simin Martin, Lisa W. Ockene, Judith K. O'Sullivan, Mary Jo Powell, Lynda H. Simon, Michael S. Van Horn, Linda Vitolins, Mara Z. Wallace, Robert B. TI Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women's Health Initiative Randomized Trials SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ESTROGEN PLUS PROGESTIN; CONJUGATED EQUINE ESTROGEN; CORONARY-HEART-DISEASE; MILD COGNITIVE IMPAIRMENT; PLACEBO-CONTROLLED TRIAL; INSOMNIA RATING-SCALE; QUALITY-OF-LIFE; POSTMENOPAUSAL WOMEN; BREAST-CANCER; REPLACEMENT THERAPY AB IMPORTANCE Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. OBJECTIVE To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. DESIGN, SETTING, AND PARTICIPANTS A total of 27 347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. INTERVENTIONS Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. MAIN OUTCOMES AND MEASURES Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. RESULTS During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged >= 65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women(aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P<.05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10 000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. C1 [Manson, JoAnn E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02215 USA. [Chlebowski, Rowan T.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Stefanick, Marcia L.] Stanford Prevent Res Ctr, Stanford, CA USA. [Aragaki, Aaron K.; Prentice, Ross L.; Anderson, Garnet; LaCroix, Andrea Z.; Beresford, Shirley A.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20892 USA. [Howard, Barbara V.] MedStar Hlth Res Inst, Washington, DC USA. [Howard, Barbara V.] Georgetown Howard Univ Ctr Clin & Translat Sci, Washington, DC USA. [Thomson, Cynthia A.] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Limacher, Marian] Univ Florida, Gainesville, FL USA. [Margolis, Karen L.] HealthPartners Inst Educ & Res, Minneapolis, MN USA. [Wassertheil-Smoller, Sylvia] Albert Einstein Coll Med, New York, NY USA. [Cauley, Jane A.; Kuller, Lewis H.] Univ Pittsburgh, Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Eaton, Charles B.] Brown Univ, Dept Family Med & Epidemiol, Alpert Med Sch, Providence, RI 02912 USA. [Gass, Margery] Cleveland Clin, North Amer Menopause Soc, Cleveland, OH 44106 USA. [Gass, Margery] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Hsia, Judith] AstraZeneca, Clin Res, Wilmington, DE USA. [Johnson, Karen C.] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Lewis, Cora E.] Univ Alabama, Dept Med, Tuscaloosa, AL 35487 USA. [Liu, Simin] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Liu, Simin] Brown Univ, Dept Med, Providence, RI 02912 USA. [Martin, Lisa W.] George Washington Univ, Div Cardiol, Sch Med & Hlth Sci, Washington, DC USA. [Ockene, Judith K.] Univ Massachusetts, Sch Med, Worcester, MA USA. [O'Sullivan, Mary Jo] Univ Miami, Dept Obstet & Gynecol, Div Res, Miami, FL USA. [Powell, Lynda H.] Rush Univ, Med Ctr, Dept Prevent Med, Chicago, IL 60612 USA. [Simon, Michael S.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Van Horn, Linda] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Vitolins, Mara Z.] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Wallace, Robert B.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. RP Manson, JE (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, 900 Commonwealth Ave,3rd Floor, Boston, MA 02215 USA. EM jmanson@rics.bwh.harvard.edu RI Liu, Simin/I-3689-2014; OI Liu, Simin/0000-0003-2098-3844; Martin, Lisa Warsinger/0000-0003-4352-0914; Cauley, Jane A/0000-0003-0752-4408 FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 321115, 32118-32119, 32122, 42107-26, 42129-32, 44221] FX The Women's Health Initiative is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 321115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Wyeth-Ayerst donated the study drugs. NR 49 TC 263 Z9 270 U1 6 U2 46 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 OCT 2 PY 2013 VL 310 IS 13 BP 1353 EP 1368 DI 10.1001/jama.2013.278040 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA 227GB UT WOS:000325098100021 PM 24084921 ER PT J AU Park, K Volkow, ND Pan, YT Du, CW AF Park, Kicheon Volkow, Nora D. Pan, Yingtian Du, Congwu TI Chronic Cocaine Dampens Dopamine Signaling during Cocaine Intoxication and Unbalances D-1 over D-2 Receptor Signaling SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SELF-ADMINISTER COCAINE; NUCLEUS-ACCUMBENS; STRIATAL NEURONS; RHESUS-MONKEYS; D2 RECEPTORS; HUMAN BRAIN; ACTIVATION; ADDICTION; REWARD; DEPENDENCE AB Dopamine increases triggered by cocaine and consequent stimulation of dopamine receptors (including D-1 and D-2) are associated with its rewarding effects. However, while facilitation of D-1 receptor (D1R) signaling enhances the rewarding effects of cocaine, facilitation of D2R signaling decreases it, which indicates that for cocaine to be rewarding it must result in a predominance of D1R over D2R signaling. Moreover, the transition to compulsive cocaine intake might result from an imbalance between D1R and D2R signaling. To test the hypothesis that chronic cocaine use unbalances D1R over D2R signaling during cocaine intoxication, we used microprobe optical imaging to compare dynamic changes in intracellular calcium ([Ca2+](i), marker of neuronal activation) to acute cocaine in striatal D1R-EGFP and D2R-EGFP-expressing neurons between control and chronically treated mice. Chronic cocaine attenuated responses to acute cocaine in D1R (blunting Ca2+ increases by 67 +/- 16%) and D2R (blunting Ca2+ decrease by 72 +/- 17%) neurons in most D1R and D2R neurons (similar to 75%). However, the dynamics of this attenuation during cocaine intoxication was longer lasting for D2R than for D1R. Thus, whereas control mice showed a fast but short-lasting predominance of D1R over D2R signaling (peaking at similar to 8 min) during acute cocaine intoxication, in chronically treated mice D1R predominance was sustained for >30 min (throughout the measurement period). Thus, chronic cocaine use dramatically reduced cocaine-induced DA signaling, shifting the balance between D1R and D2R signaling during intoxication to a predominance of D1R (stimulatory) over D2R (inhibitory) signaling, which might facilitate compulsive intake in addiction. C1 [Park, Kicheon; Pan, Yingtian; Du, Congwu] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Volkow, Nora D.] NIAAA, Bethesda, MD 20892 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, NIH, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov; congwu.Du@stonybrook.edu FU National Institutes of Health (NIH) [K25-DA021200, 1RC1DA028534, R21DA032228, R01DA029718] FX This research was supported in part by National Institutes of Health (NIH) Grants K25-DA021200 (C. D.), 1RC1DA028534 (Y.P., C. D.), R21DA032228 (Y.P., C. D.), and R01DA029718 (Y.P., C. D.); and by NIH intramural programs (N.D.V.). NR 52 TC 19 Z9 19 U1 2 U2 16 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 OCT 2 PY 2013 VL 33 IS 40 BP 15827 EP 15836 DI 10.1523/JNEUROSCI.1935-13.2013 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 229RA UT WOS:000325283600017 PM 24089490 ER PT J AU Johnson, NA London, SJ Romieu, I Wong, WH Tang, H AF Johnson, Nicholas A. London, Stephanie J. Romieu, Isabelle Wong, Wing H. Tang, Hua TI ACCURATE CONSTRUCTION OF LONG RANGE HAPLOTYPE IN UNRELATED INDIVIDUALS SO STATISTICA SINICA LA English DT Article DE Expectation maximization; graphical model; haplotype; phasing ID GENOTYPE DATA; HUMAN GENOME; INFERENCE; POPULATION; IMPUTATION; PHASE; MODELS; TRIOS; MAP AB Haplotype, or the sequence of alleles along a single chromosome, has important applications in phenotype-genotype association studies, as well as in population genetics analyses. Because haplotype cannot be experimentally assayed in diploid organisms in a high-throughput fashion, numerous statistical methods have been developed to reconstruct probable haplotype from genotype data. These methods focus primarily on accurate phasing of a short genomic region with a small number of markers, and the error rate increases rapidly for longer regions. Here we introduce a new phasing algorithm, emphases, which aims to improve long-range phasing accuracy. Using datasets from multiple populations, we found that emphases reduces long-range phasing errors by up to 50% compared to the current state-of-the-art methods. In addition to inferring the most likely haplotypes, emphases produces confidence measures, allowing downstream analyses to account for the uncertainties associated with some haplotypes. We anticipate that emphases offers a powerful tool for analyzing large-scale data generated in the genome-wide association studies (GWAS). C1 [Johnson, Nicholas A.] Google Mt View, Mountain View, CA 94043 USA. [Johnson, Nicholas A.] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. [Johnson, Nicholas A.] Google Inc, Mountain View, CA 94043 USA. [London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, Triangle, NC USA. [London, Stephanie J.] NIEHS, Lab Resp Biol, NIH, Triangle, NC USA. [London, Stephanie J.] Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Romieu, Isabelle] Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [Romieu, Isabelle] Int Agcy Res Canc, F-69372 Lyon 08, France. [Wong, Wing H.] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. [Tang, Hua] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. RP Johnson, NA (reprint author), Google Mt View, 1600 Amphitheatre Pkwy, Mountain View, CA 94043 USA. EM nickaj@gmail.com; london2@niehs.nih.gov; iromieu@gmail.com; whwong@stanford.edu; huatang@stanford.edu OI London, Stephanie/0000-0003-4911-5290 FU NIGMS [GM073059]; Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, DHHS; Stanford Genome Training Program [T32 HG000044]; Ric Weiland fellowship FX The research was supported by NIGMS grant GM073059 to HT and by the Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, DHHS, to SJL. NAJ is supported by the Stanford Genome Training Program (T32 HG000044) and a Ric Weiland fellowship. NR 28 TC 0 Z9 0 U1 1 U2 4 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 EI 1996-8507 J9 STAT SINICA JI Stat. Sin. PD OCT PY 2013 VL 23 IS 4 SI SI BP 1441 EP 1461 DI 10.5705/ss.2012.141s PG 21 WC Statistics & Probability SC Mathematics GA AL4SU UT WOS:000339125900002 ER PT J AU Shi, JX Li, P AF Shi, Jianxin Li, Peng TI TESTING ASSOCIATIONS OF COPY NUMBER VARIATIONS IN GENOME-WIDE ASSOCIATION STUDIES SO STATISTICA SINICA LA English DT Article DE Copy number variation; family-based study; genome-wide association study; Hidden Markov Model; TDT ID HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; SEGMENTATION; IMPUTATION AB Copy number variations (CNVs) are a major source of genetic variation in humans. In large-scale genome-wide association studies (GWAS), CNVs have been detected from the intensity data generated by SNP genotyping arrays and then tested for association. This strategy lacks statistical power for detecting associations with short CNVs. In this article, we propose methods for testing the association for each probe, based on a Hidden Markov Model that leverages information from nearby probes in the same CNV region. Our methods do not require specifying CNV regions, are convenient for genome-wide scan data, and work for both population-based and family-based studies. Through simulation studies, we found that loss of efficiency due to CNV calling uncertainty was very small even for short CNVs covering as few as four probes in case-control studies. The efficiency loss was larger for short CNVs in family studies. We applied our methods to a large family-based GWAS of autism in 831 trios, and identified a genomic region on chromosome 17q22 harboring deletions that may contribute to the disease risk. Our methods are computationally efficient, requiring only two hours to analyze the genome-wide intensity data of all trios using a single Linux core. C1 [Shi, Jianxin; Li, Peng] NCI, Div Canc Epidemiol & Genet, Biostat Branch, Rockville, MD 20852 USA. RP Shi, JX (reprint author), NCI, Div Canc Epidemiol & Genet, Biostat Branch, 6120 Executive Blvd,RM8040, Rockville, MD 20852 USA. EM Jianxin.Shi@nih.gov; lip4@mail.nih.gov FU Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute at the National Institutes of Health FX The authors are supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute at the National Institutes of Health. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov). NR 18 TC 1 Z9 1 U1 0 U2 4 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 EI 1996-8507 J9 STAT SINICA JI Stat. Sin. PD OCT PY 2013 VL 23 IS 4 SI SI BP 1463 EP 1477 DI 10.5705/ss.2012.071s PG 15 WC Statistics & Probability SC Mathematics GA AL4SU UT WOS:000339125900003 ER PT J AU Zhang, H Qin, J Landi, M Caporaso, N Yu, K AF Zhang, Hong Qin, Jing Landi, Maria Caporaso, Neil Yu, Kai TI A COPULA-MODEL BASED SEMIPARAMETRIC INTERACTION TEST UNDER THE CASE-CONTROL DESIGN SO STATISTICA SINICA LA English DT Article DE Case-only design; gene-environment interaction; gene-gene interaction; pseudo likelihood ID MAXIMUM-LIKELIHOOD-ESTIMATION; GENE-ENVIRONMENT INDEPENDENCE; LUNG-CANCER; SUSCEPTIBILITY LOCUS; REGRESSION-MODELS; ASSOCIATION; DEPENDENCE; VARIANTS; 5P15.33; DISEASE AB It is important to study the interaction between risk factors in molecular epidemiology studies. To improve the power for the detection of interaction, some statistical testing procedures have been proposed in the literature by incorporating certain assumptions on the underlying joint distribution of two risk factors. For example, the well known case-only test used in genetic epidemiology studies is derived under the assumption of independence between the two risk factors. However, such testing procedures could have detrimental effects on both false positive and false negative rates when assumptions are not met. We propose a parametric copula function to model the joint distribution while leaving the marginal distributions for the two risk factors unspecified. A unified approach is proposed to estimate/test the interaction effect. This approach is very flexible and can be applied to study the interaction between risk factors that are continuous or discrete. A simulation study finds that the proposed test is generally more powerful than the traditional robust test derived under the standard logistic regression, and without specifying the relationship between the two risk factors. The performance of the proposed approach is comparable with the case-only test when the two risk factors are indeed independent in the control population. Unlike the case-only test, the proposed test can still maintain the type I error rate when the independence assumption is not valid. The application of the proposed procedure is demonstrated through two cancer epidemiology studies. C1 [Zhang, Hong] Fudan Univ, Sch Life Sci, Inst Biostat, Shanghai 200433, Peoples R China. [Qin, Jing] NIAID, Biostat Res Branch, NIH MSC 7630, Bethesda, MD 20892 USA. [Landi, Maria; Caporaso, Neil] NCI, Div Canc Epidemiol & Genet, NIH MSC 9769, Bethesda, MD 20892 USA. [Yu, Kai] NCI, Div Canc Epidemiol & Genet, NIH MSC 9780, Bethesda, MD 20892 USA. RP Zhang, H (reprint author), Fudan Univ, Sch Life Sci, Inst Biostat, 220 HanDan Rd, Shanghai 200433, Peoples R China. EM zhanghfd@fudan.edu.cn; jingqin@mail.nih.gov; landim@mail.nih.gov; caporasn@mail.nih.gov; yuka@mail.nih.gov FU State Key Development Program for Basic Research of China [2012CB316500]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX We are grateful to two referees, an associate editor, and a joint editor for insightful comments. This research was supported by the State Key Development Program for Basic Research of China (Grant No. 2012CB316500) (HZ) and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (HZ, ML, NC, KY). NR 26 TC 1 Z9 1 U1 0 U2 3 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 EI 1996-8507 J9 STAT SINICA JI Stat. Sin. PD OCT PY 2013 VL 23 IS 4 SI SI BP 1505 EP 1521 DI 10.5705/ss.2012.013s PG 17 WC Statistics & Probability SC Mathematics GA AL4SU UT WOS:000339125900005 ER PT J AU Jin, M Liu, AY Chen, Z Li, ZH AF Jin, Mel Liu, Aiyi Chen, Zhen Li, Zhaohai TI SEQUENTIAL TESTING OF MEASUREMENT ERRORS IN INTER-RATER RELIABILITY STUDIES SO STATISTICA SINICA LA English DT Article DE Interim analysis; inter-rater reliability; intraclass correlation coefficient; measurement errors; sample size and power; two-way ANOVA ID INTRACLASS CORRELATION-COEFFICIENT; APPROXIMATE INTERVAL ESTIMATION; SAMPLE-SIZE REQUIREMENTS; CLINICAL-TRIALS; DESIGN AB Inter-rater reliability is usually assessed by means of the intraclass correlation coefficient. Using two-way analysis of variance to model raters and subjects as random effects, we derive group sequential testing procedures for the design and analysis of reliability studies in which multiple raters evaluate multiple subjects. Compared with the conventional fixed sample procedures, the group sequential test has smaller average sample number. The performance of the proposed technique is examined using simulation studies and critical values are tabulated for a range of two-stage design parameters. The methods are exemplified using data from the Physician Reliability Study for diagnosis of endometriosis. C1 [Jin, Mel; Li, Zhaohai] George Washington Univ, Dept Stat, Washington, DC 20052 USA. [Jin, Mel; Li, Zhaohai] Credit Risk Management, Mclean, VA USA. [Jin, Mel; Liu, Aiyi; Chen, Zhen] NICHD, Rockville, MD USA. RP Jin, M (reprint author), George Washington Univ, Dept Stat, Washington, DC 20052 USA. EM mei.jin@capitalone.com; liva@mail.nih.gov; chenzhe@mail.nih.gov; zli@gwu.edu OI Liu, Aiyi/0000-0002-6618-5082 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institutes of Health (NIH) FX Research of Zhen Chen and Aiyi Liu was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institutes of Health (NIH). The authors thank an associate editor and the referees for their valuable comments. NR 28 TC 0 Z9 0 U1 0 U2 1 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 EI 1996-8507 J9 STAT SINICA JI Stat. Sin. PD OCT PY 2013 VL 23 IS 4 SI SI BP 1743 EP 1759 DI 10.5705/ss.2012.036s PG 17 WC Statistics & Probability SC Mathematics GA AL4SU UT WOS:000339125900016 PM 25525316 ER PT J AU Barochia, AV Cui, XZ Eichacker, PQ AF Barochia, Amisha V. Cui, Xizhong Eichacker, Peter Q. TI The Surviving Sepsis Campaign's Revised Sepsis Bundles SO CURRENT INFECTIOUS DISEASE REPORTS LA English DT Article DE Sepsis; Septic shock; Bundles; Bundled care; Treatment; Surviving Sepsis Campaign ID GOAL-DIRECTED THERAPY; CRITICALLY-ILL PATIENTS; RANDOMIZED CONTROLLED-TRIAL; LACTATE-GUIDED THERAPY; CARE-UNIT PATIENTS; SEPTIC SHOCK; INTENSIVE-CARE; INTERNATIONAL GUIDELINES; EMERGENCY-DEPARTMENT; MANAGEMENT AB The Surviving Sepsis Campaign (SSC) sepsis care bundles have recently been revised. The original 6-h resuscitation bundle which included rapid antibiotic administration and hemodynamic support with early goal-directed therapy (EGDT) has been divided into two bundles; one including antibiotic and fluid support to be completed within 3 h, and the other including vasopressor support and measures of central venous pressure and oxygen saturation to be completed within 6 h. The original 24-h management bundle targeting glucose control, administration of corticosteroids and recombinant human activated protein C (rhAPC), and limitation of plateau airway pressures during mechanical ventilation is no longer recommended. Past and recent reports by the SSC and others have suggested that compliance with the original bundles was low and their impact unclear. Examination of the revised bundles in the context of issues and questions arising with the original ones suggest that while compliance with new 3-h bundle will be high, compliance with the 6-h bundle will continue to be low. C1 [Barochia, Amisha V.] NHLBI, NIH, Bethesda, MD 20892 USA. [Cui, Xizhong; Eichacker, Peter Q.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Barochia, AV (reprint author), NHLBI, NIH, Bldg 10,Room 2C145, Bethesda, MD 20892 USA. EM barochiaav@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; NIH Clinical Center, Bethesda, Maryland FX The Intramural Research Program of the National Institutes of Health and the NIH Clinical Center, Bethesda, Maryland, provided support for this study. NR 39 TC 7 Z9 12 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3847 EI 1534-3146 J9 CURR INFECT DIS REP JI Curr. Infect. Dis. Rep. PD OCT PY 2013 VL 15 IS 5 BP 385 EP 393 DI 10.1007/s11908-013-0351-3 PG 9 WC Infectious Diseases SC Infectious Diseases GA AK2YT UT WOS:000338287200006 PM 23990342 ER PT J AU Hong, CH Falvey, C Harris, T Simonsick, E Ferrucci, L Satterfield, S Metti, A Patel, K Yaffe, K AF Hong, Chang Hyung Falvey, C. Harris, T. Simonsick, E. Ferrucci, L. Satterfield, S. Metti, A. Patel, K. Yaffe, K. TI Anemia and risk of dementia in older adults: Findings from the health ABC study SO INTERNATIONAL PSYCHOGERIATRICS LA English DT Meeting Abstract C1 [Hong, Chang Hyung] Ajou Univ, Sch Med, Dept Psychiat, Suwon 441749, South Korea. [Harris, T.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Simonsick, E.; Ferrucci, L.] NIA, Clin Res Branch, Bethesda, MD 20892 USA. [Satterfield, S.] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Knoxville, TN 37996 USA. [Metti, A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Patel, K.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1041-6102 EI 1741-203X J9 INT PSYCHOGERIATR JI Int. Psychogeriatr. PD OCT PY 2013 VL 25 SU 1 MA SY21-02 BP S40 EP S40 PG 1 WC Psychology, Clinical; Geriatrics & Gerontology; Gerontology; Psychiatry; Psychology SC Psychology; Geriatrics & Gerontology; Psychiatry GA AJ5UB UT WOS:000337753100095 ER PT J AU Sosa, AL Acosta, I Albanese, E Blossom, S Dewey, M Prince, MJ Stewart, R Ferri, C Acosta, D Guerra, M Huang, Y Shuran, L Jacob, KS Jimenez-Velazquez, IZ Rodriguez, JJL Salas, A Williams, J Gonzalez-Viruet, M Hernandez, MAG AF Luisa Sosa, Ana Acosta, I. Albanese, E. Blossom, S. Dewey, M. Prince, M. J. Stewart, R. Ferri, C. Acosta, D. Guerra, M. Huang, Y. Shuran, L. Jacob, K. S. Jimenez-Velazquez, I. Z. Llibre Rodriguez, J. J. Salas, A. Williams, J. Gonzalez-Viruet, M. Guerra Hernandez, M. A. TI Association between amnesic mild cognitive impairment and neuropsychiatric symptoms: A 10/66 population-based cross-cultural survey SO INTERNATIONAL PSYCHOGERIATRICS LA English DT Meeting Abstract C1 [Luisa Sosa, Ana; Acosta, I.] Univ Nacl Autonoma Mexico, Mexico City, DF, Mexico. [Albanese, E.] NIA, Bethesda, MD 20892 USA. [Blossom, S.] Univ Cambridge, Cambridge CB2 1TN, England. [Dewey, M.; Prince, M. J.; Stewart, R.; Ferri, C.] Kings Coll London, London WC2R 2LS, England. [Acosta, D.] UNPHU, Santo Domingo, Dominican Rep. [Guerra, M.] Univ Peruana Cayetano Heredia, Lima, Peru. [Huang, Y.; Shuran, L.] Peking Univ, Beijing, Peoples R China. [Jacob, K. S.] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Jimenez-Velazquez, I. Z.] Univ Puerto Rico, San Juan, PR 00936 USA. [Llibre Rodriguez, J. J.] Med Univ Havana, Havana, Cuba. [Salas, A.] Cent Univ Venezuela, Caracas, Venezuela. [Williams, J.] Inst Community Hlth, New Delhi, India. [Gonzalez-Viruet, M.] Carlos Albizu Univ, San Juan, PR USA. [Guerra Hernandez, M. A.] Policlin Univ 27 Noviembre, Havana, Cuba. RI Ferri, Cleusa/B-2922-2010 OI Ferri, Cleusa/0000-0002-1815-7685 NR 0 TC 0 Z9 0 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1041-6102 EI 1741-203X J9 INT PSYCHOGERIATR JI Int. Psychogeriatr. PD OCT PY 2013 VL 25 SU 1 MA PS02-101 BP S167 EP S168 PG 2 WC Psychology, Clinical; Geriatrics & Gerontology; Gerontology; Psychiatry; Psychology SC Psychology; Geriatrics & Gerontology; Psychiatry GA AJ5UB UT WOS:000337753100379 ER PT J AU Prasad, V AF Prasad, Vinay TI The overdiagnosis of pneumonia SO CLEVELAND CLINIC JOURNAL OF MEDICINE LA English DT Editorial Material ID COMMUNITY-ACQUIRED PNEUMONIA; HOSPITALIZATIONS; TRENDS C1 NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, NIH, 10 Ctr Dr 10-12N226, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov NR 11 TC 1 Z9 1 U1 0 U2 0 PU CLEVELAND CLINIC PI CLEVELAND PA 9500 EUCLID AVE, CLEVELAND, OH 44106 USA SN 0891-1150 EI 1939-2869 J9 CLEV CLIN J MED JI Clevel. Clin. J. Med. PD OCT PY 2013 VL 80 IS 10 BP 616 EP 618 DI 10.3949/ccjm.80a.12180 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AI2ZL UT WOS:000336727600003 PM 24085804 ER PT J AU Stout, D Berr, SS LeBlanc, A Kalen, JD Osborne, D Price, J Schiffer, W Kuntner, C Wall, J AF Stout, David Berr, Stuart S. LeBlanc, Amy Kalen, Joseph D. Osborne, Dustin Price, Julie Schiffer, Wynne Kuntner, Claudia Wall, Jonathan TI Guidance for Methods Descriptions Used in Preclinical Imaging Papers SO MOLECULAR IMAGING LA English DT Review ID DOPPLER US; IN-VIVO; ANIMALS; MODELS; MOUSE; MICE; RAT AB Preclinical molecular imaging is a rapidly growing field, where new imaging systems, methods, and biological findings are constantly being developed or discovered. Imaging systems and the associated software usually have multiple options for generating data, which is often overlooked but is essential when reporting the methods used to create and analyze data. Similarly, the ways in which animals are housed, handled, and treated to create physiologically based data must be well described in order that the findings be relevant, useful, and reproducible. There are frequently new developments for metabolic imaging methods. Thus, specific reporting requirements are difficult to establish; however, it remains essential to adequately report how the data have been collected, processed, and analyzed. To assist with future manuscript submissions, this article aims to provide guidelines of what details to report for several of the most common imaging modalities. Examples are provided in an attempt to give comprehensive, succinct descriptions of the essential items to report about the experimental process. C1 Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. Univ Virginia, Dept Radiol & Biomed Engn, Charlottesville, VA USA. Univ Tennessee, Dept Small Anim Clin Sci, Coll Vet Med, Knoxville, TN USA. SAIC Frederick, Frederick Natl Lab Canc Res, Small Anim Imaging Program, Lab Anim Sci Program, Frederick, MD USA. Univ Tennessee, Grad Sch Med, Dept Med, Knoxville, TN USA. Univ Tennessee, Grad Sch Med, Dept Radiol, Knoxville, TN USA. Univ Pittsburgh, Sch Med, Dept Radiol, Pittsburgh, PA USA. Univ Minnesota, Ctr Magnet Resonance Res, N Bud Grossman Ctr Memory Res & Care, Sch Med, Minneapolis, MN USA. AIT Austrian Inst Technol GmbH, Dept Environm Hlth, Biomed Syst Hlth & Environm Dept, Seibersdorf, Austria. RP Berr, SS (reprint author), Univ Virginia, Dept Radiol, Snyder Bldg,Room 157,480 Ray C Hunt Dr,Box 801332, Charlottesville, VA 22908 USA. EM berr@virginia.edu RI Kuntner, Claudia/F-6049-2014; OI Kuntner, Claudia/0000-0002-5988-1434; Kalen, Joseph/0000-0002-7163-4604 FU Prothena FX Financial disclosure of authors: Jonathan Wall receives research support from Prothena and he receives support as a Luminary Site for Siemens Medical Solutions. Dustin Osborne is a part-time employee with Siemens Medical Solutions. NR 30 TC 2 Z9 2 U1 2 U2 6 PU B C DECKER INC PI HAMILTON PA 69 JOHN STREET SOUTH, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1535-3508 EI 1536-0121 J9 MOL IMAGING JI Mol. Imaging PD OCT PY 2013 VL 12 IS 7 DI 10.2310/7290.2013.00055 PG 15 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA AI2YQ UT WOS:000336725500006 ER PT J AU Olivier, KN AF Olivier, Kenneth N. TI NONTUBERCULOUS MYCOBACTERIA: UPDATES FOR CF SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract ID CYSTIC-FIBROSIS PATIENTS; LUNG-DISEASE; CLINICAL-SIGNIFICANCE; ABSCESSUS; MASSILIENSE; INFECTION; TRANSMISSION; AZITHROMYCIN; TRANSPLANT; DIAGNOSIS C1 [Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. NR 32 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD OCT PY 2013 VL 48 SU 36 BP 119 EP 121 PG 3 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA AF0FB UT WOS:000334387200015 ER PT J AU Binder, AM Adjemian, J Olivier, KN Prevots, DR AF Binder, A. M. Adjemian, J. Olivier, K. N. Prevots, D. R. TI EPIDEMIOLOGY OF NONTUBERCULOUS MYCOBACTERIAL INFECTIONS AND ASSOCIATED MACROLIDE USE AMONG PERSONS WITH CYSTIC FIBROSIS SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract C1 [Binder, A. M.; Adjemian, J.; Olivier, K. N.; Prevots, D. R.] NIAID, LCID, Epidemol Unit, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD OCT PY 2013 VL 48 SU 36 BP 303 EP 303 PG 1 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA AF0FB UT WOS:000334387200351 ER PT J AU Fink, A Marshall, BC Knapp, E Engels, EA AF Fink, A. Marshall, B. C. Knapp, E. Engels, E. A. TI RISK OF CANCER IN PATIENTS WITH CYSTIC FIBROSIS FOLLOWING LUNG TRANSPLANTATION SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract C1 [Fink, A.; Marshall, B. C.; Knapp, E.] CFF, Bethesda, MD USA. [Engels, E. A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD OCT PY 2013 VL 48 SU 36 BP 370 EP 370 PG 1 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA AF0FB UT WOS:000334387200529 ER PT J AU Okasha, HH Naga, MI Esmat, S Naguib, M Hassanein, M Hassani, M El-Kassas, M Mahdy, RE El-Gemeie, E Farag, AH Foda, AM AF Okasha, Hussein Hassan Naga, Mazen Ibrahim Esmat, Serag Naguib, Mohamed Hassanein, Mohamed Hassani, Mohamed El-Kassas, Mohamed Mahdy, Reem Ezzat El-Gemeie, Emad Farag, Ali Hassan Foda, Ayman Mohamed TI Endoscopic Ultrasound-Guided Fine Needle Aspiration versus Percutaneous Ultrasound-Guided Fine Needle Aspiration in Diagnosis of Focal Pancreatic Masses SO ENDOSCOPIC ULTRASOUND LA English DT Article DE pancreatic cancer; ultrasound; endoscopic ultrasound; fine needle aspiration ID EUS; FNA; CANCER; IMPACT; BIOPSY; TUMORS AB Objective: Pancreatic carcinoma is one of the leading cancer morbidity and mortality world-wide. Controversy has arisen about whether the percutaneous approach with computed tomography/ultrasonography-guidance fine needle aspiration (US-FNA) or endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the preferred method to obtain diagnostic tissue. Our purpose of this study is to compare between the diagnostic accuracy of EUS-FNA and percutaneous US-FNA in diagnosis of pancreatic cancer. Patients and Methods: A total of 197 patients with pancreatic masses were included in the study, 125 patients underwent US-FNA (Group 1) and 72 patients underwent EUS-FNA (Group 2). Results: EUS-FNA has nearly the same accuracy (88.9%) as US-FNA (87.2%) in diagnosis of pancreatic cancer. The sensitivity, specificity, positive predictive value and negative predictive value for EUS-FNA was 84%, 100%, 100%, 73.3% respectively. It was 85.5%, 90.4%, 94.7%, 76% respectively for US-FNA. EUS-FNA had a lower complication rate (1.38%) than US-FNA (5.6%). Conclusion: EUS-FNA has nearly the same accuracy as US-FNA of pancreatic masses with a lower complication rate. C1 [Okasha, Hussein Hassan; Naga, Mazen Ibrahim; Esmat, Serag; Naguib, Mohamed; Farag, Ali Hassan; Foda, Ayman Mohamed] Cairo Univ, Internal Med & Gastroenterol Dept, Cairo, Egypt. [Hassanein, Mohamed; Hassani, Mohamed; El-Kassas, Mohamed] NHTMRI, Cairo, Egypt. [Mahdy, Reem Ezzat] Assiut Univ, Internal Med & Gastroenterol Dept, Assiut, Egypt. [El-Gemeie, Emad] NCI, Dept Pathol, Bethesda, MD 20892 USA. RP Okasha, HH (reprint author), Cairo Univ, Internal Med & Gastroenterol Dept, Cairo, Egypt. EM okasha_hussein@hotmail.com OI Hassany, Mohamed /0000-0002-6001-8793 NR 13 TC 5 Z9 5 U1 0 U2 1 PU SPRING MEDIA PI HONG KONG PA BLDG 8, WANG KWUN RD, KIN BAY, HONG KONG, SAR 00000, PEOPLES R CHINA SN 2303-9027 EI 2226-7190 J9 ENDOSC ULTRASOUND JI Endosc. Ultrasound PD OCT-DEC PY 2013 VL 2 IS 4 BP 190 EP 193 DI 10.4103/2303-9027.121239 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AH0OF UT WOS:000335818900003 PM 24949394 ER PT J AU Gini, R Ryan, PB Brown, JS Vacchi, E Coppola, M Cazzola, W Coloma, PM Berni, R Diallo, G Avillach, P Trifiro, G Oliveira, JL Rijnbeek, PR Lei, JD Sturkenboom, MCJM Schuemie, MJ AF Gini, Rosa Ryan, Patrick B. Brown, Jeffrey S. Vacchi, Edoardo Coppola, Massimo Cazzola, Walter Coloma, Preciosa M. Berni, Roberto Diallo, Gayo Avillach, Paul Trifiro, Gianluca Oliveira, Jose L. Rijnbeek, Peter R. Lei, Johanvan Der Sturkenboom, Miriam C. J. M. Schuemie, Martijn J. TI Comparison among EU-ADR, OMOP, Mini-Sentinel and MATRICE Strategies for Data Extraction and Management SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Gini, Rosa; Berni, Roberto] Agenzia Reg Sanita Toscana, Florence, Italy. [Gini, Rosa; Coloma, Preciosa M.; Rijnbeek, Peter R.; Lei, Johanvan Der; Sturkenboom, Miriam C. J. M.; Schuemie, Martijn J.] Erasmus MC, Rotterdam, Netherlands. [Ryan, Patrick B.; Schuemie, Martijn J.] Fdn Natl Inst Hlth, Observat Med Outcomes Partnership, Bethesda, MD USA. [Brown, Jeffrey S.] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Brown, Jeffrey S.] Harvard Univ, Sch Med, Boston, MA USA. [Vacchi, Edoardo; Cazzola, Walter] Univ Milan, Dipartimento Informat, Milan, Italy. [Coppola, Massimo] CNR, Ist Sci & Tecnol Informaz, I-56100 Pisa, Italy. [Diallo, Gayo] Univ Bordeaux Segalen, LESIM ISPED Lab, Bordeaux, France. [Avillach, Paul] Univ Hosp HEGP, AP HP, Biomed Informat & Publ Hlth Dept, Paris, France. [Avillach, Paul] Univ Paris 05, Paris, France. [Trifiro, Gianluca] Univ Messina, Messina, Italy. [Oliveira, Jose L.] Univ Aveiro, Dept Elect Telecommun & Informat, P-3800 Aveiro, Portugal. [Schuemie, Martijn J.] Janssen Res & Dev LLC, Titusville, NJ USA. RI Oliveira, Jose Luis/A-2223-2012; Trifiro, Gianluca/K-9744-2016 OI Oliveira, Jose Luis/0000-0002-6672-6176; Trifiro, Gianluca/0000-0003-1147-7296 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 388 BP 189 EP 190 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876100365 ER PT J AU Zhou, YJ Boudreau, DM Freedman, AN AF Zhou, Yingjun Boudreau, Denise M. Freedman, Andrew N. TI Trends in the Use of Aspirin and Other Nonsteroidal Anti-Inflammatory Drugs in the General US Population SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Zhou, Yingjun; Freedman, Andrew N.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Boudreau, Denise M.] Grp Hlth Res Inst, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2013 VL 22 SU 1 SI SI MA 854 BP 429 EP 430 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AF7EJ UT WOS:000334876101418 ER PT J AU Horton, JA Hudak, KE Chung, EJ White, AO Scroggins, BT Burkeen, JF Citrin, DE AF Horton, Jason A. Hudak, Kathryn E. Chung, Eun Joo White, Ayla O. Scroggins, Bradley T. Burkeen, Jeffrey F. Citrin, Deborah E. TI Mesenchymal stem cells inhibit cutaneous radiation-induced fibrosis by suppressing chronic inflammation SO STEM CELLS LA English DT Article DE Ionizing radiation; Mesenchymal stem cell; Chronic inflammation; Dermal fibrosis ID ANTIGEN-PRESENTING CELLS; MARROW STROMAL CELLS; NORMAL TISSUE-INJURY; IFN-GAMMA; ACTIVATED MACROPHAGES; SKIN FIBROSIS; IN-VITRO; THERAPY; EXPRESSION; MICE AB Exposure to ionizing radiation (IR) can result in the development of cutaneous fibrosis, for which few therapeutic options exist. We tested the hypothesis that bone marrow-derived mesenchymal stem cells (BMSC) would favorably alter the progression of IR-induced fibrosis. We found that a systemic infusion of BMSC from syngeneic or allogeneic donors reduced skin contracture, thickening, and collagen deposition in a murine model. Transcriptional profiling with a fibrosis-targeted assay demonstrated increased expression of interleukin-10 (IL-10) and decreased expression of IL-1 beta in the irradiated skin of mice 14 days after receiving BMSC. Similarly, immunoassay studies demonstrated durable alteration of these and several additional inflammatory mediators. Immunohistochemical studies revealed a reduction in infiltration of proinflammatory classically activated CD80(+) macrophages and increased numbers of anti-inflammatory regulatory CD163(+) macrophages in irradiated skin of BMSC-treated mice. In vitro coculture experiments confirmed that BMSC induce expression of IL-10 by activated macrophages, suggesting polarization toward a regulatory phenotype. Furthermore, we demonstrated that tumor necrosis factor-receptor 2 (TNF-R2) mediates IL-10 production and transition toward a regulatory phenotype during coculture with BMSC. Taken together, these data demonstrate that systemic infusion of BMSC can durably alter the progression of radiation-induced fibrosis by altering macrophage phenotype and suppressing local inflammation in a TNF-R2-dependent fashion. Stem Cells 2013;31:2231-2241 C1 [Horton, Jason A.; Hudak, Kathryn E.; Chung, Eun Joo; White, Ayla O.; Scroggins, Bradley T.; Burkeen, Jeffrey F.; Citrin, Deborah E.] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Citrin, DE (reprint author), NCI, Sect Translat Radiat Oncol, Radiat Oncol Branch, Ctr Canc Res,CRC Hatfield Clin Res Ctr 10, B2-3500,10 Ctr Dr, Bethesda, MD 20892 USA. EM citrind@mail.nih.gov FU National Institutes of Health Intramural Research Program (National Cancer Institute); Radiation/Nuclear Medical Countermeasures Program (National Institute of Allergy and Infectious Diseases) FX This research was supported by the National Institutes of Health Intramural Research Program (National Cancer Institute) and the Radiation/Nuclear Medical Countermeasures Program (National Institute of Allergy and Infectious Diseases). NR 52 TC 20 Z9 22 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD OCT PY 2013 VL 31 IS 10 BP 2231 EP 2241 DI 10.1002/stem.1483 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA AD9JK UT WOS:000333581000019 PM 23897677 ER PT J AU Hall, KD Butte, NF Swinburn, BA Chow, CC AF Hall, Kevin D. Butte, Nancy F. Swinburn, Boyd A. Chow, Carson C. TI Dynamics of childhood growth and obesity: development and validation of a quantitative mathematical model SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Article ID PHYSICAL-ACTIVITY; ENERGY-EXPENDITURE; BODY-COMPOSITION; UNITED-STATES; LONGITUDINAL CHANGES; ACTIVITY PATTERNS; NORMAL-WEIGHT; CHILDREN; GAP; IMBALANCE AB Background Clinicians and policy makers need the ability to predict quantitatively how childhood bodyweight will respond to obesity interventions. Methods We developed and validated a mathematical model of childhood energy balance that accounts for healthy growth and development of obesity, and that makes quantitative predictions about weight-management interventions. The model was calibrated to reference body composition data in healthy children and validated by comparing model predictions with data other than those used to build the model. Findings The model accurately simulated the changes in body composition and energy expenditure reported in reference data during healthy growth, and predicted increases in energy intake from ages 5-18 years of roughly 1200 kcal per day in boys and 900 kcal per day in girls. Development of childhood obesity necessitated a substantially greater excess energy intake than for development of adult obesity. Furthermore, excess energy intake in overweight and obese children calculated by the model greatly exceeded the typical energy balance calculated on the basis of growth charts. At the population level, the excess weight of US children in 2003-06 was associated with a mean increase in energy intake of roughly 200 kcal per day per child compared with similar children in 1976-80. The model also suggests that therapeutic windows when children can outgrow obesity without losing weight might exist, especially during periods of high growth potential in boys who are not severely obese. Interpretation This model quantifies the energy excess underlying obesity and calculates the necessary intervention magnitude to achieve bodyweight change in children. Policy makers and clinicians now have a quantitative technique for understanding the childhood obesity epidemic and planning interventions to control it. C1 [Hall, Kevin D.; Chow, Carson C.] NIDDK, NIH, Bethesda, MD 20892 USA. [Butte, Nancy F.] Baylor Coll Med, Houston, TX 77030 USA. [Swinburn, Boyd A.] Univ Auckland, Sch Populat Hlth, Auckland 1, New Zealand. RP Hall, KD (reprint author), NIDDK, NIH, 12A South Dr, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX Funding Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 37 TC 42 Z9 42 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD OCT PY 2013 VL 1 IS 2 BP 97 EP 105 DI 10.1016/S2213-8587(13)70051-2 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AE1YD UT WOS:000333768800018 PM 24349967 ER PT J AU Fee, E AF Fee, Elizabeth TI The Stigma of HIV SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20894 USA. RP Fee, E (reprint author), NIH, Lib Operat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM feee@mail.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD OCT PY 2013 VL 103 IS 10 BP 1747 EP 1747 DI 10.2105/AJPH.2013.301414 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA3PK UT WOS:000331004600026 PM 23948007 ER PT J AU Kaplan, RM Spittel, ML Spotts, EL AF Kaplan, Robert M. Spittel, Michael L. Spotts, Erica L. TI Advancing Scientific Inquiry by Blurring Research Boundaries SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Kaplan, Robert M.; Spittel, Michael L.; Spotts, Erica L.] NIH, OBSSR, Bethesda, MD 20892 USA. RP Kaplan, RM (reprint author), NIH, OBSSR, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD OCT PY 2013 VL 103 SU 1 BP S4 EP S4 DI 10.2105/AJPH.2013.301589 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA4NC UT WOS:000331071600001 PM 23927548 ER PT J AU Spittel, ML Spotts, EL Deeds, BG AF Spittel, Michael L. Spotts, Erica L. Deeds, Bethany G. TI Integration of Behavioral, Social Science and Genetics Research: Exploring Public Health Significance SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material ID RACE; EXPERIENCE C1 [Spittel, Michael L.; Spotts, Erica L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Deeds, Bethany G.] Natl Inst Drug Abuse, Natl Inst Hlth, Bethesda, MD USA. RP Spittel, ML (reprint author), NIH, Off Behav & Social Sci Res, 31 Ctr Dr,B1-C19, Bethesda, MD 20892 USA. EM Michael.Spittel@nih.gov NR 15 TC 2 Z9 2 U1 2 U2 5 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD OCT PY 2013 VL 103 SU 1 BP S5 EP S7 DI 10.2105/AJPH.2013.301539 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA4NC UT WOS:000331071600002 PM 23927547 ER PT J AU Epstein, JS Jaffe, HW Alter, HJ Klein, HG AF Epstein, Jay S. Jaffe, Harold W. Alter, Harvey J. Klein, Harvey G. TI Blood system changes since recognition of transfusion-associated AIDS SO TRANSFUSION LA English DT Editorial Material ID NON-B-HEPATITIS; WEST-NILE-VIRUS; CHRONIC-FATIGUE-SYNDROME; NON-A-HEPATITIS; UNITED-STATES; TRYPANOSOMA-CRUZI; VIRAL-HEPATITIS; POSTTRANSFUSION HEPATITIS; TRANSMITTED VIRUSES; AUSTRALIA-ANTIGEN C1 [Epstein, Jay S.] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. [Jaffe, Harold W.] CDC, Off Associate Director Sci, Atlanta, GA 30333 USA. [Alter, Harvey J.; Klein, Harvey G.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Epstein, JS (reprint author), US FDA, Ctr Biol Evaluat & Res, HFM-300,1401 Rockville Pike, Rockville, MD 20852 USA. EM Jay.Epstein@FDA.HHS.gov NR 71 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD OCT PY 2013 VL 53 IS 10 SI SI BP 2365 EP 2374 DI 10.1111/trf.12373 PN 2 PG 10 WC Hematology SC Hematology GA 238UY UT WOS:000325978000003 PM 24032622 ER PT J AU Xu, CY Wang, RY Schechterly, CA Ge, SX Shih, JW Xia, NS Luban, NLC Alter, HJ AF Xu, Chenyu Wang, Richard Y. Schechterly, Cathy A. Ge, Shengxiang Shih, James W. Xia, Ning-Shao Luban, Naomi L. C. Alter, Harvey J. TI An assessment of hepatitis E virus (HEV) in US blood donors and recipients: no detectable HEV RNA in 1939 donors tested and no evidence for HEV transmission to 362 prospectively followed recipients SO TRANSFUSION LA English DT Article ID DEVELOPED-COUNTRIES; IGG SEROPREVALENCE; UNITED-STATES; INFECTION; TRANSFUSION; DISEASE; ANTIBODIES; LYMPHOMA; PATIENT; ASSAYS AB BackgroundHepatitis E virus (HEV) infection has become relevant to blood transfusion practice because isolated cases of blood transmission have been reported and because HEV has been found to cause chronic infection and severe liver disease in immunocompromised patients. Study Design and MethodsWe tested for immunoglobulin (Ig)G and IgM antibodies to the HEV and for HEV RNA in 1939 unselected volunteer US blood donors. Subsequently, we tested the same variables in pre- and serial posttransfusion samples from 362 prospectively followed blood recipients to assess transfusion risk. ResultsIgG anti-HEV seroprevalence in the total 1939 donations was 18.8%: 916 of these donations were made in 2006 at which time the seroprevalence was 21.8% and the remaining 1023 donations were in 2012 when the seroprevalence had decreased to 16.0% (p<0.01). A significant (p<0.001) stepwise increase in anti-HEV seroprevalence was seen with increasing age. Eight of 1939 donations (0.4%) tested anti-HEV IgM positive; no donation was HEV RNA positive. Two recipients had an apparent anti-HEV seroconversion, but temporal relationships and linked donor testing showed that these were not transfusion-transmitted HEV infections. ConclusionNo transfusion-transmitted HEV infections were observed in 362 prospectively followed blood recipients despite an anti-HEV seroprevalence among donations exceeding 16%. C1 NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Xiamen Univ, Natl Inst Diagnost & Vaccine Dev Infect Dis, Xiamen, Fujian, Peoples R China. Xiamen Univ, Sch Publ Hlth, Xiamen, Fujian, Peoples R China. George Washington Univ, Childrens Natl Med Ctr, Dept Lab Med, Ctr Canc & Blood Dis, Washington, DC USA. George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20052 USA. RP Alter, HJ (reprint author), NIH, Dept Transfus Med, Bldg 10,Room 1C-711,10 Ctr Dr, Bethesda, MD 20892 USA. EM halter@dtm.cc.nih.gov FU National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) [R01 HL67229]; NIH Clinical Center Intramural Program, TRIPS Protocol [01-CC-0231] FX This study was supported by Grant R01 HL67229 from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) and by the NIH Clinical Center Intramural Program, TRIPS Protocol 01-CC-0231. NR 26 TC 34 Z9 34 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD OCT PY 2013 VL 53 IS 10 SI SI BP 2505 EP 2511 DI 10.1111/trf.12326 PN 2 PG 7 WC Hematology SC Hematology GA 238UY UT WOS:000325978000017 PM 23829163 ER PT J AU Luby, M Hong, J Merino, JG Lynch, JK Hsia, AW Magadan, A Song, SS Latour, LL Warach, S AF Luby, M. Hong, J. Merino, J. G. Lynch, J. K. Hsia, A. W. Magadan, A. Song, S. S. Latour, L. L. Warach, S. TI Stroke Mismatch Volume with the Use of ABC/2 Is Equivalent to Planimetric Stroke Mismatch Volume SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID LESION VOLUME; DIFFUSION; PERFUSION; DESMOTEPLASE; TRIAL; INFARCT; TIME; MRI AB BACKGROUND AND PURPOSE: In the clinical setting, there is a need to perform mismatch measurements quickly and easily on the MR imaging scanner to determine the specific amount of treatable penumbra. The objective of this study was to quantify the agreement of the ABC/2 method with the established planimetric method. MATERIALS AND METHODS: Patients (n = 193) were selected from the NINDS Natural History Stroke Registry if they 1) were treated with standard intravenous rtPA, 2) had a pretreatment MR imaging with evaluable DWI and PWI, and 3) had an acute ischemic stroke lesion. A rater placed the linear diameters to measure the largest DWI and MTT lesion areas in 3 perpendicular axes-A, B, and C-and then used the ABC/2 formula to calculate lesion volumes. A separate rater measured the planimetric volumes. Multiple mismatch thresholds were used, including MTT volume - DWI volume >= 50 mL versus >= 60 mL and (MTT volume - DWI volume)/MTT volume >= 20% versus MTT/DWI = 1.8. RESULTS: Compared with the planimetric method, the ABC/2 method had high sensitivity (0.91), specificity (0.90), accuracy (0.91), PPV (0.90), and NPV (0.91) to quantify mismatch by use of the >= 50 mL definition. The Spearman correlation coefficients were 0.846 and 0.876, respectively, for the DWI and MTT measurements. The inter-rater Bland-Altman plots demonstrated 95%, 95%, and 97% agreement for the DWI, MTT, and mismatch measurements. CONCLUSIONS: The ABC/2 method is highly reliable and accurate for quantifying the specific amount of MR imaging-determined mismatch and therefore is a potential tool to quickly calculate a treatable mismatch pattern. C1 [Luby, M.; Hong, J.; Merino, J. G.; Lynch, J. K.; Hsia, A. W.; Magadan, A.; Latour, L. L.; Warach, S.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Merino, J. G.] Johns Hopkins Community Phys, Bethesda, MD USA. [Hsia, A. W.] Medstar Washington Hosp Ctr, Stroke Ctr, Washington, DC USA. [Song, S. S.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Warach, S.] NINDS Nat Hist Stroke Investigators, Bethesda, MD USA. RP Luby, M (reprint author), Sect Stroke Diagnost & Therapeut, 10 Ctr D,MSC 1063,Bldg 10,Room B1D733, Bethesda, MD 20892 USA. EM lubym@ninds.nih.gov OI Merino, Jose/0000-0002-6676-0008 FU Division of Intramural Research of the National Institutes of Health; National Institute of Neurological Disorders and Stroke FX This research was supported by the Division of Intramural Research of the National Institutes of Health and the National Institute of Neurological Disorders and Stroke. NR 18 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD OCT PY 2013 VL 34 IS 10 BP 1901 EP 1907 DI 10.3174/ajnr.A3476 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 301NQ UT WOS:000330539400011 PM 23449656 ER PT J AU Goldstein, DS AF Goldstein, David S. TI Concepts of Scientific Integrative Medicine Applied to the Physiology and Pathophysiology of Catecholamine Systems SO COMPREHENSIVE PHYSIOLOGY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; NEURALLY-MEDIATED SYNCOPE; CONGESTIVE-HEART-FAILURE; CORTICOTROPIN-RELEASING HORMONE; CARDIAC SYMPATHETIC DENERVATION; TOXIC DOPAMINE METABOLITE; INSULIN-INDUCED HYPOGLYCEMIA; NUCLEUS-TRACTUS-SOLITARII; EARLY PARKINSONS-DISEASE; GENOME-WIDE ASSOCIATION AB This review presents concepts of scientific integrative medicine and relates them to the physiology of catecholamine systems and to the pathophysiology of catecholamine-related disorders. The applications to catecholamine systems exemplify how scientific integrative medicine links systems biology with integrative physiology. Concepts of scientific integrative medicine include (i) negative feedback regulation, maintaining stability of the body's monitored variables; (ii) homeostats, which compare information about monitored variables with algorithms for responding; (iii) multiple effectors, enabling compensatory activation of alternative effectors and primitive specificity of stress response patterns; (iv) effector sharing, accounting for interactions among homeostats and phenomena such as hyperglycemia attending gastrointestinal bleeding and hyponatremia attending congestive heart failure; (v) stress, applying a definition as a state rather than as an environmental stimulus or stereotyped response; (vi) distress, using a noncircular definition that does not presume pathology; (vii) allostasis, corresponding to adaptive plasticity of feedback-regulated systems; and (viii) allostatic load, explaining chronic degenerative diseases in terms of effects of cumulative wear and tear. From computer models one can predict mathematically the effects of stress and allostatic load on the transition from wellness to symptomatic disease. The review describes acute and chronic clinical disorders involving catecholamine systems-especially Parkinson disease-and how these concepts relate to pathophysiology, early detection, and treatment and prevention strategies in the post-genome era. Published 2013. C1 NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU Intramural NIH HHS [Z01 NS003033-02, Z01 NS003034-01, Z99 NS999999] NR 328 TC 7 Z9 9 U1 2 U2 13 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2040-4603 J9 COMPR PHYSIOL JI Compr. Physiol. PD OCT PY 2013 VL 3 IS 4 BP 1569 EP 1610 DI 10.1002/cphy.c130006 PG 42 WC Physiology SC Physiology GA AA1VE UT WOS:000330883200006 PM 24265239 ER PT J AU Raggi, C Factor, VM Daekwan, S Holczbauer, A Marquardt, JU Thorgeirsson, SS AF Raggi, Chiara Factor, Valentina M. Daekwan, Seo Holczbauer, Agnes Marquardt, Jens U. Thorgeirsson, Snorri S. TI Epigenetic Reprogramming Modulates Malignant Properties of Human Liver Cancer Cells SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Raggi, Chiara; Factor, Valentina M.; Daekwan, Seo; Holczbauer, Agnes; Marquardt, Jens U.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 58 BP 235A EP 236A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201058 ER PT J AU Bezerra, JA Spino, C Magee, JC Shneider, BL Rosenthal, P Wang, KS Erlichman, J Haber, B Hertel, PM Karpen, SJ Kerkar, N Loomes, KM Molleston, JP Murray, KF Romero, R Schwarz, KB Shepherd, R Suchy, FJ Turmelle, YP Whitington, PF Moore, J Sherker, AH Robuck, PR Sokol, RJ AF Bezerra, Jorge A. Spino, Cathie Magee, John C. Shneider, Benjamin L. Rosenthal, Philip Wang, Kasper S. Erlichman, Jessi Haber, Barbara Hertel, Paula M. Karpen, Saul J. Kerkar, Nanda Loomes, Kathleen M. Molleston, Jean P. Murray, Karen F. Romero, Rene Schwarz, Kathleen B. Shepherd, Ross Suchy, Frederick J. Turmelle, Yumirle P. Whitington, Peter F. Moore, Jeffrey Sherker, Averell H. Robuck, Patricia R. Sokol, Ronald J. TI High-dose corticosteroid therapy following portoenterostomy in infants with biliary atresia does not improve outcome: The multi-center, randomized, double-blind, placebo-controlled START Trial SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Bezerra, Jorge A.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Spino, Cathie; Magee, John C.; Moore, Jeffrey] Univ Michigan, Ann Arbor, MI 48109 USA. [Shneider, Benjamin L.] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Rosenthal, Philip] Univ Calif San Francisco, Benioff Childrens Hosp, San Francisco, CA 94143 USA. [Wang, Kasper S.; Kerkar, Nanda] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Wang, Kasper S.; Kerkar, Nanda] Univ So Calif, Los Angeles, CA USA. [Erlichman, Jessi; Loomes, Kathleen M.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Haber, Barbara] Merck Res Labs, Upper Gwynedd, PA USA. [Hertel, Paula M.; Shepherd, Ross] Texas Childrens Hosp, Houston, TX 77030 USA. [Hertel, Paula M.; Shepherd, Ross] Baylor Coll Med, Houston, TX 77030 USA. [Karpen, Saul J.; Romero, Rene] Emory Univ, Sch Med, Atlanta, GA USA. [Molleston, Jean P.] James Whitcomb Riley Hosp Children, Indianapolis, IN 46202 USA. [Murray, Karen F.] Seattle Childrens Hosp, Seattle, WA USA. [Schwarz, Kathleen B.] Johns Hosp Sch Med, Baltimore, MD USA. [Suchy, Frederick J.; Sokol, Ronald J.] Childrens Hosp Colorado, Denver, CO USA. [Suchy, Frederick J.; Sokol, Ronald J.] Univ Colorado, Denver, CO 80202 USA. [Turmelle, Yumirle P.] Washington Univ, Sch Med, St Louis, MO USA. [Whitington, Peter F.] Lurie Childrens Hosp Chicago, Chicago, IL USA. [Sherker, Averell H.; Robuck, Patricia R.] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 111 BP 263A EP 263A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201111 ER PT J AU Jain, AK Deppe, RB Yates, KP Comerford, M Masuoka, HC Molleston, JP Schwimmer, JB Lavine, JE Brunt, EM Tonascia, J Kleiner, DE Chalasani, NP AF Jain, Ajay K. Deppe, Ross B. Yates, Katherine P. Comerford, Megan Masuoka, Howard C. Molleston, Jean P. Schwimmer, Jeffrey B. Lavine, Joel E. Brunt, Elizabeth M. Tonascia, James Kleiner, David E. Chalasani, Naga P. TI Serum keratin fragment 18 (CK18) levels significantly predict changes in liver histology in children and adolescents with nonalcoholic fatty liver disease (NAFLD): Results from the TONIC trial SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Jain, Ajay K.] St Louis Univ, St Louis, MO 63103 USA. [Deppe, Ross B.; Comerford, Megan; Masuoka, Howard C.; Molleston, Jean P.; Chalasani, Naga P.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Yates, Katherine P.; Tonascia, James] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. [Schwimmer, Jeffrey B.] Univ Calif San Diego, San Diego, CA 92103 USA. [Lavine, Joel E.] Columbia Univ, New York, NY USA. [Brunt, Elizabeth M.] Washington Univ, St Louis, MO USA. [Kleiner, David E.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 114 BP 264A EP 265A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201114 ER PT J AU Navarro, VJ Barnhart, HX Bonkovsky, HL Davern, TJ Fontana, RJ Grant, L Hoofnagle, JH Reddy, KR Seeff, LB Serrano, J Sherker, AH Stolz, A Talwalkar, JA Vega, M Vuppalanchi, R AF Navarro, Victor J. Barnhart, Huiman X. Bonkovsky, Herbert L. Davern, Timothy J. Fontana, Robert J. Grant, Lafaine Hoofnagle, Jay H. Reddy, K. Rajender Seeff, Leonard B. Serrano, Jose Sherker, Averell H. Stolz, Andrew Talwalkar, Jayant A. Vega, Maricruz Vuppalanchi, Raj TI The Rising Burden of Herbal and Dietary Supplement Induced Hepatotoxicity in the U. S. A SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Navarro, Victor J.; Vega, Maricruz] Albert Einstein Med Ctr, Div Hepatol, Philadelphia, PA 19141 USA. [Stolz, Andrew] Univ So Calif, Los Angeles, CA USA. [Hoofnagle, Jay H.; Serrano, Jose; Sherker, Averell H.] NIDDK, Bethesda, MD 20892 USA. [Reddy, K. Rajender] Univ Penn, Div Gastroenterol & Hepatol, Philadelphia, PA 19104 USA. [Davern, Timothy J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Bonkovsky, Herbert L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Barnhart, Huiman X.] Duke Clin Res Inst, Durham, NC USA. [Grant, Lafaine] Univ Texas Southwestern, Austin, TX USA. [Fontana, Robert J.] Univ Michigan, Ann Arbor, MI 48109 USA. [Talwalkar, Jayant A.] Mayo Clin, Rochester, MN USA. [Vuppalanchi, Raj] Indiana Univ, Indianapolis, IN 46204 USA. [Seeff, Leonard B.] CDER, Silver Spring, MD USA. NR 0 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 113 BP 264A EP 264A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201113 ER PT J AU Abdelmegeed, MA Banerjee, A Jang, S Yoo, SH Gonzalez, F Keshavarzian, A Song, BJ AF Abdelmegeed, Mohamed A. Banerjee, Atrayee Jang, Sehwan Yoo, Seong-Ho Gonzalez, Frank Keshavarzian, Ali Song, Byoung-Joon TI Ethanol-inducible CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis and apoptosis SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Abdelmegeed, Mohamed A.; Banerjee, Atrayee; Jang, Sehwan; Song, Byoung-Joon] NIH, Lab Memb Biochem Biophys, Bethesda, MD 20892 USA. [Yoo, Seong-Ho] Seoul Natl Univ, Seoul, South Korea. [Gonzalez, Frank] NCI, NIH, Bethesda, MD 20892 USA. [Keshavarzian, Ali] Rush Univ, Sch Med, Chicago, IL 60612 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 154 BP 285A EP 285A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201154 ER PT J AU Alao, HF Cha, HL Chiu, S Li, QS Liang, TJ AF Alao, Hawwa F. Cha, Helen Chiu, Stephan Li, Qisheng Liang, T. Jake TI Global microRNA profiling reveals complex interactions among hepatic microRNA regulation, hepatitis C virus infection and interferon response SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Alao, Hawwa F.; Cha, Helen; Chiu, Stephan; Li, Qisheng; Liang, T. Jake] NIH, Liver Dis Branch, Bethesda, MD 20892 USA. RI Li, Qisheng/K-1909-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 199 BP 307A EP 307A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201199 ER PT J AU Serti, E Werner, JM Chattergoon, MA Cox, A Lohmann, V Rehermann, B AF Serti, Elisavet Werner, Jens M. Chattergoon, Michael A. Cox, Andrea Lohmann, Volker Rehermann, Barbara TI Monocytes Regulate NK Cell Antiviral Function in Hepatitis C via Inflammasome-Induced IL-18 SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Serti, Elisavet; Werner, Jens M.; Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Chattergoon, Michael A.; Cox, Andrea] Johns Hopkins Sch Med, Div Infect Dis, Baltimore, MD USA. [Lohmann, Volker] Heidelberg Univ, Dept Infect Dis, Heidelberg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 201 BP 308A EP 308A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201201 ER PT J AU Andersen, JB Factor, VM Thorgeirsson, SS AF Andersen, Jesper B. Factor, Valentina M. Thorgeirsson, Snorri S. TI Genomics-based directions for targeted therapy in cholangiocarcinoma SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Andersen, Jesper B.; Factor, Valentina M.; Thorgeirsson, Snorri S.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 233 BP 324A EP 324A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201233 ER PT J AU Meissner, EG Osinusi, A Wang, HH McHutchison, JG Symonds, WT Suffredini, AF Polis, MA Masur, H Kottilil, S AF Meissner, Eric G. Osinusi, Anu Wang, Honghui McHutchison, John G. Symonds, William T. Suffredini, Anthony F. Polis, Michael A. Masur, Henry Kottilil, Shyam TI Intrahepatic Changes in the Endogenous Interferon Response are Associated with SVR in Chronic Hepatitis C, Genotype-1 Subjects Treated with Sofosbuvir and Ribavirin SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Meissner, Eric G.; Osinusi, Anu; Polis, Michael A.; Kottilil, Shyam] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Osinusi, Anu] SAIC Frederick Inc, Clin Res Directorate, CRMP, Frederick, MD USA. [Wang, Honghui; Suffredini, Anthony F.; Masur, Henry] NIH, Crit Care Med Dept, Bethesda, MD 20892 USA. [McHutchison, John G.; Symonds, William T.] Gilead Sci Inc, Foster City, CA 94404 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 238 BP 326A EP 327A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201238 ER PT J AU Lee, S Zhang, YX Tsuchiya, H Smalling, R Jetten, AM Wang, L AF Lee, Sangmin Zhang, Yuxia Tsuchiya, Hiroyuki Smalling, Rana Jetten, Anton M. Wang, Li TI The novel function of small heterodimer partner (SHP) in integrating circadian rhythm and metabolism networks in the liver SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Lee, Sangmin; Zhang, Yuxia; Tsuchiya, Hiroyuki; Smalling, Rana; Wang, Li] Univ Utah, GI Internal Med, Salt Lake City, UT USA. [Jetten, Anton M.] NIH, Div Intramural Res, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 254 BP 334A EP 335A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201254 ER PT J AU Qu, AJ Jiang, CT Li, F Tanaka, N Gao, B Shah, YM Gonzalez, FJ AF Qu, Aijuan Jiang, Changtao Li, Fei Tanaka, Naoki Gao, Bin Shah, Yatrik M. Gonzalez, Frank J. TI Hypoxia-inducible factor 2alpha activation disrupts cholesterol metabolism homeostasis of liver and accelerates atherosclerosis in apoE-null mice SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Qu, Aijuan; Jiang, Changtao; Li, Fei; Tanaka, Naoki; Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Shah, Yatrik M.] Univ Michigan, Sch Med, Div Gastroenterol, Dept Mol & Integrat Physiol & Internal Med, Ann Arbor, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 257 BP 336A EP 336A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201257 ER PT J AU Nelson, A Lee, YJ Heytens, L Wroblewski, S Symonds, WT McHutchison, JG Kottilil, S Osinusi, A AF Nelson, Amy Lee, Yu-Jin Heytens, Laura Wroblewski, Susan Symonds, William T. McHutchison, John G. Kottilil, Shyam Osinusi, Anu TI Impact of Pre-existing Mental Health Disorders on Adherence and Sustained Virologic Response with an Interferon-Free Trial of Sofosbuvir and Ribavirin for Chronic Hepatitis C SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Nelson, Amy; Lee, Yu-Jin; Kottilil, Shyam; Osinusi, Anu] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Osinusi, Anu] SAIC Frederick Inc, Frederick, MD USA. [Wroblewski, Susan] NIH, Clin Ctr Nursing, Bethesda, MD 20892 USA. [Heytens, Laura] NIH, CCMD, Bethesda, MD 20892 USA. [Symonds, William T.; McHutchison, John G.] Gilead Sci, Foster City, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 319 BP 364A EP 364A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201319 ER PT J AU Feng, DC Wang, Y Wang, H Liu, H Weng, HL Kong, XN Martin-Murphy, BV Li, YM Dooley, S Ju, C Gao, B AF Feng, Dechun Wang, Yan Wang, Hua Liu, Heng Weng, Honglei Kong, Xiaoni Martin-Murphy, Brittany V. Li, Yongmei Dooley, Steven Ju, Cynthia Gao, Bin TI Short-term and Long-term exposure of IL-22 show opposite effects on Acetaminophen induced liver injury SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Feng, Dechun; Wang, Yan; Wang, Hua; Li, Yongmei; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Liu, Heng; Weng, Honglei; Dooley, Steven] Heidelberg Univ, Med Clin, Fac Med Mannheim, Mannheim, Germany. [Kong, Xiaoni] Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai 200030, Peoples R China. [Kong, Xiaoni] Shanghai Jiao Tong Univ, Med X Res Inst, Shanghai 200030, Peoples R China. [Martin-Murphy, Brittany V.; Ju, Cynthia] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Aurora, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 347 BP 377A EP 377A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201347 ER PT J AU Teranishi, Y Matsubara, T Iwaisako, K Nakatani, K Le, TT Gonzalez, FJ Ikeda, K Kawada, N AF Teranishi, Yuga Matsubara, Tsutomu Iwaisako, Keiko Nakatani, Kazuki Le, Thuy T. Gonzalez, Frank J. Ikeda, Kazuo Kawada, Norifumi TI Influence of oxygen-binding cytoglobin expressed in hepatic stellate cells on acetaminophen-induced acute hepatocyte damage: In vivo and in vitro studies SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Teranishi, Yuga; Matsubara, Tsutomu; Iwaisako, Keiko; Nakatani, Kazuki; Le, Thuy T.; Ikeda, Kazuo; Kawada, Norifumi] Osaka City Univ, Osaka 558, Japan. [Gonzalez, Frank J.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 353 BP 380A EP 380A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201353 ER PT J AU Hayashi, PH Davern, TJ Fontana, RJ Chalasani, NP Stolz, A Talwalkar, JA Navarro, VJ Lee, WM Kleiner, DE Gu, JZ Hoofnagle, JH AF Hayashi, Paul H. Davern, Timothy J. Fontana, Robert J. Chalasani, Naga P. Stolz, Andrew Talwalkar, Jayant A. Navarro, Victor J. Lee, William M. Kleiner, David E. Gu, Jiezhun Hoofnagle, Jay H. TI Poor Adherence to Isoniazid (INH) Monitoring Guidelines is Common in Cases of INH Hepatotoxicity and Associated with More Severe Liver Injury: Experience of The Drug Induced Liver Injury Network (DILIN) SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Hayashi, Paul H.] Univ N Carolina, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. [Davern, Timothy J.] Calif Pacific Med Ctr, Div Gastroenterol, San Francisco, CA USA. [Fontana, Robert J.] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Chalasani, Naga P.] Indiana Univ Sch Med, Div Gastroenterol, Indianapolis, IN 46202 USA. [Stolz, Andrew] Univ So Calif, Div Gastroenterol, Los Angeles, CA USA. [Talwalkar, Jayant A.] Mayo Clin, Div Gastroenterol, Rochester, MN USA. [Navarro, Victor J.] Albert Einstein Med Ctr, Div Gastroenterol, Philadelphia, PA 19141 USA. [Lee, William M.] Southwestern Univ, Div Gastroenterol, Dallas, TX USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Gu, Jiezhun] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Hoofnagle, Jay H.] NIDDK, Liver Dis Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 355 BP 381A EP 381A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201355 ER PT J AU Halegoua-De Marzio, D Vega, M Weber, JS Aithal, GP Andrade, RJ Bessone, F Bjornsson, E Bjornsson, HK Larrey, DG Lizarzabal, M Lucena, MI Caliz, IM Mengual, E Olafsson, S Ripault, MP Seeff, LB Serrano, J Shouval, D Stephens, C Stickel, F Navarro, VJ AF Halegoua-De Marzio, Dina Vega, Maricruz Weber, Joel Schifter Aithal, Guruprasad P. Andrade, Raul J. Bessone, Fernando Bjornsson, Einar Bjornsson, Helgi K. Larrey, Dominique G. Lizarzabal, Maribel Lucena, M. I. Medina Caliz, Inmaculada Mengual, Edgardo Olafsson, Sigurdur Ripault, Marie-Pierre Seeff, Leonard B. Serrano, Jose Shouval, Daniel Stephens, C. Stickel, Felix Navarro, Victor J. TI An International Effort to Assess Hepatotoxicity Associated with Some Herbalife (R) Products SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Vega, Maricruz; Weber, Joel Schifter; Navarro, Victor J.] Albert Einstein Med Ctr, Philadelphia, PA 19141 USA. [Halegoua-De Marzio, Dina] Thomas Jefferson Unviers Hosp, Philadelphia, PA USA. [Aithal, Guruprasad P.] Univ Nottingham, Nottingham NG7 2RD, England. [Andrade, Raul J.; Lucena, M. I.; Medina Caliz, Inmaculada; Stephens, C.] Univ Malaga, E-29071 Malaga, Spain. [Bessone, Fernando] Univ Nacl Rosario, Sch Med, RA-2000 Rosario, Santa Fe, Argentina. [Bjornsson, Einar; Bjornsson, Helgi K.; Olafsson, Sigurdur] Landspitali Univ Hosp, Reykjavik, Iceland. [Larrey, Dominique G.; Ripault, Marie-Pierre] St Eloi Hosp, Montpellier, France. [Lizarzabal, Maribel; Mengual, Edgardo] Univ Hosp Maracaibo, Maracaibo, Venezuela. [Seeff, Leonard B.] Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Serrano, Jose] NIDDK, Bethesda, MD 20892 USA. [Shouval, Daniel] Hadassah Univ Hosp, IL-91120 Jerusalem, Israel. [Stickel, Felix] Univ Bern, Bern, Switzerland. NR 0 TC 4 Z9 4 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 360 BP 383A EP 384A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252201360 ER PT J AU Koshiol, J Kemp, TJ Castro, FA Gao, YT Nogueira, L Rashid, A Hsing, AW Hildesheim, A Pfeiffer, RM Pinto, L AF Koshiol, Jill Kemp, Troy J. Castro, Felipe A. Gao, Yu-Tang Nogueira, Leticia Rashid, Asif Hsing, Ann W. Hildesheim, Allan Pfeiffer, Ruth M. Pinto, Ligia TI Association of Immune-related Markers in Bile and Serum with Gallbladder Cancer SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Koshiol, Jill; Castro, Felipe A.; Nogueira, Leticia; Hildesheim, Allan; Pfeiffer, Ruth M.] NCI, Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kemp, Troy J.; Pinto, Ligia] SAIC Frederick Inc, HPV Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Rashid, Asif] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Hsing, Ann W.] Canc Prevent Inst Calif, Fremont, CA USA. [Hsing, Ann W.] Stanford Canc Inst, Palo Alto, CA USA. RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 506 BP 451A EP 451A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202110 ER PT J AU Wang, Y Feng, DC Wang, H Xu, MJ Park, O Li, YM Gao, B AF Wang, Yan Feng, Dechun Wang, Hua Xu, Ming-Jiang Park, Ogyi Li, Yongmei Gao, Bin TI IL-12/STAT4 plays a protective role in Con A induced T cell-mediated hepatitis SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Wang, Yan; Feng, Dechun; Wang, Hua; Xu, Ming-Jiang; Park, Ogyi; Li, Yongmei; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Wang, Yan] Peking Univ, Dept Infect Dis, Hosp 1, Beijing 100871, Peoples R China. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 507 BP 452A EP 452A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202111 ER PT J AU Puentes, YM Powell, CC Yerges-Armstrong, LM Feitosa, MF Bielak, LF Smith, AV Harris, TB Liu, JK Musani, SK Borecki, IB Peyser, PA Speliotes, EK AF Puentes, Yindra M. Powell, Corey C. Yerges-Armstrong, Laura M. Feitosa, Mary F. Bielak, Lawrence F. Smith, Albert V. Harris, Tamara B. Liu, Jiankang Musani, Solomon K. Borecki, Ingrid B. Peyser, Patricia A. Speliotes, Elizabeth K. TI A novel method using gene set enrichment based on human genome-wide association study data implicates FXR/RXR activation as a common pathway affecting blood lipids levels and nonalcoholic fatty liver disease SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Puentes, Yindra M.; Powell, Corey C.; Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Puentes, Yindra M.; Powell, Corey C.; Speliotes, Elizabeth K.] Div Gastroenterol, Ann Arbor, MI USA. [Puentes, Yindra M.; Powell, Corey C.; Speliotes, Elizabeth K.] Univ Michigan, Ann Arbor, MI 48109 USA. [Yerges-Armstrong, Laura M.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Bielak, Lawrence F.; Peyser, Patricia A.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Smith, Albert V.] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Liu, Jiankang; Musani, Solomon K.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. RI Feitosa, Mary/K-8044-2012 OI Feitosa, Mary/0000-0002-0933-2410 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 560 BP 475A EP 475A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202164 ER PT J AU Xanthakos, SA Wilson, TP Kleiner, DE Jenkins, TM Mourya, R Brandt, ML Harmon, CM Helmrath, MA Michalsky, M Courcoulas, AP Zeller, MH Inge, TH AF Xanthakos, Stavra A. Wilson, Tawny P. Kleiner, David E. Jenkins, Todd M. Mourya, Reena Brandt, Mary L. Harmon, Carroll M. Helmrath, Michael A. Michalsky, Marc Courcoulas, Anita P. Zeller, Meg H. Inge, Thomas H. TI Prevalence and determinants of nonalcoholic steatohepatitis (NASH) in a multicenter cohort of severely obese adolescents undergoing weight loss surgery SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Xanthakos, Stavra A.; Mourya, Reena] Cincinnati Childrens Hosp Med Ctr, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA. [Wilson, Tawny P.; Jenkins, Todd M.; Helmrath, Michael A.; Inge, Thomas H.] Cincinnati Childrens Hosp Med Ctr, Div Pediat Surg, Cincinnati, OH 45229 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Brandt, Mary L.] Texas Childrens Hosp, Baylor Coll Med, Div Pediat Surg, Houston, TX 77030 USA. [Harmon, Carroll M.] Univ Alabama Birmingham, Childrens Hosp Alabama, Div Pediat Surg, Birmingham, AL USA. [Michalsky, Marc] Nationwide Childrens Hosp, Ohio State Coll Med, Div Pediat Surg, Columbus, OH USA. [Courcoulas, Anita P.] Univ Pittsburgh, Dept Surg, Med Ctr, Pittsburgh, PA USA. [Zeller, Meg H.] Cincinnati Childrens Hosp Med Ctr, Div Behav Med, Cincinnati, OH 45229 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 567 BP 478A EP 479A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202171 ER PT J AU Kleiner, DE Belt, PH Wilson, L Brunt, EM Guy, CD Yeh, MM Kowdley, KV Sanyal, AJ Neuschwander-Tetri, BA AF Kleiner, David E. Belt, Patricia H. Wilson, Laura Brunt, Elizabeth M. Guy, Cynthia D. Yeh, Matthew M. Kowdley, Kris V. Sanyal, Arun J. Neuschwander-Tetri, Brent A. TI Natural History of Non-alcoholic Fatty Liver Disease in Adults: A Paired Biopsy Study from the NASH CRN SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Belt, Patricia H.; Wilson, Laura] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Brunt, Elizabeth M.] Washington Univ, St Louis, MO USA. [Guy, Cynthia D.] Duke Univ, Durham, NC USA. [Yeh, Matthew M.] Univ Washington, Seattle, WA 98195 USA. [Kowdley, Kris V.] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Sanyal, Arun J.] Virginia Commonwealth Univ, Richmond, VA USA. [Neuschwander-Tetri, Brent A.] St Louis Univ, St Louis, MO 63103 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 577 BP 483A EP 483A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202181 ER PT J AU Mellinger, J Pencina, KM Massaro, JM Hoffmann, U Seshadri, S Fox, CS O'Donnell, CJ Speliotes, EK AF Mellinger, Jessica Pencina, Karol M. Massaro, Joseph M. Hoffmann, Udo Seshadri, Sudha Fox, Caroline S. O'Donnell, Christopher J. Speliotes, Elizabeth K. TI Nonalcoholic Fatty Liver Disease Associates with Cardiovascular Disease Outcomes: The Framingham Heart Study SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Mellinger, Jessica; Speliotes, Elizabeth K.] Univ Michigan, Ann Arbor, MI 48109 USA. [Pencina, Karol M.] Boston Univ, Stat & Consulting Unit, Boston, MA 02215 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA USA. [Seshadri, Sudha] Boston Univ, Boston, MA 02215 USA. [Seshadri, Sudha; Fox, Caroline S.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Framingham, MA USA. [Speliotes, Elizabeth K.] Univ Michigan Hosp, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 579 BP 484A EP 485A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202183 ER PT J AU DiStefano, J Kingsley, C Still, CD Done, SC Gerhard, G Kleiner, DE AF DiStefano, Johanna Kingsley, Christopher Still, Christopher D. Done, Stefania Cotta Gerhard, Glenn Kleiner, David E. TI Genome-wide analysis identifies loci associated with total bilirubin levels, steatosis, and mild fibrosis in nonalcoholic fatty liver disease SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [DiStefano, Johanna; Kingsley, Christopher; Done, Stefania Cotta] Translat Genom Res Inst, Phoenix, AZ USA. [Gerhard, Glenn] Penn State Univ, Coll Med, Hershey, PA USA. [Still, Christopher D.; Gerhard, Glenn] Geisinger Hlth Syst, Danville, PA USA. [Kleiner, David E.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 588 BP 488A EP 489A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202192 ER PT J AU Nelson, JE Kleiner, DE Aouizerat, BE Kowdley, KV AF Nelson, James E. Kleiner, David E. Aouizerat, Bradley E. Kowdley, Kris V. TI Variants in the Il6 and Il1 beta Genes either Alone or in Combination with C282Y HFE Mutations Modify the Hepatic Iron Phenotype of Patients with Nonalcoholic Fatty Liver Disease SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Nelson, James E.; Kowdley, Kris V.] Benaroya Res Inst, Seattle, WA USA. [Nelson, James E.; Kowdley, Kris V.] Virginia Mason Med Ctr, Liver Ctr Excellence, Digest Dis Inst, Seattle, WA 98101 USA. [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Aouizerat, Bradley E.] UCSF, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 591 BP 490A EP 490A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202195 ER PT J AU Brunt, EM Belt, PH Wilson, L Guy, CD Yeh, MM Kowdley, KV Sanyal, AJ Neuschwander-Tetri, BA Kleiner, DE AF Brunt, Elizabeth M. Belt, Patricia H. Wilson, Laura Guy, Cynthia D. Yeh, Matthew M. Kowdley, Kris V. Sanyal, Arun J. Neuschwander-Tetri, Brent A. Kleiner, David E. TI Progression to bridging fibrosis in non-alcoholic fatty liver disease over 4 years in the NASH CRN SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Brunt, Elizabeth M.] Washington Univ, Sch Med, St Louis, MO USA. [Belt, Patricia H.; Wilson, Laura] Johns Hopkins, Epidemiol, Baltimore, MD USA. [Guy, Cynthia D.] Duke Univ, Durham, NC USA. [Yeh, Matthew M.] Univ Washington, Seattle, WA 98195 USA. [Kowdley, Kris V.] Virginia Mason Med Ctr, Inst Digest Dis, Seattle, WA 98101 USA. [Sanyal, Arun J.] Virginia Commonwealth, Internal Med, Richmond, VA USA. [Neuschwander-Tetri, Brent A.] St Louis Univ, St Louis, MO 63103 USA. [Kleiner, David E.] NCI, Pathol Labs, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 602 BP 495A EP 496A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202206 ER PT J AU Samala, N May, KP Kleiner, DE Loomba, R Terrault, N Neuschwander-Tetri, BA Hoofnagle, JH AF Samala, Niharika May, Kevin P. Kleiner, David E. Loomba, Rohit Terrault, Norah Neuschwander-Tetri, Brent A. Hoofnagle, Jay H. TI Normal Weight Nonalcoholic Steatohepatitis (NASH) SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Samala, Niharika] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [May, Kevin P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Loomba, Rohit] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Terrault, Norah] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Neuschwander-Tetri, Brent A.] St Louis Univ, Dept Internal Med, St Louis, MO 63103 USA. [Hoofnagle, Jay H.] NIDDK, Liver Dis Res Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 601 BP 495A EP 495A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202205 ER PT J AU Khalili, M Sanyal, AJ Cloonan, YK Ghany, MG Kim, WR Chung, RT Terrault, N Brunt, EM Lau, D Lisker-Melman, M Lok, AS AF Khalili, Mandana Sanyal, Arun J. Cloonan, Yona K. Ghany, Marc G. Kim, W. Ray Chung, Raymond T. Terrault, Norah Brunt, Elizabeth M. Lau, Daryl Lisker-Melman, Mauricio Lok, Anna S. TI Factors associated with diabetes and prediabetes in HBV-infected patients residing in North America: Results from the Adult Cohort Study of the NIDDK-Sponsored Hepatitis B Research Network (HBRN) SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Khalili, Mandana; Terrault, Norah] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Sanyal, Arun J.] Virginia Commonwealth Univ, Richmond, VA USA. [Cloonan, Yona K.] Univ Pittsburgh, Pittsburgh, PA USA. [Ghany, Marc G.] NIH, Bethesda, MD 20892 USA. [Kim, W. Ray] Mayo Clin, Bethesda, MD USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Brunt, Elizabeth M.; Lisker-Melman, Mauricio] Washington Univ, St Louis, MO USA. [Lau, Daryl] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Lok, Anna S.] Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 638 BP 513A EP 513A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202242 ER PT J AU Kowdley, KV Kleiner, DE Wilson, L Belt, PH Nelson, JE AF Kowdley, Kris V. Kleiner, David E. Wilson, Laura Belt, Patricia H. Nelson, James E. TI Reticuloendothelial Cell System Iron Staining is a Predictor of Progression to Borderline or Definite Steatohepatitis in Patients without Fibrosis SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Kowdley, Kris V.; Nelson, James E.] Virginia Mason Med Ctr, Inst Digest Dis, Liver Ctr Excellence, Seattle, WA 98101 USA. [Kowdley, Kris V.; Nelson, James E.] Benaroya Res Inst, Seattle, WA USA. [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Wilson, Laura; Belt, Patricia H.] Johns Hopkins, Bloomberg Sch Publ Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 644 BP 516A EP 516A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202248 ER PT J AU Guillen, MJ Martinez, AF Lipinski, R Solomon, B Everson, JL Trivedi, NS Elkahloun, AG Bataller, R Sulik, K Muenke, M AF Guillen, Maria J. Martinez, Ariel F. Lipinski, Robert Solomon, Benjamin Everson, Joshua L. Trivedi, Niraj S. Elkahloun, Abdel G. Bataller, Ramon Sulik, Kathleen Muenke, Maximilian TI Heterozygous Mutations Affecting the Sonic Hedgehog Pathway Predispose to Non-Alcoholic Fatty Liver Disease SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Guillen, Maria J.; Martinez, Ariel F.; Solomon, Benjamin; Muenke, Maximilian] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Trivedi, Niraj S.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Elkahloun, Abdel G.] NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. [Lipinski, Robert] Univ Wisconsin, Sch Vet Med, Dept Comparat Biosci, Madison, WI 53706 USA. [Everson, Joshua L.; Sulik, Kathleen] Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC USA. [Bataller, Ramon] Univ N Carolina, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 663 BP 524A EP 525A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202267 ER PT J AU Horiguchi, N Takizawa, D Kakizaki, S Tojima, H Hashizume, H Yamazaki, Y Sato, K Gao, B Mori, M AF Horiguchi, Norio Takizawa, Daichi Kakizaki, Satoru Tojima, Hiroki Hashizume, Hiroaki Yamazaki, Yuichi Sato, Ken Gao, Bin Mori, Masatomo TI Macrophage migration inhibitory factor (MIF) attenuates hepatic steatosis and fibrosis but accelarates liver tumors development in murine NAFLD model SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Horiguchi, Norio; Takizawa, Daichi; Kakizaki, Satoru; Tojima, Hiroki; Hashizume, Hiroaki; Yamazaki, Yuichi; Sato, Ken; Mori, Masatomo] Gunma Grad Univ, Sch Med, Dept Med & Mol Sci, Maebashi, Gunma, Japan. [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 675 BP 530A EP 530A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202279 ER PT J AU Das, S Seth, RK Kumar, A Kadiiska, MB Michelotti, GA Diehl, AM Chatterjee, S AF Das, Suvarthi Seth, Ratanesh K. Kumar, Ashutosh Kadiiska, Maria B. Michelotti, Gregory A. Diehl, Anna Mae Chatterjee, Saurabh TI Purinergic Receptor X7 is a Key Modulator of Metabolic Oxidative Stress - Mediated Autophagy and Inflammation in Experimental Nonalcoholic Steatohepatitis SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Das, Suvarthi; Seth, Ratanesh K.; Chatterjee, Saurabh] Univ S Carolina, Columbia, SC 29208 USA. [Kumar, Ashutosh; Kadiiska, Maria B.] NIEHS, Free Radical Metab Grp, Res Triangle Pk, NC 27709 USA. [Michelotti, Gregory A.; Diehl, Anna Mae] Duke Univ, Div Gastroenterol, Durham, NC USA. RI Seth, Ratanesh/M-3700-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 693 BP 538A EP 538A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202297 ER PT J AU Seth, RK Das, S Kumar, A Chanda, A Kadiiska, MB Michelotti, GA Diehl, AM Chatterjee, S AF Seth, Ratanesh K. Das, Suvarthi Kumar, Ashutosh Chanda, Anindya Kadiiska, Maria B. Michelotti, Gregory A. Diehl, Anna Mae Chatterjee, Saurabh TI CYP2E1-dependent and Leptin-induced CD57-positive cytotoxic T cells are crucial for progression of nonalcoholic steatohepatitis SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Seth, Ratanesh K.; Das, Suvarthi; Chanda, Anindya; Chatterjee, Saurabh] Univ S Carolina, Columbia, SC 29208 USA. [Kumar, Ashutosh; Kadiiska, Maria B.] NIEHS, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Michelotti, Gregory A.; Diehl, Anna Mae] Duke Univ, Div Gastroenterol, Durham, NC USA. RI Seth, Ratanesh/M-3700-2016 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 692 BP 538A EP 538A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202296 ER PT J AU Bettermann, K Mehta, AK Lederer, E Ernst, C Kessler, SM Chen, XT Hoshida, Y Bardeesy, N Fuchs, BC Tanabe, KK Muller, H Svendova, V Schimek, MG Mach, M Speicher, MR Mahajan, V Stumptner, C Thueringer, A Stojakovic, T Longerich, T Schirmacher, P Magin, TM Strnad, P Fuchs, CD Trauner, M Spilka, R Kiemer, AK Teufel, A Maass, T Moriggl, R Campbell, JS Thorgeirsson, SS Stauffer, J Karin, M Llovet, JM Zatloukal, K Lackner, C Hayback, J AF Bettermann, Kira Mehta, Anita Kuldeep Lederer, Eva Ernst, Christina Kessler, Sonja M. Chen, Xintong Hoshida, Yujin Bardeesy, Nabeel Fuchs, Bryan C. Tanabe, Kenneth K. Mueller, Heimo Svendova, Vendula Schimek, Michael G. Mach, Monika Speicher, Michael R. Mahajan, Vineet Stumptner, Cornelia Thueringer, Andrea Stojakovic, Tatjana Longerich, Thomas Schirmacher, Peter Magin, Thomas M. Strnad, Pavel Fuchs, Claudia D. Trauner, Michael Spilka, Rita Kiemer, Alexandra K. Teufel, Andreas Maass, Thorsten Moriggl, Richard Campbell, Jean S. Thorgeirsson, Snorri S. Stauffer, Jim Karin, Michael Llovet, Josep M. Zatloukal, Kurt Lackner, Carolin Haybaeck, Johannes TI Steatohepatitits-associated Hepatocellular Carcinoma: Evidence of a Keratinopathy SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Bettermann, Kira; Mehta, Anita Kuldeep; Lederer, Eva; Ernst, Christina; Kessler, Sonja M.; Mueller, Heimo; Mahajan, Vineet; Stumptner, Cornelia; Thueringer, Andrea; Zatloukal, Kurt; Lackner, Carolin; Haybaeck, Johannes] Med Univ Graz, Inst Pathol, Graz, Austria. [Kessler, Sonja M.; Kiemer, Alexandra K.] Univ Saarland, Dept Pharm, Saarbrucken, Germany. [Chen, Xintong; Hoshida, Yujin; Llovet, Josep M.] Icahn Sch Med Mt Sinai, Div Liver Dis, Tisch Canc Inst, Liver Canc Program, New York, NY USA. [Bardeesy, Nabeel; Fuchs, Bryan C.; Tanabe, Kenneth K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res, Boston, MA USA. [Svendova, Vendula; Schimek, Michael G.] Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria. [Mach, Monika; Speicher, Michael R.] Med Univ Graz, Inst Human Genet, Graz, Austria. [Stojakovic, Tatjana] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Longerich, Thomas; Schirmacher, Peter] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany. [Magin, Thomas M.] Univ Leipzig, Translat Ctr Regenerat Med Leipzig, D-04109 Leipzig, Germany. [Strnad, Pavel] Univ Hosp RWTH Aachen, Dept Internal Med 3, Aachen, Germany. [Fuchs, Claudia D.; Trauner, Michael] Med Univ Vienna, Dept Internal Med 3, Div Gastroenterol & Hepatol, Vienna, Austria. [Spilka, Rita] Gen Hosp Zams, Pathol Lab, Zams, Austria. [Teufel, Andreas; Maass, Thorsten] Univ Clin Regensburg, Clin & Polyclin Internal Med 1, Regensburg, Germany. [Moriggl, Richard] Ludwig Boltzmann Inst Canc Res LBI CR, Vienna, Austria. [Campbell, Jean S.] Univ Washington, Dept Med Pathol, Seattle, WA 98195 USA. [Thorgeirsson, Snorri S.] NCI, Lab Expt Carcinogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Cologne, Inst Genet, Cologne, Germany. [Stauffer, Jim] NCI, Mouse Canc Genet Program, Genet Modifiers Tumorigenesis Sect, Ctr Canc Res, Frederick, MD 21701 USA. [Karin, Michael] Univ Calif San Diego, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA. [Llovet, Josep M.] Hosp Clin Barcelona, Inst Invest Biomed, CIBERehd,Liver Unit, Hepatocellular Carcinoma Translat Res Lab,Barcelo, Barcelona, Spain. RI Kiemer, Alexandra/I-9300-2012 OI Kiemer, Alexandra/0000-0002-7224-9900 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 702 BP 543A EP 543A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252202306 ER PT J AU Lai, GY Weinstein, SJ Albanes, D Taylor, PR Virtamo, J McGlynn, KA Freedman, ND AF Lai, Gabriel Y. Weinstein, Stephanie J. Albanes, Demetrius Taylor, Philip R. Virtamo, Jarmo McGlynn, Katherine A. Freedman, Neal D. TI Association of serum alpha-tocopherol, beta-carotene and retinol with subsequent liver cancer incidence and chronic liver disease mortality in the ATBC Study SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Lai, Gabriel Y.; Weinstein, Stephanie J.; Albanes, Demetrius; Taylor, Philip R.; McGlynn, Katherine A.; Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lai, Gabriel Y.] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. RI Albanes, Demetrius/B-9749-2015; Freedman, Neal/B-9741-2015 OI Freedman, Neal/0000-0003-0074-1098 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 842 BP 607A EP 607A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252203010 ER PT J AU Werner, JM Abdalla, A Gara, N Ghany, MG Rehermann, B AF Werner, Jens M. Abdalla, Adil Gara, Naveen Ghany, Marc G. Rehermann, Barbara TI Innate And Adaptive Immune Responses Correlate to Antibody Recall Responses to Hepatitis B Booster Vaccination SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Werner, Jens M.; Abdalla, Adil; Gara, Naveen; Ghany, Marc G.; Rehermann, Barbara] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 855 BP 612A EP 613A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252203023 ER PT J AU Abdalla, A Loria, A Zhao, XC Trenbeath, J Liang, TJ Hoofnagle, JH Ghany, MG AF Abdalla, Adil Loria, Anthony Zhao, Xiongce Trenbeath, Joni Liang, T. Jake Hoofnagle, Jay H. Ghany, Marc G. TI Loss Of HBsAg Following Spontaneous Versus Treatment-Induced Clearance Of HBeAg In United States Patients With Chronic Hepatitis B SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Abdalla, Adil; Loria, Anthony; Zhao, Xiongce; Trenbeath, Joni; Liang, T. Jake; Hoofnagle, Jay H.; Ghany, Marc G.] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 883 BP 627A EP 627A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252203051 ER PT J AU Evon, DM Wahed, AS Johnson, G Khalili, M Lisker-Melman, M Hoofnagle, JH AF Evon, Donna M. Wahed, Abdus S. Johnson, Geoffrey Khalili, Mandana Lisker-Melman, Mauricio Hoofnagle, Jay H. TI Fatigue in Patients with Chronic Hepatitis B Not on Treatment from the US and Canada: Preliminary Results from the Hepatitis B Research Network (HBRN) SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Evon, Donna M.] Univ N Carolina, Chapel Hill, NC USA. [Wahed, Abdus S.; Johnson, Geoffrey] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Khalili, Mandana] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lisker-Melman, Mauricio] Washington Univ, St Louis, MO USA. [Hoofnagle, Jay H.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 891 BP 630A EP 631A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252203059 ER PT J AU Melis, M Diaz, G Kleiner, DE Lai, JP Zamboni, F Mogavero, G Tice, AB Hanson, J Rodriguez-Canales, J Emmert-Buck, MR Farci, P AF Melis, Marta Diaz, Giacomo Kleiner, David E. Lai, Jinping Zamboni, Fausto Mogavero, Giulia Tice, Ashley B. Hanson, Jeffrey Rodriguez-Canales, Jaime Emmert-Buck, Michael R. Farci, Patrizia TI HBV-Associated Hepatocellular Carcinoma (HCC): Gene Expression Profiling of Microdissected Hepatocytes Versus Whole Liver Tissue SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Melis, Marta; Tice, Ashley B.; Farci, Patrizia] NIAID, Hepat Pathogenesis Sect, Lab Infect Dis, NIH, Bethesda, MD 20892 USA. [Diaz, Giacomo] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy. [Kleiner, David E.; Lai, Jinping] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Zamboni, Fausto; Mogavero, Giulia] Hosp Brotzu, Liver Transplantat Ctr, Cagliari, Italy. [Hanson, Jeffrey; Rodriguez-Canales, Jaime; Emmert-Buck, Michael R.] NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 899 BP 634A EP 635A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252203067 ER PT J AU Hassan, MA Smith, C Li, RS Fried, MW Sterling, RK Ghany, MG Wahed, AS Kim, WR AF Hassan, Mohamed A. Smith, Coleman Li, Ruosha Fried, Michael W. Sterling, Richard K. Ghany, Marc G. Wahed, Abdus S. Kim, W. Ray TI Differences in Epidemiological and Clinical Characteristics in US-versus foreign-born Americans of African Descent with Chronic Hepatitis B Enrolled in the HBRN Cohort SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Kim, W. Ray] Mayo Clin, Coll Med, Rochester, MN USA. [Hassan, Mohamed A.; Smith, Coleman] Univ Minnesota, Minneapolis, MN USA. [Fried, Michael W.] Univ N Carolina, Chapel Hill, NC USA. [Sterling, Richard K.] Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. [Ghany, Marc G.] NIH, Bethesda, MD 20892 USA. [Li, Ruosha; Wahed, Abdus S.] Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 900 BP 635A EP 635A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252203068 ER PT J AU Guedj, J Rotman, Y Cotler, S Schmid, P Albrecht, J Haynes-Williams, V Liang, TJ Hoofnagle, JH Heller, T Dahari, H AF Guedj, Jeremie Rotman, Yaron Cotler, Scott Schmid, Peter Albrecht, Jeff Haynes-Williams, Vanessa Liang, T. Jake Hoofnagle, Jay H. Heller, Theo Dahari, Harel TI Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Guedj, Jeremie; Dahari, Harel] Los Alamos Natl Lab, Los Alamos, NM USA. [Guedj, Jeremie] Univ Paris Diderot, INSERM, UMR 738, F-75018 Paris, France. [Rotman, Yaron; Haynes-Williams, Vanessa; Liang, T. Jake; Hoofnagle, Jay H.; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Cotler, Scott; Dahari, Harel] Loyola Univ, Med Ctr, Dept Med, Div Hepatol, Maywood, IL 60153 USA. [Schmid, Peter; Albrecht, Jeff] Natl Inst Genet, Los Alamos, NM USA. RI Guedj, Jeremie/A-6842-2017 OI Guedj, Jeremie/0000-0002-5534-5482 NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 998 BP 688A EP 689A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252203165 ER PT J AU Tana, MM Shums, Z Milo, J Norman, GL Leung, PS Gershwin, ME Kleiner, DE Noureddin, M Zhao, XC Heller, T Hoofnagle, JH AF Tana, Michele M. Shums, Zakera Milo, Jay Norman, Gary L. Leung, Patrick S. Gershwin, M. Eric Kleiner, David E. Noureddin, Mazen Zhao, Xiongce Heller, Theo Hoofnagle, Jay H. TI The Significance of Autoantibody Changes Over Time in Primary Biliary Cirrhosis SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Tana, Michele M.; Noureddin, Mazen; Heller, Theo; Hoofnagle, Jay H.] NIDDK, Liver Dis Branch, Bethesda, MD 20892 USA. [Shums, Zakera; Milo, Jay; Norman, Gary L.] Inova Diagnost Inc, San Diego, CA USA. [Leung, Patrick S.; Gershwin, M. Eric] Univ Calif Davis, Div Rheumatol Allergy, Davis, CA 95616 USA. [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDK, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1192 BP 790A EP 790A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252203358 ER PT J AU Bertola, A Xu, MJ Deng, CX Gao, B AF Bertola, Adeline Xu, Ming-Jiang Deng, Chuxia Gao, Bin TI Hepatocyte- and myeloid cell-specific deletion of Sirtuin-6 prevents alcohol-induced hepatocellular damage in mice SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Bertola, Adeline; Xu, Ming-Jiang; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Deng, Chuxia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1280 BP 830A EP 830A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204064 ER PT J AU Xu, MJ Cai, Y Wang, H Bertola, A Lu, J Bataller, R Gao, B AF Xu, Ming-Jiang Cai, Yan Wang, Hua Bertola, Adeline Lu, Jim Bataller, Ramon Gao, Bin TI Long-term plus singe binge ethanol feeding induces severe steatohepatitis in mice: a novel model of human alcoholic hepatitis SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Xu, Ming-Jiang; Wang, Hua; Bertola, Adeline; Gao, Bin] NIAAA, NIH, Bethesda, MD USA. [Cai, Yan] NCI, NIH, Bethesda, MD 20892 USA. [Lu, Jim] GoPath Diagnost LLC, Chicago, IL USA. [Bataller, Ramon] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1284 BP 832A EP 832A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204068 ER PT J AU Mathews, S Feng, DC Gao, B AF Mathews, Stephanie Feng, Dechun Gao, Bin TI Natural killer T cells play an important role SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Mathews, Stephanie; Feng, Dechun; Gao, Bin] NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1293 BP 836A EP 836A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204077 ER PT J AU Kwon, HJ Won, YS Park, O Duryee, MJ Thiele, G Matsumoto, A Singh, S Kawamoto, T Abdelmegeed, MA Song, BJ Vasiliou, V Thiele, GM Gao, B AF Kwon, Hyo-Jung Won, Young-Suk Park, Ogyi Duryee, Michael J. Thiele, Geoffrey Matsumoto, Akiko Singh, Surendra Kawamoto, Toshihiro Abdelmegeed, Mohamed A. Song, Byoung-Joon Vasiliou, Vasilis Thiele, Geoffrey M. Gao, Bin TI Aldehyde dehydrogenase 2 deficiency ameliorates alcoholic fatty liver but exacerbates liver inflammation and fibrosis in mice SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Kwon, Hyo-Jung; Won, Young-Suk; Park, Ogyi; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Duryee, Michael J.; Thiele, Geoffrey; Thiele, Geoffrey M.] Omaha VA Med Ctr, Expt Immunol Lab, Omaha, NE USA. [Duryee, Michael J.; Thiele, Geoffrey; Thiele, Geoffrey M.] Univ Nebraska Med Ctr, Omaha, NE USA. [Matsumoto, Akiko; Singh, Surendra; Vasiliou, Vasilis] Univ Colorado, Dept Pharmaceut Sci, Aurora, CO USA. [Kawamoto, Toshihiro] Univ Occupat & Environm Hlth, Dept Environm Hlth, Kitakyushu, Fukuoka 807, Japan. [Abdelmegeed, Mohamed A.; Song, Byoung-Joon] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1296 BP 838A EP 838A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204080 ER PT J AU Li, YM Feng, DC Xu, MJ Wang, H Wang, Y Gao, B AF Li, Yongmei Feng, Dechun Xu, Ming-Jiang Wang, Hua Wang, Yan Gao, Bin TI Aging aggravates alcoholic liver injury in mice by downregulating hepatic Sirtuin 1 and inhibiting autophagy SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Li, Yongmei; Feng, Dechun; Xu, Ming-Jiang; Wang, Hua; Wang, Yan; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. [Li, Yongmei] Second Mil Med Univ, Dept Oncol, Changhai Hosp, Shanghai, Peoples R China. NR 0 TC 0 Z9 0 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1304 BP 841A EP 842A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204088 ER PT J AU Koh, C Uzel, G Rosenzweig, S Zhao, XC Kleiner, DE Liang, TJ Holland, SM Heller, T AF Koh, Christopher Uzel, Gulbu Rosenzweig, Sergio Zhao, Xiongce Kleiner, David E. Liang, T. Jake Holland, Steven M. Heller, Theo TI Liver Disease in X-Linked Agammaglobulinemia: A Predominance of Nodular Regenerative Hyperplasia? SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Koh, Christopher; Liang, T. Jake; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Uzel, Gulbu; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Rosenzweig, Sergio] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDK, Off Director, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1389 BP 883A EP 884A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204172 ER PT J AU Gara, N Wright, EC Sharma, NK Koh, C Kleiner, DE Sherker, AH Hoofnagle, JH Ghany, MG AF Gara, Naveen Wright, Elizabeth C. Sharma, Nalini K. Koh, Christopher Kleiner, David E. Sherker, Averell H. Hoofnagle, Jay H. Ghany, Marc G. TI Prediction of Disease Severity in Chronic Hepatitis C: Clinical Gestalt And Role of Transient Elastography SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Gara, Naveen] Georgetown Univ, Washington Hosp Ctr, Washington, DC USA. [Wright, Elizabeth C.] NIDDK, Off Director, NIH, Bethesda, MD 20892 USA. [Sharma, Nalini K.] Kaiser Permanente, Dept Gastroenterol, Bethesda, MD USA. [Gara, Naveen; Sharma, Nalini K.; Koh, Christopher; Ghany, Marc G.] NIH, Liver Dis Branch, Bethesda, MD 20892 USA. [Kleiner, David E.] NIH, Pathol Lab, Bethesda, MD 20892 USA. [Sherker, Averell H.; Hoofnagle, Jay H.] NIH, Liver Dis Res Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1461 BP 917A EP 917A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204244 ER PT J AU Li, QS Krishnamurthy, S Cha, H El-Diwany, R Chiu, S Alao, HF Liang, TJ AF Li, Qisheng Krishnamurthy, Siddharth Cha, Helen El-Diwany, Ramy Chiu, Stephan Alao, Hawwa F. Liang, T. Jake TI A genome-wide functional screen identifies the let-7 family of microRNAs as host restriction factors regulating hepatitis C virus infection SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Li, Qisheng; Krishnamurthy, Siddharth; Cha, Helen; El-Diwany, Ramy; Chiu, Stephan; Alao, Hawwa F.; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RI Li, Qisheng/K-1909-2013 NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1484 BP 927A EP 928A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204267 ER PT J AU Kirpich, I Liu, HL Falkner, KC Beier, JI Joshi-Barve, S Ramsden, C McClain, CJ Cave, MC AF Kirpich, Irina Liu, Huilin Falkner, Keith C. Beier, Juliane I. Joshi-Barve, Swati Ramsden, Christopher McClain, Craig J. Cave, Matthew C. TI Occupational Vinyl Chloride Exposures Increase Plasma Lipid Peroxidation Products (Including 13-Hode) Capable Of Causing Mitochondiral Dysfunction And Endoplasmic Reticulum Stress - Novel Modes Of Action For Toxicant Associated Steatohepatitis (TASH) SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Kirpich, Irina; Liu, Huilin; Falkner, Keith C.; Beier, Juliane I.; Joshi-Barve, Swati; McClain, Craig J.; Cave, Matthew C.] Univ Louisville, Dept Med GI, Louisville, KY 40292 USA. [McClain, Craig J.; Cave, Matthew C.] Robley Rex VAMC, Louisville, KY USA. [Ramsden, Christopher] NIEHS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1538 BP 952A EP 952A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204321 ER PT J AU Dhanda, AD Liu, BY Nussenblatt, R Lee, RW Collins, P AF Dhanda, Ashwin D. Liu, Baoying Nussenblatt, Robert Lee, Richard W. Collins, Peter TI Patients with severe alcoholic hepatitis have expanded CD14(+)CD16(+) monocytes with an anti-inflammatory phenotype SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Dhanda, Ashwin D.; Lee, Richard W.] Univ Hosp Bristol NHS Fdn Trust, Dept Liver Med, Bristol, Avon, England. [Dhanda, Ashwin D.; Collins, Peter] Univ Bristol, Sch Clin Sci, Bristol, Avon, England. [Liu, Baoying; Nussenblatt, Robert] NEI, NIH, Bethesda, MD 20892 USA. RI Lee, Richard/A-3116-2017 OI Lee, Richard/0000-0002-9480-6843 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1580 BP 970A EP 971A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204363 ER PT J AU Won, YS Kwon, HJ Park, O Feng, DC Gao, B AF Won, Young-Suk Kwon, Hyo-Jung Park, Ogyi Feng, Dechun Gao, Bin TI Prednisolone treatment delays liver repair in hepatotoxininduced hepatitis by targeting glucocorticoid receptors in macrophages and neutrophils SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Won, Young-Suk; Kwon, Hyo-Jung; Park, Ogyi; Feng, Dechun; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1579 BP 970A EP 970A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204362 ER PT J AU Carpentier, A Tesfaye, A Chu, V Major, ME Feinstone, S Liang, TJ AF Carpentier, Arnaud Tesfaye, Abeba Chu, Virginia Major, Marian E. Feinstone, Stephen Liang, T. Jake TI Engraftment and in vivo HCV infection of human hepatocytes differentiated from embryonic and induced pluripotent stem cells SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Carpentier, Arnaud; Chu, Virginia; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Tesfaye, Abeba; Major, Marian E.; Feinstone, Stephen] US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1650 BP 1003A EP 1003A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252204433 ER PT J AU Decaens, T Factor, VM Kulic, I Andersen, JB Judge, A Conner, EA MacLachlan, I Thorgeirsson, SS AF Decaens, Thomas Factor, Valentina M. Kulic, Iva Andersen, Jesper B. Judge, Adam Conner, Elizabeth A. MacLachlan, Ian Thorgeirsson, Snorri S. TI Nanoparticle based combinatorial small interfering RNA therapy against human hepatocellular carcinoma (HCC) SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Decaens, Thomas; Factor, Valentina M.; Andersen, Jesper B.; Conner, Elizabeth A.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Kulic, Iva; Judge, Adam; MacLachlan, Ian] Tekmira Pharmaceut Corp, Burnaby, BC, Canada. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1781 BP 1063A EP 1064A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252205131 ER PT J AU Katz, LH Munoz, NM Shukla, V Cortes, AC Peleg, S Shetty, K Chen, J El-Zein, R Mishra, L AF Katz, Lior H. Munoz, Nina M. Shukla, Vivek Cortes, Andrea C. Peleg, Sara Shetty, Kirti Chen, Jian El-Zein, Randa Mishra, Lopa TI Vitamin D for prevention of liver cancer in the setting of disrupted TGF-beta signaling pathway SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Katz, Lior H.; Munoz, Nina M.; Cortes, Andrea C.; Peleg, Sara; Chen, Jian; El-Zein, Randa; Mishra, Lopa] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Shukla, Vivek] NIH, Bethesda, MD 20892 USA. [Shetty, Kirti] MedStar Washington Hosp Ctr, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1819 BP 1080A EP 1081A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252205169 ER PT J AU Lu, YY Feng, F Zhang, F Gao, XD Wang, CP Chang, XJ Qu, JH Wang, H Zeng, Z Cheng, ML Yang, CZ Yang, YP AF Lu, Yin Ying Feng, Fan Zhang, Fan Gao, Xudong Wang, Chunping Chang, Xiujuan Qu, Jianhui Wang, Hong Zeng, Zhen Cheng, Mingliang Yang, Chunzhang Yang, Yongping TI A novel mechanism of PXR mediated Sorafenib drug resistance in HCC through MDR and CYP3A4 SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Lu, Yin Ying; Feng, Fan; Gao, Xudong; Wang, Chunping; Chang, Xiujuan; Qu, Jianhui; Wang, Hong; Zeng, Zhen; Yang, Yongping] Beijing 302 Hosp, Ctr Therapeut Res Hepatocarcinoma, Beijing, Peoples R China. [Zhang, Fan] Peoples Liberat Army Gen Hosp, Tumor Ctr, Beijing, Peoples R China. [Cheng, Mingliang] Guiyang Med Coll, Infect Dept, Guiyang, Peoples R China. [Yang, Chunzhang] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1826 BP 1084A EP 1084A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252205176 ER PT J AU Pfeiffer, RM Howell, CD Chen, S Wang, AS Tang, W Ryan, K Prokunina-Olsson, L O'Brien, TR AF Pfeiffer, Ruth M. Howell, Charles D. Chen, Sabrina Wang, Alan S. Tang, Wei Ryan, Kathy Prokunina-Olsson, Ludmila O'Brien, Thomas R. TI IFNL4-Delta G Genotype and Racial Differences in Treatment Response in Virahep-C SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Pfeiffer, Ruth M.; Wang, Alan S.; Tang, Wei; Prokunina-Olsson, Ludmila; O'Brien, Thomas R.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Howell, Charles D.; Ryan, Kathy] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Chen, Sabrina] Informat Management Serv Inc, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1846 BP 1093A EP 1094A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252205196 ER PT J AU Werner, JM Serti, E Chepa-Lotrea, X Stoltzfus, JD Ahlenstiel, G Feld, JJ Liang, TJ Rotman, Y Rehermann, B AF Werner, Jens M. Serti, Elisavet Chepa-Lotrea, Xenia Stoltzfus, Jonathan D. Ahlenstiel, Golo Feld, Jordan J. Liang, T. Jake Rotman, Yaron Rehermann, Barbara TI Ribavirin Resets the STAT4-Dependent IFN-gamma Responsiveness of Natural Killer Cells in Hepatitis C SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Werner, Jens M.; Serti, Elisavet; Chepa-Lotrea, Xenia; Stoltzfus, Jonathan D.; Ahlenstiel, Golo; Feld, Jordan J.; Liang, T. Jake; Rotman, Yaron; Rehermann, Barbara] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1869 BP 1106A EP 1106A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252205219 ER PT J AU Matsuura, K Iijima, S Watanabe, T Iio, E Endo, M Shinkai, N Fujiwara, K Nojiri, S Joh, T Tanaka, Y AF Matsuura, Kentaro Iijima, Sayuki Watanabe, Tsunamasa Iio, Etsuko Endo, Mio Shinkai, Noboru Fujiwara, Kei Nojiri, Shunsuke Joh, Takashi Tanaka, Yasuhito TI Suppressive genes expressions of interferon signaling pathway in peripheral blood mononuclear cells associated with IL28B genetic variants and virological response to PEG-IFN, RBV plus NS3/4 protease inhibitor SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Matsuura, Kentaro; Iijima, Sayuki; Watanabe, Tsunamasa; Iio, Etsuko; Tanaka, Yasuhito] Nagoya City Univ, Grad Sch Med Sci, Dept Virol, Nagoya, Aichi, Japan. [Matsuura, Kentaro; Iijima, Sayuki; Watanabe, Tsunamasa; Iio, Etsuko; Tanaka, Yasuhito] Nagoya City Univ, Grad Sch Med Sci, Liver Unit, Nagoya, Aichi, Japan. [Matsuura, Kentaro] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Iio, Etsuko; Endo, Mio; Shinkai, Noboru; Fujiwara, Kei; Nojiri, Shunsuke; Joh, Takashi] Nagoya City Univ, Grad Sch Med Sci, Dept Gastroenterol & Metab, Nagoya, Aichi, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1877 BP 1111A EP 1111A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252205227 ER PT J AU Harouaka, D Melis, M Tice, AB Engle, RE Wollenberg, K Zamboni, F Mogavero, G Kleiner, DE Diaz, G Farci, P AF Harouaka, Djamila Melis, Marta Tice, Ashley B. Engle, Ronald E. Wollenberg, Kurt Zamboni, Fausto Mogavero, Giulia Kleiner, David E. Diaz, Giacomo Farci, Patrizia TI Limited Hepatitis C virus (HCV) Replication and Altered Quasispecies Distribution in Tumor Tissue of Patients with Hepatocellular Carcinoma (HCC) SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Harouaka, Djamila; Melis, Marta; Tice, Ashley B.; Engle, Ronald E.; Farci, Patrizia] NIAID, Hepat Pathogenesis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Wollenberg, Kurt] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. [Zamboni, Fausto; Mogavero, Giulia] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] Brotzu Hosp, Liver Transplantat Ctr, Cagliari, Italy. [Diaz, Giacomo] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 1989 BP 1170A EP 1171A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252205339 ER PT J AU Tana, MM Zhao, XC Bradshaw, A Page, SJ Moon, MS Turner, T Rivera, EM Kleiner, DE Heller, T AF Tana, Michele M. Zhao, Xiongce Bradshaw, Alyson Page, Sandra J. Moon, Mi Sun Turner, Tiffany Rivera, Elenita M. Kleiner, David E. Heller, Theo TI Factors Associated with the Platelet Count in Patients with Chronic Hepatitis C SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Tana, Michele M.; Rivera, Elenita M.; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Bradshaw, Alyson; Page, Sandra J.; Moon, Mi Sun; Turner, Tiffany; Heller, Theo] NIDDK, Translat Hepatol Unit, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDK, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 2014 BP 1182A EP 1183A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252205364 ER PT J AU Moon, MS Bradshaw, A Koh, C Page, SJ Heller, T AF Moon, Mi Sun Bradshaw, Alyson Koh, Christopher Page, Sandra J. Heller, Theo TI Microbial Translocation in Patients with Hepatitis C Virus Infection SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Moon, Mi Sun; Bradshaw, Alyson; Koh, Christopher; Page, Sandra J.; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 2021 BP 1185A EP 1186A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252205371 ER PT J AU Wright, EC Samala, N AF Wright, Elizabeth C. Samala, Niharika TI Availability of clinical trial results in journal publications and in summaries submitted to ClinicalTrials.gov SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Wright, Elizabeth C.] NIDDK, Off Directory, NIH, Bethesda, MD 20892 USA. [Samala, Niharika] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 2047 BP 1198A EP 1198A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252205397 ER PT J AU Yamashita, T Kitao, A Matsui, O Hayashi, T Nio, K Kondo, M Okada, H Yamashita, T Mizukoshi, E Masao, H Nakanuma, Y Takamura, H Ohta, T Nakamoto, Y Yamamoto, M Takayama, T Arii, S Wang, XW Kaneko, S AF Yamashita, Taro Kitao, Azusa Matsui, Osamu Hayashi, Takehiro Nio, Kouki Kondo, Mitsumasa Okada, Hikari Yamashita, Tatsuya Mizukoshi, Eishiro Masao, Honda Nakanuma, Yasuni Takamura, Hiroyuki Ohta, Tetsuo Nakamoto, Yasunari Yamamoto, Masakazu Takayama, Tadatoshi Arii, Shigeki Wang, Xin W. Kaneko, Shuichi TI Gd-EOB-DTPA-enhanced MRI and Serum AFP Predict the Prognosis of Early-stage Hepatocellular Carcinoma SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Yamashita, Taro; Hayashi, Takehiro; Nio, Kouki; Kondo, Mitsumasa; Okada, Hikari; Yamashita, Tatsuya; Mizukoshi, Eishiro; Masao, Honda; Kaneko, Shuichi] Kanazawa Univ, Grad Sch Med Sci, Dept Gastroenterol, Kanazawa, Ishikawa, Japan. [Kitao, Azusa; Matsui, Osamu] Kanazawa Univ, Grad Sch Med Sci, Dept Radiol, Kanazawa, Ishikawa, Japan. [Nakanuma, Yasuni] Kanazawa Univ, Grad Sch Med Sci, Dept Pathol, Kanazawa, Ishikawa, Japan. [Takamura, Hiroyuki; Ohta, Tetsuo] Kanazawa Univ, Grad Sch Med Sci, Dept Gastroenterol Surg, Kanazawa, Ishikawa, Japan. [Nakamoto, Yasunari] Univ Fukui, Sch Med, Dept Internal Med 2, Fukui 910, Japan. [Yamamoto, Masakazu] Tokyo Womens Med Univ, Dept Surg, Tokyo, Japan. [Takayama, Tadatoshi] Nihon Univ, Sch Medicineers, Dept Digest Surg, Tokyo, Japan. [Arii, Shigeki] Tokyo Med & Dent Univ, Dept Hepatobiliarypancreat Surg, Tokyo, Japan. [Wang, Xin W.] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 2093 BP 1220A EP 1221A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252206045 ER PT J AU Oishi, N Ji, J Yamashita, T Ye, QH Kaneko, S Wang, XW AF Oishi, Naoki Ji, Juling Yamashita, Taro Ye, Qinghai Kaneko, Shuichi Wang, Xin W. TI Epithelial to mesenchymal transition affects the stem cell-like features of primary liver cancers SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Oishi, Naoki; Yamashita, Taro; Kaneko, Shuichi] Kanazawa Univ Hosp, Dept Gastroenterol, Kanazawa, Ishikawa, Japan. [Oishi, Naoki; Ji, Juling; Wang, Xin W.] NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Ye, Qinghai] Fudan Univ, Liver Canc Inst, Shanghai 200032, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 2111 BP 1229A EP 1229A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252206063 ER PT J AU Edlin, BR Winkelstein, ER Shu, MA Carden, MR McKnight, C Bramson, H Goli, S Busch, MP Tobler, LH Rehermann, B Jarlais, DCD Beeder, AB AF Edlin, Brian R. Winkelstein, Emily R. Shu, Marla A. Carden, Michael R. McKnight, Courtney Bramson, Heidi Goli, Srikanth Busch, Michael P. Tobler, Leslie H. Rehermann, Barbara Jarlais, Don C. Des Beeder, Ann B. TI HCV Transmission among Young IDUs in New York City: The Swan Project SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Edlin, Brian R.; Winkelstein, Emily R.; Goli, Srikanth] Natl Dev & Res Inst Inc, Inst Infect Dis, New York, NY USA. [Edlin, Brian R.; Winkelstein, Emily R.; Shu, Marla A.; Carden, Michael R.; Beeder, Ann B.] Weill Cornell Med Coll, Ctr Study Hepatitis C, New York, NY USA. [Edlin, Brian R.; Winkelstein, Emily R.; Shu, Marla A.; Carden, Michael R.; Beeder, Ann B.] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY USA. [Shu, Marla A.; McKnight, Courtney; Bramson, Heidi; Jarlais, Don C. Des] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Busch, Michael P.; Tobler, Leslie H.] Blood Syst Res Inst, San Francisco, CA USA. [Busch, Michael P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Rehermann, Barbara] NIH, Liver Dis Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 2251 BP 1296A EP 1297A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252206203 ER PT J AU Samala, N Wright, EC Vargas, V Shetty, K Reddy, R Lucey, MR Alter, HJ Ghany, MG AF Samala, Niharika Wright, Elizabeth C. Vargas, Vanessa Shetty, Kirti Reddy, Rajender Lucey, Michael R. Alter, Harvey J. Ghany, Marc G. TI Role of Hepatitis E in Decompensation Among Patients With Chronic Hepatitis C SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Samala, Niharika; Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Wright, Elizabeth C.] NIDDK, Off Director, NIH, Bethesda, MD 20892 USA. [Vargas, Vanessa; Alter, Harvey J.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Shetty, Kirti] Medstar Georgetown Univ Hosp, Dept Med, Washington, DC USA. [Reddy, Rajender] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Lucey, Michael R.] Univ Wisconsin, Dept Med, Madison, WI USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 2265 BP 1303A EP 1303A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252206217 ER PT J AU Ruhl, CE Menke, A Cowie, CC Everhart, JE AF Ruhl, Constance E. Menke, Andy Cowie, Catherine C. Everhart, James E. TI Hepatitis C Virus (HCV) Infection is Not Associated with Diabetes in the United States Population SO HEPATOLOGY LA English DT Meeting Abstract CT 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases CY NOV 01-05, 2013 CL Washington, DC SP Amer Assoc Study Liver Dis C1 [Ruhl, Constance E.; Menke, Andy] Social & Sci Syst Inc, Silver Spring, MD USA. [Cowie, Catherine C.; Everhart, James E.] NIDDKD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD OCT PY 2013 VL 58 SU 1 SI SI MA 2275 BP 1308A EP 1309A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 297JR UT WOS:000330252206227 ER PT J AU Yeung, H Takeshita, J Mehta, NN Kimmel, SE Ogdie, A Margolis, DJ Shin, DB Attor, R Troxel, AB Gelfand, JM AF Yeung, Howa Takeshita, Junko Mehta, Nehal N. Kimmel, Stephen E. Ogdie, Alexis Margolis, David J. Shin, Daniel B. Attor, Rosemary Troxel, Andrea B. Gelfand, Joel M. TI Psoriasis Severity and the Prevalence of Major Medical Comorbidity A Population-Based Study SO JAMA DERMATOLOGY LA English DT Article ID IMPROVEMENT NETWORK THIN; DIABETES-MELLITUS; VASCULAR INFLAMMATION; RHEUMATOID-ARTHRITIS; RENAL IMPAIRMENT; UNITED-KINGDOM; INCREASED RISK; CO-MORBIDITY; HEPATITIS-C; MORTALITY AB IMPORTANCE Despite the growing literature on comorbidity risks in psoriasis, there remains a critical knowledge gap on the degree to which objectively measured psoriasis severity may affect the prevalence of major medical comorbidity. OBJECTIVE To examine the prevalence of major medical comorbidity in patients with mild, moderate, or severe psoriasis, classified objectively based on body surface area involvement, compared with that in patients without psoriasis. DESIGN, SETTING, AND PARTICIPANTS Population-based cross-sectional study of patient data from United Kingdom-based electronic medical records; analysis included 9035 patients aged 25 to 64 years with psoriasis and 90 350 age-and practice-matched patients without psoriasis. MAIN OUTCOMES AND MEASURES Prevalence of major medical comorbidity included in the Charlson comorbidity index. RESULTS Among patients with psoriasis, 51.8%, 35.8%, and 12.4%, respectively, had mild, moderate, or severe disease based on body surface area criteria. The mean Charlson comorbidity index was increasingly higher in patients with mild (0.375 vs 0.347), moderate (0.398 vs 0.342), or severe psoriasis (0.450 vs 0.348) (each P < .05). Psoriasis overall was associated with higher prevalence of chronic pulmonary disease (adjusted odds ratio, 1.08; 95% CI, 1.02-1.15), diabetes mellitus (1.22; 1.11-1.35), diabetes with systemic complications (1.34; 1.11-1.62), mild liver disease (1.41; 1.12-1.76), myocardial infarction (1.34; 1.07-1.69), peptic ulcer disease (1.27; 1.03-1.58), peripheral vascular disease (1.38; 1.07-1.77), renal disease (1.28; 1.11-1.48), and rheumatologic disease (2.04; 1.71-2.42). Trend analysis revealed significant associations between psoriasis severity and each of the above comorbid diseases (each P < .05). CONCLUSIONS AND RELEVANCE The burdens of overall medical comorbidity and of specific comorbid diseases increase with increasing disease severity among patients with psoriasis. Physicians should be aware of these associations in providing comprehensive care to patients with psoriasis, especially those presenting with more severe disease. C1 [Yeung, Howa; Takeshita, Junko; Margolis, David J.; Shin, Daniel B.; Attor, Rosemary; Troxel, Andrea B.; Gelfand, Joel M.] Univ Penn, Perelman Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. [Takeshita, Junko; Kimmel, Stephen E.; Ogdie, Alexis; Margolis, David J.; Shin, Daniel B.; Troxel, Andrea B.; Gelfand, Joel M.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Mehta, Nehal N.] NHLBI, Sect Inflammat & Cardiometab Dis, NIH, Bethesda, MD 20892 USA. [Kimmel, Stephen E.] Univ Penn, Perelman Sch Med, Div Cardiol, Philadelphia, PA 19104 USA. [Ogdie, Alexis] Univ Penn, Perelman Sch Med, Div Rheumatol, Philadelphia, PA 19104 USA. RP Gelfand, JM (reprint author), Univ Penn, Perelman Sch Med, 1471 Penn Tower,1 Convent Ave, Philadelphia, PA 19104 USA. EM joel.gelfand@uphs.upenn.edu OI Ogdie, Alexis/0000-0002-4639-0775; Troxel, Andrea/0000-0002-1393-3075 FU National Institutes of Health (NIH) [T32-AR07465, T32-GM075766-6]; National Psoriasis Foundation; American College of Rheumatology; NIH [R01-HL089744] FX This study was supported by National Institutes of Health (NIH) training grants T32-AR07465 (Mr Yeung and Mr Shin) and T32-GM075766-6 (Dr Takeshita), a National Psoriasis Foundation Fellowship (Dr Takeshita), an American College of Rheumatology Investigator Award (Dr Ogdie), and NIH grant R01-HL089744 (Dr Gelfand). NR 49 TC 91 Z9 91 U1 0 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD OCT PY 2013 VL 149 IS 10 BP 1173 EP 1179 DI 10.1001/jamadermatol.2013.5015 PG 7 WC Dermatology SC Dermatology GA AA3DT UT WOS:000330973800010 PM 23925466 ER PT J AU Clifford, D McAuliffe, M Stephens, K Major, E Fox, I Milch, C Sankoh, S Provenzale, J Lev, M Freedland, E Berger, J Parikh, A AF Clifford, David McAuliffe, Megan Stephens, Kristin Major, Eugene Fox, Irving Milch, Catherine Sankoh, Serap Provenzale, James Lev, Michael Freedland, Eric Berger, Joseph Parikh, Asit TI Risk Assessment and Minimization for Progressive Multifocal Leukoencephalopathy (PML RAMP): A Program to Assess for Potential Early Signs and Symptoms of PML during Clinical Development of Vedolizumab SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 78th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 11-16, 2013 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Clifford, David] Washington Univ, Sch Med, St Louis, MO USA. [McAuliffe, Megan; Stephens, Kristin; Fox, Irving; Sankoh, Serap; Freedland, Eric] Millennium Pharmaceut Inc, Cambridge, MA USA. [Major, Eugene] NINDS, NIH, Bethesda, MD 20892 USA. [Milch, Catherine; Provenzale, James] Duke Univ, Med Ctr, Durham, NC USA. [Lev, Michael] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Berger, Joseph] Univ Kentucky, Lexington, KY USA. [Parikh, Asit] Takeda Pharmaceut Int Inc, Deerfield, IL USA. NR 0 TC 3 Z9 3 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2013 VL 108 SU 1 MA 1673 BP S502 EP S502 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 296II UT WOS:000330178102007 ER PT J AU Kotlyar, D Lewis, J Tierney, A Brensinger, C Beaugerie, L Loftus, E Blonski, W Van Domselaar, M Chaparro, M Sandilya, S Lichtenstein, G AF Kotlyar, David Lewis, James Tierney, Ann Brensinger, Colleen Beaugerie, Laurent Loftus, Edward Blonski, Wojciech Van Domselaar, Manuel Chaparro, Maria Sandilya, Sandipani Lichtenstein, Gary TI A Meta-analysis of Risk of Lymphoma in IBD Patients: A Comparison between Patients Actively Using Thiopurines and Those with Past Use SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 78th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 11-16, 2013 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Kotlyar, David] NCI, NIH, Bethesda, MD 20892 USA. [Lichtenstein, Gary] Univ Penn, Div Gastroenterol, Philadelphia, PA 19104 USA. [Chaparro, Maria] La Princesa Univ Hosp, Madrid, Spain. [Lewis, James; Tierney, Ann; Brensinger, Colleen] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Van Domselaar, Manuel] Hosp Ramon & Cajal, E-28034 Madrid, Spain. [Blonski, Wojciech] SUNY Upstate Binghamton, Dept Med, Binghamton, NY USA. [Sandilya, Sandipani] Yale Univ, Dept Med, New Haven, CT 06520 USA. [Beaugerie, Laurent] Univ Paris 06, Hop St Antoine, AP HP, Paris, France. [Loftus, Edward] Mayo Clin, Dept Med, Div Gastroenterol, Rochester, MN USA. RI Loftus, Edward/E-8304-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2013 VL 108 SU 1 MA 1842 BP S556 EP S557 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 296II UT WOS:000330178102173 ER PT J AU Simcox, T Yao, M Anaya-O'Brien, S Fuss, I Malech, H DeRavin, SS AF Simcox, Thomas Yao, Michael Anaya-O'Brien, Sandra Fuss, Ivan Malech, Harry DeRavin, Suk See TI Anti-tumor Necrosis Factor Alpha Therapy for the Treatment of Chronic Granulomatous Disease-Related Colitis SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 78th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 11-16, 2013 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Simcox, Thomas] NIDDK, NIH, Bethesda, MD 20892 USA. [Yao, Michael; Anaya-O'Brien, Sandra; Fuss, Ivan; Malech, Harry; DeRavin, Suk See] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2013 VL 108 SU 1 MA 1740 BP S525 EP S525 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 296II UT WOS:000330178102073 ER PT J AU Abramowitz, PW Bass, P Chen, D DeChristoforo, R DeLuca, R DePuy, MD Ducca, AT Firschein, BA Guenter, P Hartmann, R Klein, CN Knoer, S Lewin, JJ Mirtallo, JM Pearlstein, L Reilly, C Rosner, JM Russell, WL Scott, B Schwartz, L Schwartz, R Van Hook, M VanEeckhout, J Witmer, DR AF Abramowitz, Paul W. Bass, Paula Chen, David DeChristoforo, Robert DeLuca, Ruth DePuy, Marjorie D. Ducca, Anita T. Firschein, Ben A. Guenter, Peggi Hartmann, Ron Klein, Catherine N. Knoer, Scott Lewin, John J., III Mirtallo, Jay M. Pearlstein, Lisa Reilly, Cynthia Rosner, Jeffrey M. Russell, Wayne L. Scott, Bruce Schwartz, Lisa Schwartz, Rowena Van Hook, Matthew VanEeckhout, John Witmer, David R. TI Summary of the executive session on critical threats to the pharmacy supply chain and the effects on patient care SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article ID ASHP NATIONAL-SURVEY; DRUG SHORTAGES C1 [Abramowitz, Paul W.; Klein, Catherine N.; Witmer, David R.] Amer Soc Hlth Syst Pharmacists, Orlando, FL 32804 USA. [Bass, Paula] Amgen Inc, Pharm Affairs, Thousand Oaks, CA USA. [Chen, David] Amer Soc Hlth Syst Pharmacists, Pharm Practice Sect, Orlando, FL USA. [Chen, David] Amer Soc Hlth Syst Pharmacists, Sect Pharm Practice Managers, Orlando, FL USA. [DeChristoforo, Robert] NIH, Ctr Clin, Bethesda, MD USA. [DeLuca, Ruth] Biotechnol Ind Org, Sci & Regulatory Affairs, Washington, DC USA. [DePuy, Marjorie D.] Healthcare Distribut Management Assoc, Ind Relat & Alliance Dev, Arlington, VA USA. [Ducca, Anita T.] Healthcare Distribut Management Assoc, Regulatory Affairs, Arlington, VA USA. [Firschein, Ben A.] US Pharmacopeial Convent Inc, Govt Affairs & Policy, Rockville, MD USA. [Guenter, Peggi; Mirtallo, Jay M.] Amer Soc Parenteral & Enteral Nutr, Silver Spring, MD USA. [Hartmann, Ron] Pharm MedAssets, Plano, TX USA. [Knoer, Scott; Rosner, Jeffrey M.] Cleveland Clin, Cleveland, OH USA. [Lewin, John J., III] Johns Hopkins Med Inst, Soc Crit Care Med, Baltimore, MD USA. [Pearlstein, Lisa] Amer Soc Anesthesiologists, Washington, DC USA. [Reilly, Cynthia] Amer Soc Hlth Syst Pharmacists, Practice Dev Div, Orlando, FL USA. [Russell, Wayne L.] Premier Inc, Charlotte, NC USA. [Schwartz, Lisa] Natl Community Pharmacists Assoc, Washington, DC USA. [Schwartz, Rowena] Hematol Oncol Pharm Assoc, Hlth Policy Comm, Drug Shortage Workgrp, Chicago, IL USA. [Van Hook, Matthew] US Pharmacopeial Convent Inc, Rockville, MD USA. [VanEeckhout, John] Childrens Hosp Assoc, Clin Serv, Kansas City, MO USA. RP Abramowitz, PW (reprint author), Amer Soc Hlth Syst Pharmacists, Orlando, FL 32804 USA. FU Amgen FX Based on an executive session that was sponsored by Amgen. NR 34 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD OCT 1 PY 2013 VL 70 IS 19 BP 1689 EP 1698 DI 10.2146/ajhp120771 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 298MC UT WOS:000330327000016 ER PT J AU Tan, PH Cheng, L Rioux-Leclercq, N Merino, MJ Netto, G Reuter, VE Shen, SS Grignon, DJ Montironi, R Egevad, L Srigley, JR Delahunt, B Moch, H AF Tan, Puay Hoon Cheng, Liang Rioux-Leclercq, Nathalie Merino, Maria J. Netto, George Reuter, Victor E. Shen, Steven S. Grignon, David J. Montironi, Rodolfo Egevad, Lars Srigley, John R. Delahunt, Brett Moch, Holger CA ISUP Renal Tumor Panel TI Renal Tumors Diagnostic and Prognostic Biomarkers SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE renal cell carcinoma; immunohistochemistry; CK7; Pax 2; Pax 8; translocation carcinoma; International Society of Urological Pathology ID CARBONIC-ANHYDRASE-IX; ADRENAL-CORTICAL LESIONS; SPINDLE-CELL CARCINOMA; CENTRAL-NERVOUS-SYSTEM; HIPPEL-LINDAU GENE; CLEAR-CELL; DIFFERENTIAL-DIAGNOSIS; IMMUNOHISTOCHEMICAL-MARKERS; TISSUE MICROARRAY; PHASE-3 TRIAL AB The International Society of Urological Pathology convened a consensus conference on renal cancer, preceded by an online survey, to address issues relating to the diagnosis and reporting of renal neoplasia. In this report, the role of biomarkers in the diagnosis and assessment of prognosis of renal tumors is addressed. In particular we focused upon the use of immunohistochemical markers and the approach to specific differential diagnostic scenarios. We enquired whether cytogenetic and molecular tools were applied in practice and asked for views on the perceived prognostic role of biomarkers. Both the survey and conference voting results demonstrated a high degree of consensus in participants' responses regarding prognostic/ predictive markers and molecular techniques, whereas it was apparent that biomarkers for these purposes remained outside the diagnostic realm pending clinical validation. Although no individual antibody or panel of antibodies reached consensus for classifying renal tumors, or for confirming renal metastatic disease, it was noted from the online survey that 87% of respondents used immunohistochemistry to subtype renal tumors sometimes or occasionally, and a majority (87%) used immunohistochemical markers (Pax 2 or Pax 8, renal cell carcinoma [RCC] marker, panel of pan- CK, CK7, vimentin, and CD10) in confirming the diagnosis of metastatic RCC. There was consensus that immunohistochemistry should be used for histologic subtyping and applied before reaching a diagnosis of unclassified RCC. At the conference, there was consensus that TFE3 and TFEB analysis ought to be requested when RCC was diagnosed in a young patient or when histologic appearances were suggestive of the translocation subtype; whereas Pax 2 and/ or Pax 8 were considered to be the most useful markers in the diagnosis of a renal primary. C1 [Tan, Puay Hoon] Singapore Gen Hosp, Dept Pathol, Singapore 169856, Singapore. [Cheng, Liang; Grignon, David J.] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. [Merino, Maria J.] NCI, Dept Pathol, Bethesda, MD 20892 USA. [Netto, George] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Reuter, Victor E.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Shen, Steven S.] Cornell Univ, Methodist Hosp, Dept Pathol & Genom Med, Houston, TX USA. [Shen, Steven S.] Cornell Univ, Weill Med Coll, Houston, TX USA. [Rioux-Leclercq, Nathalie] CHU Pontchaillou, Serv Anat & Cytol Pathol, Rennes, France. [Montironi, Rodolfo] Polytech Univ Marche Reg, Inst Pathol Anat & Histopathol, Ancona, Italy. [Egevad, Lars] Karolinska Inst, Stockholm, Sweden. [Srigley, John R.] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada. [Delahunt, Brett] Univ Otago, Dept Pathol & Mol Med, Wellington, New Zealand. [Moch, Holger] Univ Zurich, Inst Surg Pathol, Zurich, Switzerland. RP Tan, PH (reprint author), Singapore Gen Hosp, Dept Pathol, 20 Coll Rd,Level 7 Diagnost Tower, Singapore 169856, Singapore. EM tan.puay.hoon@sgh.com.sg RI rioux-leclercq, nathalie/I-2820-2015; BAYDAR, DILEK/I-9610-2013; OI Orozco, Roberto/0000-0002-3785-2827; Furusato, Bungo/0000-0003-4614-9882; Shabaik, Ahmed/0000-0003-1987-3453; Samaratunga, Hemamali/0000-0001-5796-1791 FU NCI NIH HHS [P30 CA006973] NR 81 TC 57 Z9 63 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2013 VL 37 IS 10 BP 1518 EP 1531 PG 14 WC Pathology; Surgery SC Pathology; Surgery GA 299YB UT WOS:000330430500005 PM 24025522 ER PT J AU Miettinen, M Wang, ZF Sarlomo-Rikala, M Abdullaev, Z Pack, SD Fetsch, JF AF Miettinen, Markku Wang, Zengfeng Sarlomo-Rikala, Maarit Abdullaev, Ziedulla Pack, Svetlana D. Fetsch, John F. TI ERG Expression in Epithelioid Sarcoma A Diagnostic Pitfall SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE epithelioid sarcoma; angiosarcoma; ERG; INI1; SMARCB1; immunohistochemistry; FISH ID ENDOTHELIAL-CELL DIFFERENTIATION; TRANSCRIPTION FACTOR ERG; PROSTATE-CANCER; MONOCLONAL-ANTIBODY; INI1 EXPRESSION; TUMORS; IMMUNOHISTOCHEMISTRY; HEMANGIOENDOTHELIOMA; ONCOPROTEIN; PATHOLOGY AB ERG transcription factor is constitutively expressed in endothelial cells. Because benign and malignant vascular endothelia retain the ERG expression, ERG is considered a useful marker for angiosarcomas and related tumors. ERG is also expressed in a subset of prostate carcinomas and Ewing sarcomas due to ERG-involved translocations; therefore, this marker is also of high interest in the study of these malignancies. In this study, we evaluated 109 epithelioid sarcomas for ERG expression, on the basis of an initial observation of an ERG-positive case. We also studied expression of other endothelial antigens in epithelioid sarcoma. ERG was expressed in 38% of epithelioid sarcomas (41/109), usually with a uniform nuclear staining, similar to that seen in angiosarcomas. However, all epithelioid sarcomas were negative for ERG gene rearrangement indicating that ERG expression is not likely related to ERG-involving translocations in epithelioid sarcoma. Other endothelial markers, CD31, claudin 5, and Prox1, were absent in epithelioid sarcomas. The only exception was a pulmonary metastasis of epithelioid sarcoma showing focal CD31 expression, which probably resulted from antigen adsorption onto tumor cell surfaces. However, podoplanin was commonly (7/9) expressed in epithelioid sarcoma; therefore, this marker is not useful in distinguishing epithelioid sarcoma from angiosarcoma. INI1/SMARCB1 gene product was absent in all epithelioid sarcomas (considered here a definitional feature) but was absent from only 1 epithelioid angiosarcoma, indicating its relative specificity for epithelioid sarcoma in this differential diagnostic setting. ERG expression is fairly common in epithelioid sarcoma and should be recognized as a diagnostic pitfall in the differential diagnosis of epithelioid sarcoma and epithelioid angiosarcoma. General lack of endothelial cell-specific markers in epithelioid sarcoma helps in this distinction. C1 [Miettinen, Markku; Wang, Zengfeng; Abdullaev, Ziedulla; Pack, Svetlana D.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Fetsch, John F.] Joint Pathol Ctr, Silver Spring, MD USA. [Sarlomo-Rikala, Maarit] HUSLab, Helsinki, Finland. RP Miettinen, M (reprint author), NCI, Pathol Lab, 9000 Rockville Pike,Bldg 10,Rm 2B50, Bethesda, MD 20892 USA. EM miettinenmm@mail.nih.gov RI Pack, Svetlana/C-2020-2014 FU NCI's intramural research program FX Supported as a part of NCI's intramural research program. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 24 TC 31 Z9 33 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2013 VL 37 IS 10 BP 1580 EP 1585 PG 6 WC Pathology; Surgery SC Pathology; Surgery GA 299YB UT WOS:000330430500012 PM 23774169 ER PT J AU McShane, LM Polley, MYC AF McShane, Lisa M. Polley, Mei-Yin C. TI Development of omics-based clinical tests for prognosis and therapy selection: The challenge of achieving statistical robustness and clinical utility SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT University-of-Pennsylvania 5th Annual Conference on Statistical Issues in Clinical Trials - Emerging Statistical Issues in Biomarker Validation for Clinical Trials CY 2012 CL Univ Penn, Philadelphia, PA HO Univ Penn ID CELL LUNG-CANCER; RISK PREDICTION; BREAST-CANCER; VALIDATION; CHEMOTHERAPY; BIOMARKERS; MICROARRAY; SURVIVAL; TRIALS; ASSAY AB Background Many articles have been published in biomedical journals reporting on the development of prognostic and therapy-guiding biomarkers or predictors developed from high-dimensional data generated by omics technologies. Few of these tests have advanced to routine clinical use. Purpose We discuss statistical issues in the development and evaluation of prognostic and therapy-guiding biomarkers and omics-based tests. Methods Concepts relevant to the development and evaluation of prognostic and therapy-guiding clinical tests are illustrated through discussion and examples. Some differences between statistical approaches for test evaluation and therapy evaluation are explained. The additional complexities introduced in the evaluation of omics-based tests are highlighted. Results Distinctions are made between clinical validity of a test and clinical utility. To establish clinical utility for prognostic tests, it is explained why absolute risk should be evaluated in addition to relative risk measures. The critical role of an appropriate control group is emphasized for evaluation of therapy-guiding tests. Common pitfalls in the development and evaluation of tests generated from high-dimensional omics data such as model overfitting and inappropriate methods for test performance evaluation are explained, and proper approaches are suggested. Limitations The cited references do not comprise an exhaustive list of useful references on this topic, and a systematic review of the literature was not performed. Instead, a few key points were highlighted and illustrated with examples drawn from the oncology literature. Conclusions Approaches for the development and statistical evaluation of clinical tests useful for predicting prognosis and selecting therapy differ from standard approaches for therapy evaluation. Proper evaluation requires an understanding of the clinical setting and what information is likely to influence clinical decisions. Specialized expertise relevant to building mathematical predictor models from high-dimensional data is helpful to avoid common pitfalls in the development and evaluation of omics-based tests. C1 [McShane, Lisa M.; Polley, Mei-Yin C.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP McShane, LM (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, MSC 9735, Bethesda, MD 20892 USA. EM lm5h@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 23 TC 4 Z9 4 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD OCT PY 2013 VL 10 IS 5 BP 653 EP 665 DI 10.1177/1740774513499458 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 301IP UT WOS:000330526300003 PM 24000377 ER PT J AU DeMets, D Wittes, J Siegel, J Mietlowski, W Sargent, D Rubin, E McShane, L Ellenberg, S Pennello, G Wang, SB Liao, J Tandon, PK Gilbert, H Chappell, R AF DeMets, David Wittes, Janet Siegel, Jay Mietlowski, William Sargent, Dan Rubin, Eric McShane, Lisa Ellenberg, Susan Pennello, Gene Wang, Songbai Liao, Jason Tandon, P. K. Gilbert, Houston Chappell, Richard TI University of Pennsylvania 5th annual conference on statistical issues in clinical trials: Emerging statistical issues in biomarker validation (Morning Session) SO CLINICAL TRIALS LA English DT Editorial Material C1 [DeMets, David; Chappell, Richard] Univ Wisconsin, Madison, WI 53706 USA. [Siegel, Jay] Johnson & Johnson, New Brunswick, NJ USA. [Sargent, Dan] Mayo Clin, Rochester, MN USA. [McShane, Lisa] NCI, Bethesda, MD 20892 USA. [Ellenberg, Susan] Univ Penn, Philadelphia, PA 19104 USA. [Pennello, Gene] US FDA, Rockville, MD 20857 USA. [Wang, Songbai] Ortho Clin Diagnost, Rochester, NY USA. [Liao, Jason] Penn State Hershey Canc Inst, Hershey, PA USA. [Tandon, P. K.] Genzyme Corp, Cambridge, MA USA. [Gilbert, Houston] Genentech Inc, South San Francisco, CA USA. RP DeMets, D (reprint author), Univ Wisconsin, Madison, WI 53706 USA. FU NCI NIH HHS [5R13CA132565-05] NR 2 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD OCT PY 2013 VL 10 IS 5 BP 680 EP 689 DI 10.1177/1740774513500388 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 301IP UT WOS:000330526300006 PM 24130200 ER PT J AU Dodd, LE Korn, EL Freidlin, B Gu, WJ Abrams, JS Bushnell, WD Canetta, R Doroshow, JH Gray, RJ Sridhara, R AF Dodd, Lori E. Korn, Edward L. Freidlin, Boris Gu, Wenjuan Abrams, Jeffrey S. Bushnell, William D. Canetta, Renzo Doroshow, James H. Gray, Robert J. Sridhara, Rajeshwari TI An audit strategy for time-to-event outcomes measured with error: Application to five randomized controlled trials in oncology SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT University-of-Pennsylvania 5th Annual Conference on Statistical Issues in Clinical Trials - Emerging Statistical Issues in Biomarker Validation for Clinical Trials CY 2012 CL Univ Penn, Philadelphia, PA HO Univ Penn ID METASTATIC BREAST-CANCER; CLINICAL-TRIALS; PLUS CAPECITABINE; PROGRESSION; LAPATINIB; SURVIVAL AB Background Measurement error in time-to-event end points complicates interpretation of treatment effects in clinical trials. Non-differential measurement error is unlikely to produce large bias [1]. When error depends on treatment arm, bias is of greater concern. Blinded-independent central review (BICR) of all images from a trial is commonly undertaken to mitigate differential measurement-error bias that may be present in hazard ratios (HRs) based on local evaluations. Similar BICR and local evaluation HRs may provide reassurance about the treatment effect, but BICR adds considerable time and expense to trials. Methods We describe a BICR audit strategy [2] and apply it to five randomized controlled trials to evaluate its use and to provide practical guidelines. The strategy requires BICR on a subset of study subjects, rather than a complete-case BICR, and makes use of an auxiliary-variable estimator. Results When the effect size is relatively large, the method provides a substantial reduction in the size of the BICRs. In a trial with 722 participants and a HR of 0.48, an average audit of 28% of the data was needed and always confirmed the treatment effect as assessed by local evaluations. More moderate effect sizes and/or smaller trial sizes required larger proportions of audited images, ranging from 57% to 100% for HRs ranging from 0.55 to 0.77 and sample sizes between 209 and 737. Limitations The method is developed for a simple random sample of study subjects. In studies with low event rates, more efficient estimation may result from sampling individuals with events at a higher rate. Conclusion The proposed strategy can greatly decrease the costs and time associated with BICR, by reducing the number of images undergoing review. The savings will depend on the underlying treatment effect and trial size, with larger treatment effects and larger trials requiring smaller proportions of audited data. C1 [Dodd, Lori E.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Korn, Edward L.; Freidlin, Boris] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Gu, Wenjuan] NCI, Biostat Res Branch, SAIC Frederick Inc, Frederick, MD 21701 USA. [Abrams, Jeffrey S.] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Canetta, Renzo] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Gray, Robert J.] Harvard Univ, Dept Biostat, Boston, MA 02115 USA. [Sridhara, Rajeshwari] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. RP Dodd, LE (reprint author), NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM doddl@mail.nih.gov FU PHS HHS [HHSN261200800001E] NR 13 TC 1 Z9 1 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD OCT PY 2013 VL 10 IS 5 BP 754 EP 760 DI 10.1177/1740774513493973 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 301IP UT WOS:000330526300015 PM 23935162 ER PT J AU Kulkarni, V Rosati, M Valentin, A Jalah, R Alicea, C Yu, L Guan, YJ Shen, XY Tomaras, GD LaBranche, C Montefiori, DC Irene, C Prattipati, R Pinter, A Sullivan, SM Pavlakis, GN Felber, BK AF Kulkarni, Viraj Rosati, Margherita Valentin, Antonio Jalah, Rashmi Alicea, Candido Yu, Lei Guan, Yongjun Shen, Xiaoying Tomaras, Georgia D. LaBranche, Celia Montefiori, David C. Irene, Carmela Prattipati, Rajasekhar Pinter, Abraham Sullivan, Sean M. Pavlakis, George N. Felber, Barbara K. TI Vaccination with Vaxfectin (R) adjuvanted SIV DNA induces long-lasting humoral immune responses able to reduce SIVmac251 Viremia SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article DE adjuvant; HIV; SIVsmE660; antibody; SIVmac239; neutralizing antibody; V1 and V2 antibodies; avidity; saliva; rectal fluid; Rhesus macaques; systemic immunity; mucosal immunity ID IMMUNODEFICIENCY VIRUS CHALLENGE; T-CELL RESPONSES; PLASMID DNA; RHESUS MACAQUES; IN-VIVO; ANTIBODY-RESPONSES; HIV-1 INFECTION; CLINICAL AIDS; B-CELL; VACCINES AB We evaluated the immunogenicity and efficacy of Vaxfectin (R) adjuvanted SIV DNA vaccines in mice and macaques. Vaccination of mice with Vaxfectin (R) adjuvanted SIV gag DNA induced higher humoral immune responses than administration of unadjuvanted DNA, whereas similar levels of cellular immunity were elicited. Vaxfectin (R) adjuvanted SIVmac251 gag and env DNA immunization of rhesus macaques was used to examine magnitude, durability, and efficacy of humoral immunity. Vaccinated macaques elicited potent neutralizing antibodies able to cross-neutralize the heterologous SIVsmE660 Env. We found remarkable durability of Gag and Env humoral responses, sustained during similar to 2 y of follow-up. The Env-specific antibody responses induced by Vaxfectin (R) adjuvanted env DNA vaccination disseminated into mucosal tissues, as demonstrated by their presence in saliva, including responses to the V1-V2 region, and rectal fluids. The efficacy of the immune responses was evaluated upon intrarectal challenge with low repeated dose SIVmac251. Although 2 of the 3 vaccinees became infected, these animals showed significantly lower peak virus loads and lower chronic viremia than non-immunized infected controls. Thus, Vaxfectin (R) adjuvanted DNA is a promising vaccine approach for inducing potent immune responses able to control the highly pathogenic SIVmac251. C1 [Kulkarni, Viraj; Jalah, Rashmi; Alicea, Candido; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Rosati, Margherita; Valentin, Antonio; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Yu, Lei; Guan, Yongjun] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Yu, Lei; Guan, Yongjun] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Shen, Xiaoying; Tomaras, Georgia D.; LaBranche, Celia; Montefiori, David C.] Duke Human Vaccine Inst, Durham, NC USA. [Irene, Carmela; Prattipati, Rajasekhar; Pinter, Abraham] Univ Med & Dent New Jersey, Publ Hlth Res Inst, Newark, NJ 07103 USA. [Sullivan, Sean M.] Vical Inc, Pharmaceut Sci, San Diego, CA USA. RP Pavlakis, GN (reprint author), NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. EM pavlakig@mail.nih.gov; felberb@mail.nih.gov RI Tomaras, Georgia/J-5041-2016 NR 62 TC 8 Z9 8 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD OCT PY 2013 VL 9 IS 10 BP 2069 EP 2080 DI 10.4161/hv.25442 PG 12 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA 299FQ UT WOS:000330381600014 PM 23820294 ER PT J AU Kulkarni, V Rosati, M Bear, J Pilkington, GR Jalah, R Bergamaschi, C Singh, AK Alicea, C Chowdhury, B Zhang, GM Kim, EY Wolinsky, SM Huang, WS Guan, YJ LaBranche, C Montefiori, DC Broderick, KE Sardesai, NY Valentin, A Felber, BK Pavlakis, GN AF Kulkarni, Viraj Rosati, Margherita Bear, Jenifer Pilkington, Guy R. Jalah, Rashmi Bergamaschi, Cristina Singh, Ashish K. Alicea, Candido Chowdhury, Bhabadeb Zhang, Gen-Mu Kim, Eun-Young Wolinsky, Steven M. Huang, Wensheng Guan, Yongjun LaBranche, Celia Montefiori, David C. Broderick, Kate E. Sardesai, Niranjan Y. Valentin, Antonio Felber, Barbara K. Pavlakis, George N. TI Comparison of intradermal and intramuscular delivery followed by in vivo electroporation of SIV Env DNA in macaques SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article DE intradermal; intramuscular; in vivo electroporation; DNA vaccine; HIV; SIVsmE660; SIVmac239; SIVmac251; transmitted Env; binding antibody; neutralizing antibody; avidity; transitional memory; effector memory ID SIMIAN IMMUNODEFICIENCY VIRUS; CELLULAR IMMUNE-RESPONSES; RHESUS MACAQUES; PLASMID DNA; SIVMAC251 CHALLENGE; GENE-TRANSFER; NEUTRALIZATION SENSITIVITY; NONHUMAN-PRIMATES; VACCINE DELIVERY; T-CELLS AB A panel of SIVmac251 transmitted Env sequences were tested for expression, function and immunogenicity in mice and macaques. The immunogenicity of a DNA vaccine cocktail expressing SIVmac239 and three transmitted SIVmac251 Env sequences was evaluated upon intradermal or intramuscular injection followed by in vivo electroporation in macaques using sequential vaccination of gp160, gp120 and gp140 expressing DNAs. Both intradermal and intramuscular vaccination regimens using the gp160 expression plasmids induced robust humoral immune responses, which further improved using the gp120 expressing DNAs. The responses showed durability of binding and neutralizing antibody titers and high avidity for >1 y. The intradermal DNA delivery regimen induced higher cross-reactive responses able to neutralize the heterologous tier 1B-like SIVsmE660_CG7V. Analysis of cellular immune responses showed induction of Env-specific memory responses and cytotoxic granzyme B+ T cells in both vaccine groups, although the magnitude of the responses were similar to 10x higher in the intramuscular/electroporation group. The cellular responses induced by both regimens were long lasting and could be detected similar to 1 y after the last vaccination. These data show that both DNA delivery methods are able to induce robust and durable immune responses in macaques. C1 [Kulkarni, Viraj; Bear, Jenifer; Pilkington, Guy R.; Jalah, Rashmi; Bergamaschi, Cristina; Alicea, Candido; Zhang, Gen-Mu; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Rosati, Margherita; Singh, Ashish K.; Chowdhury, Bhabadeb; Zhang, Gen-Mu; Valentin, Antonio; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Kim, Eun-Young; Wolinsky, Steven M.] Northwestern Univ, Div Infect Dis, Feinberg Sch Med, Chicago, IL 60611 USA. [Huang, Wensheng; Guan, Yongjun] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Inst Human Virol, Baltimore, MD 21201 USA. [LaBranche, Celia; Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Lab AIDS Vaccine Res & Dev, Durham, NC 27710 USA. [Broderick, Kate E.; Sardesai, Niranjan Y.] Inovio Pharmaceut Inc, Blue Bell, PA USA. RP Felber, BK (reprint author), NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. EM felberb@mail.nih.gov; pavlakig@mail.nih.gov RI bebarta, vikhyat/K-3476-2015; OI Wolinsky, Steven/0000-0002-9625-6697 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH); NIH HHSN [27201100016C] FX We are grateful to D Weiss, J Treece, I Kalisz, R Pal and staff at Advanced BioScience Laboratories, Inc., Rockville, for their expert help. We thank A von Gegerfelt, B Keele, JJS Cadwell, and E Chertova for discussions, R Desrosiers, R Pal, and NIAID for SIVmac251 virus and macaque plasma samples, and T Jones for editorial assistance. pNL4-3. LucR-E- was provided by NIH AIDS Research and Reference reagent program, Division of AIDS, NIAID. This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH) and by NIH HHSN 27201100016C. NR 64 TC 8 Z9 8 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD OCT PY 2013 VL 9 IS 10 BP 2081 EP 2094 DI 10.4161/hv.25473 PG 14 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA 299FQ UT WOS:000330381600015 PM 23811579 ER PT J AU Akilzhanova, A Zhannur, N Gulbanu, A Zhaxybay, Z Kuvat, M Shtefanov, I Makishev, A Rakhypbekov, T Takamura, N AF Akilzhanova, A. Zhannur, N. Gulbanu, A. Zhaxybay, Z. Kuvat, M. Shtefanov, I. Makishev, A. Rakhypbekov, T. Takamura, N. TI HOMOCYSTEINE LEVEL, MTHFR POLYMORPHISMS AND RISK OF BREAST CANCER SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Meeting Abstract C1 [Akilzhanova, A.; Zhannur, N.; Zhaxybay, Z.] Nazarbayev Univ, Ctr Life Sci, Dept Genom & Personalised Med, Astana, Kazakhstan. [Akilzhanova, A.; Zhannur, N.; Kuvat, M.] Natl Biotechnol Ctr, Astana, Kazakhstan. [Akilzhanova, A.; Takamura, N.] Nagasaki Univ, Atom Bomb Dis Inst, Dept Global Hlth Med & Welf, Nagasaki, Japan. [Gulbanu, A.] Reg Matern Hosp, City Hosp 1, Pavlodar, Kazakhstan. [Shtefanov, I.; Makishev, A.] Astana State Med Univ, Ctr Oncol, Astana, Kazakhstan. [Rakhypbekov, T.] Semey State Med Univ, Ctr Oncol, Semey, Kazakhstan. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD OCT PY 2013 VL 23 IS 8 SU 1 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 299EW UT WOS:000330379501313 ER PT J AU Bakkum-Gamez, J Wentzensen, N Maurer, M Sherman, M Podratz, K Shridhar, V AF Bakkum-Gamez, J. Wentzensen, N. Maurer, M. Sherman, M. Podratz, K. Shridhar, V. TI USING TAMPONS FOR EARLY DETECTION OF ENDOMETRIAL CANCER SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Meeting Abstract C1 [Bakkum-Gamez, J.; Maurer, M.; Podratz, K.; Shridhar, V.] Mayo Clin, Rochester, MN USA. [Wentzensen, N.; Sherman, M.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD OCT PY 2013 VL 23 IS 8 SU 1 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 299EW UT WOS:000330379500061 ER PT J AU Davaasambuu, G Rich-Edwards, JWR Frazier, LF Hoover, RH Troisi, RT AF Davaasambuu, G. Rich-Edwards, J. W. R. Frazier, L. F. Hoover, R. H. Troisi, R. T. TI HORMONE CONCENTRATIONS IN POPULATIONS AT LOW AND HIGH RISK OF BREAST CANCER SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Meeting Abstract C1 [Davaasambuu, G.; Rich-Edwards, J. W. R.; Frazier, L. F.] Harvard Univ, Sch Med, Boston, MA USA. [Hoover, R. H.; Troisi, R. T.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD OCT PY 2013 VL 23 IS 8 SU 1 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 299EW UT WOS:000330379500101 ER PT J AU Kissin, EY Garg, A Grayson, PC Dubreuil, M Vradii, D York, M Simms, RW AF Kissin, Eugene Y. Garg, Amit Grayson, Peter C. Dubreuil, Maureen Vradii, Diana York, Michael Simms, Robert W. TI Ultrasound Assessment of Subcutaneous Compressibility A Potential Adjunctive Diagnostic Tool in Eosinophilic Fasciitis SO JCR-JOURNAL OF CLINICAL RHEUMATOLOGY LA English DT Article DE eosinophilic fasciitis; ultrasonography; systemic sclerosis; diabetic cheiroarthropathy; hypodermis ID MRI AB Background: Eosinophilic fasciitis (EF) is an autoimmune, fibrotic disorder described initially with scleroderma-like skin changes where deep soft tissue sampling that includes fascia is frequently felt to be necessary to confirm the diagnosis. Objective: The objective of this study was to distinguish forearm involvement by EF from other fibrosing diseases and from control subjects with normal skin and fascia using B-mode ultrasound. Methods: A cross-sectional study over a 4-year period in which clinically involved forearm skin of consecutive patients with EF (n = 12), diabetic cheiroarthropathy (n = 8), diffuse systemic sclerosis (n = 23), and control subjects (n = 8) was evaluated by 12-MHz, B-mode ultrasound for degree of subcutaneous tissue compressibility, and this finding was compared with the criterion standard of clinical diagnostic criteria for each disease process. Results: Subcutaneous compressibility in EF was significantly reduced when compared with diffuse systemic sclerosis and with control subjects. Subcutaneous thinning was observed in some patients with EF (4/12), diabetic cheiroarthropathy (4/8), and diffuse systemic sclerosis (6/23), but not in control subjects. Diabetic cheiroarthropathy and diffuse systemic sclerosis patients with subcutaneous thinning had less than 20% subcutaneous compressibility, whereas only 1 of 12 EF patients had compressibility of more than 20% regardless of subcutaneous thinning. Conclusions: A 12-MHz, B-mode ultrasound may be used to measure subcutaneous compressibility, thereby serving as an adjunct tool in distinguishing EF from diffuse systemic sclerosis, especially when tissue sampling is less feasible or when the result of tissue sampling is equivocal. C1 [Kissin, Eugene Y.; Dubreuil, Maureen; Vradii, Diana; York, Michael; Simms, Robert W.] Boston Univ, Sch Med, Div Rheumatol, Boston, MA 02118 USA. [Garg, Amit] Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA. [Grayson, Peter C.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Kissin, EY (reprint author), Boston Univ, Sch Med, 72 East Concord Str,E-506 Arthrit Ctr, Boston, MA 02118 USA. EM eukissin@bu.edu NR 20 TC 5 Z9 6 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-1608 EI 1536-7355 J9 JCR-J CLIN RHEUMATOL JI JCR-J. Clin. Rheumatol. PD OCT PY 2013 VL 19 IS 7 BP 382 EP 385 DI 10.1097/RHU.0000000000000020 PG 4 WC Rheumatology SC Rheumatology GA 300KF UT WOS:000330462100005 PM 24048117 ER PT J AU Kantarjian, HM Fojo, T Mathisen, M Zwelling, LA AF Kantarjian, Hagop M. Fojo, Tito Mathisen, Michael Zwelling, Leonard A. TI Cancer Drugs in the United States: Justum Pretium-The Just Price SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RENAL-CELL CARCINOMA; CHRONIC MYELOID-LEUKEMIA; PHASE-III TRIAL; DIAGNOSED CHRONIC-PHASE; CLINICAL-TRIALS; INTERFERON-ALPHA; COST-EFFECTIVENESS; FOLLOW-UP; MELANOMA; SURVIVAL C1 [Kantarjian, Hagop M.; Mathisen, Michael; Zwelling, Leonard A.] MD Anderson Canc Ctr, Houston, TX 77030 USA. [Fojo, Tito] NCI, NIH, Bethesda, MD 20892 USA. RP Kantarjian, HM (reprint author), MD Anderson Canc Ctr, 1400 Holcombe Blvd,Unit 428, Houston, TX 77030 USA. EM hkantarj@mdanderson.org FU Pfizer; Bristol-Myers Squibb; Novartis FX Research Funding: starHagop M. Kantarjian, Pfizer, Bristol-Myers Squibb, Novartis NR 48 TC 100 Z9 101 U1 2 U2 9 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 OCT 1 PY 2013 VL 31 IS 28 BP 3600 EP 3604 DI 10.1200/JCO.2013.49.1845 PG 5 WC Oncology SC Oncology GA 301NM UT WOS:000330539000021 PM 23650428 ER PT J AU Tao, RY Xiong, XW DePinho, RA Deng, CX Dong, XC AF Tao, Rongya Xiong, Xiwen DePinho, Ronald A. Deng, Chu-Xia Dong, X. Charlie TI Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6 SO JOURNAL OF LIPID RESEARCH LA English DT Article DE gene regulation; transcription; histone acetylation; epigenetics; sirtuin 6; forkhead box O3 transcription factor; sterol-regulatory element binding protein 2 ID INSULIN-RESISTANCE; HUMAN LONGEVITY; PROTECTS CARDIOMYOCYTES; PROMOTES FORMATION; GENE-EXPRESSION; CANCER-CELLS; LIFE-SPAN; C-JUN; MICE; LIVER AB Cholesterol homeostasis is crucial for cellular function and organismal health. The key regulator for the cholesterol biosynthesis is sterol-regulatory element binding protein (SREBP)-2. The biochemical process and physiological function of SREBP-2 have been well characterized; however, it is not clear how this gene is epigenetically regulated. Here we have identified sirtuin (Sirt)6 as a critical factor for Srebp2 gene regulation. Hepatic deficiency of Sirt6 in mice leads to elevated cholesterol levels. On the mechanistic level, Sirt6 is recruited by forkhead box O (FoxO)3 to the Srebp2 gene promoter where Sirt6 deacetylates histone H3 at lysines 9 and 56, thereby promoting a repressive chromatin state. Remarkably, Sirt6 or FoxO3 overexpression improves hypercholesterolemia in diet-induced or genetically obese mice. In summary, our data suggest an important role of hepatic Sirt6 and FoxO3 in the regulation of cholesterol homeostasis. C1 [Tao, Rongya; Xiong, Xiwen; Dong, X. Charlie] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [DePinho, Ronald A.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Dong, XC (reprint author), Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. EM xcdong@iu.edu RI tao, rongya/B-8042-2014; deng, chuxia/N-6713-2016 OI tao, rongya/0000-0002-3316-5587; FU National Institute of Diabetes and Digestive and Kidney Diseases [R00DK-077505, R01DK-091592] FX This work was supported by the grants R00DK-077505 and R01DK-091592 (to X.C.D.) from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 69 TC 24 Z9 26 U1 3 U2 24 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD OCT PY 2013 VL 54 IS 10 BP 2745 EP 2753 DI 10.1194/jlr.M039339 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 301LO UT WOS:000330534000017 PM 23881913 ER PT J AU Fan, M Sidhu, R Fujiwara, H Tortelli, B Zhang, J Davidson, C Walkley, SU Bagel, JH Vite, C Yanjanin, NM Porter, FD Schaffer, JE Ory, DS AF Fan, Martin Sidhu, Rohini Fujiwara, Hideji Tortelli, Brett Zhang, Jessie Davidson, Cristin Walkley, Steven U. Bagel, Jessica H. Vite, Charles Yanjanin, Nicole M. Porter, Forbes D. Schaffer, Jean E. Ory, Daniel S. TI Identification of Niemann-Pick C1 disease biomarkers through sphingolipid profiling SO JOURNAL OF LIPID RESEARCH LA English DT Article DE metabolomics; neurodegeneration; sphingolipids ID NEURONAL CHOLESTEROL; LYSOSOMAL STORAGE; MURINE MODEL; HUMAN PLASMA; MICE; BRAIN; MOUSE; NPC1; GLUCOSYLCERAMIDE; CYCLODEXTRIN AB Niemann-Pick type C (NPC) 1 is a rare neurodegenerative disease for which treatment options are limited. A major barrier to development of effective treatments has been the lack of validated biomarkers to monitor disease progression or serve as outcome measures in clinical trials. Using targeted metabolomics to exploit the complex lipid storage phenotype that is the hallmark of NPC1 disease, we broadly surveyed Npc1(-/-)mouse tissues and identified elevated species across multiple sphingolipid classes that increased with disease progression. There was a striking accumulation of sphingoid bases, monohexosylceramides (MCs), and GM2 gangliosides in liver, and sphingoid bases and GM2 and GM3 gangliosides in brain. These lipids were modestly decreased following miglustat treatment, but markedly decreased in response to treatment with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), two drugs that have shown efficacy in NPC1 animal models. Extending these studies to human subjects led to identification of sphingolipid classes that were significantly altered in the plasma of NPC1 patients. Plasma MCs and ceramides were elevated, whereas sphingoid bases were reduced in NPC1 subjects. Intervention with miglustat in NPC1 patients was accompanied by striking alterations in plasma (reductions in GM1 and GM3 gangliosides) and cerebrospinal fluid (CSF) (increased MCs) sphingolipids. Similar alterations were observed in the CSF from the NPC1 feline model following (HP-beta-CD) treatment. Our findings suggest that these lipid biomarkers may prove useful as outcome measures for monitoring efficacy of therapy in clinical trials. C1 [Fan, Martin; Sidhu, Rohini; Fujiwara, Hideji; Tortelli, Brett; Zhang, Jessie; Schaffer, Jean E.; Ory, Daniel S.] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63130 USA. [Fan, Martin; Sidhu, Rohini; Fujiwara, Hideji; Tortelli, Brett; Zhang, Jessie; Schaffer, Jean E.; Ory, Daniel S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Davidson, Cristin; Walkley, Steven U.] Albert Einstein Coll Med, Rose F Kennedy Ctr, Dominick P Purpura Dept Neurosci, Bronx, NY 10467 USA. [Bagel, Jessica H.; Vite, Charles] Univ Penn, Sch Vet Med, Dept Clin Studies, Philadelphia, PA 19104 USA. [Yanjanin, Nicole M.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Ory, DS (reprint author), Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63130 USA. EM dory@wustl.edu RI Sidhu, Rohini/G-3547-2012; Davidson, Cristin/F-4889-2017 OI Davidson, Cristin/0000-0002-5508-8113 FU Dana's Angels Research Trust; Hide and Seek Foundation for Lysosomal Disease Research; Ara Parseghian Medical Research Foundation; National Niemann-Pick Disease Foundation; NIH [NCRR-02512, R01 NS-081985, NS-053677, CTSA213S, R01 NS-073661]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health Clinical Center FX This work was performed in the Metabolomics Facility at Washington University (NIH P60 DK-020579). The authors received support from Dana's Angels Research Trust (D.S.O., S.U.W., and N.M.Y.), the Hide and Seek Foundation for Lysosomal Disease Research (D.S.O. and S.U.W.), and the Ara Parseghian Medical Research Foundation (D.S.O. and N.M.Y.). Support for the cat colony was provided by the National Niemann-Pick Disease Foundation (C.V.) and NIH NCRR-02512. Support was also provided by NIH R01 NS-081985 (D.S.O. and J.E.S.), NIH NS-053677 (S.U.W.), NIH CTSA213S (D.S.O. and C.V.), and R01 NS-073661 (C.V.). This work was supported in part by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and a Bench to Bedside Award through the National Institutes of Health Clinical Center (F.D.P. and D.S.O.). NR 50 TC 23 Z9 23 U1 2 U2 14 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD OCT PY 2013 VL 54 IS 10 BP 2800 EP 2814 DI 10.1194/jlr.M040618 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 301LO UT WOS:000330534000023 PM 23881911 ER PT J AU Goldner, WS Sandler, DP Yu, F Shostrom, V Hoppin, JA Kamel, F LeVan, TD AF Goldner, Whitney S. Sandler, Dale P. Yu, Fang Shostrom, Valerie Hoppin, Jane A. Kamel, Freya LeVan, Tricia D. TI Hypothyroidism and Pesticide Use Among Male Private Pesticide Applicators in the Agricultural Health Study SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID THYROID-FUNCTION; ENVIRONMENTAL CHEMICALS; PROSPECTIVE COHORT; DIOXIN EXPOSURE; ORGANOCHLORINES; PREVALENCE; ENDOCRINE; DISEASE; DISRUPTION; DISORDERS AB Objective: Evaluate the association between thyroid disease and use of insecticides, herbicides, and fumigants/fungicides in male applicators in the Agricultural Health Study. Methods: We examined the association between use of 50 specific pesticides and self-reported hypothyroidism, hyperthyroidism, and "other" thyroid disease among 22,246 male pesticide applicators. Results: There was increased odds of hypothyroidism with ever use of the herbicides 2,4-D (2,4-dichlorophenoxyacetic acid), 2,4,5-T (2,4,5-trichlorophenoxyacetic acid), 2,4,5-TP (2,4,5-trichlorophenoxy-propionic acid), alachlor, dicamba, and petroleum oil. Hypothyroidism was also associated with ever use of eight insecticides: organochlorines chlordane, dichlorodiphenyltrichloroethane (DDT), heptachlor, lindane, and toxaphene; organophosphates diazinon and malathion; and the carbamate carbofuran. Exposure-response analysis showed increasing odds with increasing level of exposure for the herbicides alachlor and 2,4-D and the insecticides aldrin, chlordane, DDT, lindane, and parathion. Conclusion: There is an association between hypothyroidism and specific herbicides and insecticides in male applicators, similar to previous results for spouses. C1 [Goldner, Whitney S.] Univ Nebraska Med Ctr, Diabet Endocrinol & Metab Div, Dept Internal Med, Omaha, NE 68198 USA. [Yu, Fang; Shostrom, Valerie] Univ Nebraska Med Ctr, Dept Biostat, Coll Publ Hlth, Omaha, NE 68198 USA. [LeVan, Tricia D.] Univ Nebraska Med Ctr, Pulm Crit Care Sleep & Allergy Div, Dept Internal Med, Omaha, NE 68198 USA. [LeVan, Tricia D.] Univ Nebraska Med Ctr, Pulm Crit Care Sleep & Allergy Div, Dept Epidemiol, Omaha, NE 68198 USA. [Sandler, Dale P.; Hoppin, Jane A.; Kamel, Freya] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [LeVan, Tricia D.] VA Nebraska Western Iowa Hlth Care Syst Res Serv, Dept Vet Affairs Med Ctr, Omaha, NE USA. RP Goldner, WS (reprint author), Univ Nebraska Med Ctr, Diabet Endocrinol & Metab Div, Dept Internal Med, 984120 Nebraska Med Ctr, Omaha, NE 68198 USA. EM wgoldner@unmc.edu OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the National Institutes ofHealth; National Institute of Environmental Health Sciences [Z01-ES049030]; National Cancer Institute [Z01-CP-1-119] FX This work was supported in part by the Intramural Research Program of the National Institutes ofHealth, National Institute of Environmental Health Sciences (Z01-ES049030), and National Cancer Institute (Z01-CP-1-119). NR 31 TC 11 Z9 11 U1 3 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD OCT PY 2013 VL 55 IS 10 BP 1171 EP 1178 DI 10.1097/JOM.0b013e31829b290b PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 300FC UT WOS:000330448800007 PM 24064777 ER PT J AU Nomani, F Kamal, AK AF Nomani, Fauzia Kamal, Ayeesha Kamran TI LOAD: A pilot study of the safety of loading of Aspirin & Clopidogrel in acute ischaemic stroke and transient ischaemic attack. Is the loading dose of Aspirin and Clopidogrel a good alternative for patients with acute ischaemic stroke and TIA? How this will impact our clinical practice? SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Kamal, Ayeesha Kamran] Aga Khan Univ Hosp, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. Aga Khan Univ Hosp, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ Hosp, Stroke Serv & Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [D43TW008660, D43 TW008660] NR 1 TC 0 Z9 0 U1 0 U2 5 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD OCT PY 2013 VL 63 IS 10 BP 1316 EP 1316 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 298MR UT WOS:000330328500025 PM 24392571 ER PT J AU McIntyre, S Blair, E Badawi, N Keogh, J Nelson, KB AF McIntyre, Sarah Blair, Eve Badawi, Nadia Keogh, John Nelson, Karin B. TI Antecedents of Cerebral Palsy and Perinatal Death in Term and Late Preterm Singletons SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID NEONATAL ENCEPHALOPATHY; RISK-FACTORS; CHILDREN; IMPAIRMENT; ETIOLOGY AB OBJECTIVE: To examine the antecedents of cerebral palsy and of perinatal death in singletons born at or after 35 weeks of gestation. METHODS: From a total population of singletons born at or after 35 weeks of gestation, we identified 494 with cerebral palsy and 508 neonates in a matched control group, 100 neonatal deaths, and 73 intrapartum stillbirths (all deaths in selected birth years). Neonatal death and cerebral palsy were categorized as without encephalopathy, after neonatal encephalopathy, or after neonatal encephalopathy considered hypoxic-ischemic. We examined the contribution of potentially asphyxial birth events, inflammation, fetal growth restriction, and birth defects recognized by age 6 years to each of these outcomes and to intrapartum stillbirths. RESULTS: The odds of total cerebral palsy after potentially asphyxial birth events or inflammation were modestly increased (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.1-3.2 and OR 2.2, 95% CI 1.0-4.2, respectively). However, potentially asphyxial birth events occurred in 34% of intrapartum stillbirths and 21.6% of cerebral palsy after hypoxic-ischemic encephalopathy. Inflammatory markers occurred in 13.9% and 11.9% of these outcomes, respectively. Growth restriction contributed significantly to all poor outcome groups. Birth defects were recognized in 5.5% of neonates in the control group compared with 60% of neonatal deaths and more than half of cases of cerebral palsy without hypoxic-ischemic encephalopathy. In children with cerebral palsy, a potentially asphyxial birth event, inflammation, or both were experienced by 12.6%, whereas growth restriction, a birth defect, or both were experienced by 48.6% (P<.001). CONCLUSION: Fetal growth restriction and birth defects recognized by age 6 years were more substantial contributors to cerebral palsy and neonatal death than potentially asphyxial birth events and inflammation. C1 [McIntyre, Sarah] Univ Notre Dame Australia, Univ Sydney, Cerebral Palsy Alliance, Darlinghurst, NSW 1300, Australia. Univ Western Australia, Telethon Inst Child Hlth Res, Ctr Child Hlth Res, Perth, WA 6009, Australia. Univ Notre Dame Australia, Cerebral Palsy Alliance, Grace Ctr Newborn Care, Childrens Hosp, Westmead, NSW, Australia. Univ Sydney, Sydney, NSW 2006, Australia. Univ Sydney, Sydney Adventist Hosp, Sydney, NSW 2006, Australia. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. Natl Inst Neurol Disorder & Stroke, Natl Inst Hlth, Bethesda, MD USA. RP McIntyre, S (reprint author), Univ Notre Dame Australia, Univ Sydney, Cerebral Palsy Alliance, POB 560, Darlinghurst, NSW 1300, Australia. EM smcintyre@cerebralpalsy.org.au RI Badawi, Nadia/A-3179-2014 FU Cerebral Palsy Research Foundation; National Health and Medical Research Council [353514]; Macquarie Group Foundation FX Supported by the Cerebral Palsy Research Foundation (S. M.), National Health and Medical Research Council program grant no. 353514 (CCCP study and E. B.), and the Macquarie Group Foundation and Cerebral Palsy Research Foundation (N.B.). NR 29 TC 26 Z9 26 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD OCT PY 2013 VL 122 IS 4 BP 869 EP 877 DI 10.1097/AOG.0b013e3182a265ab PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 300EJ UT WOS:000330446900021 PM 24084547 ER PT J AU Jansen, RJ Robinson, DP Stolzenberg-Solomon, RZ Bamlet, WR Tan, XL Cunningham, JM Li, Y Rider, DN Oberg, AL Rabe, KG Anderson, KE Sinha, R Petersen, GM AF Jansen, Rick J. Robinson, Dennis P. Stolzenberg-Solomon, Rachael Z. Bamlet, William R. Tan, XiangLin Cunningham, Julie M. Li, Ying Rider, David N. Oberg, Ann L. Rabe, Kari G. Anderson, Kristin E. Sinha, Rashmi Petersen, Gloria M. TI Polymorphisms in Metabolism/Antioxidant Genes May Mediate the Effect of Dietary Intake on Pancreatic Cancer Risk SO PANCREAS LA English DT Article DE pancreatic cancer; dietary risk factors; interaction; case-control; genetic risk factors ID MANGANESE SUPEROXIDE-DISMUTASE; GLUTATHIONE-S-TRANSFERASE; DIPHOSPHO-GLUCURONOSYLTRANSFERASE 1A1; SMALL INTESTINAL-MUCOSA; BREAST-CANCER; VEGETABLE CONSUMPTION; CRUCIFEROUS VEGETABLES; METABOLIZING-ENZYMES; ANTIOXIDANT STATUS; PROMOTER REGION AB Objectives: A source of variation for inconsistent dietary-pancreatic cancer associations may be individuals carrying constitutional metabolism/antioxidant gene variants that differentially benefit compared to homozygous individuals. Seventy-six tag single-nucleotide polymorphisms were genotyped in 13 candidate genes to test differential associations with pancreatic adenocarcinoma. Methods: A clinic-based case-control design was used to rapidly ascertain 251 cases and 970 frequency matched controls who provided blood samples and completed a 144-item food frequency questionnaire. Single-nucleotide polymorphisms were evaluated using a dominant genetic model and dietary categories split on controls' median intake. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusted for potential confounders. Results: Significant increased associations (Bonferroni corrected P <= 0.0007) were observed for carriers of greater than or equal to 1 minor allele for rs3816257 (glucosidase, alpha; acid [GAA]) and lower intake of deep-yellow vegetables (1.90 [1.28-2.83]); and carriers of no minor allele for rs12807961 (catalase [CAT]) and high total grains intake (2.48 [1.50-4.09]), whereas those with greater than or equal to 1 minor allele had a decreasing slope (across grains). The reference group was no minor alleles with low dietary intake. Conclusions: Interindividual variation in metabolism/antioxidant genes could interact with dietary intake to influence pancreatic cancer risk. C1 [Jansen, Rick J.; Tan, XiangLin; Petersen, Gloria M.] Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Robinson, Dennis P.; Bamlet, William R.; Cunningham, Julie M.; Li, Ying; Rider, David N.; Oberg, Ann L.; Rabe, Kari G.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Stolzenberg-Solomon, Rachael Z.] NIH, Dept Epidemiol, Bethesda, MD 20892 USA. [Anderson, Kristin E.] Univ Minnesota, Dept Epidemiol & Community Hlth, Minneapolis, MN USA. [Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Jansen, RJ (reprint author), Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, 200 First St SW, Rochester, MN 55905 USA. EM Jansen.Rick@mayo.edu RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU Mayo Clinic SPORE in Pancreatic Cancer [P50 CA102701]; Molecular Cancer Genetic Epidemiology Training Program [R25 CA92049]; National Institutes of Health FX This study was supported by the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701) and the Molecular Cancer Genetic Epidemiology Training Program (R25 CA92049; funded by grant from the National Institutes of Health). NR 96 TC 4 Z9 6 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD OCT PY 2013 VL 42 IS 7 BP 1043 EP 1053 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 300MM UT WOS:000330468000001 PM 24051964 ER PT J AU Ballard, ED Horowitz, LM Jobes, DA Wagner, BM Pao, M Teach, SJ AF Ballard, Elizabeth D. Horowitz, Lisa M. Jobes, David A. Wagner, Barry M. Pao, Maryland Teach, Stephen J. TI Association of Positive Responses to Suicide Screening Questions With Hospital Admission and Repeated Emergency Department Visits in Children and Adolescents SO PEDIATRIC EMERGENCY CARE LA English DT Article DE suicide; screening; psychiatric emergency ID PEDIATRIC EMERGENCY; MENTAL-HEALTH; BEHAVIOR; PREVENTION; PREVALENCE; CARE; TOOL AB Objectives: Although validated suicide screening tools exist for use among children and adolescents presenting to emergency departments (EDs), the associations between screening positive for suicide risk and immediate psychiatric hospital admission or subsequent ED use, stratified by age, have not been examined. Methods: This is a retrospective cohort study of a consecutive case series of patients aged 8 to 18 years presenting with psychiatric chief complaints during a 9-month period to a single urban tertiary care pediatric ED. Eligible patients were administered a subset of questions from the Risk of Suicide Questionnaire. Outcomes included the odds of psychiatric hospitalization at the index visit and repeated ED visits for psychiatric complaints within the following year, stratified by age. Results: Of the 568 patients presenting during the study period, responses to suicide screening questions were available for 442 patients (78%). A total of 159 (36%) of 442 were hospitalized and 130 (29%) of 442 had 1 or more ED visits within the following year. The proportion of patients providing positive responses to 1 or more suicide screening questions did not differ between patients aged 8 to 12 years and those aged 13 to 18 years (77/154 [50%] vs 137/288 [48%], P = 0.63). A positive response to 1 or more of the questions was significantly associated with increased odds of psychiatric hospitalization in the older age group [adjusted odds ratio, 3.82; 95% confidence interval, 2.24-6.54) and with repeated visits to the ED in the younger age group (adjusted odds ratio, 3.55 95% confidence interval, 1.68-7.50). Conclusions: Positive responses to suicide screening questions were associated with acute psychiatric hospitalization and repeated ED visits. Suicide screening in a pediatric ED may identify children and adolescents with increased need of psychiatric resources. C1 [Ballard, Elizabeth D.] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Horowitz, Lisa M.; Pao, Maryland] NIMH, NIH, Bethesda, MD 20892 USA. [Jobes, David A.; Wagner, Barry M.] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. [Teach, Stephen J.] Childrens Natl Med Ctr, Div Emergency Med, Washington, DC 20010 USA. RP Ballard, ED (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 550 North Broadway,931, Baltimore, MD 21287 USA. EM Eballar3@jhmi.edu FU Intramural Research Program of the National Institutes of Health; National Institute of Mental Health FX The research in this article was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Mental Health. NR 27 TC 5 Z9 5 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-5161 EI 1535-1815 J9 PEDIATR EMERG CARE JI Pediatr. Emerg. Care PD OCT PY 2013 VL 29 IS 10 BP 1070 EP 1074 PG 5 WC Emergency Medicine; Pediatrics SC Emergency Medicine; Pediatrics GA 300NS UT WOS:000330471300004 PM 24076609 ER PT J AU Nussinov, R AF Nussinov, Ruth TI How Can PLOS Computational Biology Help the Biological Sciences? SO PLOS COMPUTATIONAL BIOLOGY LA English DT Editorial Material C1 [Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Canc & Inflammat Program, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Dept Human Genet & Mol Med, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Sci Program, SAIC Frederick Inc, Canc & Inflammat Program, Frederick, MD 21701 USA. EM NussinoR@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD OCT PY 2013 VL 9 IS 10 AR e1003262 DI 10.1371/journal.pcbi.1003262 PG 1 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 298WN UT WOS:000330355300024 PM 24098104 ER PT J AU Olson, DR Konty, KJ Paladini, M Viboud, C Simonsen, L AF Olson, Donald R. Konty, Kevin J. Paladini, Marc Viboud, Cecile Simonsen, Lone TI Reassessing Google Flu Trends Data for Detection of Seasonal and Pandemic Influenza: A Comparative Epidemiological Study at Three Geographic Scales SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID SYNDROMIC SURVEILLANCE; COMMUNICABLE DISEASES; H1N1 INFLUENZA; SEVERITY; FRANCE; HEALTH; EXPERIENCE; EPIDEMICS; MORTALITY; OUTBREAKS AB The goal of influenza-like illness (ILI) surveillance is to determine the timing, location and magnitude of outbreaks by monitoring the frequency and progression of clinical case incidence. Advances in computational and information technology have allowed for automated collection of higher volumes of electronic data and more timely analyses than previously possible. Novel surveillance systems, including those based on internet search query data like Google Flu Trends (GFT), are being used as surrogates for clinically-based reporting of influenza-like-illness (ILI). We investigated the reliability of GFT during the last decade (2003 to 2013), and compared weekly public health surveillance with search query data to characterize the timing and intensity of seasonal and pandemic influenza at the national (United States), regional (Mid-Atlantic) and local (New York City) levels. We identified substantial flaws in the original and updated GFT models at all three geographic scales, including completely missing the first wave of the 2009 influenza A/H1N1 pandemic, and greatly overestimating the intensity of the A/H3N2 epidemic during the 2012/2013 season. These results were obtained for both the original (2008) and the updated (2009) GFT algorithms. The performance of both models was problematic, perhaps because of changes in internet search behavior and differences in the seasonality, geographical heterogeneity and age-distribution of the epidemics between the periods of GFT model-fitting and prospective use. We conclude that GFT data may not provide reliable surveillance for seasonal or pandemic influenza and should be interpreted with caution until the algorithm can be improved and evaluated. Current internet search query data are no substitute for timely local clinical and laboratory surveillance, or national surveillance based on local data collection. New generation surveillance systems such as GFT should incorporate the use of near-real time electronic health data and computational methods for continued model-fitting and ongoing evaluation and improvement. C1 [Olson, Donald R.; Konty, Kevin J.; Paladini, Marc] New York City Dept Hlth & Mental Hyg, New York, NY 10013 USA. [Viboud, Cecile; Simonsen, Lone] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Simonsen, Lone] George Washington Univ, Dept Global Hlth, Washington, DC USA. RP Olson, DR (reprint author), New York City Dept Hlth & Mental Hyg, New York, NY 10013 USA. EM dolson@health.nyc.gov OI Simonsen, Lone/0000-0003-1535-8526 FU Markle Foundation [081005BP-Q, 101003BP-B]; Alfred P. Sloan Foundation, Syndromic Surveillance Evaluation Project (NYC DOHMH) [2010-12-14]; RAPIDD (Research and Policy for Infectious Disease Dynamics) program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center FX DRO acknowledges support from the Markle Foundation, through the Distributed Surveillance Taskforce for Real-time Influenza Burden Tracking and Evaluation (DiSTRIBuTE) Project (081005BP-Q and 101003BP-B), and the Alfred P. Sloan Foundation, Syndromic Surveillance Evaluation Project (NYC DOHMH, 2010-12-14). LS acknowledges support from the RAPIDD (Research and Policy for Infectious Disease Dynamics) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 70 Z9 72 U1 3 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD OCT PY 2013 VL 9 IS 10 AR e1003256 DI 10.1371/journal.pcbi.1003256 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 298WN UT WOS:000330355300019 PM 24146603 ER PT J AU Davis, LK Yu, DM Keenan, CL Gamazon, ER Konkashbaev, AI Derks, EM Neale, BM Yang, J Lee, SH Evans, P Barr, CL Bellodi, L Benarroch, F Berrio, GB Bienvenu, OJ Bloch, MH Blom, RM Bruun, RD Budman, CL Camarena, B Campbell, D Cappi, C Silgado, JCC Cath, DC Cavallini, MC Chavira, DA Chouinard, S Conti, DV Cook, EH Coric, V Cullen, BA Deforce, D Delorme, R Dion, Y Edlund, CK Egberts, K Falkai, P Fernandez, TV Gallagher, PJ Garrido, H Geller, D Girard, SL Grabe, HJ Grados, MA Greenberg, BD Gross-Tsur, V Haddad, S Heiman, GA Hemmings, SMJ Hounie, AG Illmann, C Jankovic, J Jenike, MA Kennedy, JL King, RA Kremeyer, B Kurlan, R Lanzagorta, N Leboyer, M Leckman, JF Lennertz, L Liu, C Lochner, C Lowe, TL Macciardi, F McCracken, JT McGrath, LM Restrepo, SCM Moessner, R Morgan, J Muller, H Murphy, DL Naarden, AL Ochoa, WC Ophoff, RA Osiecki, L Pakstis, AJ Pato, MT Pato, CN Piacentini, J Pittenger, C Pollak, Y Rauch, SL Renner, TJ Reus, VI Richter, MA Riddle, MA Robertson, MM Romero, R Rosario, MC Rosenberg, D Rouleau, GA Ruhrmann, S Ruiz-Linares, A Sampaio, AS Samuels, J Sandor, P Sheppard, B Singer, HS Smit, JH Stein, DJ Strengman, E Tischfield, JA Duarte, AVV Vallada, H Van Nieuwerburgh, F Veenstra-VanderWeele, J Walitza, S Wang, Y Wendland, JR Westenberg, HGM Shugart, YY Miguel, EC McMahon, W Wagner, M Nicolini, H Posthuma, D Hanna, GL Heutink, P Denys, D Arnold, PD Oostra, BA Nestadt, G Freimer, NB Pauls, DL Wray, NR Stewart, SE Mathews, CA Knowles, JA Cox, NJ Scharf, JM AF Davis, Lea K. Yu, Dongmei Keenan, Clare L. Gamazon, Eric R. Konkashbaev, Anuar I. Derks, Eske M. Neale, Benjamin M. Yang, Jian Lee, S. Hong Evans, Patrick Barr, Cathy L. Bellodi, Laura Benarroch, Fortu Berrio, Gabriel Bedoya Bienvenu, Oscar J. Bloch, Michael H. Blom, Rianne M. Bruun, Ruth D. Budman, Cathy L. Camarena, Beatriz Campbell, Desmond Cappi, Carolina Silgado, Julio C. Cardona Cath, Danielle C. Cavallini, Maria C. Chavira, Denise A. Chouinard, Sylvain Conti, David V. Cook, Edwin H. Coric, Vladimir Cullen, Bernadette A. Deforce, Dieter Delorme, Richard Dion, Yves Edlund, Christopher K. Egberts, Karin Falkai, Peter Fernandez, Thomas V. Gallagher, Patience J. Garrido, Helena Geller, Daniel Girard, Simon L. Grabe, Hans J. Grados, Marco A. Greenberg, Benjamin D. Gross-Tsur, Varda Haddad, Stephen Heiman, Gary A. Hemmings, Sian M. J. Hounie, Ana G. Illmann, Cornelia Jankovic, Joseph Jenike, Michael A. Kennedy, James L. King, Robert A. Kremeyer, Barbara Kurlan, Roger Lanzagorta, Nuria Leboyer, Marion Leckman, James F. Lennertz, Leonhard Liu, Chunyu Lochner, Christine Lowe, Thomas L. Macciardi, Fabio McCracken, James T. McGrath, Lauren M. Restrepo, Sandra C. Mesa Moessner, Rainald Morgan, Jubel Muller, Heike Murphy, Dennis L. Naarden, Allan L. Ochoa, William Cornejo Ophoff, Roel A. Osiecki, Lisa Pakstis, Andrew J. Pato, Michele T. Pato, Carlos N. Piacentini, John Pittenger, Christopher Pollak, Yehuda Rauch, Scott L. Renner, Tobias J. Reus, Victor I. Richter, Margaret A. Riddle, Mark A. Robertson, Mary M. Romero, Roxana Rosario, Maria C. Rosenberg, David Rouleau, Guy A. Ruhrmann, Stephan Ruiz-Linares, Andres Sampaio, Aline S. Samuels, Jack Sandor, Paul Sheppard, Brooke Singer, Harvey S. Smit, Jan H. Stein, Dan J. Strengman, E. Tischfield, Jay A. Duarte, Ana V. Valencia Vallada, Homero Van Nieuwerburgh, Filip Veenstra-VanderWeele, Jeremy Walitza, Susanne Wang, Ying Wendland, Jens R. Westenberg, Herman G. M. Shugart, Yin Yao Miguel, Euripedes C. McMahon, William Wagner, Michael Nicolini, Humberto Posthuma, Danielle Hanna, Gregory L. Heutink, Peter Denys, Damiaan Arnold, Paul D. Oostra, Ben A. Nestadt, Gerald Freimer, Nelson B. Pauls, David L. Wray, Naomi R. Stewart, S. Evelyn Mathews, Carol A. Knowles, James A. Cox, Nancy J. Scharf, Jeremiah M. TI Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture SO PLOS GENETICS LA English DT Article ID MISSING HERITABILITY; TIC DISORDERS; NEUROPSYCHIATRIC DISORDERS; COMPLEX DISEASES; COMMON SNPS; GILLES; FAMILY; BRAIN; EXPRESSION; AUTISM AB The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures. 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[Robertson, Mary M.] Sch Med, London, England. [Romero, Roxana] Hosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa Rica. [Rosario, Maria C.] Univ Fed Sao Paulo, Dept Psychiat, Child & Adolescent Psychiat Unit UPIA, Sao Paulo, Brazil. [Rosenberg, David] Wayne State Univ, Dept Psychiat & Behav Neurosci, Detroit, MI 48207 USA. [Rosenberg, David] Detroit Med Ctr, Detroit, MI USA. [Rouleau, Guy A.] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada. [Ruhrmann, Stephan] Univ Cologne, Dept Psychiat & Psychotherapy, D-50931 Cologne, Germany. [Sampaio, Aline S.] Univ Fed Bahia, Univ Hlth Care Serv SMURB, Salvador, BA, Brazil. [Sandor, Paul] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Sandor, Paul] Univ Hlth Network, Toronto Western Res Inst, Toronto, ON, Canada. [Sandor, Paul] Youthdale Treatment Ctr, Toronto, ON, Canada. [Singer, Harvey S.] Johns Hopkins Univ Sch Med, Baltimore, MD USA. [Stein, Dan J.] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Strengman, E.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Veenstra-VanderWeele, Jeremy] Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Psychiat, Nashville, TN 37235 USA. [Veenstra-VanderWeele, Jeremy] Vanderbilt Univ, Kennedy Ctr Res Human Dev, Dept Pediat & Pharmacol, Nashville, TN 37235 USA. [Veenstra-VanderWeele, Jeremy] Vanderbilt Univ, Inst Brain, Nashville, TN 37235 USA. [Walitza, Susanne] Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland. [Walitza, Susanne] Univ Wurzburg, Dept Child & Adolescent Psychiat, D-97070 Wurzburg, Germany. [Westenberg, Herman G. M.] Univ Amsterdam, Acad Med Ctr, Ctr Psychiat, NL-1105 BC Amsterdam, Netherlands. [Westenberg, Herman G. M.; Denys, Damiaan] Inst Royal Netherlands Acad Arts & Sci NIN KNAW, Netherlands Inst Neurosci, Amsterdam, Netherlands. [Shugart, Yin Yao] NIMH Intramural Res Program, Unit Stat Genom, Bethesda, MD USA. [McMahon, William] Univ Utah, Dept Psychiat, Salt Lake City, UT USA. 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[Scharf, Jeremiah M.] Brigham & Womens Hosp, Div Cognit & Behav Neurol, Boston, MA 02115 USA. [Scharf, Jeremiah M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Davis, LK (reprint author), Univ Chicago, Dept Med, Med Genet Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM lea.k.davis@gmail.com; jscharf@partners.org RI Renner, Tobias/I-2120-2013; Derks, Eske/A-1652-2017; Lee, Sang Hong/A-2569-2011; Wray, Naomi/C-8639-2015; Van Nieuwerburgh, Filip/H-9697-2015; reus, victor/I-7923-2015; Veenstra-VanderWeele, Jeremy/K-1935-2015; Vallada, Homero/D-1333-2014; Macciardi, Fabio/N-3768-2014; Wagner, Michael/E-2325-2011; Yang, Jian/A-5852-2010; Stein, Dan/A-1752-2008 OI Hemmings, Sian/0000-0001-8461-1017; Gamazon, Eric/0000-0003-4204-8734; Lanzagorta, Nuria/0000-0001-6769-6813; Campbell, Desmond/0000-0003-1085-714X; Nicolini, Humberto/0000-0003-2494-0067; Hanna, Gregory/0000-0002-0742-6990; Samuels, Jack/0000-0002-6715-7905; Walitza, Susanne/0000-0002-8161-8683; Barr, Cathy/0000-0003-0361-0106; Fernandez, Thomas V/0000-0003-0830-022X; Tischfield, Jay/0000-0003-3217-8287; Derks, Eske/0000-0002-6292-6883; Lee, Sang Hong/0000-0001-9701-2718; Wray, Naomi/0000-0001-7421-3357; Van Nieuwerburgh, Filip/0000-0001-8815-5485; reus, victor/0000-0002-8193-5697; Veenstra-VanderWeele, Jeremy/0000-0002-6349-1076; Vallada, Homero/0000-0001-5123-8295; Macciardi, Fabio/0000-0003-0537-4266; Wagner, Michael/0000-0003-2589-6440; Yang, Jian/0000-0003-2001-2474; Stein, Dan/0000-0001-7218-7810 FU Judah Foundation; NIH [NS40024, NS16648, MH079489, MH073250, NS037484, 1R01MH079487-01A1, K20 MH01065, R01 MH58376, MH085057, MH079494, HHSN268200782096C]; Tourette Syndrome Association International Consortium for Genetics (TSAICG); New Jersey Center for Tourette Syndrome and Associated Disorders; NIMH [R01MH092293]; Obsessive Compulsive Foundation; Ontario Mental Health Foundation; Tourette Syndrome Association; American Academy of Child and Adolescent Psychiatry (AACAP); Anxiety Disorders Association of America (ADAA); University of British Columbia; Michael Smith Foundation; American Recovery and Re-investment Act (ARRA) [NS40024-07S1, NS16648-29S1]; Australian Research Council [FT0991360, DE130100614]; Australian National Health and Medical Research Council [1047956, 1052684]; German Research Foundation [DFG GR 1912/1-1]; NIH Genes, Environment and Health Initiative [GEI] [U01 HG004422]; Gene Environment Association Studies (GENEVA) under GEI; NIH GEI [U01HG004438]; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; [R01 MH090937]; [P50MH094267] FX This work was supported by a grant from the Judah Foundation, NIH grant NS40024 to DLP/JMS and the Tourette Syndrome Association International Consortium for Genetics (TSAICG), NIH grant NS16648, MH079489, and MH073250 to DLP, NIH grant NS037484 to NBF, NIH grant 1R01MH079487-01A1 to JTM, New Jersey Center for Tourette Syndrome and Associated Disorders and NIMH (R01MH092293) to GAH/RAK/JAT, NIH grant K20 MH01065 and R01 MH58376 and a grant from the Obsessive Compulsive Foundation to GLH, Ontario Mental Health Foundation grant to PR and JLK, and a grant from the Tourette Syndrome Association and NIH grant MH085057 to JMS, MH079494 to JAK and the OCD Collaborative Genetics Association Study which supported the imputation, by an American Academy of Child and Adolescent Psychiatry (AACAP) Early Investigator Research Grant, an Anxiety Disorders Association of America (ADAA) Junior Investigator Research Grant, the University of British Columbia and a Michael Smith Foundation Clinical Research Scholar Award to SES, and American Recovery and Re-investment Act (ARRA) awards NS40024-07S1 to DLP/JMS and NS16648-29S1 to DLP. Additional support for analysis was provided by R01 MH090937 and P50MH094267 awarded to NJC. Support was also provided by the Australian Research Council FT0991360 (NRW), DE130100614 (SHL) and the Australian National Health and Medical Research Council: 1047956 (NRW), 1052684 (JY), and the German Research Foundation (DFG GR 1912/1-1) to HJG and to PF, SR, MW. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392), and the Family Study of Cocaine Dependence (FSCD; R01 DA013423), and R01-MH-50214 (GN). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease" (HHSN268200782096C). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs00 0092.v1.p1 through dbGaP accession number phs000092.v1.p. None of the funding agencies for this project (NINDS, NIMH, the Tourette Syndrome Association and the Judah Foundation) had any influence or played any role in a) the design or conduct of the study; b) management, analysis or interpretation of the data; c) preparation, review or approval of the manuscript. NR 61 TC 74 Z9 74 U1 5 U2 37 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2013 VL 9 IS 10 AR e1003864 DI 10.1371/journal.pgen.1003864 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 299AR UT WOS:000330367200041 PM 24204291 ER PT J AU Drummond, MC Friderici, KH AF Drummond, Meghan C. Friderici, Karen H. TI A Novel Actin mRNA Splice Variant Regulates ACTG1 Expression SO PLOS GENETICS LA English DT Article ID C2C12 MYOBLAST DIFFERENTIATION; GAMMA-ACTIN; BETA-ACTIN; MUSCULAR-DYSTROPHY; NONCODING REGIONS; NONSENSE CODONS; DECAY; GENE; TRANSCRIPTS; TROPOMYOSIN AB Cytoplasmic actins are abundant, ubiquitous proteins in nucleated cells. However, actin expression is regulated in a tissue- and development-specific manner. We identified a novel cytoplasmic-gamma-actin (Actg1) transcript that includes a previously unidentified exon (3a). Inclusion of this exon introduces an in-frame termination codon. We hypothesized this alternatively-spliced transcript down-regulates gamma-actin production by targeting these transcripts for nonsense-mediated decay (NMD). To address this, we investigated conservation between mammals, tissue-specificity in mice, and developmental regulation using C2C12 cell culture. Exon 3a is 80% similar among mammals and varies in length from 41 nucleotides in humans to 45 in mice. Though the predicted amino acid sequences are not similar between all species, inclusion of exon 3a consistently results in the in the introduction of a premature termination codon within the alternative Actg1 transcript. Of twelve tissues examined, exon 3a is predominantly expressed in skeletal muscle, cardiac muscle, and diaphragm. Splicing to include exon 3a is concomitant with previously described down-regulation of Actg1 in differentiating C2C12 cells. Treatment of differentiated C2C12 cells with an inhibitor of NMD results in a 7-fold increase in exon 3a-containing transcripts. Therefore, splicing to generate exon 3a-containing transcripts may be one component of Actg1 regulation. We propose that this post-transcriptional regulation occurs via NMD, in a process previously described as "regulated unproductive splicing and translation" (RUST). C1 [Drummond, Meghan C.; Friderici, Karen H.] Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. RP Drummond, MC (reprint author), NIDCD, NIH, Rockville, MD 20850 USA. EM frideric@msu.edu FU NIDCD [R01DC4568] FX This work received funding from the NIDCD (www.nidcd.nih.gov), grant R01DC4568. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 2 Z9 2 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2013 VL 9 IS 10 AR e1003743 DI 10.1371/journal.pgen.1003743 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 299AR UT WOS:000330367200002 PM 24098136 ER PT J AU Deribe, K Tomczyk, S Tekola-Ayele, F AF Deribe, Kebede Tomczyk, Sara Tekola-Ayele, Fasil TI Ten Years of Podoconiosis Research in Ethiopia SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID NON-FILARIAL ELEPHANTIASIS; SOUTHERN ETHIOPIA; WEST ETHIOPIA; WOREDA C1 [Deribe, Kebede] Brighton & Sussex Med Sch, Brighton, E Sussex, England. [Deribe, Kebede] Univ Addis Ababa, Sch Publ Hlth, Addis Ababa, Ethiopia. [Tomczyk, Sara] Inst Trop Med, B-2000 Antwerp, Belgium. [Tekola-Ayele, Fasil] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Deribe, K (reprint author), Brighton & Sussex Med Sch, Brighton, E Sussex, England. EM kebededeka@yahoo.com OI Deribe, Kebede/0000-0002-8526-6996; Tekola-Ayele, Fasil/0000-0003-4194-9370 FU Wellcome Trust [099876] NR 15 TC 7 Z9 7 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD OCT PY 2013 VL 7 IS 10 AR e2301 DI 10.1371/journal.pntd.0002301 PG 4 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 299DW UT WOS:000330376500003 PM 24130908 ER PT J AU Lopez, JE Wilder, HK Hargrove, R Brooks, CP Peterson, KE Beare, PA Sturdevant, DE Nagarajan, V Raffel, SJ Schwan, TG AF Lopez, Job E. Wilder, Hannah K. Hargrove, Reid Brooks, Christopher P. Peterson, Karin E. Beare, Paul A. Sturdevant, Daniel E. Nagarajan, Vijayaraj Raffel, Sandra J. Schwan, Tom G. TI Development of Genetic System to Inactivate a Borrelia turicatae Surface Protein Selectively Produced within the Salivary Glands of the Arthropod Vector SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID LYME-DISEASE SPIROCHETE; OUTER-MEMBRANE PROTEIN; BORNE RELAPSING FEVER; ORNITHODOROS-TURICATA; FACTOR-H; BURGDORFERI; HERMSII; INFECTION; PLASMINOGEN; CULTIVATION AB Background: Borrelia turicatae, an agent of tick-borne relapsing fever, is an example of a pathogen that can adapt to disparate conditions found when colonizing the mammalian host and arthropod vector. However, little is known about the genetic factors necessary during the tick-mammalian infectious cycle, therefore we developed a genetic system to transform this species of spirochete. We also identified a plasmid gene that was up-regulated in vitro when B. turicatae was grown in conditions mimicking the tick environment. This 40 kilodalton protein was predicted to be surface localized and designated the Borrelia repeat protein A (brpA) due to the redundancy of the amino acid motif Gln-Gly-Asn-Val-Glu. Methodology/Principal Findings: Quantitative reverse-transcriptase polymerase chain reaction using RNA from B. turicatae infected ticks and mice indicated differential regulation of brpA during the tick-mammalian infectious cycle. The surface localization was determined, and production of the protein within the salivary glands of the tick was demonstrated. We then applied a novel genetic system for B. turicatae to inactivate brpA and examined the role of the gene product for vector colonization and the ability to establish murine infection. Conclusions/Significance: These results demonstrate the complexity of protein production in a population of spirochetes within the tick. Additionally, the development of a genetic system is important for future studies to evaluate the requirement of specific B. turicatae genes for vector colonization and transmission. C1 [Lopez, Job E.; Wilder, Hannah K.; Hargrove, Reid; Brooks, Christopher P.] Mississippi State Univ, Dept Biol Sci, Starkville, MS 39759 USA. [Peterson, Karin E.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Beare, Paul A.] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Sturdevant, Daniel E.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. [Nagarajan, Vijayaraj] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Hamilton, MT USA. [Raffel, Sandra J.; Schwan, Tom G.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Lopez, JE (reprint author), Mississippi State Univ, Dept Biol Sci, Starkville, MS 39759 USA. EM JLopez@biology.msstate.edu FU [1 K22AI091652-01A1] FX This research was supported by an 1 K22AI091652-01A1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 4 Z9 4 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD OCT PY 2013 VL 7 IS 10 AR e2514 DI 10.1371/journal.pntd.0002514 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 299DW UT WOS:000330376500045 PM 24205425 ER PT J AU Sato, T Coler-Reilly, A Utsunomiya, A Araya, N Yagishita, N Ando, H Yamauchi, J Inoue, E Ueno, T Hasegawa, Y Nishioka, K Nakajima, T Jacobson, S Izumo, S Yamano, Y AF Sato, Tomoo Coler-Reilly, Ariella Utsunomiya, Atae Araya, Natsumi Yagishita, Naoko Ando, Hitoshi Yamauchi, Junji Inoue, Eisuke Ueno, Takahiko Hasegawa, Yasuhiro Nishioka, Kusuki Nakajima, Toshihiro Jacobson, Steven Izumo, Shuji Yamano, Yoshihisa TI CSF CXCL10, CXCL9, and Neopterin as Candidate Prognostic Biomarkers for HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID I-ASSOCIATED MYELOPATHY; VIRUS TYPE-I; HTLV-1 ASSOCIATED MYELOPATHY; T-CELL LEUKEMIA; CEREBROSPINAL-FLUID; PROVIRAL LOAD; CLINICAL-FEATURES; 1-ASSOCIATED MYELOPATHY; DISEASE PROGRESSION; HAM/TSP PATIENTS AB Background: Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. Since the disease course of HAM/TSP varies among patients, there is a dire need for biomarkers capable of predicting the rate of disease progression. However, there have been no studies to date that have compared the prognostic values of multiple potential biomarkers for HAM/TSP. Methodology/Principal Findings: Peripheral blood and cerebrospinal fluid (CSF) samples from HAM/TSP patients and HTLV-1-infected control subjects were obtained and tested retrospectively for several potential biomarkers, including chemokines and other cytokines, and nine optimal candidates were selected based on receiver operating characteristic (ROC) analysis. Next, we evaluated the relationship between these candidates and the rate of disease progression in HAM/TSP patients, beginning with a first cohort of 30 patients (Training Set) and proceeding to a second cohort of 23 patients (Test Set). We defined "deteriorating HAM/TSP" as distinctly worsening function (>= 3 grades on Osame's Motor Disability Score (OMDS)) over four years and "stable HAM/TSP" as unchanged or only slightly worsened function (1 grade on OMDS) over four years, and we compared the levels of the candidate biomarkers in patients divided into these two groups. The CSF levels of chemokine (C-X-C motif) ligand 10 (CXCL10), CXCL9, and neopterin were well-correlated with disease progression, better even than HTLV-1 proviral load in PBMCs. Importantly, these results were validated using the Test Set. Conclusions/Significance: As the CSF levels of CXCL10, CXCL9, and neopterin were the most strongly correlated with rate of disease progression, they represent the most viable candidates for HAM/TSP prognostic biomarkers. The identification of effective prognostic biomarkers could lead to earlier detection of high-risk patients, more patient-specific treatment options, and more productive clinical trials. C1 [Sato, Tomoo; Coler-Reilly, Ariella; Araya, Natsumi; Yagishita, Naoko; Ando, Hitoshi; Yamauchi, Junji; Izumo, Shuji] St Marianna Univ, Sch Med, Inst Med Sci, Dept Rare Dis Res, Kawasaki, Kanagawa, Japan. [Utsunomiya, Atae] Imamura Bun In Hosp, Dept Hematol, Kagoshima, Japan. [Inoue, Eisuke] Kitasato Univ, Sch Pharm, Dept Biostat, Tokyo, Japan. [Ueno, Takahiko] St Marianna Univ, Sch Med, Med Stat Unit, Kawasaki, Kanagawa, Japan. [Hasegawa, Yasuhiro] St Marianna Univ, Sch Med, Dept Internal Med, Div Neurol, Kawasaki, Kanagawa, Japan. [Nishioka, Kusuki; Nakajima, Toshihiro] Tokyo Med Univ, Inst Med Sci, Tokyo 1608402, Japan. [Nakajima, Toshihiro] Osaka Inst Technol, Dept Biomed Engn, Osaka 535, Japan. [Jacobson, Steven] NIH, Viral Immunol Sect, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Izumo, Shuji] Kagoshima Univ, Ctr Chron Viral Dis, Kagoshima 890, Japan. RP Sato, T (reprint author), St Marianna Univ, Sch Med, Inst Med Sci, Dept Rare Dis Res, Kawasaki, Kanagawa, Japan. EM yyamano@marianna-u.ac.jp FU "Research on Measures for Intractable Diseases" Project of the Ministry of Health, Labour, and Welfare, the MEXT-Supported Program for the Strategic Research Foundation at Private Universities; Ministry of Education, Culture, Sports, Science and Technology; Takeda Science Foundation FX This work was supported by the "Research on Measures for Intractable Diseases" Project of the Ministry of Health, Labour, and Welfare, the MEXT-Supported Program for the Strategic Research Foundation at Private Universities, 2008-2012, the Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, and the Takeda Science Foundation. The funders had no role in study design, data collection or analysis, decision to publish, or preparation of the manuscript. NR 44 TC 11 Z9 11 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD OCT PY 2013 VL 7 IS 10 AR e2479 DI 10.1371/journal.pntd.0002479 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 299DW UT WOS:000330376500019 PM 24130912 ER PT J AU De Muylder, G Daulouede, S Lecordier, L Uzureau, P Morias, Y Van Den Abbeele, J Caljon, G Herin, M Holzmuller, P Semballa, S Courtois, P Vanhamme, L Stijlemans, B De Baetselier, P Barrett, MP Barlow, JL McKenzie, ANJ Barron, L Wynn, TA Beschin, A Vincendeau, P Pays, E AF De Muylder, Geraldine Daulouede, Sylvie Lecordier, Laurence Uzureau, Pierrick Morias, Yannick Van Den Abbeele, Jan Caljon, Guy Herin, Michel Holzmuller, Philippe Semballa, Silla Courtois, Pierrette Vanhamme, Luc Stijlemans, Benoit De Baetselier, Patrick Barrett, Michael P. Barlow, Jillian L. McKenzie, Andrew N. J. Barron, Luke Wynn, Thomas A. Beschin, Alain Vincendeau, Philippe Pays, Etienne TI A Trypanosoma brucei Kinesin Heavy Chain Promotes Parasite Growth by Triggering Host Arginase Activity SO PLOS PATHOGENS LA English DT Article ID EXPERIMENTAL AFRICAN TRYPANOSOMIASIS; NITRIC-OXIDE PRODUCTION; INDUCIBLE EXPRESSION SYSTEM; MASS-SPECTROMETRY DATA; IN-VITRO CULTURE; SURFACE GLYCOPROTEIN; INFECTION; RESISTANCE; MACROPHAGES; GAMMA AB Background: In order to promote infection, the blood-borne parasite Trypanosoma brucei releases factors that upregulate arginase expression and activity in myeloid cells. Methodology/Principal findings: By screening a cDNA library of T. brucei with an antibody neutralizing the arginase-inducing activity of parasite released factors, we identified a Kinesin Heavy Chain isoform, termed TbKHC1, as responsible for this effect. Following interaction with mouse myeloid cells, natural or recombinant TbKHC1 triggered SIGN-R1 receptor-dependent induction of IL-10 production, resulting in arginase-1 activation concomitant with reduction of nitric oxide (NO) synthase activity. This TbKHC1 activity was IL-4R alpha-independent and did not mirror M2 activation of myeloid cells. As compared to wild-type T. brucei, infection by TbKHC1 KO parasites was characterized by strongly reduced parasitaemia and prolonged host survival time. By treating infected mice with ornithine or with NO synthase inhibitor, we observed that during the first wave of parasitaemia the parasite growth-promoting effect of TbKHC1-mediated arginase activation resulted more from increased polyamine production than from reduction of NO synthesis. In late stage infection, TbKHC1-mediated reduction of NO synthesis appeared to contribute to liver damage linked to shortening of host survival time. Conclusion: A kinesin heavy chain released by T. brucei induces IL-10 and arginase-1 through SIGN-R1 signaling in myeloid cells, which promotes early trypanosome growth and favors parasite settlement in the host. Moreover, in the late stage of infection, the inhibition of NO synthesis by TbKHC1 contributes to liver pathogenicity. C1 [De Muylder, Geraldine; Lecordier, Laurence; Uzureau, Pierrick; Vanhamme, Luc; Beschin, Alain; Vincendeau, Philippe] Univ Libre Brussels, IBMM, Mol Parasitol Lab, Gosselies, Belgium. [Daulouede, Sylvie; Holzmuller, Philippe; Semballa, Silla; Courtois, Pierrette; Pays, Etienne] Univ Bordeaux, IRD CIRAD, Parasitol Lab, UMR 177, Bordeaux, France. [Morias, Yannick; Caljon, Guy; Stijlemans, Benoit; De Baetselier, Patrick; Beschin, Alain] VIB Brussels, Myeloid Cell Immunol Lab, Brussels, Belgium. [Morias, Yannick; Caljon, Guy; Stijlemans, Benoit; De Baetselier, Patrick; Beschin, Alain] Vrije Univ Brussel, Cellular & Mol Immunol Unit, Brussels, Belgium. [Van Den Abbeele, Jan; Caljon, Guy] Prins Leopold Inst Trop Med Antwerp, Dept Biomed Sci, Vet Protozool Unit, Antwerp, Belgium. [Herin, Michel] Inst Pathol & Genet, Dept Pathol, Gosselies, Belgium. [Barrett, Michael P.] Univ Glasgow, Coll Med Vet & Life Sci, Wellcome Trust Ctr Mol Parasitol, Inst Infect Immun & Inflammat, Glasgow, Lanark, Scotland. [Barrett, Michael P.] Univ Glasgow, Glasgow Poly Facil, Glasgow, Lanark, Scotland. [Barlow, Jillian L.; McKenzie, Andrew N. J.] MRC, Mol Biol Lab, Cambridge CB2 2QH, England. [Barron, Luke; Wynn, Thomas A.] NIAID, Parasit Dis Lab, Immunopathogenesis Sect, NIH, Bethesda, MD 20892 USA. RP De Muylder, G (reprint author), Univ Libre Brussels, IBMM, Mol Parasitol Lab, Gosselies, Belgium. EM abeschin@ulb.ac.be RI De Baetselier, Patrick/D-3866-2014; Caljon, Guy/E-1310-2017; OI Caljon, Guy/0000-0002-4870-3202; Stijlemans, Benoit/0000-0003-0082-9751; Barrett, Mike/0000-0001-9447-3519 FU Belgian National Fund for Scientific Research (FRSM); J. Brachet Fund; Interuniversity Attraction Poles Programme - Belgian Science Policy; Conseil Regional d'Aquitaine (France); IWT-Vlaanderen FX The work was supported by the Belgian National Fund for Scientific Research (FRSM, http://www2.frs-fnrs.be/), the J. Brachet Fund (http://www.ulb.ac.be/brachet/actions.htm), the Interuniversity Attraction Poles Programme - Belgian Science Policy (http://www.belspo.be) and the Conseil Regional d'Aquitaine (France, www.aquitaine.fr/institution/conseil-regional/). GDM is Research Fellow at the FRIA (http://www2.frs-fnrs.be/). YM is funded by the IWT-Vlaanderen (www.iwt.be/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 12 Z9 12 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2013 VL 9 IS 10 AR e1003731 DI 10.1371/journal.ppat.1003731 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 299GJ UT WOS:000330383800090 PM 24204274 ER PT J AU Mehedi, M Hoenen, T Robertson, S Ricklefs, S Dolan, MA Taylor, T Falzarano, D Ebihara, H Porcella, SF Feldmann, H AF Mehedi, Masfique Hoenen, Thomas Robertson, Shelly Ricklefs, Stacy Dolan, Michael A. Taylor, Travis Falzarano, Darryl Ebihara, Hideki Porcella, Stephen F. Feldmann, Heinz TI Ebola Virus RNA Editing Depends on the Primary Editing Site Sequence and an Upstream Secondary Structure SO PLOS PATHOGENS LA English DT Article ID MESSENGER-RNA; MOLECULAR-DYNAMICS; WEB SERVER; TRANSCRIPTION; REPLICATION; PROTEIN; GP; POLYMERASE; PREDICTION; SYSTEMS AB Ebolavirus (EBOV), the causative agent of a severe hemorrhagic fever and a biosafety level 4 pathogen, increases its genome coding capacity by producing multiple transcripts encoding for structural and nonstructural glycoproteins from a single gene. This is achieved through RNA editing, during which non-template adenosine residues are incorporated into the EBOV mRNAs at an editing site encoding for 7 adenosine residues. However, the mechanism of EBOV RNA editing is currently not understood. In this study, we report for the first time that minigenomes containing the glycoprotein gene editing site can undergo RNA editing, thereby eliminating the requirement for a biosafety level 4 laboratory to study EBOV RNA editing. Using a newly developed dual-reporter minigenome, we have characterized the mechanism of EBOV RNA editing, and have identified cis-acting sequences that are required for editing, located between 9 nt upstream and 9 nt downstream of the editing site. Moreover, we show that a secondary structure in the upstream cis-acting sequence plays an important role in RNA editing. EBOV RNA editing is glycoprotein gene-specific, as a stretch encoding for 7 adenosine residues located in the viral polymerase gene did not serve as an editing site, most likely due to an absence of the necessary cis-acting sequences. Finally, the EBOV protein VP30 was identified as a trans-acting factor for RNA editing, constituting a novel function for this protein. Overall, our results provide novel insights into the RNA editing mechanism of EBOV, further understanding of which might result in novel intervention strategies against this viral pathogen. C1 [Mehedi, Masfique; Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Mehedi, Masfique; Hoenen, Thomas; Robertson, Shelly; Taylor, Travis; Falzarano, Darryl; Ebihara, Hideki; Feldmann, Heinz] NIAID, Virol Lab, Rocky Mt Labs, Div Intramural Res,NIH, Hamilton, MT USA. [Ricklefs, Stacy; Porcella, Stephen F.] NIAID, Res Technol Branch, Genom Unit, Rocky Mt Labs,NIH, Hamilton, MT USA. [Dolan, Michael A.] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. RP Mehedi, M (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. EM feldmannh@niaid.nih.gov RI Mehedi, masfique/J-6618-2014; OI Mehedi, masfique/0000-0003-1728-3126; Hoenen, Thomas/0000-0002-5829-6305 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. This work is part of the Ph.D. thesis of MM, Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 17 Z9 18 U1 2 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2013 VL 9 IS 10 AR e1003677 DI 10.1371/journal.ppat.1003677 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 299GJ UT WOS:000330383800047 PM 24146620 ER PT J AU Saijo, E Kang, HE Bian, JF Bowling, KG Browning, S Kim, S Hunter, N Telling, GC AF Saijo, Eri Kang, Hae-Eun Bian, Jifeng Bowling, Kristi G. Browning, Shawn Kim, Sehun Hunter, Nora Telling, Glenn C. TI Epigenetic Dominance of Prion Conformers SO PLOS PATHOGENS LA English DT Article ID TRANSGENIC MICE; SPONGIFORM ENCEPHALOPATHY; NATURAL SCRAPIE; SHEEP SCRAPIE; OVINE PRP; MOUSE LINES; PROTEIN; ISOLATE; TRANSMISSION; CONFORMATION AB Although they share certain biological properties with nucleic acid based infectious agents, prions, the causative agents of invariably fatal, transmissible neurodegenerative disorders such as bovine spongiform encephalopathy, sheep scrapie, and human Creutzfeldt Jakob disease, propagate by conformational templating of host encoded proteins. Once thought to be unique to these diseases, this mechanism is now recognized as a ubiquitous means of information transfer in biological systems, including other protein misfolding disorders such as those causing Alzheimer's and Parkinson's diseases. To address the poorly understood mechanism by which host prion protein (PrP) primary structures interact with distinct prion conformations to influence pathogenesis, we produced transgenic (Tg) mice expressing different sheep scrapie susceptibility alleles, varying only at a single amino acid at PrP residue 136. Tg mice expressing ovine PrP with alanine (A) at (OvPrP-A136) infected with SSBP/1 scrapie prions propagated a relatively stable (S) prion conformation, which accumulated as punctate aggregates in the brain, and produced prolonged incubation times. In contrast, Tg mice expressing OvPrP with valine (V) at 136 (OvPrP-V136) infected with the same prions developed disease rapidly, and the converted prion was comprised of an unstable (U), diffusely distributed conformer. Infected Tg mice co-expressing both alleles manifested properties consistent with the U conformer, suggesting a dominant effect resulting from exclusive conversion of OvPrP-V136 but not OvPrP-A136. Surprisingly, however, studies with monoclonal antibody (mAb) PRC5, which discriminates OvPrP-A136 from OvPrP-V136, revealed substantial conversion of OvPrP-A136. Moreover, the resulting OvPrP-A136 prion acquired the characteristics of the U conformer. These results, substantiated by in vitro analyses, indicated that co-expression of OvPrP-V136 altered the conversion potential of OvPrP-A136 from the S to the otherwise unfavorable U conformer. This epigenetic mechanism thus expands the range of selectable conformations that can be adopted by PrP, and therefore the variety of options for strain propagation. C1 [Saijo, Eri; Kang, Hae-Eun; Bian, Jifeng; Kim, Sehun; Telling, Glenn C.] Colorado State Univ, PRC, Ft Collins, CO 80523 USA. [Saijo, Eri; Kang, Hae-Eun; Bian, Jifeng; Kim, Sehun; Telling, Glenn C.] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Saijo, Eri; Bowling, Kristi G.; Browning, Shawn] Univ Kentucky, Dept Microbiol Immunol & Mol Genet, Lexington, KY USA. [Hunter, Nora] Roslin Inst, Roslin, Midlothian, Scotland. [Hunter, Nora] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. [Hunter, Nora] Colorado State Univ, Cellular & Mol Biol CMB Program, Ft Collins, CO 80523 USA. [Hunter, Nora] Colorado State Univ, Cellular Integrated Neurosci MCIN Program, Ft Collins, CO 80523 USA. RP Saijo, E (reprint author), NIAID, LPVD, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM glenn.telling@colostate.edu FU NIH [RO1 NS040334, PO1 AI077774]; Defra UK [SE1440] FX This work was supported by NIH grants RO1 NS040334 (GCT), PO1 AI077774 (GCT), and by Defra UK for project SE1440 (NH and GCT, http://www.nih.gov; http://www.defra.gov.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 8 Z9 9 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2013 VL 9 IS 10 AR e1003692 DI 10.1371/journal.ppat.1003692 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 299GJ UT WOS:000330383800061 PM 24204258 ER PT J AU Tong, SX Zhu, XY Li, Y Shi, M Zhang, J Bourgeois, M Yang, H Chen, XF Recuenco, S Gomez, J Chen, LM Johnson, A Tao, Y Dreyfus, C Yu, WL McBride, R Carney, PJ Gilbert, AT Chang, J Guo, Z Davis, CT Paulson, JC Stevens, J Rupprecht, CE Holmes, EC Wilson, IA Donis, RO AF Tong, Suxiang Zhu, Xueyong Li, Yan Shi, Mang Zhang, Jing Bourgeois, Melissa Yang, Hua Chen, Xianfeng Recuenco, Sergio Gomez, Jorge Chen, Li-Mei Johnson, Adam Tao, Ying Dreyfus, Cyrille Yu, Wenli McBride, Ryan Carney, Paul J. Gilbert, Amy T. Chang, Jessie Guo, Zhu Davis, Charles T. Paulson, James C. Stevens, James Rupprecht, Charles E. Holmes, Edward C. Wilson, Ian A. Donis, Ruben O. TI New World Bats Harbor Diverse Influenza A Viruses SO PLOS PATHOGENS LA English DT Article ID HEMAGGLUTININ MEMBRANE GLYCOPROTEIN; MAXIMUM-LIKELIHOOD; VIRAL POLYMERASE; PB2 PROTEIN; SARS-LIKE; SEGMENT 3; NEURAMINIDASE; BINDING; HOST; CORONAVIRUSES AB Aquatic birds harbor diverse influenza A viruses and are a major viral reservoir in nature. The recent discovery of influenza viruses of a new H17N10 subtype in Central American fruit bats suggests that other New World species may similarly carry divergent influenza viruses. Using consensus degenerate RT-PCR, we identified a novel influenza A virus, designated as H18N11, in a flat-faced fruit bat (Artibeus planirostris) from Peru. Serologic studies with the recombinant H18 protein indicated that several Peruvian bat species were infected by this virus. Phylogenetic analyses demonstrate that, in some gene segments, New World bats harbor more influenza virus genetic diversity than all other mammalian and avian species combined, indicative of a long-standing host-virus association. Structural and functional analyses of the hemagglutinin and neuraminidase indicate that sialic acid is not a ligand for virus attachment nor a substrate for release, suggesting a unique mode of influenza A virus attachment and activation of membrane fusion for entry into host cells. Taken together, these findings indicate that bats constitute a potentially important and likely ancient reservoir for a diverse pool of influenza viruses. C1 [Tong, Suxiang; Li, Yan; Zhang, Jing; Chen, Xianfeng; Tao, Ying] Ctr Dis Control & Prevent, Div Viral Dis, Atlanta, GA 30332 USA. [Zhu, Xueyong; Dreyfus, Cyrille; Yu, Wenli; Paulson, James C.; Wilson, Ian A.] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Shi, Mang; Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Shi, Mang; Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Bourgeois, Melissa; Yang, Hua; Chen, Li-Mei; Johnson, Adam; Carney, Paul J.; Chang, Jessie; Guo, Zhu; Davis, Charles T.; Stevens, James; Donis, Ruben O.] Ctr Dis Control & Prevent, Influenza Div, Atlanta, GA USA. [Recuenco, Sergio; Gilbert, Amy T.; Rupprecht, Charles E.] Ctr Dis Control & Prevent, Div High Consequence Pathogens & Pathol, Atlanta, GA USA. [Gomez, Jorge] Minist Salud MINSA, Direcc Gen Epidemiol, Lima, Peru. [McBride, Ryan; Paulson, James C.] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. [Rupprecht, Charles E.] Scripps Res Inst, Global Alliance Rabies Control, La Jolla, CA 92037 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. RP Tong, SX (reprint author), Ctr Dis Control & Prevent, Div Viral Dis, Atlanta, GA 30332 USA. EM sot1@cdc.gov; fwb4@cdc.gov; charles_rupprecht@yahoo.com; edward.holmes@sydney.edu.au; wilson@scripps.edu; rvd6@cdc.gov OI Recuenco-Cabrera, Sergio/0000-0002-8446-7411; Holmes, Edward/0000-0001-9596-3552 FU NIH [AI058113, GM062116, GM098791, GM080533-06]; CDC; Skaggs Institute for Chemical Biology; DOE Office of Biological and Environmental Research; NIH, National Center for Research Resources, Biomedical Technology Program [P41RR001209]; National Institute of General Medical Sciences; National Cancer Institute [Y1-CO-1020]; NIGMS [Y1-GM-1104]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357, W-31-109-Eng-38]; Global Disease Detection program TSC funds in the Centers for Disease Control and Prevention, Atlanta, Georgia; collaborative Centers for Disease Control and Prevention-University of Georgia Seed Award FX The work was supported in part by NIH grant AI058113 (IAW and JCP), a contract from the CDC (JCP), and the Skaggs Institute for Chemical Biology. Portions of this research were conducted at SSRL, a national user facility operated by Stanford University on behalf of the U. S. Department of Energy (DOE), Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by NIH, National Center for Research Resources, Biomedical Technology Program (P41RR001209), and the National Institute of General Medical Sciences. The GM/CA CAT 23-ID-D beamline has been funded in whole or in part with federal funds from National Cancer Institute (Y1-CO-1020) and NIGMS (Y1-GM-1104). Supporting institutions for SER-CAT 22-ID may be found at www.ser-cat.org/members.html. Use of the Advanced Photon Source (APS) was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract no. DE-AC02-06CH11357 and contract no. W-31-109-Eng-38. Glycans for the arrays were provided by the Consortium for Functional Glycomics funded by NIH grants GM062116 and GM098791. This is publication 21954 from The Scripps Research Institute. ECH was supported in part by NIH grant GM080533-06. The study was supported in part by the Global Disease Detection program TSC funds in the Centers for Disease Control and Prevention, Atlanta, Georgia (ST) and in part by a collaborative Centers for Disease Control and Prevention-University of Georgia Seed Award (ST). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 314 Z9 345 U1 19 U2 102 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2013 VL 9 IS 10 AR e1003657 DI 10.1371/journal.ppat.1003657 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 299GJ UT WOS:000330383800029 PM 24130481 ER PT J AU Xu, K Rockx, B Xie, YH DeBuysscher, BL Fusco, DL Zhu, ZY Chan, YP Xu, Y Luu, T Cer, RZ Feldmann, H Mokashi, V Dimitrov, DS Bishop-Lilly, KA Broder, CC Nikolov, DB AF Xu, Kai Rockx, Barry Xie, Yihu DeBuysscher, Blair L. Fusco, Deborah L. Zhu, Zhongyu Chan, Yee-Peng Xu, Yan Truong Luu Cer, Regina Z. Feldmann, Heinz Mokashi, Vishwesh Dimitrov, Dimiter S. Bishop-Lilly, Kimberly A. Broder, Christopher C. Nikolov, Dimitar B. TI Crystal Structure of the Hendra Virus Attachment G Glycoprotein Bound to a Potent Cross-Reactive Neutralizing Human Monoclonal Antibody SO PLOS PATHOGENS LA English DT Article ID TO-PERSON TRANSMISSION; NIPAH VIRUS; HIV-1; INFECTION; THERAPEUTICS; BANGLADESH; FUSION; MODEL; PG16 AB The henipaviruses, represented by Hendra (HeV) and Nipah (NiV) viruses are highly pathogenic zoonotic paramyxoviruses with uniquely broad host tropisms responsible for repeated outbreaks in Australia, Southeast Asia, India and Bangladesh. The high morbidity and mortality rates associated with infection and lack of licensed antiviral therapies make the henipaviruses a potential biological threat to humans and livestock. Henipavirus entry is initiated by the attachment of the G envelope glycoprotein to host cell membrane receptors. Previously, henipavirus-neutralizing human monoclonal antibodies (hmAb) have been isolated using the HeV-G glycoprotein and a human naive antibody library. One cross-reactive and receptor-blocking hmAb (m102.4) was recently demonstrated to be an effective post-exposure therapy in two animal models of NiV and HeV infection, has been used in several people on a compassionate use basis, and is currently in development for use in humans. Here, we report the crystal structure of the complex of HeV-G with m102.3, an m102.4 derivative, and describe NiV and HeV escape mutants. This structure provides detailed insight into the mechanism of HeV and NiV neutralization by m102.4, and serves as a blueprint for further optimization of m102.4 as a therapeutic agent and for the development of entry inhibitors and vaccines. C1 [Xu, Kai; Xie, Yihu; Xu, Yan; Nikolov, Dimitar B.] Mem Sloan Kettering Canc Ctr, Struct Biol Program, New York, NY 10021 USA. [Rockx, Barry] Univ Texas Med Branch, Dept Pathol, Sealy Ctr Vaccine Dev, Galveston, TX 77555 USA. [Rockx, Barry] Univ Texas Med Branch, Dept Microbiol & Immunol, Sealy Ctr Vaccine Dev, Galveston, TX 77555 USA. [DeBuysscher, Blair L.; Feldmann, Heinz] NIH, Virol Lab, Rocky Mt Labs, Hamilton, MT USA. [DeBuysscher, Blair L.] Univ Montana, Div Biol Sci, Missoula, MT 59812 USA. [DeBuysscher, Blair L.] Univ Montana, Missoula, MT 59812 USA. [Fusco, Deborah L.; Chan, Yee-Peng; Broder, Christopher C.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Zhu, Zhongyu; Dimitrov, Dimiter S.] NIH, Prot Interact Grp, CCRNP, CCR,Frederick Natl Lab Canc Res, Frederick, MD USA. [Truong Luu; Cer, Regina Z.; Mokashi, Vishwesh; Bishop-Lilly, Kimberly A.] NMRC Frederick, Naval Med Res Ctr, Ft Detrick, MD USA. [Truong Luu; Cer, Regina Z.; Bishop-Lilly, Kimberly A.] Henry M Jackson Fdn, Bethesda, MD USA. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Xu, K (reprint author), Mem Sloan Kettering Canc Ctr, Struct Biol Program, 1275 York Ave, New York, NY 10021 USA. EM nikolovd@mskcc.org FU Department of Health and Human Services, National Institutes of Health [AI054715, AI077995, NS38586]; CCR, NCI, NIH FX These studies were supported in part by the Department of Health and Human Services, National Institutes of Health, grants AI054715 and AI077995 to CCB, NS38586 to DBN and by the Intramural Research Program of the CCR, NCI, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 6 Z9 6 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2013 VL 9 IS 10 AR e1003684 DI 10.1371/journal.ppat.1003684 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 299GJ UT WOS:000330383800053 PM 24130486 ER PT J AU Parent, CA Weiner, OD AF Parent, Carole A. Weiner, Orion D. TI The symphony of cell movement: how cells orchestrate diverse signals and forces to control migration Editorial overview SO CURRENT OPINION IN CELL BIOLOGY LA English DT Editorial Material C1 [Parent, Carole A.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Weiner, Orion D.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA. [Weiner, Orion D.] Dept Biochem & Biophys, San Francisco, CA 94158 USA. RP Parent, CA (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM parentc@mail.nih.gov; orion.weiner@ucsf.edu RI Weiner, Orion/F-2576-2011 OI Weiner, Orion/0000-0002-1778-6543 FU NIGMS NIH HHS [R01 GM084040] NR 0 TC 7 Z9 7 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD OCT PY 2013 VL 25 IS 5 BP 523 EP 525 DI 10.1016/j.ceb.2013.07.011 PG 3 WC Cell Biology SC Cell Biology GA 294FY UT WOS:000330030200001 PM 23927870 ER PT J AU Jin, T AF Jin, Tian TI Gradient sensing during chemotaxis SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID LEADING-EDGE; EUKARYOTIC CHEMOTAXIS; LIVING CELLS; G-PROTEIN; NEUTROPHIL CHEMOTAXIS; INTERACTION DYNAMICS; MEDIATED ACTIVATION; CELLULAR MOTILITY; SIGNALING EVENTS; LYMPHOID ORGANS AB Eukaryotic cells have the ability to sense chemoattractant gradients and to migrate toward the sources of attractants. The chemical gradient-guided cell movement is referred to as chemotaxis. Chemoattractants are detected by members of G-protein-coupled receptors (GPCRs) that link to heterotrimeric G-proteins. The GPCR/G-protein sensing machinery is able to translate external chemoattractants fields into intercellular cues, which direct reorganization of the actin cytoskeleton that drives cell movement. Here, I review our current understanding of the formation of chemoattractant gradients in vivo, the GPCR-mediated gradient sensing, and the sophisticated signaling network that guides the function of the actin cytoskeleton. C1 NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH,Twinbrook Facil 2, Rockville, MD 20852 USA. RP Jin, T (reprint author), NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH,Twinbrook Facil 2, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM tjin@niaid.nih.gov FU NIAID, NIH FX Jin is supported by intramural fund from NIAID, NIH. NR 57 TC 22 Z9 23 U1 2 U2 14 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD OCT PY 2013 VL 25 IS 5 BP 532 EP 537 DI 10.1016/j.ceb.2013.06.007 PG 6 WC Cell Biology SC Cell Biology GA 294FY UT WOS:000330030200003 PM 23880435 ER PT J AU Plotnikov, SV Waterman, CM AF Plotnikov, Sergey V. Waterman, Clare M. TI Guiding cell migration by tugging SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID FOCAL ADHESION MATURATION; NONMUSCLE MYOSIN-II; ACTIN-FILAMENTS; SUBSTRATE RIGIDITY; STRESS-FIBER; MECHANICAL INTERACTIONS; NEUTROPHIL MIGRATION; MOLECULAR MOTORS; LIVING CELLS; INTEGRIN AB The ability of cells to move directionally toward areas of stiffer extracellular matrix (ECM) via a process known as 'durotaxis' is thought to be critical for development and wound healing, but durotaxis can also drive cancer metastasis. Migration is driven by integrin-mediated focal adhesions (FAs), protein assemblies that couple contractile actomyosin bundles to the plasma membrane, transmit force generated by the cytoskeleton to the ECM, and convert the mechanical properties of the microenvironment into biochemical signals. To probe the stiffness of the ECM, motile fibroblasts modulate FA mechanics on the nanoscale and exert forces that are reminiscent of repeated tugging on the ECM. Within a single cell, all FAs tug autonomously and thus act as local rigidity sensors, allowing discernment of differences in the extracellular matrix rigidity at high spatial resolution. In this article, we review current advances that may shed light on the mechanism of traction force fluctuations within FAs. We also examine plausible downstream effectors of tugging forces which may regulate cytoskeletal and FA dynamics to guide cell migration in response to ECM stiffness gradients. C1 [Plotnikov, Sergey V.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Waterman, CM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM watermancm@nhlbi.nih.gov OI Waterman, Clare/0000-0001-6142-6775 FU Division of Intramural Research, National Heart Lung and Blood Institute FX The authors are grateful to Dr. Jian Liu for helpful discussion on the molecular basis of force fluctuations. We thank Dr. Gregory Alushin for careful reading and commenting on the manuscript. This research was supported by the Division of Intramural Research, National Heart Lung and Blood Institute. NR 87 TC 43 Z9 43 U1 4 U2 57 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD OCT PY 2013 VL 25 IS 5 BP 619 EP 626 DI 10.1016/j.ceb.2013.06.003 PG 8 WC Cell Biology SC Cell Biology GA 294FY UT WOS:000330030200014 PM 23830911 ER PT J AU Doyle, AD Petrie, RJ Kutys, ML Yamada, KM AF Doyle, Andrew D. Petrie, Ryan J. Kutys, Matthew L. Yamada, Kenneth M. TI Dimensions in cell migration SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID 3-DIMENSIONAL COLLAGEN MATRICES; PERICELLULAR PROTEOLYSIS; ACTIN CYTOSKELETON; FOCAL ADHESIONS; DISTINCT ROLES; MYOSIN-IIA; INVASION; FIBROBLASTS; RIGIDITY; METASTASIS AB The importance of cell migration for both normal physiological functions and disease processes has been clear for the past 50 years. Although investigations of two-dimensional (2D) migration in regular tissue culture have elucidated many important molecular mechanisms, recent evidence suggests that cell migration depends profoundly on the dimensionality of the extracellular matrix (ECM). Here we review a number of evolving concepts revealed when cell migration is examined in different dimensions. C1 [Doyle, Andrew D.; Petrie, Ryan J.; Kutys, Matthew L.; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Doyle, AD (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. EM adoyle@mail.nih.gov; kenneth.yamada@nih.gov OI Kutys, Matthew /0000-0002-0752-649X FU National Institute of Dental and Craniofacial Research at the National Institutes of Health FX We thank Emily Joo and Duy Tran for critically reviewing this manuscript and Tim Lammermann for helpful suggestions. Support was provided by the intramural research program of the National Institute of Dental and Craniofacial Research at the National Institutes of Health. NR 64 TC 55 Z9 55 U1 4 U2 33 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD OCT PY 2013 VL 25 IS 5 BP 642 EP 649 DI 10.1016/j.ceb.2013.06.004 PG 8 WC Cell Biology SC Cell Biology GA 294FY UT WOS:000330030200017 PM 23850350 ER PT J AU Moskvina, V Harold, D Russo, G Vedemikov, A Sharma, M Saad, M Holmans, P Bras, JM Bettella, F Keller, MF Nicolaou, N Simon-Sanchez, J Gibbs, JR Schulte, C Durr, A Guerreiro, R Hernandez, D Brice, A Stefansson, H Majamaa, K Gasser, T Heutink, P Wood, N Martinez, M Singleton, AB Nalls, MA Hardy, J Owen, MJ O'Donovan, MC Williams, J Morris, HR Williams, NM AF Moskvina, Valentina Harold, Denise Russo, GianCarlo Vedemikov, Alexey Sharma, Manu Saad, Mohamad Holmans, Peter Bras, Jose M. Bettella, Francesco Keller, Margaux F. Nicolaou, Nayia Simon-Sanchez, Javier Gibbs, J. Raphael Schulte, Claudia Durr, Alexandra Guerreiro, Rita Hernandez, Dena Brice, Alexis Stefansson, Hreinn Majamaa, Kari Gasser, Thomas Heutink, Peter Wood, Nick Martinez, Maria Singleton, Andrew B. Nalls, Michael A. Hardy, John Owen, Michael J. O'Donovan, Michael C. Williams, Julie Morris, Huw R. Williams, Nigel M. CA IPDGC Investigator GERAD Investigator TI Analysis of Genome-Wide Association Studies of Alzheimer Disease and of Parkinson Disease to Determine If These 2 Diseases Share a Common Genetic Risk SO JAMA NEUROLOGY LA English DT Article ID HEXANUCLEOTIDE REPEAT; IDENTIFIES VARIANTS; DEMENTIA; STRATIFICATION; METAANALYSIS; RELATIVES; MEDICINE; PATHWAY; C9ORF72; REGION AB IMPORTANCE Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders. OBJECTIVE To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD. DESIGN Combined GWA analysis. SETTING Data sets from the United Kingdom, Germany, France, and the United States. PARTICIPANTS Thousands of patients with AD or PD and their controls. MAIN OUTCOMES AND MEASURES Meta-analysis of GWA studies of AD and PD. METHODS To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies. We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD. RESULTS Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD. CONCLUSION AND RELEVANCE Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be "downstream" of the primary susceptibility genes that increase the risk of each disease. C1 [Moskvina, Valentina; Harold, Denise; Russo, GianCarlo; Vedemikov, Alexey; Holmans, Peter; Owen, Michael J.; O'Donovan, Michael C.; Williams, Julie; Morris, Huw R.; Williams, Nigel M.] Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, MRC,Ctr Neuropsychiat Genet & Genom, Cardiff CF14 4XN, S Glam, Wales. [Sharma, Manu; Schulte, Claudia; Gasser, Thomas] Univ Tubingen, Dept Neurodegenerat Dis, Hertie Inst Clin Brain Res, Tubingen, Germany. [Sharma, Manu; Schulte, Claudia; Gasser, Thomas] Univ Tubingen, Insitute Clin Epidemiol & Appl Biometry, Tubingen, Germany. [Saad, Mohamad; Durr, Alexandra; Martinez, Maria] Fac Med Toulouse, INSERM, UMR1043, Ctr Physiopathol Toulouse Purpan, F-31073 Toulouse, France. [Saad, Mohamad; Martinez, Maria] Univ Toulouse 3, F-31062 Toulouse, France. [Bras, Jose M.; Gibbs, J. Raphael; Guerreiro, Rita; Hernandez, Dena; Wood, Nick; Hardy, John] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Bettella, Francesco; Stefansson, Hreinn] deCODE Genet, Sci Serv, Reykjavik, Iceland. [Keller, Margaux F.; Gibbs, J. Raphael; Hernandez, Dena; Singleton, Andrew B.; Nalls, Michael A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Nicolaou, Nayia; Simon-Sanchez, Javier; Heutink, Peter] Vrije Univ Amsterdam, Med Ctr, Sect Med Genom, Dept Clin Genet, Amsterdam, Netherlands. [Schulte, Claudia; Gasser, Thomas] German Ctr Neurodegenerat Dis, Tubingen, Germany. [Durr, Alexandra; Brice, Alexis] Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975, Paris, France. [Durr, Alexandra; Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Dept Genet, Paris, France. [Brice, Alexis] INSERM, Paris, France. [Brice, Alexis] CNRS, UMR 7225, Paris, France. [Majamaa, Kari] Univ Oulu, Dept Neurol, Inst Clin Med, SF-90100 Oulu, Finland. [Wood, Nick] UCL, Genet Inst, London, England. RP Moskvina, V (reprint author), Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, MRC,Ctr Neuropsychiat Genet & Genom, Henry Wellcome Bldg,Heath Pk, Cardiff CF14 4XN, S Glam, Wales. EM moskvinav1@cf.ac.uk RI Morris, Huw/B-8527-2008; Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009; Bras, Jose/A-1428-2011; Holmans, Peter/F-4518-2015; Martinez, Maria/B-3111-2013; Guerreiro, Rita/A-1327-2011; corvol, jean-christophe/I-6387-2012; Trabzuni, Daniah/C-4034-2012; OI Escott-Price, Valentina/0000-0003-1784-5483; Morris, Huw/0000-0002-5473-3774; Holmans, Peter/0000-0003-0870-9412; Martinez, Maria/0000-0003-2180-4537; corvol, jean-christophe/0000-0001-7325-0199; Bras, Jose/0000-0001-8186-0333; Stefansson, Hreinn/0000-0002-9331-6666; O'Donovan, Michael/0000-0001-7073-2379; Trabzuni, Daniah/0000-0003-4826-9570; Harold, Denise/0000-0001-5195-0143; Plagnol, Vincent/0000-0002-5597-9215; Bhatia, Kailash/0000-0001-8185-286X FU Parkinson's United Kingdom [K0906, 8047, J-0804]; Medical Research Council [G0700943]; Department of Health National Institute for Health Research Biomedical Research Centre; German National Genome Network from the German Ministry for Education and Research [01GS08134]; National Institute on Aging, National Institutes of Health, Department of Health and Human Services [ZO1AG000949-06, ZO1AG000950-10]; French National Agency of Research [ANR-08-MNP-012]; National Research Funding Agency [ANR-08-NEUR-004-01] FX This work was supported by Parkinson's United Kingdom (formerly The PD society; reference K0906; grants 8047 and J-0804) and the Medical Research Council (grant G0700943). In addition, part of the study was undertaken at the University College Hospital/University College London (UCL) using funding from the Department of Health National Institute for Health Research Biomedical Research Centre. The German work was also supported by the German National Genome Network (plus grant 01GS08134 from the German Ministry for Education and Research). This work was also supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services (projects ZO1AG000949-06 and ZO1AG000950-10). The French GWA scan work was supported by the French National Agency of Research (www.agence-nationale-recherche.fr; grant ANR-08-MNP-012) and by the National Research Funding Agency (grant ANR-08-NEUR-004-01) in the ERA-NET NEURON framework (www.neuron-eranet.eu). NR 38 TC 23 Z9 23 U1 1 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD OCT PY 2013 VL 70 IS 10 BP 1268 EP 1276 DI 10.1001/jamaneurol.2013.448 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 295KG UT WOS:000330114400010 PM 23921447 ER PT J AU Kang, JH Irwin, DJ Chen-Plotkin, AS Siderowf, A Caspell, C Coffey, CS Waligorska, T Taylor, P Pan, S Frasier, M Marek, K Kieburtz, K Jennings, D Simuni, T Tanner, CM Singleton, A Toga, AW Chowdhury, S Mollenhauer, B Trojanowski, JQ Shaw, LM AF Kang, Ju-Hee Irwin, David J. Chen-Plotkin, Alice S. Siderowf, Andrew Caspell, Chelsea Coffey, Christopher S. Waligorska, Teresa Taylor, Pegg Pan, Sarah Frasier, Mark Marek, Kenneth Kieburtz, Karl Jennings, Danna Simuni, Tanya Tanner, Caroline M. Singleton, Andrew Toga, Arthur W. Chowdhury, Sohini Mollenhauer, Brit Trojanowski, John Q. Shaw, Leslie M. CA Parkinson's Progression Markers TI Association of Cerebrospinal Fluid beta-Amyloid 1-42, T-tau, P-tau(181), and alpha-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease SO JAMA NEUROLOGY LA English DT Article ID DATA-DRIVEN APPROACH; ALZHEIMERS-DISEASE; LEWY BODIES; CSF BIOMARKERS; COGNITIVE IMPAIRMENT; INCIDENT DEMENTIA; MOTOR SUBTYPE; HETEROGENEITY; DECLINE; PHOSPHORYLATION AB IMPORTANCE We observed a significant correlation between cerebrospinal fluid (CSF) levels of tau proteins and alpha-synuclein, but not beta-amyloid 1-42 (A beta 1-42), and lower concentration of CSF biomarkers, as compared with healthy controls, in a cohort of entirely untreated patients with Parkinson disease (PD) at the earliest stage of the disease studied so far. OBJECTIVE To evaluate the baseline characteristics and relationship to clinical features of CSF biomarkers (A beta 1-42, total tau [T-tau], tau phosphorylated at threonine 181 [P-tau(181)], and alpha-synuclein) in drug-naive patients with early PD and demographically matched healthy controls enrolled in the Parkinson's Progression Markers Initiative (PPMI) study. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of the initial 102 research volunteers (63 patients with PD and 39 healthy controls) of the PPMI cohort. MAIN OUTCOMES AND MEASURES The CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (A beta 1-42, T-tau, and P-tau(181); Innogenetics Inc) or by enzyme-linked immunosorbent assay (alpha-synuclein). Clinical features including diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments, and DaTscan were systematically assessed according to the PPMI study protocol. RESULTS Slightly, but significantly, lower levels of A beta 1-42, T-tau, P-tau(181), alpha-synuclein, and T-tau/A beta 1-42 were seen in subjects with PD compared with healthy controls but with a marked overlap between groups. Using multivariate regression analysis, we found that lower A beta 1-42 and P-tau(181) levels were associated with PD diagnosis and that decreased CSF T-tau and alpha-synuclein were associated with increased motor severity. Notably, when we classified patients with PD by their motor phenotypes, lower CSF A beta 1-42 and P-tau(181) concentrations were associated with the postural instability-gait disturbance-dominant phenotype but not with the tremor-dominant or intermediate phenotype. Finally, we found a significant correlation of the levels of alpha-synuclein with the levels of T-tau and P-tau(181). CONCLUSIONS AND RELEVANCE In this first report of CSF biomarkers in PPMI study subjects, we found that measures or CSF A beta 1-42, T-tau, P-tau(181), and alpha-synuclein have prognostic and diagnostic potential in early-stage PD. Further investigations using the entire PPMI cohort will test the predictive performance of CSF biomarkers for PD progression. C1 [Kang, Ju-Hee; Waligorska, Teresa; Pan, Sarah; Trojanowski, John Q.; Shaw, Leslie M.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Kang, Ju-Hee] Inha Univ, Sch Med, Dept Pharmacol, Inchon, South Korea. [Irwin, David J.; Chen-Plotkin, Alice S.] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Irwin, David J.; Chen-Plotkin, Alice S.; Trojanowski, John Q.] Univ Penn, Perelman Sch Med, Morris K Udall Ctr Excellence Parkinsons Dis Res, Philadelphia, PA 19104 USA. [Siderowf, Andrew] Avid Radiopharmaceut, Philadelphia, PA USA. [Caspell, Chelsea; Coffey, Christopher S.] Univ Iowa, Coll Publ Hlth, Dept Biostat, Iowa City, IA USA. [Taylor, Pegg] Covance Inc, Dedham, MA USA. [Frasier, Mark; Chowdhury, Sohini] Michael J Fox Fdn Parkinsons Res, New York, NY USA. [Marek, Kenneth; Jennings, Danna] Inst Neurodegenerat Disorders, New Haven, CT USA. [Kieburtz, Karl] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. [Kieburtz, Karl] Univ Rochester, Clin Trials Coordinat Ctr, Rochester, NY USA. [Simuni, Tanya] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA. [Tanner, Caroline M.] Parkinsons Inst, Sunnyvale, CA USA. [Singleton, Andrew] NIA, Mol Genet Sect, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. [Toga, Arthur W.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Lab Neuro Imaging, Los Angeles, CA 90095 USA. [Mollenhauer, Brit] Paracelsus Elena Klin, Kassel, Germany. [Mollenhauer, Brit] Univ Gottingen, Dept Neurosurg & Neuropathol, D-37073 Gottingen, Germany. [Trojanowski, John Q.] Univ Penn, Perelman Sch Med, Inst Aging Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA. RP Shaw, LM (reprint author), Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, 7103 Founders Pavil,3400 Spruce St, Philadelphia, PA 19104 USA. EM les.shaw@uphs.upenn.edu RI Singleton, Andrew/C-3010-2009 FU Michael J. Fox Foundation for Parkinson's Research; Abbott; Avid Radiopharmaceuticals; Biogen Idec; Covance; Elan; Eli Lilly and Co; F. Hoffman-La Roche Ltd; GE Healthcare; Genentech; GlaxoSmithKline; Merck and Co; Pfizer Inc; UCB Pharma SA; Morris K. Udall Center of Excellence for Parkinson's Disease Research [P50 NS053488-05]; National Institute on Aging, National Institutes of Health [T32-AG000255, ZO1AG000949-06]; National Institute of Mental Health [1K23MH092735] FX This work was supported by The Michael J. Fox Foundation for Parkinson's Research, Abbott, Avid Radiopharmaceuticals, Biogen Idec, Covance, Elan, Eli Lilly and Co, F. Hoffman-La Roche Ltd, GE Healthcare, Genentech, GlaxoSmithKline, Merck and Co, Pfizer Inc, and UCB Pharma SA. Trojanowski and Chen-Plotkin were supported by core grant P50 NS053488-05 from the Morris K. Udall Center of Excellence for Parkinson's Disease Research. Irwin was supported by Training in Age-Related Neurodegenerative Diseases grant T32-AG000255 from the National Institute on Aging, National Institutes of Health. Singleton was supported by grant ZO1AG000949-06 from the Intramural Research Program, National Institute on Aging, National Institutes of Health. Alberto Espay was supported by career development award 1K23MH092735 from the National Institute of Mental Health. NR 52 TC 105 Z9 108 U1 3 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD OCT PY 2013 VL 70 IS 10 BP 1277 EP 1287 DI 10.1001/jamaneurol.2013.3861 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 295KG UT WOS:000330114400011 PM 23979011 ER PT J AU Reich, DS Rao, A Butman, J Cortese, I AF Reich, D. S. Rao, A. Butman, J. Cortese, I. TI Postcontrast T2-FLAIR MRI detects leptomeningeal inflammation in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 29th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis / 18th Annual Conference of Rehabilitation in MS CY OCT 02-05, 2013 CL Copenhagen, DENMARK SP European Comm Treatment & Res Multiple Sclerosis C1 [Reich, D. S.; Butman, J.; Cortese, I.] NIH, Bethesda, MD 20892 USA. [Rao, A.] George Washington Univ, Washington, DC USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 3 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2013 VL 19 IS 11 SU S BP 67 EP 68 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 276LI UT WOS:000328751400107 ER PT J AU Oh, J Sotirchos, E Saidha, S Whetstone, A Chen, M Newsome, S Zackowski, K Diener-West, M Prince, J Reich, D Calabresi, P AF Oh, J. Sotirchos, E. Saidha, S. Whetstone, A. Chen, M. Newsome, S. Zackowski, K. Diener-West, M. Prince, J. Reich, D. Calabresi, P. TI Relationships between quantitative spinal cord MRI and retinal layers in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 29th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis / 18th Annual Conference of Rehabilitation in MS CY OCT 02-05, 2013 CL Copenhagen, DENMARK SP European Comm Treatment & Res Multiple Sclerosis C1 [Oh, J.; Sotirchos, E.; Saidha, S.; Whetstone, A.; Chen, M.; Newsome, S.; Zackowski, K.; Diener-West, M.; Prince, J.; Calabresi, P.] Johns Hopkins Univ, Baltimore, MD USA. [Reich, D.] NINDS, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2013 VL 19 IS 11 SU S BP 71 EP 71 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 276LI UT WOS:000328751400115 ER PT J AU Oh, J Sotirchos, E Saidha, S Vidal-Jordana, A Chen, M Newsome, S Zackowski, K Prince, J Diener-West, M Shiee, N Pham, D Calabresi, P Reich, D AF Oh, J. Sotirchos, E. Saidha, S. Vidal-Jordana, A. Chen, M. Newsome, S. Zackowski, K. Prince, J. Diener-West, M. Shiee, N. Pham, D. Calabresi, P. Reich, D. TI Relative clinical utility of measures of grey matter atrophy in the brain and quantitative spinal cord MRI in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 29th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis / 18th Annual Conference of Rehabilitation in MS CY OCT 02-05, 2013 CL Copenhagen, DENMARK SP European Comm Treatment & Res Multiple Sclerosis C1 [Oh, J.; Sotirchos, E.; Saidha, S.; Chen, M.; Newsome, S.; Zackowski, K.; Prince, J.; Diener-West, M.; Calabresi, P.] Johns Hopkins Univ, Baltimore, MD USA. [Vidal-Jordana, A.] Hosp Univ Vall dHebron, Barcelona, Spain. [Shiee, N.; Pham, D.; Reich, D.] Natl Inst Hlth, Bethesda, MD USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2013 VL 19 IS 11 SU S BP 167 EP 168 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 276LI UT WOS:000328751401193 ER PT J AU Harrison, D Whetstone, A Vidal-Jordana, A Chen, M Reich, D Calabresi, P AF Harrison, D. Whetstone, A. Vidal-Jordana, A. Chen, M. Reich, D. Calabresi, P. TI Short term increase in fractional anisotropy paradoxically predicts long term disability progression in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 29th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis / 18th Annual Conference of Rehabilitation in MS CY OCT 02-05, 2013 CL Copenhagen, DENMARK SP European Comm Treatment & Res Multiple Sclerosis C1 [Harrison, D.; Whetstone, A.; Chen, M.; Calabresi, P.] Johns Hopkins Univ, Baltimore, MD USA. [Vidal-Jordana, A.] Hosp Univ Vall dHebron, Barcelona, Spain. [Reich, D.] NINDS, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2013 VL 19 IS 11 SU S BP 423 EP 424 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 276LI UT WOS:000328751402373 ER PT J AU Maggi, P Macri, SMC Gaitan, MI Leibovitch, E Wholer, JE Wu, T Silva, A Massacesi, L Jacobson, S Westmoreland, S Reich, DS AF Maggi, P. Macri, S. M. Cummings Gaitan, M. I. Leibovitch, E. Wholer, J. E. Wu, T. Silva, A. Massacesi, L. Jacobson, S. Westmoreland, S. Reich, D. S. TI The formation of inflammatory demyelinating lesions: MRI and pathology in a primate model of multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 29th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis / 18th Annual Conference of Rehabilitation in MS CY OCT 02-05, 2013 CL Copenhagen, DENMARK SP European Comm Treatment & Res Multiple Sclerosis C1 [Maggi, P.; Massacesi, L.] Univ Florence, Florence, Italy. [Maggi, P.; Gaitan, M. I.; Leibovitch, E.; Wholer, J. E.; Wu, T.; Silva, A.; Massacesi, L.; Jacobson, S.; Reich, D. S.] NIH, Bethesda, MD 20892 USA. [Macri, S. M. Cummings; Westmoreland, S.] Harvard Univ, Sch Med, Southborough, MA 01772 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2013 VL 19 IS 11 SU S BP 427 EP 428 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 276LI UT WOS:000328751402380 ER PT J AU Zhang, J Mitiku, N Mariani, J Kramer, E Argaw, A Asp, L Dutta, D Akira, S Hennighausen, L John, G AF Zhang, J. Mitiku, N. Mariani, J. Kramer, E. Argaw, A. Asp, L. Dutta, D. Akira, S. Hennighausen, L. John, G. TI Differential regulation of oligodendrocyte and neuron viability by Stat3 versus Stat1 in vivo SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 29th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis / 18th Annual Conference of Rehabilitation in MS CY OCT 02-05, 2013 CL Copenhagen, DENMARK SP European Comm Treatment & Res Multiple Sclerosis C1 [Zhang, J.; Mitiku, N.; Mariani, J.; Kramer, E.; Argaw, A.; Asp, L.; Dutta, D.; John, G.] Mt Sinai Sch Med, New York, NY USA. [Akira, S.] Osaka Univ, Osaka, Japan. [Hennighausen, L.] NIDDK, NIH, Bethesda, MD 20892 USA. RI Akira, Shizuo/C-3134-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD OCT PY 2013 VL 19 IS 11 SU S BP 473 EP 473 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 276LI UT WOS:000328751403083 ER PT J AU Shi, TJ Fillmore, TL Gao, YQ Zhao, R He, JT Schepmoes, AA Nicora, CD Wu, CC Chambers, JL Moore, RJ Kagan, J Srivastava, S Liu, AY Rodland, KD Liu, T Camp, DG Smith, RD Qian, WJ AF Shi, Tujin Fillmore, Thomas L. Gao, Yuqian Zhao, Rui He, Jintang Schepmoes, Athena A. Nicora, Carrie D. Wu, Chaochao Chambers, Justin L. Moore, Ronald J. Kagan, Jacob Srivastava, Sudhir Liu, Alvin Y. Rodland, Karin D. Liu, Tao Camp, David G., II Smith, Richard D. Qian, Wei-Jun TI Long-Gradient Separations Coupled with Selected Reaction Monitoring for Highly Sensitive, Large Scale Targeted Protein Quantification in a Single Analysis SO ANALYTICAL CHEMISTRY LA English DT Article ID TANDEM MASS-SPECTROMETRY; PEPTIDE IMMUNOAFFINITY ENRICHMENT; LIQUID-CHROMATOGRAPHY; PLASMA-PROTEINS; BIOMARKER DISCOVERY; PROTEOMIC ANALYSIS; ANTIBODY-FREE; HUMAN SERUM; QUANTITATION; REVEALS AB Long-gradient separations coupled to tandem mass spectrometry (MS) were recently demonstrated to provide a deep proteome coverage for global proteomics; however, such long-gradient separations have not been explored for targeted proteomics. Herein, we investigate the potential performance of the long-gradient separations coupled with selected reaction monitoring (LG-SRM) for targeted protein quantification. Direct comparison of LG-SRM (5 h gradient) and conventional liquid chromatography (LC)-SRM (45 min gradient) showed that the long-gradient separations significantly reduced background interference levels and provided an 8- to 100-fold improvement in limit of quantification (LOQ) for target proteins in human female serum. On the basis of at least one surrogate peptide per protein, an LOQ of 10 ng/mL was achieved for the two spiked proteins in nondepleted human serum. The LG-SRM detection of seven out of eight endogenous plasma. proteins expressed at ng/mL or subng/mL levels in clinical patient sera was also demonstrated. A correlation coefficient of > 0.99 was observed for the results of LG-SRM and enzyme-linked immunosorbent assay (ELISA) measurements for prostate-specific antigen (PSA) in selected patient sera. Further enhancement of LG-SRM sensitivity was achieved by applying front-end IgY14 immunoaffinity depletion. Besides improved sensitivity, LG-SRM potentially offers much higher multiplexing capacity than conventional LC-SRM due to an increase in average peak widths (similar to 3-fold) for a 300 min gradient compared to a 45 min gradient. Therefore, LG-SRM holds great potential for bridging the gap between global and targeted proteomics due to its advantages in both sensitivity and multiplexing capacity. C1 [Shi, Tujin; Gao, Yuqian; He, Jintang; Schepmoes, Athena A.; Nicora, Carrie D.; Wu, Chaochao; Chambers, Justin L.; Moore, Ronald J.; Rodland, Karin D.; Liu, Tao; Camp, David G., II; Smith, Richard D.; Qian, Wei-Jun] Pacific NW Natl Lab, Biol Sci Div, Richland, WA 99352 USA. [Fillmore, Thomas L.; Zhao, Rui] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [Kagan, Jacob; Srivastava, Sudhir] NCI, Canc Prevent Div, Rockville, MD 20892 USA. [Liu, Alvin Y.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. RP Shi, TJ (reprint author), Pacific NW Natl Lab, Biol Sci Div, Richland, WA 99352 USA. EM tujin.shi@pnnl.gov; weijun.qian@pnnl.gov RI Smith, Richard/J-3664-2012; Shi, Tujin/O-1789-2014 OI Smith, Richard/0000-0002-2381-2349; FU NIH [DP2OD006668, U24CA160019, U01CA111244, P41GM103493]; NCI Early Detection Research Network Interagency Agreement [Y01-CN-05013-29]; DOE; DOE [DE-AC05-76RL0 1830] FX We thank Drs. Lori Sokoll and Daniel Chan at the Johns Hopkins Medical Institutions for providing the clinical serum samples. Portions of this work were supported by the NIH New Innovator Award Program DP2OD006668, U24CA160019, U01CA111244, and P41GM103493 and NCI Early Detection Research Network Interagency Agreement Y01-CN-05013-29. The experimental work described herein was performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the DOE and located at Pacific Northwest National Laboratory, which is operated by Battelle Memorial Institute for the DOE under Contract DE-AC05-76RL0 1830. NR 56 TC 20 Z9 20 U1 2 U2 34 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD OCT 1 PY 2013 VL 85 IS 19 BP 9196 EP 9203 DI 10.1021/ac402105s PG 8 WC Chemistry, Analytical SC Chemistry GA 294BN UT WOS:000330017500044 PM 24004026 ER PT J AU Zimmerman, SP Hueschen, CL Malide, D Milgram, SL Playford, MP AF Zimmerman, Seth P. Hueschen, Christina L. Malide, Daniela Milgram, Sharon L. Playford, Martin P. TI Sorting nexin 27 (SNX27) associates with zonula occludens-2 (ZO-2) and modulates the epithelial tight junction SO BIOCHEMICAL JOURNAL LA English DT Article DE endosome; sorting nexin 27 (SNX27); tight junction; zonula occludens-2 (ZO-2) ID PDZ DOMAIN INTERACTION; PROTEIN ZO-2; REGULATES TRAFFICKING; BINDING PARTNERS; CELLS; MEMBRANE; ENDOCYTOSIS; SCAFFOLDS; INTERACTS; CLAUDINS AB Proteins of the SNX (sorting nexin) superfamily are characterized by the presence of a PX (Phox homology) domain and associate with PtdIns3P (phosphatidylinositol-3-monophosphate)rich regions of the endosomal system. SNX27 is the only sorting nexin that contains a PDZ domain. In the present study, we used a proteomic approach to identify a novel interaction between SNX27 and ZO-2 [zonula occludens-2; also known as TJP2 (tight junction protein 2)], a component of the epithelial tight junction. The SNX27 ZO-2 interaction requires the PDZ domain of SNX27 and the C-terminal PDZ-binding motif of ZO-2. When tight junctions were perturbed by chelation of extracellular Ca2+, ZO-2 transiently localized to SNX27-positive early endosomes. Depletion of SNX27 in mpkCCD (mouse primary kidney cortical collecting duct) cell monolayers resulted in a decrease in the rate of ZO-2, but not ZO-1, mobility at cell cell contact regions after photobleaching and an increase in junctional permeability to large solutes. The findings of the present study identify an important new SNX27-binding partner and suggest a role for endocytic pathways in the intracellular trafficking of ZO-2 and possibly other tight junction proteins. Our results also indicate a role for SNX27 ZO-2 interactions in tight junction maintenance and function. C1 [Zimmerman, Seth P.; Hueschen, Christina L.; Milgram, Sharon L.; Playford, Martin P.] NIH, Cell Biol & Physiol Ctr, Bethesda, MD 20982 USA. [Malide, Daniela] NHLBI, NHLBI Light Microscopy Core, NIH, Bethesda, MD 20982 USA. RP Playford, MP (reprint author), NIH, Cell Biol & Physiol Ctr, Bethesda, MD 20982 USA. EM playfordmp@nhlbi.nih.gov FU NIH FX This work was supported by the NIH intramural research program. NR 40 TC 3 Z9 4 U1 0 U2 4 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD OCT 1 PY 2013 VL 455 BP 95 EP 106 DI 10.1042/BJ20121755 PN 1 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 291QF UT WOS:000329843200010 PM 23826934 ER PT J AU Matsui, K Giri, N Alter, BP Pinto, LA AF Matsui, Ken Giri, Neelam Alter, Blanche P. Pinto, Ligia A. TI Cytokine production by bone marrow mononuclear cells in inherited bone marrow failure syndromes SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE monocytes; bone marrow; cytokines; immunology; inherited bone marrow failure syndromes ID SHWACHMAN-DIAMOND-SYNDROME; TUMOR-NECROSIS-FACTOR; COMMON VARIABLE IMMUNODEFICIENCY; HEMATOPOIETIC STEM-CELLS; MEMORY T-CELLS; FANCONI-ANEMIA; DYSKERATOSIS-CONGENITA; IMMUNE FUNCTION; MONOCYTE FUNCTION; PROGENITOR CELLS AB Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anaemia (DBA), and Shwachman-Diamond syndrome (SDS) are characterized by the progressive development of bone marrow failure. Overproduction of tumour necrosis factor-alpha (TNF-alpha) from activated bone marrow T-cells has been proposed as a mechanism of FA-related aplasia. Whether such overproduction occurs in the other syndromes is unknown. We conducted a comparative study on bone marrow mononuclear cells to examine the cellular subset composition and cytokine production. We found lower proportions of haematopoietic stem cells in FA, DC, and SDS, and a lower proportion of monocytes in FA, DC, and DBA compared with controls. The T- and B-lymphocyte proportions were similar to controls, except for low B-cells in DC. We did not observe overproduction of TNF-alpha or IFN-gamma by T-cells in any patients. Induction levels of TNF-alpha, interleukin (IL)-6, IL-1 beta, IL-10, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor in monocytes stimulated with high-dose lipopolysaccharide (LPS) were similar at 4h but lower at 24h when compared to controls. Unexpectedly, patient samples showed a trend toward higher cytokine level in response to low-dose (0 center dot 001 mu g/ml) LPS. Increased sensitivity to LPS may have clinical implications and could contribute to the development of pancytopenia by creating a chronic subclinical inflammatory micro-environment in the bone marrow. C1 [Matsui, Ken; Pinto, Ligia A.] SAIC Frederick Inc, Human Papillomavirus Immunol Lab, Sci Applicat Int Corp, Frederick Natl Lab Canc Res, Frederick, MD USA. [Giri, Neelam; Alter, Blanche P.] NCI, Div Canc Epidemiol, NIH, Bethesda, MD 20892 USA. [Giri, Neelam; Alter, Blanche P.] NCI, Genet Clin Genet Branch, NIH, Bethesda, MD 20892 USA. RP Pinto, LA (reprint author), SAIC Frederick Inc, Human Papilloma Virus Immunol Lab, Frederick Natl Lab Canc Res, Bldg 469,Room 111, Frederick, MD 21702 USA. EM pintol@mail.nih.gov FU Fanconi Anaemia Research Fund; National Institutes of Health; National Cancer Institute; Westat, Incorporated [N02-CP-91026, N02-CP-11019, HHSN261200655001C]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors would like to thank Pan Yuaji for helpful discussion on the statistics and Gloriana Shelton for her managerial and technical contributions. We also would like to thank Sharon A. Savage, MD for samples from patients with dyskeratosis congenita. We thank Mark H. Greene, MD for his thoughtful comments and suggestions. The study was supported by a research grant from Fanconi Anaemia Research Fund (Fanconi.org) to N.G. This research was supported in part by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute (B.P.A., N.G.), and by contracts N02-CP-91026, N02-CP-11019 and HHSN261200655001C with Westat, Incorporated. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 53 TC 6 Z9 6 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD OCT PY 2013 VL 163 IS 1 BP 81 EP 92 DI 10.1111/bjh.12475 PG 12 WC Hematology SC Hematology GA 216YQ UT WOS:000324323300011 PM 23889587 ER PT J AU Ohana, E Shcheynikov, N Moe, OW Muallem, S AF Ohana, Ehud Shcheynikov, Nikolay Moe, Orson W. Muallem, Shmuel TI SLC26A6 and NaDC-1 Transporters Interact to Regulate Oxalate and Citrate Homeostasis SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID FUNCTIONAL-CHARACTERIZATION; DICARBOXYLATE TRANSPORTER; CYSTIC-FIBROSIS; HCO3-SECRETION; CFTR; CL; MECHANISM; EXCHANGE; FAMILY; KIDNEY C1 [Ohana, Ehud; Shcheynikov, Nikolay; Muallem, Shmuel] Natl Inst Dent & Craniofacial Res, Epithelial Signaling & Transport Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Moe, Orson W.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dept Physiol, Dallas, TX 75390 USA. [Moe, Orson W.] Univ Texas SW Med Ctr Dallas, Charles & Jane Pak Ctr Mineral Metab, Dallas, TX 75390 USA. RP Muallem, S (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bldg 10,Room 1N-112, Bethesda, MD 20892 USA. EM shmuel.muallem@nih.gov FU Intramural Research Program of the NIH, National Institute of Craniofacial and Dental Research [ZIA-DE000735] FX This work was supported by Intramural Research Program of the NIH, National Institute of Craniofacial and Dental Research grant ZIA-DE000735. NR 37 TC 10 Z9 10 U1 0 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2013 VL 24 IS 10 BP 1617 EP 1626 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 277JN UT WOS:000328815000014 PM 23833257 ER PT J AU Endo, Y Ishiwata-Endo, H Yamada, KM AF Endo, Yukinori Ishiwata-Endo, Hiroko Yamada, Kenneth M. TI Cloning and characterization of chicken alpha 5 integrin: Endogenous and experimental expression in early chicken embryos SO MATRIX BIOLOGY LA English DT Article DE alpha 5 integrin; Fibronectin; Extracellular matrix; Chicken embryo; Neural crest ID CREST CELL-MIGRATION; NEURAL CREST; FIBRONECTIN RECEPTOR; EXTRACELLULAR-MATRIX; MONOCLONAL-ANTIBODY; MESSENGER-RNAS; ADHESION; LAMININ; SUBUNIT; ATTACHMENT AB Key roles for fibronectin and its integrin receptors have been postulated in the multiple cell-matrix interactions essential for chick embryo morphogenesis. However, mechanistic studies of these processes have been hampered by the current absence of sequence data and chicken cDNA clones for the major fibronectin receptor subunit, integrin alpha 5 (ITGA5). We report here the sequence, endogenous expression pattern, and transfection of full-length chicken integrin alpha 5. During early chicken embryonic development, alpha 5 is highly expressed in cranial neural folds and migrating neural crest cells, suggesting potential roles in neural crest formation and migration. In fact, over-expression of this integrin in early neural tube selectively induces BMP5, a growth factor recently implicated in neural crest formation. Availability of these alpha 5 integrin tools should facilitate studies of its functions in early embryonic development. Published by Elsevier B.V. C1 [Endo, Yukinori; Ishiwata-Endo, Hiroko; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Yamada, KM (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM yukinorishiko@yahoo.co.jp; Kenneth.Yamada@nih.gov FU Intramural Research Program of the NIDCR, NIH; Japan Society for the Promotion of Science Research (JSPS), Japan FX We thank Dr. Alan (Rick) Horwitz for the CHO-B2 cells, Drs. Martin Humphries and Timothy Springer for the alpha 5 and alpha IIb expression plasmids, respectively, Drs. Shunsuke Yaguchi and Kentaro Hozumi for their kind advice on RACE kit and cell adhesion assay, respectively, and members of the Yamada laboratory for comments. Supported by the Intramural Research Program of the NIDCR, NIH. Y.E. was partially supported by the Japan Society for the Promotion of Science Research (JSPS), Japan. NR 44 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X EI 1569-1802 J9 MATRIX BIOL JI Matrix Biol. PD OCT-NOV PY 2013 VL 32 IS 7-8 BP 381 EP 386 DI 10.1016/j.matbio.2013.04.002 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 285VN UT WOS:000329423200003 PM 23587661 ER PT J AU Johannesdottir, F Aspelund, T Reeve, J Poole, KE Sigurdsson, S Harris, TB Gudnason, VG Sigurdsson, G AF Johannesdottir, Fjola Aspelund, Thor Reeve, Jonathan Poole, Kenneth E. Sigurdsson, Sigurdur Harris, Tamara B. Gudnason, Vilmundur G. Sigurdsson, Gunnar TI Similarities and Differences Between Sexes in Regional Loss of Cortical and Trabecular Bone in the Mid-Femoral Neck: The AGES-Reykjavik Longitudinal Study SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE CORTICAL THICKNESS; PROXIMAL END OF FEMUR; AGING; LONGITUDINAL; QCT ID GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; QUANTITATIVE COMPUTED-TOMOGRAPHY; INTRACAPSULAR HIP FRACTURE; MINERAL DENSITY; PROXIMAL FEMUR; POSTMENOPAUSAL WOMEN; PHYSICAL-ACTIVITY; SKELETAL SITES; OLDER MEN; OSTEOPOROSIS AB The risk of hip fracture rises rapidly with age, and is notably higher in women. After falls and prior fragility fractures, the main clinically recognized risk factor for hip fracture is reduced bone density. To better understand the extent to which femoral neck density and structure change with age in each sex, we carried out a longitudinal study in subjects not treated with agents known to influence bone mineral density (BMD), to investigate changes in regional cortical thickness, as well as cortical and trabecular BMD at the mid-femoral neck. Segmental quantitative computed tomography (QCT) analysis was used to assess bone measurements in two anatomic subregions, the superolateral (superior) and inferomedial (inferior). A total of 400 older individuals (100 men and 300 women, aged 66-90 years) who were participants in the Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik), were studied. Participants had two QCT scans of the hip over a median follow-up of 5.1 years (mean baseline age 74 years). Changes in bone values during follow-up were estimated from mixed effects regression models. At baseline women had lower bone values in the superior region than men. At follow-up all bone values were lower in women, except cortical volumetric bone mineral density (vBMD) inferiorly. The relative losses in all bone values estimated in the superior region were substantially (about threefold) and significantly greater compared to those estimated in the inferior region in both sexes. Women lost cortical thickness and cortical vBMD more rapidly than men in both regions; and this was only weakly reflected in total femoral neck dual-energy X-ray absorptiometry (DXA)-like results. The higher rate of bone loss in women at critical locations may contribute materially to the greater femoral neck fracture incidence among women than men. (c) 2013 American Society for Bone and Mineral Research. C1 [Johannesdottir, Fjola] Univ Iceland, Fac Ind Engn Mech Engn & Comp Sci, Reykjavik, Iceland. [Aspelund, Thor; Sigurdsson, Sigurdur; Gudnason, Vilmundur G.; Sigurdsson, Gunnar] Iceland Heart Assoc, Kopavogur, Iceland. [Aspelund, Thor] Univ Iceland, Ctr Publ Hlth Sci, Reykjavik, Iceland. [Reeve, Jonathan] Univ Oxford, Inst Musculoskeletal Sci, NIHR Musculoskeletal Biomed Res Unit, Oxford, England. [Poole, Kenneth E.] Univ Cambridge, Dept Med, Div Rheumatol, Cambridge CB2 2QQ, England. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. [Gudnason, Vilmundur G.; Sigurdsson, Gunnar] Univ Iceland, Fac Med, Reykjavik, Iceland. [Sigurdsson, Gunnar] Landspitali Univ Hosp, Dept Endocrinol & Metab, IS-108 Reykjavik, Iceland. RP Sigurdsson, G (reprint author), Landspitali Univ Hosp, IS-108 Reykjavik, Iceland. EM gunnars@landspitali.is RI Reeve, Jonathan/C-7551-2012; Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Reeve, Jonathan/0000-0002-4364-2682; Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU NIH [N01-AG-1-2100]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); memorial fund of Helga Jonsdottir and Sigurlidi Kristjansson; University of Iceland Research Fund; Arthritis Research UK; Cambridge NIHR Biomedical Research Centre; EU FP7 Integrated Project Grant GEFOS [201865] FX This study was funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), the Althingi (the Icelandic Parliament), and the memorial fund of Helga Jonsdottir and Sigurlidi Kristjansson. GS acknowledges support from the University of Iceland Research Fund. The study was approved by the Icelandic National Bioethics Committee (VSN 00-063). KEP acknowledges the support of Arthritis Research UK and the Cambridge NIHR Biomedical Research Centre. JR was supported in part by the EU FP7 Integrated Project Grant GEFOS Reference: 201865. The researchers are indebted to the participants for their willingness to participate in the study. We thank Keenan Brown (Mindways Software, TX, USA) for his assistance. NR 59 TC 14 Z9 14 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2013 VL 28 IS 10 BP 2165 EP 2176 DI 10.1002/jbmr.1960 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 282EM UT WOS:000329153100012 PM 23609070 ER PT J AU Rasmussen, LJ Shiloh, Y Bergersen, LH Sander, M Bohr, VA Tonjum, T AF Rasmussen, Lene Juel Shiloh, Yosef Bergersen, Linda H. Sander, Miriam Bohr, Vilhelm A. Tonjum, Tone TI DNA damage response, bioenergetics, and neurological disease: The challenge of maintaining brain health in an aging human population SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Editorial Material DE Genome dynamics; Neuroscience; DNA repair; Bioenergetics; Epigenetics ID HUNTINGTONS-DISEASE; ESCHERICHIA-COLI; GENOME DYNAMICS; MOUSE MODEL; STRESS; ACCUMULATION; MITOCHONDRIA; DYSFUNCTION; MUTATION; REPAIR C1 [Rasmussen, Lene Juel; Bergersen, Linda H.] Univ Copenhagen, Fac Hlth Sci, Ctr Hlth Aging, DK-1168 Copenhagen, Denmark. [Shiloh, Yosef] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, David & Inez Myers Lab Canc Res, IL-69978 Tel Aviv, Israel. [Bergersen, Linda H.] Univ Oslo, Dept Anat, Ctr Mol Biol & Neurosci, N-0316 Oslo, Norway. [Sander, Miriam] Page One Editorial Serv, Boulder, CO USA. [Bohr, Vilhelm A.] NIA, Dept Mol Gerontol, NIH, Bethesda, MD 20892 USA. [Tonjum, Tone] Univ Oslo, Ctr Mol Biol & Neurosci, Dept Microbiol, N-0316 Oslo, Norway. [Tonjum, Tone] Oslo Univ Hosp, Ctr Mol Biol & Neurosci, Dept Microbiol, Oslo, Norway. RP Tonjum, T (reprint author), Univ Oslo, Oslo Univ Hosp, Dept Microbiol, Ctr Mol Biol & Neurosci, N-0316 Oslo, Norway. EM tone.tonjum@medisin.uio.no OI Tonjum, Tone/0000-0002-1709-6921 FU NINDS NIH HHS [R01 NS031763] NR 23 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD OCT PY 2013 VL 134 IS 10 SI SI BP 427 EP 433 DI 10.1016/j.mad.2013.05.001 PG 7 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 282CR UT WOS:000329148400001 PM 23665461 ER PT J AU Sykora, P Wilson, DM Bohr, VA AF Sykora, Peter Wilson, David M., III Bohr, Vilhelm A. TI Base excision repair in the mammalian brain: Implication for age related neurodegeneration SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE BER; Neurodegeneration; DNA repair; Aging ID DNA-POLYMERASE-BETA; GLOBAL CEREBRAL-ISCHEMIA; OXIDATIVE GENOME DAMAGE; AGING RAT NEURONS; APURINIC/APYRIMIDINIC ENDONUCLEASE; MITOCHONDRIAL-DNA; LIGASE III; APURINIC ENDONUCLEASE-1; APE/REF-1 RESPONSES; ALZHEIMERS-DISEASE AB The repair of damaged DNA is essential to maintain longevity of an organism. The brain is a matrix of different neural cell types including proliferative astrocytes and post-mitotic neurons. Post-mitotic DNA repair is a version of proliferative DNA repair, with a reduced number of available pathways and most of these attenuated. Base excision repair (BER) is one pathway that remains robust in neurons; it is this pathway that resolves the damage due to oxidative stress. This oxidative damage is an unavoidable byproduct of respiration, and considering the high metabolic activity of neurons this type of damage is particularly pertinent in the brain. The accumulation of oxidative DNA damage over time is a central aspect of the theory of aging and repair of such chronic damage is of the highest importance. We review research conducted in BER mouse models to clarify the role of this pathway in the neural system. The requirement for BER in proliferating cells also correlates with high levels of many of the BER enzymes in neurogenesis after DNA damage. However, the pathway is also necessary for normal neural maintenance as larger infarct volumes after ischemic stroke are seen in some glycosylase deficient animals. Further, the requirement for DNA polymerase 13 in post-mitotic BER is potentially more important than in proliferating cells due to reduced levels of replicative polymerases. The BER response may have particular relevance for the onset and progression of many neurodegenerative diseases associated with an increase in oxidative stress including Alzheimer's. Published by Elsevier Ireland Ltd. C1 [Sykora, Peter; Wilson, David M., III; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Intramural Res Program, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Intramural Res Program, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM vbohr@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. We thank Dr. Evandro Fang and Dr. Jennifer Illuzzi for the critical reading of this manuscript. NR 86 TC 22 Z9 24 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD OCT PY 2013 VL 134 IS 10 SI SI BP 440 EP 448 DI 10.1016/j.mad.2013.04.005 PG 9 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 282CR UT WOS:000329148400003 PM 23643943 ER PT J AU Lee, RWY Conley, SK Gropman, A Porter, FD Baker, EH AF Lee, Ryan W. Y. Conley, Sandra K. Gropman, Andrea Porter, Forbes D. Baker, Eva H. TI Brain Magnetic Resonance Imaging Findings in Smith-Lemli-Opitz Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Smith-Lemli-Opitz syndrome (SLOS); magnetic resonance imaging (MRI); brain ID DEFECTIVE CHOLESTEROL-BIOSYNTHESIS; MULTIPLE CONGENITAL-ANOMALIES; AUTISM SPECTRUM DISORDERS; SONIC-HEDGEHOG; LIPID RAFTS; SEPTI PELLUCIDI; OPTIZ-SYNDROME; METABOLISM; FOREBRAIN; PHENOTYPE AB Smith-Lemli-Opitz syndrome (SLOS) is a neurodevelopmental disorder caused by inborn errors of cholesterol metabolism resulting from mutations in 7-dehydrocholesterol reductase (DHCR7). There are only a few studies describing the brain imaging findings in SLOS. This study examines the prevalence of magnetic resonance imaging (MRI) abnormalities in the largest cohort of patients with SLOS to date. Fifty-five individuals with SLOS (27 M, 28 F) between age 0.17 years and 25.4 years (mean=6.2, SD=5.8) received a total of 173 brain MRI scans (mean=3.1 per subject) on a 1.5T GE scanner between September 1998 and December 2003, or on a 3T Philips scanner between October 2010 and September 2012; all exams were performed at the Clinical Center of the National Institutes of Health. We performed a retrospective review of these imaging studies for both major and minor brain anomalies. Aberrant MRI findings were observed in 53 of 55 (96%) SLOS patients, with abnormalities of the septum pellucidum the most frequent (42/55, 76%) finding. Abnormalities of the corpus callosum were found in 38 of 55 (69%) patients. Other findings included cerebral atrophy, cerebellar atrophy, colpocephaly, white matter lesions, arachnoid cysts, Dandy-Walker variant, and type I Chiari malformation. Significant correlations were observed when comparing MRI findings with sterol levels and somatic malformations. Individuals with SLOS commonly have anomalies involving the midline and para-midline structures of the brain. Further studies are required to examine the relationship between structural brain abnormalities and neurodevelopmental disability in SLOS. (c) 2013 Wiley Periodicals, Inc. C1 [Lee, Ryan W. Y.] Kennedy Krieger Inst, Dept Neurol & Dev Med, Baltimore, MD 21205 USA. [Lee, Ryan W. Y.; Conley, Sandra K.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Gropman, Andrea] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Baker, Eva H.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Lee, RWY (reprint author), Kennedy Krieger Inst, Dept Neurol & Dev Med, 716 North Broadway St, Baltimore, MD 21205 USA. EM leer@kennedykrieger.org FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH Clinical Center; NIH Office of Rare Diseases; RSH/Smith-Lemli-Opitz Foundation FX Grant sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development; Grant sponsor: NIH Clinical Center; Grant sponsor: NIH Office of Rare Diseases; Grant sponsor: RSH/Smith-Lemli-Opitz Foundation. NR 50 TC 15 Z9 15 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD OCT PY 2013 VL 161 IS 10 BP 2407 EP 2419 DI 10.1002/ajmg.a.36096 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 264FP UT WOS:000327862700002 PM 23918729 ER PT J AU Guo, MH Stoler, J Lui, JL Nilsson, O Bianchi, DW Hirschhorn, JN Dauber, A AF Guo, Michael H. Stoler, Joan Lui, Julian Nilsson, Ola Bianchi, Diana W. Hirschhorn, Joel N. Dauber, Andrew TI Redefining the Progeroid Form of Ehlers-Danlos Syndrome: Report of the Fourth Patient With B4GALT7 Deficiency and Review of the Literature SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE proteoglycans; growth disorder; Ehlers-Danlos syndrome; whole exome sequencing ID GALACTOSYLTRANSFERASE-I BETA-4GALT-7; HEPARAN-SULFATE PROTEOGLYCANS; DISTINCT VARIANT; GENE; FIBROBLASTS; MUTATIONS; DEFECTS; BIOSYNTHESIS; SUBSTITUTION; EXPRESSION AB Proteoglycans are a component of the extracellular matrix and are critical for cellular and tissue function. Mutations in proteoglycan components and enzymes involved in proteoglycan synthesis have been implicated in several growth disorders, with common features including short stature and skeletal dysplasia. For example, mutations in B4GALT7, a gene whose protein product catalyzes proteoglycan synthesis, have been associated with the rare progeroid variant of Ehlers-Danlos syndrome. Here, we conducted exome sequencing in a patient with a previously undiagnosed growth disorder and identified compound heterozygous mutations in B4GALT7. This patient is just the fourth individual with genetically confirmed progeroid variant of Ehlers-Danlos syndrome. The mutations include a previously characterized c.808C>T p.Arg270Cys substitution, and a novel c.122T>C p.Leu41Pro substitution. We demonstrate that the novel mutation caused decreased levels of the enzyme, supporting the pathogenicity of the mutation. Our report identifies a novel mutation in B4GALT7 causing the progeroid variant of Ehlers-Danlos syndrome and contributes an extensive phenotypic characterization of a patient with the syndrome. We also reviewed the previous literature in addition to the present patient, and conclude that the key features associated with B4GALT7 deficiency are short stature, developmental anomalies of the forearm bones and elbow, and bowing of the extremities, in addition to the classic features of Ehlers-Danlos syndrome. This report helps define the phenotype of the progeroid variant of Ehlers-Danlos syndrome and furthers our understanding of the effect of proteoglycan defects in growth disorders. (c) 2013 Wiley Periodicals, Inc. C1 [Guo, Michael H.] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA USA. [Stoler, Joan] Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Lui, Julian; Nilsson, Ola] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Nilsson, Ola] Karolinska Inst, Dept Womens & Childrens Hlth, Ctr Mol Med, Stockholm, Sweden. [Nilsson, Ola] Karolinska Inst, Pediat Endocrinol Unit, Stockholm, Sweden. [Nilsson, Ola] Karolinska Univ Hosp, Stockholm, Sweden. [Bianchi, Diana W.] Tufts Med Ctr, Mother Infant Res Inst, Boston, MA USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Hirschhorn, Joel N.; Dauber, Andrew] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Hirschhorn, Joel N.; Dauber, Andrew] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP Dauber, A (reprint author), Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. EM andrew.dauber@childrens.harvard.edu RI Lui, Chun Kin Julian/E-2253-2012; OI Nilsson, Ola/0000-0002-9986-8138 FU Harvard Catalyst, The Harvard Clinical and Translational Science Center [UL1 RR 025758]; NIH [1K23HD073351-01]; Genentech Center for Clinical Research in Endocrinology; March of Dimes [6-FY09-507]; Translational Research Program, Boston Children's Hospital; Swedish Research Council [K2007-52X-20316-01-4, K2012-99X-21998-01-3]; Stockholm County Council; Swedish Society of Medicine; Her Royal Highness Crown Princess Lovisa's Foundation for Pediatric Care; Wera Ekstrom's Foundation for Pediatric Research; Marta och Gunnar V Philipson's Foundation; Sallskapet Barnavard; Karolinska Institutet FX Grant sponsor: Harvard Catalyst, The Harvard Clinical and Translational Science Center; Grant number: UL1 RR 025758; Grant sponsor: NIH; Grant number: 1K23HD073351-01; Grant sponsor: Genentech Center for Clinical Research in Endocrinology; Grant sponsor: March of Dimes; Grant number: 6-FY09-507; Grant sponsor: Translational Research Program, Boston Children's Hospital; Grant sponsor: Swedish Research Council; Grant numbers: K2007-52X-20316-01-4, K2012-99X-21998-01-3; Grant sponsor: Stockholm County Council; Grant sponsor: Swedish Society of Medicine; Grant sponsor: Her Royal Highness Crown Princess Lovisa's Foundation for Pediatric Care; Grant sponsor: Wera Ekstrom's Foundation for Pediatric Research; Grant sponsor: Marta och Gunnar V Philipson's Foundation; Grant sponsor: Sallskapet Barnavard; Grant sponsor: Karolinska Institutet. NR 26 TC 12 Z9 12 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD OCT PY 2013 VL 161 IS 10 BP 2519 EP 2527 DI 10.1002/ajmg.a.36128 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 264FP UT WOS:000327862700013 PM 23956117 ER PT J AU De, S Stanley, RJ Lu, C Long, R Antani, S Thoma, G Zuna, R AF De, Soumya Stanley, R. Joe Lu, Cheng Long, Rodney Antani, Sameer Thoma, George Zuna, Rosemary TI A fusion-based approach for uterine cervical cancer histology image classification SO COMPUTERIZED MEDICAL IMAGING AND GRAPHICS LA English DT Article DE Image processing; Data fusion; Cervical intraepithelial neoplasia; Feature analysis; Histology ID INTRAEPITHELIAL NEOPLASIA CIN; SYSTEM; SELECTION; LESIONS AB Expert pathologists commonly perform visual interpretation of histology slides for cervix tissue abnormality diagnosis. We investigated an automated, localized, fusion-based approach for cervix histology image analysis for squamous epithelium classification into Normal, CIN1, CIN2, and CIN3 grades of cervical intraepithelial neoplasia (CIN). The epithelium image analysis approach includes medial axis determination, vertical segment partitioning as medial axis orthogonal cuts, individual vertical segment feature extraction and classification, and image-based classification using a voting scheme fusing the vertical segment CIN grades. Results using 61 images showed at least 15.5% CIN exact grade classification improvement using the localized vertical segment fusion versus global image features. (C) 2013 Elsevier Ltd. All rights reserved. C1 [De, Soumya; Stanley, R. Joe; Lu, Cheng] Missouri Univ Sci & Technol, Dept Elect & Comp Engn, Rolla, MO 65409 USA. [Long, Rodney; Antani, Sameer; Thoma, George] NIH, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, DHHS, Bethesda, MD 20894 USA. [Zuna, Rosemary] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73117 USA. RP Stanley, RJ (reprint author), Missouri Univ Sci & Technol, Dept Elect & Comp Engn, Rolla, MO 65409 USA. EM stanleyj@mst.edu OI Antani, Sameer/0000-0002-0040-1387 FU National Institutes of Health (NIH), National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) [HHSN276201200028C]; National Cancer Institute Division of Cancer Epidemiology and Genetics (DCEG) FX This research was supported (in part) by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM), and Lister Hill National Center for Biomedical Communications (LHNCBC) under contract number HHSN276201200028C. In addition, we acknowledge the expert medical support of Dr. Mark Schiffman and Dr. Nicolas Wentzensen, both of the National Cancer Institute Division of Cancer Epidemiology and Genetics (DCEG). NR 35 TC 3 Z9 3 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-6111 EI 1879-0771 J9 COMPUT MED IMAG GRAP JI Comput. Med. Imaging Graph. PD OCT-DEC PY 2013 VL 37 IS 7-8 BP 475 EP 487 DI 10.1016/j.compmedimag.2013.08.001 PG 13 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 275EF UT WOS:000328658400007 PM 24075360 ER PT J AU Mabry, PL Milstein, B Abraido-Lanza, AF Livingood, WC Allegrante, JP AF Mabry, Patricia L. Milstein, Bobby Abraido-Lanza, Ana F. Livingood, William C. Allegrante, John P. TI Opening a Window on Systems Science Research in Health Promotion and Public Health SO HEALTH EDUCATION & BEHAVIOR LA English DT Editorial Material C1 [Mabry, Patricia L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Milstein, Bobby] ReThink Hlth, Hygeia Dynam Policy Studio, Morristown, NJ USA. [Milstein, Bobby] MIT, Boston, MA USA. [Abraido-Lanza, Ana F.; Allegrante, John P.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Livingood, William C.] Univ Florida, Coll Med, Jacksonville, FL USA. [Allegrante, John P.] Columbia Univ, Teachers Coll, New York, NY 10027 USA. RP Mabry, PL (reprint author), NIH, Off Behav & Social Sci Res, 31 Ctr Dr,Bldg 31,Rm B1-C19,MSC 2027, Bethesda, MD 20892 USA. EM mabryp@od.nih.gov NR 30 TC 5 Z9 5 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 EI 1552-6127 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD OCT PY 2013 VL 40 SU 1 BP 5S EP 8S DI 10.1177/1090198113503343 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 275TC UT WOS:000328699500001 PM 24084401 ER PT J AU Mabry, PL Kaplan, RM AF Mabry, Patricia L. Kaplan, Robert M. TI Systems Science: A Good Investment for the Public's Health SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE systems science; quantitative methods; behavioral and social sciences research; federal funding ID CESSATION TREATMENT; SIMULATION; POLICY AB This supplement of Health Education & Behavior showcases the current state of the field of systems science applications in health promotion and public health. Behind this work lies a steady stream of public dollars at the federal level. This perspective details nearly a decade of investment by the National Institutes of Health's Office of Behavioral and Social Sciences Research. These investments have included funding opportunity announcements, training programs, developing resources for researchers, cross-disciplinary fertilization, and publication. While much progress has been made, continuing investment is needed in the future to ensure the viability and sustainability of this young but increasingly important field. C1 [Mabry, Patricia L.; Kaplan, Robert M.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP Mabry, PL (reprint author), NIH, Off Behav & Social Sci Res, Bldg 10, Bethesda, MD 20892 USA. EM mabryp@od.nih.gov NR 19 TC 11 Z9 11 U1 2 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 EI 1552-6127 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD OCT PY 2013 VL 40 SU 1 BP 9S EP 12S DI 10.1177/1090198113503469 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 275TC UT WOS:000328699500002 PM 24084406 ER PT J AU Ip, EH Rahmandad, H Shoham, DA Hammond, R Huang, TTK Wang, YF Mabry, PL AF Ip, Edward H. Rahmandad, Hazhir Shoham, David A. Hammond, Ross Huang, Terry T. -K. Wang, Youfa Mabry, Patricia L. TI Reconciling Statistical and Systems Science Approaches to Public Health SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE agent-based model; childhood obesity; complex systems; computational model; Levins framework; social network analysis; statistical model; system dynamics model ID HIDDEN MARKOV-MODELS; GOOD EMPIRICAL FITS; POPULATION BIOLOGY; CHILDHOOD OBESITY; PASHLER 2000; STRATEGY; 21ST-CENTURY; SIMULATION; ROBERTS; BEGIN AB Although systems science has emerged as a set of innovative approaches to study complex phenomena, many topically focused researchers including clinicians and scientists working in public health are somewhat befuddled by this methodology that at times appears to be radically different from analytic methods, such as statistical modeling, to which the researchers are accustomed. There also appears to be conflicts between complex systems approaches and traditional statistical methodologies, both in terms of their underlying strategies and the languages they use. We argue that the conflicts are resolvable, and the sooner the better for the field. In this article, we show how statistical and systems science approaches can be reconciled, and how together they can advance solutions to complex problems. We do this by comparing the methods within a theoretical framework based on the work of population biologist Richard Levins. We present different types of models as representing different tradeoffs among the four desiderata of generality, realism, fit, and precision. C1 [Ip, Edward H.] Wake Forest Univ, Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Rahmandad, Hazhir] Virginia Tech, Falls Church, VA USA. [Shoham, David A.] Loyola Univ, Maywood, IL 60153 USA. [Hammond, Ross] Brookings Inst, Washington, DC 20036 USA. [Huang, Terry T. -K.] Univ Nebraska Med Ctr, Omaha, NE USA. [Wang, Youfa] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. [Mabry, Patricia L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP Ip, EH (reprint author), Wake Forest Univ, Sch Med, Dept Biostat Sci, Med Ctr Blvd,WC23, Winston Salem, NC 27157 USA. EM eip@wakehealth.edu RI Rahmandad, Hazhir/B-4474-2013 OI Rahmandad, Hazhir/0000-0002-2784-9042 FU NHLBI NIH HHS [1U01HL101066-01, U01 HL101066]; NIA NIH HHS [1R21AG042761-01, R21 AG042761]; NICHD NIH HHS [1R01HD064685-01A1, 1R01HD08023, F32 HD008023, R01 HD061978, R01 HD064685, R01HD061978, U54 HD070725, U54HD070725]; NLM NIH HHS [HHSN276201000004C] NR 56 TC 6 Z9 6 U1 2 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 EI 1552-6127 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD OCT PY 2013 VL 40 SU 1 BP 123S EP 131S DI 10.1177/1090198113493911 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 275TC UT WOS:000328699500013 PM 24084395 ER PT J AU Jahouh, F Xu, P Vann, WF Kovac, P Banoub, JH AF Jahouh, Farid Xu, Peng Vann, Willie F. Kovac, Pavol Banoub, Joseph H. TI Mapping the glycation sites in the neoglycoconjugate from hexasaccharide antigen of Vibrio cholerae, serotype Ogawa and the recombinant tetanus toxin C-fragment carrier SO JOURNAL OF MASS SPECTROMETRY LA English DT Article DE nano-LC-ESI-QqTOF-MS; MS; neoglycoconjugate vaccine; recombinant tetanus toxin C-fragment (rTT-Hc); Trypsin digestion; GluC V8 digestion; MALDI-TOF-MS ID TANDEM MASS-SPECTROMETRY; SWISS-MODEL; O-PS; TRANSCUTANEOUS IMMUNIZATION; PROTECTIVE IMMUNITY; PROTEIN CARRIER; H-C; CONJUGATION; VACCINES; OLIGOSACCHARIDES AB We report herein the glycation sites in a vaccine candidate for cholera formed by conjugation of the synthetic hexasaccharide fragment of the O-specific polysaccharide of Vibrio cholerae, serotype Ogawa, to the recombinant tetanus toxin C-fragment (rTT-Hc) carrier. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis of the vaccine revealed that it is composed of a mixture of neoglycoconjugates with carbohydrate:protein ratios of 1.9:1, 3.0:1, 4.0:1, 4.9:1, 5.9:1, 6.9:1, 7.9:1 and 9.1:1. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of the tryptic and GluC V8 digests allowed identification of 12 glycation sites in the carbohydrate-protein neoglycoconjugate vaccine. The glycation sites are located exclusively on lysine (Lys) residues and are listed as follows: Lys 22, Lys 61, Lys 145, Lys 239, Lys 278, Lys 318, Lys 331, Lys 353, Lys 378, Lys 389, Lys 396 and Lys 437. Based on the 3-D representation of the rTT-Hc protein, all the glycation sites correspond to lysines located at the outer surface of the protein. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Jahouh, Farid; Banoub, Joseph H.] Mem Univ Newfoundland, Dept Biochem, St John, NF A1B 3X7, Canada. [Xu, Peng; Kovac, Pavol] NIDDK, NIH, Lbc Bethesda, MD 20892 USA. [Vann, Willie F.] US FDA, Lab Bacterial Toxins OVRR, CBER, Bethesda, MD 20892 USA. [Banoub, Joseph H.] Fisheries & Oceans Canada, Sci Branch, Special Projects, St John, NF A1C 5X1, Canada. RP Banoub, JH (reprint author), Fisheries & Oceans Canada, Sci Branch, Special Projects, POB 5667, St John, NF A1C 5X1, Canada. EM Joe.Banoub@dfo-mpo.gc.ca RI Xu, Peng/K-7036-2012 FU Intramural NIH HHS [Z99 DK999999, ZIA DK059701-39] NR 29 TC 4 Z9 4 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1076-5174 EI 1096-9888 J9 J MASS SPECTROM JI J. Mass Spectrom. PD OCT PY 2013 VL 48 IS 10 BP 1083 EP 1090 DI 10.1002/jms.3258 PG 8 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA 272PU UT WOS:000328473500003 PM 24130011 ER PT J AU Goodman, MF Woodgate, R AF Goodman, Myron F. Woodgate, Roger TI Translesion DNA Polymerases SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID SOS-INDUCED MUTAGENESIS; ESCHERICHIA-COLI DINB; SULFOLOBUS-SOLFATARICUS P2; DAMAGE-INDUCED MUTAGENESIS; THYMINE-THYMINE DIMER; Y-FAMILY POLYMERASES; ERROR-PRONE; SACCHAROMYCES-CEREVISIAE; UV-MUTAGENESIS; RECA PROTEIN AB Living cells are continually exposed to DNA-damaging agents that threaten their genomic integrity. Although DNA repair processes rapidly target the damaged DNA for repair, some lesions nevertheless persist and block genome duplication by the cell's replicase. To avoid the deleterious consequence of a stalled replication fork, cells use specialized polymerases to traverse the damage. This process, termed "translesion DNA synthesis" (TLS), affords the cell additional time to repair the damage before the replicase returns to complete genome duplication. In many cases, this damage-tolerance mechanism is error-prone, and cell survival is often associated with an increased risk of mutagenesis and carcinogenesis. Despite being tightly regulated by a variety of transcriptional and posttranslational controls, the low-fidelity TLS polymerases also gain access to undamaged DNA where their inaccurate synthesis may actually be beneficial for genetic diversity and evolutionary fitness. C1 [Goodman, Myron F.] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Goodman, Myron F.] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. [Woodgate, Roger] NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. EM woodgate@nih.gov FU NIH/NICHD; NIH [GM21422, ES012259] FX We thank Alexandra Vaisman (National Institutes of Health/National Institute of Child Health and Human Development) for the graphic artwork depicted in this review. R. W. is supported by funds from the NIH/NICHD Intramural Research Program and M. F. G. by NIH grants GM21422 and ES012259. NR 173 TC 50 Z9 50 U1 4 U2 15 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD OCT PY 2013 VL 5 IS 10 AR a010363 DI 10.1101/cshperspect.a010363 PG 20 WC Cell Biology SC Cell Biology GA 262MR UT WOS:000327740000004 PM 23838442 ER PT J AU Scholle, SO Ypma, RJF Lloyd, AL Koelle, K AF Scholle, Stacy O. Ypma, Rolf J. F. Lloyd, Alun L. Koelle, Katia TI Viral Substitution Rate Variation Can Arise from the Interplay between Within-Host and Epidemiological Dynamics SO AMERICAN NATURALIST LA English DT Article DE substitution rate variation; RNA virus evolution; within-host dynamics; epidemiological model; disease dynamics ID HEMATOPOIETIC NECROSIS VIRUS; HEMORRHAGIC SEPTICEMIA VIRUS; POPULATION-DYNAMICS; INFECTIOUS-DISEASE; EVOLUTION; TRANSMISSION; MODELS; REPLICATION; EPIDEMICS; PATHOGENS AB The evolutionary rates of RNA viruses can differ from one another by several orders of magnitude. Much of this variation has been explained by differences in viral mutation rates and selective environments. However, substitution rates also vary considerably across viral populations belonging to the same species. In particular, viral lineages from epidemic regions tend to have higher substitution rates than those from endemic regions, and lineages from populations with higher contact rates tend to have higher substitution rates than those from populations with lower contact rates. We address the mechanism behind these patterns by using a nested modeling approach, whereby we integrate within-host viral replication dynamics with a population-level epidemiological model. Through numerical simulations and analytical approximations, we show that variation in viral substitution rates over the course of an infection, coupled with differences in age of infection of transmitting hosts under different epidemiological scenarios, can explain these evolutionary patterns. We further derive analytical estimates of expected substitution rate differences under epidemic versus endemic epidemiological conditions. By comparing these estimates to empirical data for four viral species, we show that these factors are sufficient to explain observed variation in substitution rates in three of four cases. This work shows that even in neutrally evolving viral populations, epidemiological dynamics can alter substitution rates via the interplay between within-host replication dynamics and population-level disease dynamics. C1 [Scholle, Stacy O.; Koelle, Katia] Duke Univ, Dept Biol, Durham, NC 27708 USA. [Ypma, Rolf J. F.] Natl Inst Publ Hlth & Environm, Ctr Infect Dis Control, NL-3720 BA Bilthoven, Netherlands. [Ypma, Rolf J. F.] Univ Med Ctr, Julius Ctr Hlth Res & Primary Care, Utrecht, Netherlands. [Lloyd, Alun L.] N Carolina State Univ, Grad Program Biomath, Raleigh, NC 27695 USA. [Lloyd, Alun L.; Koelle, Katia] Fogarty Int Ctr, NIH, Bethesda, MD 20892 USA. RP Scholle, SO (reprint author), Duke Univ, Dept Biol, Durham, NC 27708 USA. EM stacy.scholle@duke.edu FU National Science Foundation [NSF-EF-08-27416]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We thank A. Rodrigo and members of the Koelle lab for useful discussions and helpful feedback. This work was supported by National Science Foundation grant NSF-EF-08-27416 (K. K.). K. K. and A. L. L. were further supported by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. NR 45 TC 2 Z9 2 U1 0 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0003-0147 EI 1537-5323 J9 AM NAT JI Am. Nat. PD OCT 1 PY 2013 VL 182 IS 4 BP 494 EP 513 DI 10.1086/672000 PG 20 WC Ecology; Evolutionary Biology SC Environmental Sciences & Ecology; Evolutionary Biology GA 264SW UT WOS:000327901800026 PM 24021402 ER PT J AU Broder, CC Xu, K Nikolov, DB Zhu, ZY Dimitrov, DS Middleton, D Pallister, J Geisbert, TW Bossart, KN Wang, LF AF Broder, Christopher C. Xu, Kai Nikolov, Dimitar B. Zhu, Zhongyu Dimitrov, Dimiter S. Middleton, Deborah Pallister, Jackie Geisbert, Thomas W. Bossart, Katharine N. Wang, Lin-Fa TI A treatment for and vaccine against the deadly Hendra and Nipah viruses SO ANTIVIRAL RESEARCH LA English DT Review DE Hendra virus; Nipah virus; Vaccine; Monoclonal antibody; G glycoprotein; Horse ID SUBUNIT VACCINE; HAMSTER MODEL; RIBAVIRIN TREATMENT; G-GLYCOPROTEIN; INFECTION; ENCEPHALITIS; PARAMYXOVIRUS; CHALLENGE; FUSION; HENIPAVIRUSES AB Hendra virus and Nipah virus are bat-borne paramyxoviruses that are the prototypic members of the genus Henipavirus. The henipaviruses emerged in the 1990s, spilling over from their natural bat hosts and causing serious disease outbreaks in humans and livestock. Hendra virus emerged in Australia and since 1994 there have been 7 human infections with 4 case fatalities. Nipah virus first appeared in Malaysia and subsequent outbreaks have occurred in Bangladesh and India. In total, there have been an estimated 582 human cases of Nipah virus and of these, 54% were fatal. Their broad species tropism and ability to cause fatal respiratory and/or neurologic disease in humans and animals make them important transboundary biological threats. Recent experimental findings in animals have demonstrated that a human monoclonal antibody targeting the viral G glycoprotein is an effective post-exposure treatment against Hendra and Nipah virus infection. In addition, a subunit vaccine based on the G glycoprotein of Hendra virus affords protection against Hendra and Nipah virus challenge. The vaccine has been developed for use in horses in Australia and is the first vaccine against a Biosafety Level-4 (BSL-4) agent to be licensed and commercially deployed. Together, these advances offer viable approaches to address Hendra and Nipah virus infection of livestock and people. Published by Elsevier B.V. C1 [Broder, Christopher C.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. [Xu, Kai; Nikolov, Dimitar B.] Mem Sloan Kettering Canc Ctr, Struct Biol Program, New York, NY 10021 USA. [Zhu, Zhongyu; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, NIH, Frederick, MD 21702 USA. [Middleton, Deborah; Pallister, Jackie; Wang, Lin-Fa] CSIRO Livestock Ind, Australian Anim Hlth Lab, Geelong, Vic, Australia. [Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77550 USA. [Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77550 USA. [Bossart, Katharine N.] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Bossart, Katharine N.] Boston Univ, Sch Med, Natl Emerging Infect Dis Labs Inst, Boston, MA 02118 USA. RP Broder, CC (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM christopher.broder@usuhs.edu FU United States, Department of Health and Human Services, National Institutes of Health (NIH); Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The views expressed in the manuscript are solely those of the authors, and they do not represent official views or opinions of the Department of Defense or The Uniformed Services University of the Health Sciences. CCB, KNB and TWG are supported in part by grants from the United States, Department of Health and Human Services, National Institutes of Health (NIH). ZZ and DSD are supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 58 TC 14 Z9 15 U1 3 U2 62 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD OCT PY 2013 VL 100 IS 1 BP 8 EP 13 DI 10.1016/j.antiviral.2013.06.012 PG 6 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 268OB UT WOS:000328179300002 PM 23838047 ER PT J AU Bente, DA Forrester, NL Watts, DM McAuley, AJ Whitehouse, CA Bray, M AF Bente, Dennis A. Forrester, Naomi L. Watts, Douglas M. McAuley, Alexander J. Whitehouse, Chris A. Bray, Mike TI Crimean-Congo hemorrhagic fever: History, epidemiology, pathogenesis, clinical syndrome and genetic diversity SO ANTIVIRAL RESEARCH LA English DT Review DE Crimean-Congo hemorrhagic fever virus; Tick-borne virus; Arbovirus; Nairovirus; Bunyavirus; Viral hemorrhagic fever ID M-RNA SEGMENT; SALIVA-ACTIVATED TRANSMISSION; VIRUS NUCLEOCAPSID PROTEIN; ADULT HYALOMMA-TRUNCATUM; BORNE ENCEPHALITIS-VIRUS; RECEPTOR-KNOCKOUT MICE; INFLUENZA-LIKE VIRUS; HEALTH-CARE WORKERS; RT-PCR ASSAY; NOSOCOMIAL OUTBREAK AB Crimean-Congo hemorrhagic fever (CCHF) is the most important tick-borne viral disease of humans, causing sporadic cases or outbreaks of severe illness across a huge geographic area, from western China to the Middle East and southeastern Europe and throughout most of Africa. CCHFV is maintained in vertical and horizontal transmission cycles involving ixodid ticks and a variety of wild and domestic vertebrates, which do not show signs of illness. The virus circulates in a number of tick genera, but Hyalomma ticks are the principal source of human infection, probably because both immature and adult forms actively seek hosts for the blood meals required at each stage of maturation. CCHF occurs most frequently among agricultural workers following the bite of an infected tick, and to a lesser extent among slaughterhouse workers exposed to the blood and tissues of infected livestock and medical personnel through contact with the body fluids of infected patients. CCHFV is the most genetically diverse of the arboviruses, with nucleotide sequence differences among isolates ranging from 20% for the viral S segment to 31% for the M segment. Viruses with diverse sequences can be found within the same geographic area, while closely related viruses have been isolated in far distant regions, suggesting that widespread dispersion of CCHFV has occurred at times in the past, possibly by ticks carried on migratory birds or through the international livestock trade. Reassortment among genome segments during co-infection of ticks or vertebrates appears to have played an important role in generating diversity, and represents a potential future source of novel viruses. In this article, we first review current knowledge of CCHFV, summarizing its molecular biology, maintenance and transmission, epidemiology and geographic range. We also include an extensive discussion of CCHFV genetic diversity, including maps of the range of the virus with superimposed phylogenetic trees. We then review the features of CCHF, including the clinical syndrome, diagnosis, treatment, pathogenesis, vaccine development and laboratory animal models of CCHF. The paper ends with a discussion of the possible future geographic range of the virus. For the benefit of researchers, we include a Supplementary Table listing all published reports of CCHF cases and outbreaks in the English-language literature, plus some principal articles in other languages, with total case numbers, case fatality rates and all CCHFV strains on GenBank. (C) 2013 Elsevier B.V. All rights reserved. C1 [Bente, Dennis A.; McAuley, Alexander J.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Forrester, Naomi L.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Watts, Douglas M.] Univ Texas El Paso, Dept Vet Serv, El Paso, TX 79968 USA. [Whitehouse, Chris A.] US Geol Survey, Natl Wildlife Hlth Ctr, Madison, WI 53711 USA. [Bray, Mike] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Bente, DA (reprint author), Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. EM dabente@utmb.edu OI McAuley, Alexander/0000-0002-7632-9633 FU NIAID NIH HHS [UC6 AI058588] NR 273 TC 114 Z9 119 U1 7 U2 57 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD OCT PY 2013 VL 100 IS 1 BP 159 EP 189 DI 10.1016/j.antiviral.2013.07.006 PG 31 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 268OB UT WOS:000328179300018 PM 23906741 ER PT J AU Dasgupta, B Al-Mubaid, H Saeed, F AF Dasgupta, Bhaskar Al-Mubaid, Hisham Saeed, Fahad TI FOREWORD TO THE SPECIAL ISSUE ON SELECTED PAPERS FROM THE 5TH INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND COMPUTATIONAL BIOLOGY (BICoB 2013) SO JOURNAL OF BIOINFORMATICS AND COMPUTATIONAL BIOLOGY LA English DT Editorial Material C1 [Dasgupta, Bhaskar] Univ Illinois, Chicago, IL 60607 USA. [Al-Mubaid, Hisham] Univ Houston Clear Lake, Houston, TX USA. [Saeed, Fahad] NIH, Bethesda, MD USA. RP Dasgupta, B (reprint author), Univ Illinois, Chicago, IL 60607 USA. NR 5 TC 0 Z9 0 U1 0 U2 1 PU IMPERIAL COLLEGE PRESS PI LONDON PA 57 SHELTON ST, COVENT GARDEN, LONDON WC2H 9HE, ENGLAND SN 0219-7200 EI 1757-6334 J9 J BIOINF COMPUT BIOL JI J. Bioinform. Comput. Biol. PD OCT PY 2013 VL 11 IS 5 AR UNSP 1302002 DI 10.1142/S0219720013020022 PG 2 WC Biochemical Research Methods; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Mathematical & Computational Biology GA 268IS UT WOS:000328164200001 PM 24131048 ER PT J AU Xiao, L Rao, JN Zou, TT Liu, L Cao, S Martindale, JL Su, WJ Chung, HK Gorospe, M Wang, JY AF Xiao, Lan Rao, Jaladanki N. Zou, Tongtong Liu, Lan Cao, Shan Martindale, Jennifer L. Su, Weijie Chung, Hee Kyoung Gorospe, Myriam Wang, Jian-Ying TI miR-29b represses intestinal mucosal growth by inhibiting translation of cyclin-dependent kinase 2 SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MESSENGER-RNA TRANSLATION; EPITHELIAL BARRIER FUNCTION; CUG-BINDING PROTEIN-1; CELL-PROLIFERATION; C-MYC; POLYAMINE DEPLETION; SELF-RENEWAL; EXPRESSION; CANCER; HUR AB The epithelium of the intestinal mucosa is a rapidly self-renewing tissue in the body, and defects in the renewal process occur commonly in various disorders. microRNAs (miRNAs) posttranscriptionally regulate gene expression and are implicated in many aspects of cellular physiology. Here we investigate the role of miRNA-29b (miR-29b) in the regulation of normal intestinal mucosal growth and further validate its target mRNAs. miRNA expression profiling studies reveal that growth inhibition of the small intestinal mucosa is associated with increased expression of numerous miRNAs, including miR-29b. The simple systemic delivery of locked nucleic acid-modified, anti-miR-29b-reduced endogenous miR-29b levels in the small intestinal mucosa increases cyclin-dependent kinase 2 (CDK2) expression and stimulates mucosal growth. In contrast, overexpression of the miR-29b precursor in intestinal epithelial cells represses CDK2 expression and results in growth arrest in G1 phase. miR-29b represses CDK2 translation through direct interaction with the cdk2 mRNA via its 3'-untranslated region (3'-UTR), whereas point mutation of miR-29b binding site in the cdk2 3'-UTR prevents miR-29b-induced repression of CDK2 translation. These results indicate that miR-29b inhibits intestinal mucosal growth by repressing CDK2 translation. C1 [Xiao, Lan; Rao, Jaladanki N.; Zou, Tongtong; Liu, Lan; Cao, Shan; Su, Weijie; Chung, Hee Kyoung; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. [Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Xiao, Lan; Rao, Jaladanki N.; Zou, Tongtong; Liu, Lan; Cao, Shan; Su, Weijie; Chung, Hee Kyoung; Wang, Jian-Ying] Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Martindale, Jennifer L.; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Wang, JY (reprint author), Univ Maryland, Sch Med, Dept Surg, Cell Biol Grp, Baltimore, MD 21201 USA. EM jwang@smail.umaryland.edu FU U.S. Department of Veterans Affairs; National Institutes of Health [DK57819, DK61972, DK68491]; National Institute on Aging-Intramural Research Program, National Institutes of Health FX This work was supported by Merit Review Grants to J.-Y.W. and J.N.R. from the U.S. Department of Veterans Affairs and by National Institutes of Health Grants DK57819, DK61972, and DK68491 to J.-Y.W. M. G. is supported by the National Institute on Aging-Intramural Research Program, National Institutes of Health. J.-Y.W. is a Senior Research Career Scientist, Medical Research Service, U.S. Department of Veterans Affairs. NR 46 TC 22 Z9 23 U1 0 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD OCT 1 PY 2013 VL 24 IS 19 BP 3038 EP 3046 DI 10.1091/mbc.E13-05-0287 PG 9 WC Cell Biology SC Cell Biology GA 267UH UT WOS:000328123200004 PM 23904268 ER PT J AU Restifo, NP Gattinoni, L AF Restifo, Nicholas P. Gattinoni, Luca TI Lineage relationship of effector and memory T cells SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID SUPERIOR ANTITUMOR IMMUNITY; ADOPTIVE IMMUNOTHERAPY; IN-VIVO; TRANSFER THERAPY; CUTTING EDGE; STEM-CELLS; DIFFERENTIATION; SUBSETS; LYMPHOCYTES; EXPRESSION AB Adaptive immunity is characterized by the ability to form long-lived immunological memory. Upon re-exposure to antigen, memory T cells respond more rapidly and robustly than naive T cells, providing better clearance of pathogens. Recent reviews have reinforced the text-book view that memory T cells arise from effector cells. Although this notion is teleologically appealing, emerging data are more consistent with a model where naive cells directly develop into memory cells without transitioning through an effector stage. A clear understanding of the lineage relationships between memory and effector cells has profound implications for the design of vaccines and for the development of effective T cell-based therapies. C1 [Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gattinoni, Luca] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; OI Gattinoni, Luca/0000-0003-2239-3282; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [ZIA BC010763-07] NR 65 TC 45 Z9 45 U1 0 U2 17 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 EI 1879-0372 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD OCT PY 2013 VL 25 IS 5 BP 556 EP 563 DI 10.1016/j.coi.2013.09.003 PG 8 WC Immunology SC Immunology GA 261OZ UT WOS:000327675800003 PM 24148236 ER PT J AU Severson, PL Tokar, EJ Vrba, L Waalkes, MP Futscher, BW AF Severson, Paul L. Tokar, Erik J. Vrba, Lukas Waalkes, Michael P. Futscher, Bernard W. TI Coordinate H3K9 and DNA methylation silencing of ZNFs in toxicant-induced malignant transformation SO EPIGENETICS LA English DT Article DE C2H2 zinc finger genes; DNA methylation; H3K27me3; H3K4me3; H3K9me3; arsenic; epigenetics; malignant transformation ID ZINC-FINGER PROTEIN; MAPK SIGNALING PATHWAY; INHIBITS TRANSCRIPTIONAL ACTIVITIES; ENDOGENOUS RETROVIRUSES; TUMOR-SUPPRESSOR; EPITHELIAL-CELLS; HISTONE H3; GENES; CANCER; MICROARRAY AB Genome-wide disruption of the epigenetic code is a hallmark of malignancy that encompasses many distinct, highly interactive modifications. Delineating the aberrant epigenome produced during toxicant-mediated malignant transformation will help identify the underlying epigenetic drivers of environmental toxicant-induced carcinogenesis. Gene promoter DNA methylation and gene expression profiling of arsenite-transformed prostate epithelial cells showed a negative correlation between gene expression changes and DNA methylation changes; however, less than 10% of the genes with increased promoter methylation were downregulated. Studies described herein confirm that a majority of the DNA hypermethylation events occur at H3K27me3 marked genes that were already transcriptionally repressed. In contrast to aberrant DNA methylation targeting H3K27me3 pre-marked silent genes, we found that actively expressed C2H2 zinc finger genes (ZNFs) marked with H3K9me3 on their 3 ends, were the favored targets of DNA methylation linked gene silencing. DNA methylation coupled, H3K9me3 mediated gene silencing of ZNF genes was widespread, occurring at individual ZNF genes on multiple chromosomes and across ZNF gene family clusters. At ZNF gene promoters, H3K9me3 and DNA hypermethylation replaced H3K4me3, resulting in a widespread downregulation of ZNF gene expression, which accounted for 8% of all the downregulated genes in the arsenical-transformed cells. In summary, these studies associate toxicant exposure with widespread silencing of ZNF genes by DNA hypermethylation-linked H3K9me3 spreading, further implicating epigenetic dysfunction as a driver of toxicant associated carcinogenesis. C1 [Severson, Paul L.; Futscher, Bernard W.] Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, Tucson, AZ 85721 USA. [Tokar, Erik J.; Waalkes, Michael P.] NIEHS, Natl Toxicol Program Lab, Res Triangle Pk, NC 27709 USA. [Vrba, Lukas; Futscher, Bernard W.] Univ Arizona, Ctr Canc, Tucson, AZ USA. RP Futscher, BW (reprint author), Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, Tucson, AZ 85721 USA. EM BFutscher@uacc.arizona.edu RI Vrba, Lukas/J-9268-2015 OI Vrba, Lukas/0000-0003-3042-6275 FU National Institutes of Health [P42 ES04940, ES006694, CA23074, 5T32ES16652-3, 2T32ES007091-31] FX This work was supported by the National Institutes of Health (P42 ES04940, ES006694, CA23074, 5T32ES16652-3 and 2T32ES007091-31 to PLS). 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 herein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the US government. NR 55 TC 12 Z9 12 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 EI 1559-2308 J9 EPIGENETICS-US JI Epigenetics PD OCT 1 PY 2013 VL 8 IS 10 BP 1080 EP 1088 DI 10.4161/epi.25926 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 260UJ UT WOS:000327619700010 PM 23974009 ER PT J AU Fee, E AF Fee, Elizabeth TI LEAD WARS: THE POLITICS OF SCIENCE AND THE FATE OF AMERICA'S CHILDREN SO HEALTH AFFAIRS LA English DT Book Review C1 [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Fee, E (reprint author), NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM feee@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD OCT PY 2013 VL 32 IS 10 BP 1853 EP 1853 PG 1 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 250GG UT WOS:000326837900026 ER PT J AU Roselli, M Cereda, V di Bari, MG Formica, V Spila, A Jochems, C Farsaci, B Donahue, R Gulley, JL Schlom, J Guadagni, F AF Roselli, Mario Cereda, Vittore di Bari, Maria Giovanna Formica, Vincenzo Spila, Antonella Jochems, Caroline Farsaci, Benedetto Donahue, Renee Gulley, James L. Schlom, Jeffrey Guadagni, Fiorella TI Effects of conventional therapeutic interventions on the number and function of regulatory T cells SO ONCOIMMUNOLOGY LA English DT Article DE carcinoma; chemotherapy; drug therapy; T lymphocytes; Tregs ID RESISTANT PROSTATE-CANCER; TUMOR MICROENVIRONMENT; COMBINATION THERAPY; IMMUNE SUPPRESSION; CARCINOMA PATIENTS; SUNITINIB; VACCINE; IMMUNOTHERAPY; CHEMOTHERAPY; SURVIVAL AB Several lines of investigation have revealed the apparent interplay between the immune system of the host and many conventional, standard-of-care anticancer therapies, including chemotherapy and small molecule targeted therapeutics. In particular, preclinical and clinical studies have demonstrated the important role of regulatory T cells (Tregs) in inhibiting immune responses elicited by immunotherapeutic regimens such as those based on anticancer vaccines or checkpoint inhibitors. However, how the number and immunosuppressive function of Tregs change in cancer patients undergoing treatment with non-immune anticancer therapies remains to be precisely elucidated. To determine whether immunostimulatory therapies can be employed successfully in combination with conventional anticancer regimens, we have investigated both the number and function of Tregs obtained from the peripheral blood of carcinoma patients before the initiation and during the course of chemotherapeutic and targeted agent regimens. Our studies show that the treatment of breast cancer patients with tamoxifen plus leuprolide, a gonadotropin releasing hormone agonist, has minimal effects on Tregs, while sunitinib appears to exert differential effects on Tregs among patients with metastatic renal carcinoma. However, the administration of docetaxel to patients with metastatic prostate or breast cancer, as well as that of cisplatin plus vinorelbine to non-small cell lung cancer patients, appears to significantly increase the ratio between effector T cells and Tregs and to reduce the immunosuppressive activity of the latter in the majority of patients. These studies provide the rationale for the selective use of active immunotherapy regimens in combination with specific standard-of-care therapies to achieve the most beneficial clinical outcome among carcinoma patients. C1 [Roselli, Mario; Cereda, Vittore; Formica, Vincenzo] Univ Roma Tor Vergata, Dept Internal Med, Tor Vergata Univ Clin Ctr, Rome, Italy. [di Bari, Maria Giovanna; Spila, Antonella; Guadagni, Fiorella] IRCCS San Raffaele Pisana, Dept Lab Med & Adv Biotechnol, Interinst Multidisciplinary Biobank BioBIM, Rome, Italy. [Jochems, Caroline; Farsaci, Benedetto; Donahue, Renee; Gulley, James L.; Schlom, Jeffrey] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gulley, James L.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Farsaci, Benedetto/L-9837-2014; Gulley, James/K-4139-2016; OI Farsaci, Benedetto/0000-0001-8275-2561; Gulley, James/0000-0002-6569-2912; Roselli, Mario/0000-0002-2431-6689 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. This work has been partially performed within the Ph.D. program in "Oncology rehabilitation" XXV Ciclo. The authors thank Debra Weingarten for her editorial assistance in the preparation of the manuscript. NR 42 TC 17 Z9 19 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 EI 2162-402X J9 ONCOIMMUNOLOGY JI OncoImmunology PD OCT 1 PY 2013 VL 2 IS 10 AR e27025 DI 10.4161/onci.27025 PG 12 WC Oncology; Immunology SC Oncology; Immunology GA 262LO UT WOS:000327737000013 ER PT J AU Hamilton, DH Litzinger, MT Jales, A Huang, B Fernando, RI Hodge, JW Ardiani, A Apelian, D Schlom, J Palena, C AF Hamilton, Duane H. Litzinger, Mary T. Jales, Alessandra Huang, Bruce Fernando, Romaine I. Hodge, James W. Ardiani, Andressa Apelian, David Schlom, Jeffrey Palena, Claudia TI Immunological targeting of tumor cells undergoing an epithelial-mesenchymal transition via a recombinant brachyury-yeast vaccine SO ONCOTARGET LA English DT Article DE epithelial-mesenchymal transition; brachyury; T-box transcription factor; cancer vaccine; T-cell immunotherapy ID TRANSCRIPTION FACTOR BRACHYURY; HUMAN CARCINOMA-CELLS; CANCER STEM-CELLS; DENDRITIC CELLS; MESODERM FORMATION; T-GENE; ANTIGEN; IMMUNOTHERAPY; PROGRESSION; MATURATION AB The embryonic T-box transcription factor brachyury is aberrantly expressed in a range of human tumors. Previous studies have demonstrated that brachyury is a driver of the epithelial-mesenchymal transition (EMT), a process associated with cancer progression. Brachyury expression in human tumor cells enhances tumor invasiveness in vitro and metastasis in vivo, and induces resistance to various conventional therapeutics including chemotherapy and radiation. These characteristics, and the selective expression of brachyury for a range of human tumor types vs. normal adult tissues, make brachyury an attractive tumor target. Due to its intracellular localization and the "undruggable" character of transcription factors, available options to target brachyury are currently limited. Here we report on the development and characterization of an immunological platform for the efficient targeting of brachyury-positive tumors consisting of a heat-killed, recombinant Saccharomyces cerevisiae (yeast)-brachyury vector-based vaccine (designated as GI-6301) that expresses the full-length human brachyury protein. We demonstrate that human dendritic cells treated with recombinant yeast-brachyury can activate and expand brachyury-specific CD4(+) and CD8(+) T cells in vitro that, in turn, can effectively lyse human tumor cells expressing the brachyury protein. Vaccination of mice with recombinant yeast-brachyury is also shown here to elicit brachyury-specific CD4(+) and CD8(+) T-cell responses, and to induce anti-tumor immunity in the absence of toxicity. Based on these results, a Phase I clinical trial of GI-6301 is currently ongoing in patients with advanced tumors; to our knowledge, this is the first vaccine platform aimed at targeting a driver of tumor EMT that has successfully reached the clinical stage. C1 [Hamilton, Duane H.; Litzinger, Mary T.; Jales, Alessandra; Huang, Bruce; Fernando, Romaine I.; Hodge, James W.; Ardiani, Andressa; Schlom, Jeffrey; Palena, Claudia] NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Apelian, David] GlobeImmune Inc, Louisville, CO USA. RP Palena, C (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM palenac@mail.nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Center for Cancer Research, National Cancer Institute, NIH; GlobeImmune, Inc.; National Cancer Institute FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, and a Cooperative Research and Development Agreement between GlobeImmune, Inc., and the National Cancer Institute. NR 33 TC 29 Z9 32 U1 0 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT PY 2013 VL 4 IS 10 BP 1777 EP 1790 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 257QP UT WOS:000327401100024 PM 24125763 ER PT J AU Chanock, SJ AF Chanock, Stephen J. TI Introduction: Sifting Through the Characterization of Hematologic Malignancies SO SEMINARS IN HEMATOLOGY LA English DT Editorial Material ID CANCER GENOME; HETEROGENEITY; EVOLUTION; GENES C1 NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Chanock, SJ (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2013 VL 50 IS 4 BP 284 EP 285 DI 10.1053/j.seminhematol.2013.10.002 PG 2 WC Hematology SC Hematology GA 263TA UT WOS:000327829700002 PM 24246695 ER PT J AU Slager, SL Caporaso, NE de Sanjose, S Goldin, LR AF Slager, Susan L. Caporaso, Neil E. de Sanjose, Silvia Goldin, Lynn R. TI Genetic Susceptibility to Chronic Lymphocytic Leukemia SO SEMINARS IN HEMATOLOGY LA English DT Article ID B-CELL LYMPHOCYTOSIS; GENOME-WIDE ASSOCIATION; HODGKIN-LYMPHOMA SUBTYPES; AFRICAN-AMERICANS; COMMON VARIATION; RISK; VARIANTS; FAMILIES; LOCI; CLL AB Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the West and is an incurable malignancy. No firmly established evidence exists for environmental risk factors in the etiology of CLL. However, CLL is estimated to have one of the highest familial risks for a hematologic malignancy; this along with other evidence strongly supports an inherited genetic component. In the past 5 years, genome-wide association studies (GWAS) have provided the foundation for new avenues in the investigation of pathogenesis of this disease with 22 susceptibility loci currently identified. We review here the advances made in identifying these loci, the potential to translate these findings into clinical practice, and future directions needed to advance our understanding of the genetic susceptibility of CLL. (C) 2013 Elsevier Inc. All rights reserved. C1 [Slager, Susan L.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Caporaso, Neil E.; Goldin, Lynn R.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [de Sanjose, Silvia] IDIBELL, Inst Catala Oncol, Unit Infect & Canc, Canc Epidemiol Res Programme, Barcelona, Spain. [de Sanjose, Silvia] Ctr Invest Biomed Red Epidemiol & Salud Publ CIBE, Barcelona, Spain. RP Slager, SL (reprint author), Mayo Clin, Coll Med, Dept Hlth Sci Res, 200 1st St SW, Rochester, MN 55905 USA. EM slager@mayo.edu RI de Sanjose Llongueras, Silvia/H-6339-2014 FU National Cancer Institute/NIH Grants [R01 CA11844, R01 CA92153]; Intramural research program of the NIH, NCI FX Supported in part by the National Cancer Institute/NIH Grants R01 CA11844, R01 CA92153; the Intramural research program of the NIH, NCI. NR 55 TC 9 Z9 10 U1 1 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2013 VL 50 IS 4 BP 296 EP 302 DI 10.1053/j.seminhematol.2013.09.007 PG 7 WC Hematology SC Hematology GA 263TA UT WOS:000327829700004 PM 24246697 ER PT J AU Khincha, PP Savage, SA AF Khincha, Payal P. Savage, Sharon A. TI Genomic Characterization of the Inherited Bone Marrow Failure Syndromes SO SEMINARS IN HEMATOLOGY LA English DT Article ID DIAMOND-BLACKFAN ANEMIA; ABSENT RADIUS SYNDROME; TELOMERASE REVERSE-TRANSCRIPTASE; DOMINANT DYSKERATOSIS-CONGENITA; HOYERAAL-HREIDARSSON-SYNDROME; EXOME SEQUENCING REVEALS; DNA-REPAIR ENDONUCLEASE; FANCONI-ANEMIA; APLASTIC-ANEMIA; AUTOSOMAL-DOMINANT AB The inherited bone marrow failure syndromes (IBMFS) are a set of clinically related yet heterogeneous disorders in which at least one hematopoietic cell lineage is significantly reduced. Many of the IBMFS have notably increased cancer risks, as well as other physical findings. Highly penetrant germline mutations in key pathways, such as DNA repair, telomere biology, or ribosomal biogenesis, are causative of Fanconi anemia (FA), dyskeratosis congenita (DC), and Diamond-Blackfan anemia (DBA), respectively. Next-generation sequencing (NGS) generally refers to high-throughput, large-scale sequencing technologies and is being used more frequently to understand disease etiology. In the IBMFS, NGS has facilitated the discovery of germline mutations that cause thomboc-ytopenia absent radii syndrome (TAR), a subset of DC and DBA, and other uncharacterized, but related, disorders. Panels of large numbers of genes are being used to molecularly characterize patients with IBMFS, such as FA and DBA. NGS is also accelerating the discovery of the genetic etiology of previously unclassified IBMFS. In this review, we will highlight recent studies that have employed NGS to ascertain the genetic etiology of IBMFS, namely, FA, DC, DBA, and TAR, and discuss the translational utility of these findings. Published by Elsevier Inc. C1 [Khincha, Payal P.; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Khincha, Payal P.] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E 454, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health FX This work was supported by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health. The authors thank Drs Blanche P. Alter, Bari J. Ballew, and Neelam Giri, NCI, for their helpful comments. NR 105 TC 17 Z9 19 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2013 VL 50 IS 4 BP 333 EP 347 DI 10.1053/j.seminhematol.2013.09.002 PG 15 WC Hematology SC Hematology GA 263TA UT WOS:000327829700008 PM 24246701 ER PT J AU Machiela, MJ Chanock, SJ AF Machiela, Mitchell J. Chanock, Stephen J. TI Detectable Clonal Mosaicism in the Human Genome SO SEMINARS IN HEMATOLOGY LA English DT Article ID MCCUNE-ALBRIGHT-SYNDROME; ACUTE MYELOID-LEUKEMIA; COPY-NUMBER VARIATION; CHRONIC LYMPHOCYTIC-LEUKEMIA; MITOCHONDRIAL-DNA MUTATIONS; PATERNAL GONADAL MOSAICISM; TETRASOMY 5P MOSAICISM; STIMULATORY G-PROTEIN; CELL LUNG-CANCER; ACTIVATING MUTATIONS AB Human genetic mosaicism is the presence of two or more cellular populations with distinct genotypes in an individual who developed from a single fertilized ovum. While initially observed across a spectrum of rare genetic disorders, detailed assessment of data from genome-wide association studies now reveal that detectable clonal mosaicism involving large structural alterations (>2 Mb) can also be seen in populations of apparently healthy individuals. The first generation of descriptive studies has generated new interest in understanding the molecular basis of the affected genomic regions, percent of the cellular subpopulation involved, and developmental timing of the underlying mutational event, which could reveal new insights into the initiation, clonal expansion, and phenotypic manifestations of mosaic events. Early evidence indicates detectable clonal mosaicism increases in frequency with age and could preferentially occur in males. The observed pattern of recurrent events affecting specific chromosomal regions indicates some regions are more susceptible to these events, which could reflect inter-individual differences in genomic stability. Moreover, it is also plausible that the presence of large structural events could be associated with cancer risk. The characterization of detectable genetic mosaicism reveals that there could be important dynamic changes in the human genome associated with the aging process, which could be associated with risk for common disorders, such as cancer, cardiovascular disease, diabetes, and neurological disorders. Published by Elsevier Inc. C1 [Machiela, Mitchell J.; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Chanock, SJ (reprint author), Lab Translat Gen, 8717 Grovemont Cir,ATC Room 134D, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov OI Machiela, Mitchell/0000-0001-6538-9705 FU Intramural NIH HHS [ZIC CP010178-09, Z01 CP010178-06, Z01 CP010178-07, ZIA CP010187-05, ZIA CP010187-06, ZIA CP010187-07, ZIA CP010187-08, ZIA CP010187-9, ZIA CP010201-01, ZIA CP010201-02, ZIA CP010201-03, ZIA CP010201-7, ZIC CP010178-08, ZIC CP010178-10, ZIC CP010178-11, ZIC CP010178-12] NR 102 TC 11 Z9 11 U1 0 U2 13 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2013 VL 50 IS 4 BP 348 EP 359 DI 10.1053/j.seminhematol.2013.09.001 PG 12 WC Hematology SC Hematology GA 263TA UT WOS:000327829700009 PM 24246702 ER PT J AU Hooten, NN Fitzpatrick, M Wood, WH De, S Ejiogu, N Zhang, YQ Mattison, JA Becker, KG Zonderman, AB Evans, MK AF Hooten, Nicole Noren Fitzpatrick, Megan Wood, William H., III De, Supriyo Ejiogu, Ngozi Zhang, Yongqing Mattison, Julie A. Becker, Kevin G. Zonderman, Alan B. Evans, Michele K. TI Age-related changes in microRNA levels in serum SO AGING-US LA English DT Article DE circulating; miRNA; noncoding RNA; age; aging; biomarker; exRNA; extracellular RNA ID LIFE-SPAN; EXPRESSION; CELL; GENOME; CENTENARIANS; SENESCENCE; SEQUENCES; ELEGANS; DISEASE; BIOLOGY AB microRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression by targeting specific mRNAs. Altered expression of circulating miRNAs have been associated with age-related diseases including cancer and cardiovascular disease. Although we and others have found an age-dependent decrease in miRNA expression in peripheral blood mononuclear cells (PBMCs), little is known about the role of circulating miRNAs in human aging. Here, we examined miRNA expression in human serum from young (mean age 30 years) and old (mean age 64 years) individuals using next generation sequencing technology and real-time quantitative PCR. Of the miRNAs that we found to be present in serum, three were significantly decreased in 20 older individuals compared to 20 younger individuals: miR-151a-5p, miR-181a- 5p and miR-1248. Consistent with our data in humans, these miRNAs are also present at lower levels in the serum of elderly rhesus monkeys. In humans, miR-1248 was found to regulate the expression of mRNAs involved in inflammatory pathways and miR-181a was found to correlate negatively with the pro-inflammatory cytokines IL-6 and TNF alpha and to correlate positively with the anti-inflammatory cytokines TGF beta and IL-10. These results suggest that circulating miRNAs may be a biological marker of aging and could also be important for regulating longevity. Identification of stable miRNA biomarkers in serum could have great potential as a noninvasive diagnostic tool as well as enhance our understanding of physiological changes that occur with age. C1 [Hooten, Nicole Noren; Fitzpatrick, Megan; Ejiogu, Ngozi; Zonderman, Alan B.; Evans, Michele K.] NIH, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA. [Wood, William H., III; De, Supriyo; Zhang, Yongqing; Becker, Kevin G.] NIH, Genet Lab, Baltimore, MD 21224 USA. [Mattison, Julie A.] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. RP Evans, MK (reprint author), NIH, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA. EM me42v@nih.gov OI De, Supriyo/0000-0002-2075-7655; Becker, Kevin/0000-0002-6794-6656; Zonderman, Alan B/0000-0002-6523-4778 FU National Institutes of Health, National Institute on Aging FX This study was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The authors wish to thank the HANDLS staff for care of participants and sample acquisition, Althaf Lohani for various technical assistance and Myriam Gorospe and Kotb Abdelmohsen for valuable discussions and critical reading of the manuscript. NR 46 TC 46 Z9 46 U1 2 U2 12 PU IMPACT JOURNALS LLC PI ORCHARD PARK PA 6666 E QUAKER ST, STE 1, ORCHARD PARK, NY 14127 USA SN 1945-4589 J9 AGING-US JI Aging-US PD OCT PY 2013 VL 5 IS 10 BP 725 EP 740 PG 16 WC Cell Biology SC Cell Biology GA 258RX UT WOS:000327477500005 ER PT J AU Kato, H Zhou, BR Feng, HQ Bai, YW AF Kato, Hidenori Zhou, Bing-Rui Feng, Hanqiao Bai, Yawen TI An evolving tail of centromere histone variant CENP-A SO CELL CYCLE LA English DT Editorial Material ID RECOGNITION; NUCLEOSOMES; COMPLEX C1 [Kato, Hidenori; Zhou, Bing-Rui; Feng, Hanqiao; Bai, Yawen] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov NR 8 TC 1 Z9 1 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD OCT 1 PY 2013 VL 12 IS 19 BP 3133 EP 3134 DI 10.4161/cc.26353 PG 2 WC Cell Biology SC Cell Biology GA 257KG UT WOS:000327381700005 PM 24013416 ER PT J AU Do, K Doroshow, JH Kummar, S AF Do, Khanh Doroshow, James H. Kummar, Shivaani TI Wee1 kinase as a target for cancer therapy SO CELL CYCLE LA English DT Review DE cyclin-dependent kinase; G2 checkpoint; cell cycle; DNA damage; MK 1775 ID CYCLIN-DEPENDENT KINASES; DOUBLE-STRAND BREAKS; DNA-DAMAGING AGENTS; CELL-CYCLE; HOMOLOGOUS RECOMBINATION; CHECKPOINT CONTROL; TYROSINE KINASE; TUMOR-CELLS; S PHASE; INHIBITION AB Wee1, a protein kinase, regulates the G(2) checkpoint in response to DNA damage. Preclinical studies have elucidated the role of wee1 in DNA damage repair and the stabilization of replication forks, supporting the validity of wee1 inhibition as a viable therapeutic target in cancer. MK-1775, a selective and potent small-molecule inhibitor of wee1, is under clinical development as a potentiator of DNA damage caused by cytotoxic chemotherapies. We present a review of the role of wee1 in the cell cycle and DNA replication and summarize the clinical development to date of this novel class of anticancer agents. C1 [Do, Khanh; Doroshow, James H.; Kummar, Shivaani] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Doroshow, James H.; Kummar, Shivaani] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Kummar, S (reprint author), NCI, Ctr Canc Res, Bethesda, MD 20892 USA. EM kummars@mail.nih.gov NR 46 TC 49 Z9 49 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD OCT 1 PY 2013 VL 12 IS 19 BP 3159 EP 3164 DI 10.4161/cc.26062 PG 6 WC Cell Biology SC Cell Biology GA 257KG UT WOS:000327381700009 PM 24013427 ER PT J AU Ahn, M Murugan, RN Jacob, B Hyun, JK Cheong, C Hwang, E Park, HN Seo, JH Srinivasrao, G Lee, KS Shin, SY Bang, JK AF Ahn, Mija Murugan, Ravichandran N. Jacob, Binu Hyun, Jae-Kyung Cheong, Chaejoon Hwang, Eunha Park, Hyo-Nam Seo, Ji-Hyung Srinivasrao, G. Lee, Kyung S. Shin, Song Yub Bang, Jeong Kyu TI Discovery of novel histidine-derived lipo-amino acids: Applied in the synthesis of ultra-short antimicrobial peptidomimetics having potent antimicrobial activity, salt resistance and protease stability SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Histidine-derived amino acid; Antimicrobial peptidomimetics; Salt resistance; Anti-MRSA activity; Protease stability ID PLAUSIBLE MODE; ANTIBACTERIAL; PEPTIDES; LIPOPEPTIDES; ANTIFUNGAL; CONJUGATION; PYRIDINIUM AB Here we report for the first time the synthesis of Histidine (His) derived lipo-amino acids having pendant lipid tails at N(tau)- and N(pi)-positions on imidazole group of His and applied it into synthesis of lipo-peptides. The attachment of His-derived lipo-amino acid into the very short inactive cationic peptides endows potent antimicrobial activity against Gram-positive and Gram-negative bacteria without hemolytic activity. Furthermore, our designed His-derived lipo-peptidomimetics (HDLPs) consisting of two or three residues displayed strong anti-MRSA activity and protease stability as well as retained potent antimicrobial activity under high salt concentration. Our results demonstrate that the novel lipo-amino acid is highly flexible to synthesize and carry out the extensive structure activity relationship (SAR) on lipo-antimicrobial peptidomimetics and represents a unique amenable platform for modifying parameters important for antimicrobial activity. Through this study, we proved that the discovery of His-derived lipo-amino acid and the corresponding HDLPs are an excellent candidate as a lead compound for the development of novel antimicrobial agents. (C) 2013 Elsevier Masson SAS. All rights reserved. C1 [Ahn, Mija; Murugan, Ravichandran N.; Cheong, Chaejoon; Hwang, Eunha; Seo, Ji-Hyung; Srinivasrao, G.; Bang, Jeong Kyu] Korea Basic Sci Inst, Div Magnet Resonance, Cheongwon 363883, Chung Buk, South Korea. [Hyun, Jae-Kyung; Park, Hyo-Nam] Korea Basic Sci Inst, Div Electron Microscop Res, Taejon 305333, South Korea. [Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jacob, Binu; Shin, Song Yub] Chosun Univ, Dept Biomat, Grad Sch, Kwangju 501759, South Korea. [Jacob, Binu; Shin, Song Yub] Chosun Univ, Dept Cellular & Mol Med, Sch Med, Kwangju 501759, South Korea. RP Bang, JK (reprint author), Korea Basic Sci Inst, Div Magnet Resonance, Cheongwon 363883, Chung Buk, South Korea. EM syshin@chosun.ac.kr; bangjk@kbsi.re.kr RI Jacob, Binu/K-7621-2016 OI Jacob, Binu/0000-0002-2770-8741 FU Korea Basic Science Institute's research grant [T33418, T33518]; National Cancer Institute's Intramural Research grant; Korea Research Foundation; Korean Government [KRF-2011-0009039] FX This work was supported in part by the Korea Basic Science Institute's research grant T33418 (J.K.B), T33518 (J-K Hyun), the National Cancer Institute's Intramural Research grant (K.S.L) and the Korea Research Foundation funded by the Korean Government (KRF-2011-0009039 to S.Y. Shin). NR 24 TC 11 Z9 13 U1 1 U2 25 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD OCT PY 2013 VL 68 BP 10 EP 18 DI 10.1016/j.ejmech.2013.07.008 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 251BH UT WOS:000326902300002 PM 23933046 ER PT J AU Lim, KS Lee, H Kim, SE Ha, TH Ann, J Son, K Choi, S Sun, W Pearce, LV DeAndrea-Lazarus, IA Blumberg, PM Lee, J AF Lim, Kwang Su Lee, Hobin Kim, Sung Eun Ha, Tae-Hwan Ann, Jihyae Son, Karam Choi, Sun Sun, Wei Pearce, Larry V. DeAndrea-Lazarus, Ian A. Blumberg, Peter M. Lee, Jeewoo TI The carbonate analogues of 5 '-halogenated resiniferatoxin as TRPV1 ligands SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE TRPV1 agonist; TRPV1 antagonist; Partial agonist; Halogenation; Resiniferatoxin; Molecular modelling ID VANILLOID RECEPTOR ANTAGONIST; POLYFUNCTIONAL DITERPENES; IODO-RESINIFERATOXIN; GANGLION NEURONS; CAPSAICIN; VR1; DESENSITIZATION; AGONIST; BINDING; ESTERS AB A series of carbonate analogues of 5'-halogenated RTX have been investigated in order to examine the effect of the carbonate group as a linker and the role of halogens in the reversal of activity from agonism to antagonism for rat and human TRPV1 heterologously expressed in Chinese hamster ovary cells. The carbonate analogues showed similar activities to the corresponding RTX derivatives in rat TRPV1 but lower potency in human TRPV1. 5-Halogenation converted the agonists to partial agonists or full antagonists and the extent of antagonism reflected the order of I > Br > Cl > F, with a somewhat greater extent of antagonism for the derivatives of the 4-amino RTX surrogates compared to the corresponding derivatives of RTX itself. The carbonate analogues of I-RTX: (60) and 5-bromo-4-amino-RTX (66) were potent and full antagonists with K-i(ant) = 2.23 and 2.46 nM, respectively, for rat TRPV1, which were ca. 5-fold more potent than I-RTX (2) under our conditions. The conformational analysis of the I-RTX-carbonate (60) indicated that its bent conformation was similar to that of I-RTX, consistent with compound 60 and I-RTX showing comparable potent antagonism. (C) 2013 Elsevier Masson SAS. All rights reserved. C1 [Lim, Kwang Su; Lee, Hobin; Kim, Sung Eun; Ha, Tae-Hwan; Ann, Jihyae; Sun, Wei; Lee, Jeewoo] Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Seoul 151742, South Korea. [Son, Karam; Choi, Sun] Ewha Womans Univ, Natl Leading Res Lab NLRL Mol Modeling & Drug Des, Div Life & Pharmaceut Sci, Coll Pharm, Seoul 120750, South Korea. [Son, Karam; Choi, Sun] Ewha Womans Univ, Global Res Program Top5, Seoul 120750, South Korea. [Sun, Wei] Shenyang Pharmaceut Univ, Shenyang 110016, Liaoning, Peoples R China. [Pearce, Larry V.; DeAndrea-Lazarus, Ian A.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU National Research Foundation of Korea (NRF) [R11-2007-107-02001-0]; National Leading Research Lab (NLRL) [2011-0028885]; Ministry of Education, Science and Technology (MEST); National Research Foundation of Korea (NRF); National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z1A BC 005270] FX This research was supported by Grant R11-2007-107-02001-0 from the National Research Foundation of Korea (NRF), by Grants from the National Leading Research Lab (NLRL) program (2011-0028885) funded by the Ministry of Education, Science and Technology (MEST) and the National Research Foundation of Korea (NRF), and by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Z1A BC 005270). NR 26 TC 0 Z9 0 U1 1 U2 6 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD OCT PY 2013 VL 68 BP 233 EP 243 DI 10.1016/j.ejmech.2013.07.042 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 251BH UT WOS:000326902300025 PM 23981530 ER PT J AU Brand, J AF Brand, Jeffrey TI Beyond Consequentialism SO PHILOSOPHICAL REVIEW LA English DT Book Review C1 [Brand, Jeffrey] George Washington Univ, Washington, DC 20052 USA. [Brand, Jeffrey] NIH, Bethesda, MD USA. RP Brand, J (reprint author), George Washington Univ, Washington, DC 20052 USA. NR 4 TC 0 Z9 0 U1 0 U2 2 PU CORNELL UNIV SAGE SCHOOL PHILOSOPHY PI ITHACA PA PHILOSOPHICAL REVIEW , CORNELL UNIV, B7 MCGRAW HALL220 GOLDWIN SMITH HALL, ITHACA, NY 14853-4601 USA SN 0031-8108 J9 PHILOS REV JI Philos. Rev. PD OCT PY 2013 VL 122 IS 4 BP 657 EP 661 DI 10.1215/00318108-2315351 PG 5 WC Philosophy SC Philosophy GA 252HH UT WOS:000326995200007 ER PT J AU Palumbo, S Bosetti, F AF Palumbo, Sara Bosetti, Francesca TI Alterations of brain eicosanoid synthetic pathway in multiple sclerosis and in animal models of demyelination: Role of cyclooxygenase-2 SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Review DE Arachidonic acid; Cyclooxigenases; Multiple sclerosis; NSAID; Cuprizone; EAE; Theiler's virus ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; CUPRIZONE-INDUCED DEMYELINATION; FLU-LIKE SYMPTOMS; CEREBROSPINAL-FLUID; FUTURE-PROSPECTS; AXONAL DAMAGE; EXPRESSION; COX-2; PATHOGENESIS AB Inflammation is a physiological response to exogenous and endogenous stimuli and, together with demyelination and immune system activation, is one of the key features of multiple sclerosis (MS). Arachidonic acid (AA) metabolism by cyclooxygenase (COX) and lipoxygenase (LO) enzymes leads to the production of proinflammatory eicosanoids, and stimulates cytokine production and activation of microglia and astrocytes, thereby contributing to MS pathology. Current therapies target the immune system but do not specifically target AA-related inflammatory pathway. Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently associated with immunomodulatory therapies to treat flu-like adverse effects. Few clinical and mounting preclinical data in MS show that AA metabolism contributes to immune system activation, demyelination and motor disabilities, and administration of NSAIDs reduces these symptoms. The beneficial effect of NSAIDs seems to be a prerogative of COX-2 selective inhibitors and suggests that NSAIDs selective for COX-2 may be more effective than mixed COX-1/2 inhibitors. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Palumbo, Sara; Bosetti, Francesca] NIA, Mol Neurosci Unit, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Palumbo, S (reprint author), Univ Pisa, Dept Surg Med & Mol Pathol, Via Roma 54,Bldg 43, I-56100 Pisa, Italy. EM palumbosar@gmail.com RI palumbo, sara/B-1603-2013 OI palumbo, sara/0000-0002-3809-6058 NR 57 TC 8 Z9 8 U1 3 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0952-3278 EI 1532-2823 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD OCT PY 2013 VL 89 IS 5 BP 273 EP 278 DI 10.1016/j.plefa.2013.08.008 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 259XD UT WOS:000327558700001 PM 24095587 ER PT J AU Kuzmin, A Chefer, V Bazov, I Meis, J Ogren, SO Shippenberg, T Bakalkin, G AF Kuzmin, A. Chefer, V. Bazov, I. Meis, J. Ogren, S. O. Shippenberg, T. Bakalkin, G. TI Upregulated dynorphin opioid peptides mediate alcohol-induced learning and memory impairment SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE alcohol; dynorphin; glutamate; kappa-opioid receptor; learning; memory ID CHRONIC ETHANOL-CONSUMPTION; BINALTORPHIMINE NOR-BNI; EXCITATORY AMINO-ACIDS; LONG-TERM DEPRESSION; ACETYLCHOLINE-RELEASE; COGNITIVE IMPAIRMENT; RECEPTOR ACTIVATION; PREFRONTAL CORTEX; PYRAMIDAL NEURONS; HEAVY DRINKING AB The dynorphin opioid peptides control glutamate neurotransmission in the hippocampus. Alcohol-induced dysregulation of this circuit may lead to impairments in spatial learning and memory. This study examines whether changes in the hippocampal dynorphin and glutamate systems are related, and contribute to impairment of spatial learning and memory in a rat model of cognitive deficit associated with alcohol binge drinking. Hippocampal dynorphins (radioimmunoassay) and glutamate (in vivo microdialysis) were analyzed in Wistar rats exposed to repeated moderate-dose ethanol bouts that impair spatial learning and memory in the Water Maze Task (WMT). The highly selective, long-acting k-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was administered systemically or into the hippocampal CA3 region to test a role of dynorphins in alcohol-induced dysregulations in glutamate neurotransmission and behavior in the WMT. The ethanol treatment impaired learning and memory, upregulated dynorphins and increased glutamate overflow in the CA3 region. Administration of nor-BNI after cessation of ethanol exposure reversed ethanol-induced changes in glutamate neurotransmission in animals exposed to ethanol and normalized their performance in the WMT. The findings suggest that impairments of spatial learning and memory by binge-like ethanol exposure are mediated through the KOR activation by upregulated dynorphins resulting in elevation in glutamate levels. Selective KOR antagonists may correct alcohol-induced pathological processes, thus representing a novel pharmacotherapy for treating of ethanol-related cognitive deficits. C1 [Kuzmin, A.; Ogren, S. O.] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. [Chefer, V.; Meis, J.; Shippenberg, T.] NIDA, Integrat Neurosci Sect, Intramural Res Program, NIH,US Dept HHS, Baltimore, MD USA. [Bazov, I.; Bakalkin, G.] Uppsala Univ, Div Biol Res Drug Dependence, Dept Pharmaceut Biosci, S-75124 Uppsala, Sweden. RP Bakalkin, G (reprint author), Uppsala Univ, Div Biol Res Drug Dependence, Dept Pharmaceut Biosci, Box 591, S-75124 Uppsala, Sweden. EM Georgy.Bakalkin@farmbio.uu.se OI Bakalkin, Georgy/0000-0002-8074-9833; Ogren, Sven Ove/0000-0003-2573-5276 FU Swedish Council for Working Life and Social Research (FAS); Swedish Science Research Council; Swedish Research Council FORMAS; AFA Forsakring; Alcohol Research Council of the Swedish Retailing Monopoly; Uppsala University FX We thank Dr Tzvetomira Philipova for technical assistance. This work was supported by grants from the Swedish Council for Working Life and Social Research (FAS), Swedish Science Research Council, Swedish Research Council FORMAS, AFA Forsakring, Alcohol Research Council of the Swedish Retailing Monopoly and Uppsala University. NR 77 TC 5 Z9 6 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD OCT PY 2013 VL 3 AR e310 DI 10.1038/tp.2013.72 PG 8 WC Psychiatry SC Psychiatry GA 258QC UT WOS:000327472800003 PM 24105441 ER PT J AU Linard, C Tatem, AJ Gilbert, M AF Linard, Catherine Tatem, Andrew J. Gilbert, Marius TI Modelling spatial patterns of urban growth in Africa SO APPLIED GEOGRAPHY LA English DT Article DE Africa; Urban growth; Modelling; Spatial pattern; Boosted regression trees ID CONSTRAINED CELLULAR-AUTOMATA; BOOSTED REGRESSION TREES; LAND-USE CHANGE; STRUCTURAL ADJUSTMENT; DEVELOPING-COUNTRIES; ECOSYSTEM SERVICES; CLIMATE-CHANGE; HYDE 3.1; CITIES; FORM AB The population of Africa is predicted to double over the next 40 years, driving exceptionally high urban expansion rates that will induce significant socio-economic, environmental and health changes. In order to prepare for these changes, it is important to better understand urban growth dynamics in Africa and better predict the spatial pattern of rural-urban conversions. Previous work on urban expansion has been carried out at the city level or at the global level with a relatively coarse 5-10 km resolution. The main objective of the present paper was to develop a modelling approach at an intermediate scale in order to identify factors that influence spatial patterns of urban expansion in Africa. Boosted Regression Tree models were developed to predict the spatial pattern of rural-urban conversions in every large African city. Urban change data between circa 1990 and circa 2000 available for 20 large cities across Africa were used as training data. Results showed that the urban land in a 1 km neighbourhood and the accessibility to the city centre were the most influential variables. Results obtained were generally more accurate than results obtained using a distance-based urban expansion model and showed that the spatial pattern of small, compact and fast growing cities were easier to simulate than cities with lower population densities and a lower growth rate. The simulation method developed here will allow the production of spatially detailed urban expansion forecasts for 2020 and 2025 for Africa, data that are increasingly required by global change modellers. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Linard, Catherine; Gilbert, Marius] Univ Libre Brussels, B-1050 Brussels, Belgium. [Linard, Catherine; Gilbert, Marius] Fonds Natl Rech Sci FRS FNRS, B-1000 Brussels, Belgium. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton SO17 1BJ, Hants, England. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Linard, C (reprint author), Univ Libre Brussels, CP 160-12,Av FD Roosevelt 50, B-1050 Brussels, Belgium. EM linard.catherine@gmail.com; andy.tatem@gmail.com; Marius.Gilbert@ulb.ac.be OI Gilbert, Marius/0000-0003-3708-3359 FU NIAID NIH HHS [U19 AI089674] NR 62 TC 27 Z9 27 U1 3 U2 53 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0143-6228 EI 1873-7730 J9 APPL GEOGR JI Appl. Geogr. PD OCT PY 2013 VL 44 BP 23 EP 32 DI 10.1016/j.apgeog.2013.07.009 PG 10 WC Geography SC Geography GA 249IE UT WOS:000326770100003 PM 25152552 ER PT J AU Munn, S Heindel, J AF Munn, Sharon Heindel, Jerrold TI Assessing the risk of exposures to endocrine disrupting chemicals SO CHEMOSPHERE LA English DT Editorial Material C1 [Munn, Sharon] Commiss European Communities, Joint Res Ctr, I-21020 Ispra, Italy. [Heindel, Jerrold] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Munn, S (reprint author), Commiss European Communities, Joint Res Ctr, I-21020 Ispra, Italy. EM Sharon.Munn@ec.europa.eu; heindelj@niehs.nih.gov NR 1 TC 2 Z9 2 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 EI 1879-1298 J9 CHEMOSPHERE JI Chemosphere PD OCT PY 2013 VL 93 IS 6 BP 845 EP 846 DI 10.1016/j.chemosphere.2013.07.007 PG 2 WC Environmental Sciences SC Environmental Sciences & Ecology GA 250MW UT WOS:000326857900001 PM 23911261 ER PT J AU Beausoleil, C Ormsby, JN Gies, A Hass, U Heindel, JJ Holmer, ML Nielsen, PJ Munn, S Schoenfelder, G AF Beausoleil, Claire Ormsby, Jean-Nicolas Gies, Andreas Hass, Ulla Heindel, Jerrold J. Holmer, Marie Louise Nielsen, Pia Juul Munn, Sharon Schoenfelder, Gilbert TI Low dose effects and non-monotonic dose responses for endocrine active chemicals: Science to practice workshop: Workshop summary SO CHEMOSPHERE LA English DT Editorial Material DE Low dose effects; Non-monotonic dose responses; Endocrine disruptors; Risk assessment ID DISRUPTING CHEMICALS; STATEMENT; HEALTH AB A workshop was held in Berlin September 12-14th 2012 to assess the state of the science of the data supporting low dose effects and non-monotonic dose responses ("low dose hypothesis") for chemicals with endocrine activity (endocrine disrupting chemicals or EDCs). This workshop consisted of lectures to present the current state of the science of EDC action and also the risk assessment process. These lectures were followed by breakout sessions to integrate scientists from various backgrounds to discuss in an open and unbiased manner the data supporting the "low dose hypothesis". While no consensus was reached the robust discussions were helpful to inform both basic scientists and risk assessors on all the issues. There were a number of important ideas developed to help continue the discussion and improve communication over the next few years. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved. C1 [Beausoleil, Claire; Ormsby, Jean-Nicolas] French Agcy Food Environm & Occupat Hlth & Safety, F-94701 Maisons Alfort, France. [Gies, Andreas] Fed Environm Agcy UBA, D-14193 Berlin, Germany. [Hass, Ulla] Tech Univ Denmark, Natl Food Inst, DK-2860 Soborg, Denmark. [Heindel, Jerrold J.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Holmer, Marie Louise; Nielsen, Pia Juul] Environm Protect Agcy, Danish Minist Environm, DK-1401 Copenhagen K, Denmark. [Munn, Sharon] Commiss European Communities, Joint Res Ctr, I-21027 Ispra, VA, Italy. [Schoenfelder, Gilbert] Charite, D-10117 Berlin, Germany. RP Heindel, JJ (reprint author), NIEHS, Div Extramural Res & Training, POB 12233,MD KY 3-15, Res Triangle Pk, NC 27709 USA. EM heindelj@niehs.nih.gov; Sharon.munn@ec.europa.eu OI Schonfelder, Gilbert/0000-0001-6134-1990 NR 9 TC 31 Z9 31 U1 1 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 EI 1879-1298 J9 CHEMOSPHERE JI Chemosphere PD OCT PY 2013 VL 93 IS 6 BP 847 EP 856 DI 10.1016/j.chemosphere.2013.06.043 PG 10 WC Environmental Sciences SC Environmental Sciences & Ecology GA 250MW UT WOS:000326857900002 PM 23932820 ER PT J AU Jiang, HM Fang, ZZ Cao, YF Hu, CM Sun, XY Hong, M Yang, L Ge, GB Liu, Y Zhang, YY Dong, Q Liu, RJ AF Jiang, Hua-Mao Fang, Zhong-Ze Cao, Yun-Feng Hu, Cui-Min Sun, Xiao-Yu Hong, Mo Yang, Ling Ge, Guang-Bo Liu, Yong Zhang, Yan-Yan Dong, Qiang Liu, Ren-Jie TI New insights for the risk of bisphenol A: Inhibition of UDP-glucuronosyltransferases (UGTs) SO CHEMOSPHERE LA English DT Article DE Bisphenol A; UDP-glucuronosyltransferase (UGT); Risk evaluation; Recombinant enzymes ID GLUCURONIDATION; EXPOSURE; ISOFORMS; 4-METHYLUMBELLIFERONE; POLYMORPHISM; ASSOCIATION; UGT2B7; ENZYME; ACID; CITY AB Bisphenol A (BPA), the important endocrine-disrupting chemical (EDC), has been reported to be able to induce various toxicity. The present study aims to understand the toxicity behavior of bisphenol A through evaluating the inhibition profile of bisphenol A towards UDP-glucuronosyltransferase (UGT) isoforms. In vitro recombinant UGTs-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employed as probe reaction for all the tested UGT isoforms. The results showed that bisphenol A exerted stronger inhibition towards UGT2B isoforms than UGT1A isoforms. Furthermore, the inhibition kinetic type and parameters (K-i) were determined for the inhibition of bisphenol A towards UGT2B4, 2B7, 2B15, and 2B17. Bisphenol A exhibited the competitive inhibition towards UGT2B4, and noncompetitive inhibition towards UGT2B7, 2B15 and 2B17. The inhibition kinetic parameters (K-i) were calculated to be 1.1, 32.6, 5.6, and 19.9 mu M for UGT2B4, 2B7, 2B15 and 2B17, respectively. In combination with the in vivo concentration of bisphenol A, the elevation of exposure dose was predicted to increase by 29.1%, 1%, 5.7%, and 1.6% for UGT2B4, 2B7, 2B15, and 2B17, indicating the high influence of bisphenol A towards the in vivo UGT2B isofroms-mediated metabolism of xenobiotics and endogenous substances. All these data provide the supporting information for deeper understanding of toxicology of bisphenol A. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Jiang, Hua-Mao; Fang, Zhong-Ze; Hu, Cui-Min; Dong, Qiang; Liu, Ren-Jie] Liaoning Med Univ, Jinzhou, Liaoning, Peoples R China. [Fang, Zhong-Ze; Cao, Yun-Feng; Sun, Xiao-Yu; Hong, Mo; Zhang, Yan-Yan] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian 116023, Peoples R China. [Fang, Zhong-Ze; Cao, Yun-Feng; Sun, Xiao-Yu; Hong, Mo; Zhang, Yan-Yan] Liaoning Med Univ, Affiliated Hosp 1, Dalian 116023, Peoples R China. [Fang, Zhong-Ze] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Yang, Ling; Ge, Guang-Bo; Liu, Yong] Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Peoples R China. [Hu, Cui-Min] Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20057 USA. RP Jiang, HM (reprint author), Liaoning Med Univ, Jinzhou, Liaoning, Peoples R China. EM lyyyjhm@163.com RI Liu, Yong/A-1289-2011 OI Liu, Yong/0000-0002-4638-0788 FU 973 Program of China [2013CB531800, 2009CB522808]; National Natural Science Foundation of China [81202586, 81001473, 81102507, 81273590] FX This work was supported by 973 Program of China (2013CB531800 & 2009CB522808), the National Natural Science Foundation of China (No. 81202586, 81001473, 81102507 & 81273590). NR 31 TC 12 Z9 12 U1 1 U2 29 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 EI 1879-1298 J9 CHEMOSPHERE JI Chemosphere PD OCT PY 2013 VL 93 IS 6 BP 1189 EP 1193 DI 10.1016/j.chemosphere.2013.06.070 PG 5 WC Environmental Sciences SC Environmental Sciences & Ecology GA 250MW UT WOS:000326857900048 PM 23948605 ER PT J AU Marshall, HM Bowman, RV Yang, IA Fong, KM Berg, CD AF Marshall, Henry M. Bowman, Rayleen V. Yang, Ian A. Fong, Kwun M. Berg, Christine D. TI Screening for lung cancer with low-dose computed tomography: a review of current status SO JOURNAL OF THORACIC DISEASE LA English DT Review DE Lung neoplasms/mortality; mass screening tomography; helical computed; early detection of cancer/methods ID SMALL PULMONARY NODULES; MAXIMUM INTENSITY PROJECTION; TERM-FOLLOW-UP; TRIAL NELSON; FLEISCHNER-SOCIETY; COST-EFFECTIVENESS; RISK PREDICTION; SPIRAL CT; CHEST CT; RANDOMIZED FEASIBILITY AB Screening using low-dose computed tomography (CT) represents an exciting new development in the struggle to improve outcomes for people with lung cancer. Randomised controlled evidence demonstrating a 20% relative lung cancer mortality benefit has led to endorsement of screening by several expert bodies in the US and funding by healthcare providers. Despite this pivotal result, many questions remain regarding technical and logistical aspects of screening, cost-effectiveness and generalizability to other settings. This review discusses the rationale behind screening, the results of on-going trials, potential harms of screening and current knowledge gaps. C1 [Marshall, Henry M.; Bowman, Rayleen V.; Yang, Ian A.; Fong, Kwun M.] Prince Charles Hosp, Dept Thorac Med, Brisbane, Qld 4032, Australia. [Marshall, Henry M.; Bowman, Rayleen V.; Yang, Ian A.; Fong, Kwun M.; Berg, Christine D.] Univ Queensland, Sch Med, Thorac Res Ctr, Brisbane, Qld, Australia. [Berg, Christine D.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Marshall, HM (reprint author), Prince Charles Hosp, Dept Thorac Med, Rode Rd, Chermside, Qld 4032, Australia. EM Henry_Marshall@health.qld.gov.au RI Yang, Ian/B-9609-2008; Berg , Christine/K-1047-2014; Marshall, Henry/F-2567-2011 OI Yang, Ian/0000-0001-8338-1993; Marshall, Henry/0000-0002-9626-8014 FU National Health and Medical Research Council (NHMRC); Cancer Council Queensland; Queensland Smart State project grants; Office of Health and Medical Research (OHMR); Prince Charles Hospital Foundation; University of Queensland FX This work was supported by National Health and Medical Research Council (NHMRC) project grants, NHMRC Practitioner Fellowship (KF), NHMRC Career Development Award (IY), Cancer Council Queensland Senior Research Fellowship (KF), Cancer Council Queensland project grants, Queensland Smart State project grants, Office of Health and Medical Research (OHMR) project grants, The Prince Charles Hospital Foundation, NHMRC Postgraduate Medical Scholarship (HM), University of Queensland PhD Scholarship (HM). NR 146 TC 24 Z9 24 U1 0 U2 11 PU PIONEER BIOSCIENCE PUBL CO PI HONG KONG PA 9A GOLD SHINE TOWER, 346-348 QUEEN'S RD CENTRAL, SHEUNG WAN, HONG KONG, 00000, PEOPLES R CHINA SN 2072-1439 EI 2077-6624 J9 J THORAC DIS JI J. Thorac. Dis. PD OCT PY 2013 VL 5 SU 5 BP S524 EP S539 DI 10.3978/j.issn.2072-1439.2013.09.06 PG 16 WC Respiratory System SC Respiratory System GA 253OZ UT WOS:000327100000008 PM 24163745 ER PT J AU Chapman, S Dobrovolskai, M Farahani, K Goodwin, A Joshi, A Lee, H Meade, T Pomper, M Ptak, K Rao, JH Singh, R Sridhar, S Stern, S Wang, A Weaver, JB Woloschak, G Yang, L AF Chapman, Sandra Dobrovolskai, Marina Farahani, Keyvan Goodwin, Andrew Joshi, Amit Lee, Hakho Meade, Thomas Pomper, Martin Ptak, Krzysztof Rao, Jianghong Singh, Ravi Sridhar, Srinivas Stern, Stephan Wang, Andrew Weaver, John B. Woloschak, Gayle Yang, Lily TI Nanoparticles for cancer imaging: The good, the bad, and the promise SO NANO TODAY LA English DT Article DE Nanonnedicine; Cancer; Imaging; Detection; Screening ID PARTICLES; CLEARANCE; MOLECULES AB Recent advances in molecular imaging and nanotechnology are providing new opportunities for biomedical imaging with great promise for the development of novel imaging agents. The unique optical, magnetic, and chemical properties of materials at the scale of nanometers allow the creation of imaging probes with better contrast enhancement, increased sensitivity, controlled biodistribution, better spatial and temporal information, multi-functionality and multi-modal imaging across MRI, PET, SPECT, and ultrasound. These features could ultimately translate to clinical advantages such as earlier detection, real time assessment of disease progression and personalized medicine. However, several years of investigation into the application of these materials to cancer research has revealed challenges that have delayed the successful application of these agents to the field of biomedical imaging. Understanding these challenges is critical to take full advantage of the benefits offered by nano-sized imaging agents. Therefore, this article presents the lessons learned and challenges encountered by a group of leading researchers in this field, and suggests ways forward to develop nanoparticle probes for cancer imaging. Published by Elsevier Ltd. C1 [Chapman, Sandra] NCI, Off Canc Nanotechnol Res, Ctr Strateg Sci Initiat, NIH, Bethesda, MD 20892 USA. [Dobrovolskai, Marina; Stern, Stephan] SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Res Facil, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Farahani, Keyvan] NCI, Image Guided Intervent Branch, Canc Imaging Program, Rockville, MD 20852 USA. [Goodwin, Andrew] Univ Colorado Boulder, Dept Chem & Biol Engn, Boulder, CO 80303 USA. [Joshi, Amit] Baylor Coll Med, Dept Radiol, TBMM Grad Program, Houston, TX 77030 USA. [Joshi, Amit] Baylor Coll Med, Dept Mol Physiol & Biophys, TBMM Grad Program, Houston, TX 77030 USA. [Lee, Hakho] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Meade, Thomas] Northwestern Univ, Dept Chem, Evanston, IL 60208 USA. [Meade, Thomas] Northwestern Univ, Dept Mol Biosci, Evanston, IL 60208 USA. [Meade, Thomas] Northwestern Univ, Dept Radiol, Evanston, IL 60208 USA. [Pomper, Martin] Johns Hopkins Med Sch, Baltimore, MD 21287 USA. [Ptak, Krzysztof] NCI, Off Canc Ctr, Off Director, NIH, Bethesda, MD 20892 USA. [Rao, Jianghong] Stanford Univ, Mol Imaging Program Stanford, Dept Radiol, Stanford, CA 94305 USA. [Singh, Ravi] Wake Forest Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. [Sridhar, Srinivas] Northeastern Univ, Nanomedicine Sci & Technol Ctr, Boston, MA 02115 USA. [Sridhar, Srinivas] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Wang, Andrew] Univ N Carolina, Dept Radiat Oncol, Carolina Ctr Nanotechnol Excellence, Chapel Hill, NC 27599 USA. [Weaver, John B.] Dartmouth Coll, Geisel Sch Med, Dept Radiol, Hanover, NH 03755 USA. [Woloschak, Gayle] Northwestern Univ, Dept Radiat Oncol, Robert E Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Woloschak, Gayle] Northwestern Univ, Dept Radiol, Robert E Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Woloschak, Gayle] Northwestern Univ, Dept Cell & Mol Biol, Robert E Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Yang, Lily] Emory Univ Sch Med, Dept Surg, Atlanta, GA 30322 USA. RP Chapman, S (reprint author), NCI, Off Canc Nanotechnol Res, Ctr Strateg Sci Initiat, NIH, Bethesda, MD 20892 USA. EM chapmansandra.e@gmail.com; jrao@stanford.edu; s.sridhar@neu.edu; g-woloschak@northwestern.edu RI Chapman, Sandra/I-8889-2014; Nanotechnology Characterization Lab, NCL/K-8454-2012; Singh, Ravi/A-5740-2011; Woloschak, Gayle/A-3799-2017; OI Chapman, Sandra/0000-0002-9202-336X; Singh, Ravi/0000-0003-0750-1804; Woloschak, Gayle/0000-0001-9209-8954; Wang, Andrew/0000-0002-9781-4494 FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [R01 CA178748, HHSN261200800001E, R00 CA154006] NR 16 TC 37 Z9 37 U1 6 U2 70 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1748-0132 EI 1878-044X J9 NANO TODAY JI Nano Today PD OCT PY 2013 VL 8 IS 5 BP 454 EP 460 DI 10.1016/j.nantod.2013.06.001 PG 7 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 252HK UT WOS:000326995500005 PM 25419228 ER PT J AU Mannelli, P Wu, LT Peindl, KS Gorelick, DA AF Mannelli, Paolo Wu, Li-Tzy Peindl, Kathleen S. Gorelick, David A. TI Smoking and Opioid Detoxification: Behavioral Changes and Response to Treatment SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID ILLICIT DRUG-USE; CIGARETTE-SMOKING; METHADONE-MAINTENANCE; TOBACCO USE; NICOTINE DEPENDENCE; CESSATION TREATMENT; ADDICTION TREATMENT; SUBSTANCE-ABUSE; UNITED-STATES; SELF-QUITTERS AB Introduction: The relevance of tobacco use in opioid addiction (OA) has generated a demand for available and more effective interventions. Thus, further analysis of less explored nicotine-opioid clinical interactions is warranted. Methods: A post-hoc analysis of OA participants in a double-blind, randomized very low dose naltrexone (VLNTX) inpatient detoxification trial evaluated measures of opioid withdrawal and tobacco use. Intreatment smokers were compared with nonsmokers, or smokers who were not allowed to smoke. Results: A total of 141 (81%) of 174 OA participants were smokers, all nicotine-dependent. Inpatient smoking was a predictor of opioid withdrawal discomfort. Intreatment smokers (n = 96) showed significantly higher opioid craving (F = 3.7, p < .001) and lower detoxification completion rate (chi(2) = 7.9, p < .02) compared with smokers who were not allowed to smoke (n = 45) or nonsmokers (n = 33). Smoking during treatment was associated with more elevated cigarette craving during detoxification (F = 4.1, p < .001) and a higher number of cigarettes smoked at follow-up (F = 3.6, p < .02). Among intreatment smokers, VLNTX addition to methadone taper was effective in easing opioid withdrawal and craving more than other treatments, whereas the combination VLNTX-clonidine was associated with significantly reduced cigarette craving and smoking during detoxification. Conclusions: Failure to address tobacco use may negatively affect pharmacologically managed opioid discontinuation. Opioid detoxification may offer a window of opportunity to expand smoking cessation treatment, hence improving OA outcomes. The observed effects support testing of VLNTX-clonidine in smoking cessation trials among individuals with or without substance abuse. C1 [Mannelli, Paolo; Wu, Li-Tzy; Peindl, Kathleen S.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27705 USA. [Gorelick, David A.] NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Mannelli, P (reprint author), Duke Univ, Med Ctr, 2218 Elder St,Suite 123, Durham, NC 27705 USA. EM paolo.mannelli@duke.edu FU National Institute on Drug Abuse [DA 15469]; Intramural Research Program, NIDA, National Institutes of Health (NIH) FX This work was supported by the National Institute on Drug Abuse (DA 15469 to PM). DAG was supported by the Intramural Research Program, NIDA, National Institutes of Health (NIH). NR 69 TC 5 Z9 5 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD OCT PY 2013 VL 15 IS 10 BP 1705 EP 1713 DI 10.1093/ntr/ntt046 PG 9 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 252AR UT WOS:000326977100009 PM 23572466 ER PT J AU Lagunin, AA Filimonov, DA Gloriozova, TA Tarasova, OA Zakharov, AV Guasch, L Nicklaus, MC Poroikov, VV AF Lagunin, A. A. Filimonov, D. A. Gloriozova, T. A. Tarasova, O. A. Zakharov, A. V. Guasch, L. Nicklaus, M. C. Poroikov, V. V. TI VIRTUAL SCREENING FOR POTENTIAL SUBSTANCES FOR THE PROPHYLAXIS OF HIV INFECTION IN LIBRARIES OF COMMERCIALLY AVAILABLE ORGANIC COMPOUNDS SO PHARMACEUTICAL CHEMISTRY JOURNAL LA English DT Article DE HIV/AIDS; prophylaxis; treatment; reverse transcriptase inhibitors; integrase strand transfer inhibitors; CD4; gp120; CCR5; CXCR4; gp41 inhibitors; virtual screening; PASS; PharmaExpert; ChemNavigator ID DESIGNED MULTIPLE LIGANDS; DRUG DISCOVERY PARADIGM; REVERSE-TRANSCRIPTASE; BIOLOGICAL EVALUATION; CHEMICAL-COMPOUNDS; ACTIVITY SPECTRA; PASS; PREDICTION; MICROBICIDES; INHIBITION AB The search for new substances for the treatment and prophylaxis of HIV-AIDS remains relevant despite advances in highly active antiretroviral therapy (HAART), both because of the appearance of resistance to existing agents and because of their side effects and toxicity. Preventing the spread of HIV infection via sexual contacts by treating the uninfected partner has some advantage, as prophylactic effects can be obtained using simpler treatment (for example, using one agent rather than combinations of three drugs), as the need is to block the transfer of small numbers of infective virions. On the other hand, agents acting on the uninfected partner must be relatively nontoxic as they have to be used for long periods of time in healthy people. Effective chemoprophylaxis can be obtained using agents blocking the life cycle of the virus before integration into the human genome. Two widely used classes of agent therefore have potential - non-nucleoside reverse transcriptase (RT) inhibitors and integrase (IN) strand transfer inhibitors. In addition, proteins such as CD4, gp120, CCR5, CXCR4, and gp41 can be regarded as potential targets, as their functional roles at different stages in the interaction between virion and host cell have been established. As it is now known that all antiretroviral agents approved for medical use induce resistant viral strains, new anti-HIV agents must have chemical structures which are significantly different from known drugs and (if possible) must act on multiple pharmacological targets. Candidates can be sought by virtual screening of libraries of commercially available samples of chemical compounds; such libraries currently contain several million structural formulas for compounds which have been synthesized and are available for biological testing. Virtual screening can be performed using the computer programs PASS and PharmaExpert, allowing identification of substances with potential for experimental studies on the basis of a number of prognostic criteria (presence of the required types of activity, absence of side and toxic effects, appropriate physicochemical properties).We present here data on the current state of the search for new agents for the treatment and prophylaxis of HIV/AIDS, our approach to virtual screening for new potential substances for the prophylaxis of HIV/AIDS, and the results of using this approach in databases of chemical compounds available for screening. The potential for detection of anti-HIV compounds acting on multiple pharmacological targets among substances which have already been synthesized is discussed. We conclude that there is potential for the rational design of such drugs using computerized drug construction methods. C1 [Lagunin, A. A.; Filimonov, D. A.; Gloriozova, T. A.; Tarasova, O. A.; Poroikov, V. V.] Russian Acad Med Sci, VN Orekhovich Sci Res Inst Biomed Chem, Moscow, Russia. [Zakharov, A. V.; Guasch, L.; Nicklaus, M. C.] NCI, Comp Aided Drug Design Grp, Biol Chem Lab, Ctr Canc Res,NIH,Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. RP Lagunin, AA (reprint author), Russian Acad Med Sci, VN Orekhovich Sci Res Inst Biomed Chem, Moscow, Russia. RI Poroikov, Vladimir/O-2769-2013; Nicklaus, Marc/N-4183-2014; Lagunin, Alexey/G-3745-2010; Tarasova, Olga/F-1248-2017 OI Poroikov, Vladimir/0000-0001-7937-2621; Lagunin, Alexey/0000-0003-1757-8004; Tarasova, Olga/0000-0002-3723-7832 FU Russian Foundation for Basic Research/NIH [12-04-91445-NIZ A/RUB1-31081-MO-12] FX This study was supported by the Russian Foundation for Basic Research/NIH (Project No. 12-04-91445-NIZ A/RUB1-31081-MO-12). NR 55 TC 0 Z9 0 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-150X EI 1573-9031 J9 PHARM CHEM J+ JI Pharm. Chem. J. PD OCT PY 2013 VL 47 IS 7 BP 343 EP 360 DI 10.1007/s11094-013-0958-6 PG 18 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 253MS UT WOS:000327092500001 ER PT J AU Reddy, UM Abuhamad, A Saade, GR AF Reddy, Uma M. Abuhamad, Alfred Saade, George R. TI Fetal imaging SO SEMINARS IN PERINATOLOGY LA English DT Editorial Material C1 [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Abuhamad, Alfred] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. [Saade, George R.] Univ Texas Med Branch, Galveston, TX 77555 USA. RP Reddy, UM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd,Rm 4B03F, Bethesda, MD 20892 USA. EM reddyu@mail.nih.gov; abuhamaz@evms.edu; gsaade@utmb.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0146-0005 EI 1558-075X J9 SEMIN PERINATOL JI Semin. Perinatol. PD OCT PY 2013 VL 37 IS 5 BP 289 EP 289 DI 10.1053/j.semperi.2013.06.001 PG 1 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 251FG UT WOS:000326912600001 PM 24176146 ER PT J AU Lindsay, RW Ouellette, I Arendt, HE Martinez, J DeStefano, J Lopez, M Pavlakis, GN Chiuchiolo, MJ Parks, CL King, CR AF Lindsay, Ross W. Ouellette, Ian Arendt, Heather E. Martinez, Jennifer DeStefano, Joanne Lopez, Mary Pavlakis, George N. Chiuchiolo, Maria J. Parks, Christopher L. King, C. Richter TI SIV antigen-specific effects on immune responses induced by vaccination with DNA electroporation and plasmid IL-12 SO VACCINE LA English DT Article DE DNA; IL-12; Adenovirus; T cell; Antibody ID CD8(+) T-CELLS; RHESUS MACAQUES; IN-VIVO; SYSTEMIC IMMUNIZATION; COMPARATIVE ABILITY; NITRIC-OXIDE; INFECTION; INTERLEUKIN-12; CHALLENGE; ADJUVANT AB Molecular adjuvants are important for augmenting or modulating immune responses induced by DNA vaccination. Promising results have been obtained using IL-12 expression plasmids in a variety of disease models including the SIV model of HIV infection. We used a mouse model to evaluate plasmid IL-12 (pIL-12) in a DNA prime, recombinant adenovirus serotype 5 (rAd5) boost regimen specifically to evaluate the effect of IL-12 expression on cellular and humoral immunity induced against both SIVmac239 Gag and Env antigens. Priming with electroporated (EP) DNA + pIL-12 resulted in a 2-4-fold enhanced frequency of Gag-specific CD4 T cells which was maintained through the end of the study irrespective of the pIL-12 dose, while memory Env-specific CD4+ T cells were maintained only at the low dose of pIL-12. There was little positive effect of pIL-12 on the humoral response to Env, and in fact, high dose pIL-12 dramatically reduced Sly Env-specific IgG. Additionally, both doses of pIL-12 diminished the frequency of CD8 T-cells after DNA prime, although a rAd5 boost recovered CD8 responses regardless of the pIL-12 dose. In this prime-boost regimen, we have shown that a high dose pIL-12 can systemically reduce Env-specific humoral responses and CD4T cell frequency, but not Gag-specific CD4+ T cells. These data indicate that it is important to independently characterize individual SW or HIV antigen immunogenicity in multi-antigenic vaccines as a function of adjuvant dose. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved. C1 [Lindsay, Ross W.; Ouellette, Ian; Arendt, Heather E.; Martinez, Jennifer; DeStefano, Joanne; Lopez, Mary; Chiuchiolo, Maria J.; Parks, Christopher L.; King, C. Richter] Int AIDS Vaccine Initiat, Brooklyn, NY 11220 USA. [Pavlakis, George N.] NCI, Frederick, MD 21702 USA. RP Lindsay, RW (reprint author), Int AIDS Vaccine Initiat, AIDS Vaccine Design & Dev Lab, 140 58th St,Bldg A,Suite 8J, Brooklyn, NY 11220 USA. EM rlindsay@iavi.org NR 46 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD OCT 1 PY 2013 VL 31 IS 42 BP 4749 EP 4758 DI 10.1016/j.vaccine.2013.08.011 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 249IY UT WOS:000326772100014 PM 23954384 ER PT J AU Verguet, S Murphy, S Anderson, B Johansson, KA Glass, R Rheingans, R AF Verguet, Stephane Murphy, Shane Anderson, Benjamin Johansson, Kjell Arne Glass, Roger Rheingans, Richard TI Public finance of rotavirus vaccination in India and Ethiopia: An extended cost-effectiveness analysis SO VACCINE LA English DT Article DE Rotavirus; Vaccination; Child health; Financial risk protection; Equity; Extended cost-effectiveness analysis (ECEA); Low- and middle-income settings ID MIDDLE-INCOME COUNTRIES; GAVI-ELIGIBLE COUNTRIES; ECONOMIC-IMPACT; HEALTH-CARE; CHILD-MORTALITY; BIRTH COHORT; DIARRHEA; EPIDEMIOLOGY; BENEFITS; VACCINES AB Background: An estimated 4% of global child deaths (approximately 300,000 deaths) were attributed to rotavirus in 2010. About a third of these deaths occurred in India and Ethiopia. Public finance of rotavirus vaccination in these two countries could substantially decrease child mortality and also reduce rotavirus-related hospitalizations, prevent health-related impoverishment and bring significant cost savings to households. Methods: We use a methodology of 'extended cost-effectiveness analysis' (ECEA) to evaluate a hypothetical publicly financed program for rotavirus vaccination in India and Ethiopia. We measure program impact along four dimensions: 1) rotavirus deaths averted; 2) household expenditures averted; 3) financial risk protection afforded; 4) distributional consequences across the wealth strata of the country populations. Results: In India and Ethiopia, the program would lead to a substantial decrease in rotavirus deaths, mainly among the poorer; it would reduce household expenditures across all income groups and it would effectively provide financial risk protection, mostly concentrated among the poorest. Potential indirect benefits of vaccination (herd immunity) would increase program benefits among all income groups, whereas potentially decreased vaccine efficacy among poorer households would reduce the equity benefits of the program. Conclusions: Our approach incorporates financial risk protection and distributional consequences into the systematic economic evaluation of vaccine policy, illustrated here with the case study of public finance for rotavirus vaccination. This enables selection of vaccine packages based on the quantitative inclusion of information on equity and on how much financial risk protection is being bought per dollar expenditure on vaccine policy, in addition to how much health is being bought. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Verguet, Stephane; Murphy, Shane] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Anderson, Benjamin; Rheingans, Richard] Univ Florida, Dept Environm & Global Hlth, Gainesville, FL USA. [Johansson, Kjell Arne] Univ Bergen, Dept Publ Hlth, Res Grp Global Hlth Eth Econ & Culture, Bergen, Norway. [Johansson, Kjell Arne] Univ Bergen, Ctr Int Hlth, Bergen, Norway. [Glass, Roger] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Rheingans, Richard] Univ Florida, Ctr African Studies, Gainesville, FL USA. [Rheingans, Richard] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. RP Verguet, S (reprint author), 325 9th Ave,Box 359931, Seattle, WA 98104 USA. EM verguet@uw.edu OI Murphy, Shane/0000-0002-9805-4909 FU Bill & Melinda Gates Foundation through the Disease Control Priorities Network grant FX We thank the Bill & Melinda Gates Foundation for funding through the Disease Control Priorities Network grant to the University of Washington. We are indebted to Dean Jamison for his advice and guidance. We would like to thank Arindam Nandi and Ashvin Ashok for help with obtaining data. We received valuable comments from Ginger Zhe Jin, Margaret Kruk, Ramanan Laxminarayan, Carol Levin, Andrew Mirelman, Arindam Nandi, Rachel Nugent, Zachary Olson, Toby Ord, Damian Walker, Neff Walker, Abdo Yazbeck, and from two anonymous reviewers. NR 54 TC 29 Z9 29 U1 1 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD OCT 1 PY 2013 VL 31 IS 42 BP 4902 EP 4910 DI 10.1016/j.vaccine.2013.07.014 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 249IY UT WOS:000326772100035 PM 23871824 ER PT J AU Smith, BM Prince, MR Hoffman, EA Bluemke, DA Liu, CY Rabinowitz, D Hueper, K Parikh, MA Gomes, AS Michos, ED Lima, JAC Barr, RG AF Smith, Benjamin M. Prince, Martin R. Hoffman, Eric A. Bluemke, David A. Liu, Chia-Ying Rabinowitz, Dan Hueper, Katja Parikh, Megha A. Gomes, Antoinette S. Michos, Erin D. Lima, Joao A. C. Barr, R. Graham TI Impaired Left Ventricular Filling in COPD and Emphysema: Is It the Heart or the Lungs? The Multi-Ethnic Study of Atherosclerosis COPD Study SO CHEST LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; CHRONIC COR-PULMONALE; LEFT ATRIAL SIZE; DIASTOLIC DYSFUNCTION; MAGNETIC-RESONANCE; EJECTION FRACTION; ECHOCARDIOGRAPHIC EVALUATION; COMPUTED-TOMOGRAPHY; FAILURE; VOLUME AB Background: COPD and heart failure with preserved ejection fraction overlap clinically, and impaired left ventricular (LV) filling is commonly reported in COPD. The mechanism underlying these observations is uncertain, but may include upstream pulmonary dysfunction causing low LV preload or intrinsic LV dysfunction causing high LV preload. The objective of this study is to determine if COPD and emphysema are associated with reduced pulmonary vein dimensions suggestive of low LV preload. Methods: The population-based Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers aged 50 to 79 years who were free of clinical cardiovascular disease. COPD was defined by spirometry. Percent emphysema was defined as regions, < -910 Hounsfield units on full-lung CT scan. Ostial pulmonary vein cross-sectional area was measured by contrast-enhanced cardiac magnetic resonance and expressed as the sum of all pulmonary vein areas. Linear regression was used to adjust for age, sex, race/ethnicity, body size, and smoking. Results: Among 165 participants, the mean (+/- SD) total pulmonary vein area was 558 +/- 159 mm(2) in patients with COPD and 623 +/- 145 mm(2) in control subjects. Total pulmonary vein area was smaller in patients with COPD (-57 mm(2); 95% CI, -106 to -7 mm(2); P = .03) and inversely associated with percent emphysema (P < .001) in fully adjusted models. Significant decrements in total pulmonary vein area were observed among participants with COPD alone, COPD with emphysema on CT scan, and emphysema without spirometrically defined COPD. Conclusions: Pulmonary vein dimensions were reduced in COPD and emphysema. These findings support a mechanism of upstream pulmonary causes of underfilling of the LV in COPD and in patients with emphysema on CT scan. C1 [Smith, Benjamin M.; Parikh, Megha A.; Barr, R. Graham] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Prince, Martin R.] Columbia Univ Coll Phys & Surg, Dept Radiol, New York, NY 10032 USA. [Smith, Benjamin M.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Hoffman, Eric A.] Univ Iowa, Dept Radiol, Carver Coll Med, Iowa City, IA 52242 USA. [Bluemke, David A.] NIH, Bethesda, MD 20892 USA. [Liu, Chia-Ying] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Hueper, Katja; Michos, Erin D.; Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Rabinowitz, Dan] Columbia Univ, Dept Stat, Mailman Sch Publ Hlth, New York, NY USA. [Barr, R. Graham] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Gomes, Antoinette S.] David Geffen UCLA Sch Med, Los Angeles, CA USA. RP Barr, RG (reprint author), Presbyterian Hosp, Room 9E-105,622 W 168th St, New York, NY 10032 USA. EM rgb9@columbia.edu RI Hueper, Katja/J-9566-2016; Prince, Martin/S-6850-2016; OI Hueper, Katja/0000-0002-3195-4400; Bluemke, David/0000-0002-8323-8086; Prince, Martin/0000-0002-9883-0584 FU National Institutes of Health/National Heart, Lung, and Blood Institute [R01-HL093081, R01-HL077612, R01-HL075476, N01-HC95159-HC95169]; Fonds de la recherche en sante Quebec FX This study was funded by the National Institutes of Health/National Heart, Lung, and Blood Institute [Grants R01-HL093081, R01-HL077612, R01-HL075476, and N01-HC95159-HC95169]; and Fonds de la recherche en sante Quebec. NR 59 TC 24 Z9 25 U1 0 U2 9 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 EI 1931-3543 J9 CHEST JI Chest PD OCT PY 2013 VL 144 IS 4 BP 1143 EP 1151 DI 10.1378/chest.13-0183 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 241JJ UT WOS:000326162600017 PM 23764937 ER PT J AU Vinetz, JM Beeching, NJ White, AC AF Vinetz, Joseph M. Beeching, Nicholas J. White, A. Clinton TI Editorial introduction SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Editorial Material C1 [Vinetz, Joseph M.] Johns Hopkins Sch Med, Baltimore, MD 21218 USA. [Vinetz, Joseph M.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Vinetz, Joseph M.] Natl Inst Hlth, Bethesda, MD USA. [Vinetz, Joseph M.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Beeching, Nicholas J.] Royal Liverpool Univ Hosp, Infect Dis Unit, London, England. [White, A. Clinton] Univ Texas Med Branch, Dept Internal Med, Div Infect Dis, Galveston, TX 77555 USA. RP Vinetz, JM (reprint author), Johns Hopkins Sch Med, Baltimore, MD 21218 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7375 EI 1473-6527 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD OCT PY 2013 VL 26 IS 5 DI 10.1097/QCO.0000000000000011 PG 2 WC Infectious Diseases SC Infectious Diseases GA 249WI UT WOS:000326810600014 ER PT J AU Olive, M Kley, RA Goldfarb, LG AF Olive, Montse Kley, Rudolf A. Goldfarb, Lev G. TI Myofibrillar myopathies: new developments SO CURRENT OPINION IN NEUROLOGY LA English DT Review DE hereditary myopathy with early respiratory failure; laser microdissection; myofibrillar myopathy; next generation sequencing; proteomics; reducing body myopathy ID REDUCING BODY MYOPATHY; EARLY RESPIRATORY-FAILURE; RIGHT-VENTRICULAR CARDIOMYOPATHY; ONSET DISTAL MYOPATHY; MUSCULAR-DYSTROPHY 1A; RIGID SPINE SYNDROME; HEREDITARY MYOPATHY; ELECTRON-MICROSCOPY; LASER MICRODISSECTION; PROTEIN AGGREGATION AB Purpose of reviewMyofibrillar myopathies (MFMs) are a heterogeneous group of skeletal and cardiac muscle diseases. In this review, we highlight recent discoveries of new genes and disease mechanisms involved in this group of disorders.Recent findingsThe advent of next-generation sequencing technology, laser microdissection and mass spectrometry-based proteomics has facilitated the discovery of new MFM causative genes and pathomechanisms. New mutations have also been discovered in older' genes, helping to find a classification niche for MFM-linked disorders showing variant phenotypes. Cell transfection experiments using primary cultured myoblasts and newer animal models provide insights into the pathogenesis of MFMs.SummaryAn increasing number of genes are involved in the causation of variant subtypes of MFM. The application of modern technologies in combination with classical histopathological and ultrastructural studies is helping to establish the molecular diagnosis and reach a better understanding of the pathogenic mechanisms of each MFM subtype, thus putting an emphasis on the development of specific means for prevention and therapy of these incapacitating and frequently fatal diseases. C1 [Olive, Montse] IDIBELL Hosp Univ Bellvitge, Inst Neuropathol, Dept Pathol, Barcelona 08907, Spain. [Olive, Montse] IDIBELL Hosp Univ Bellvitge, Neuromuscular Unit, Barcelona 08907, Spain. [Olive, Montse] Inst Salud Carlos III, CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain. [Kley, Rudolf A.] Ruhr Univ Bochum, Univ Hosp Bergmannsheil, Dept Neurol, Neuromuscular Ctr Ruhrgebiet, Bochum, Germany. [Goldfarb, Lev G.] NINDS, NIH, Bethesda, MD 20892 USA. RP Olive, M (reprint author), IDIBELL Hosp Univ Bellvitge, Inst Neuropathol, Dept Pathol, Feixa Llarga Sn, Barcelona 08907, Spain. EM 25169mop@comb.cat OI Olive, Montse/0000-0001-5727-0165 FU Spanish Instituto de Salud Carlos III [PI08-574, PI11-0150]; German Research Foundation [KL2487/1-1, FOR1228]; National Institute of Neurological Disorders and Stroke FX This work was supported in part by the Spanish Instituto de Salud Carlos III (PI08-574 and PI11-0150) (M.O.), the German Research Foundation (KL2487/1-1 and FOR1228) (R.K.) and the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (L.G.). NR 78 TC 16 Z9 17 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 EI 1473-6551 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD OCT PY 2013 VL 26 IS 5 BP 527 EP 535 DI 10.1097/WCO.0b013e328364d6b1 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 249YG UT WOS:000326816400012 PM 23995273 ER PT J AU Burns, KM Pearson, GD Kaltman, JR AF Burns, Kristin M. Pearson, Gail D. Kaltman, Jonathan R. TI Novel initiatives of the National Institutes of Health to support congenital heart disease research SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE congenital heart disease; paediatric cardiology; research ID PEDIATRIC RESEARCH; NORWOOD PROCEDURE; INFANTS; CHILDREN; NETWORK; LUNG; MULTICENTER; RATIONALE; MORTALITY; PROGRAM AB Purpose of reviewIn fiscally challenging times, scientists must seek creative strategies and leverage existing resources to advance research. Recent findingsThis review describes programmes supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) to promote research in paediatric cardiology and congenital heart disease (CHD). SummaryAn understanding of NHLBI-supported research programmes will help investigators identify opportunities to collaborate with existing systems and use scientific results from existing efforts to catalyse future research in CHD. C1 [Burns, Kristin M.; Pearson, Gail D.; Kaltman, Jonathan R.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Kaltman, JR (reprint author), NHLBI, Heart Dev & Struct Dis Branch, Div Cardiovasc Sci, NIH, 6701 Rockledge Dr,Room 8222, Bethesda, MD 20892 USA. EM kaltmanj@nhlbi.nih.gov NR 22 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 EI 1531-698X J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD OCT PY 2013 VL 25 IS 5 BP 585 EP 590 DI 10.1097/MOP.0b013e328364b8a7 PG 6 WC Pediatrics SC Pediatrics GA 248XI UT WOS:000326738700005 PM 23995430 ER PT J AU Chatzi, A Sideris, DP Katrakili, N Pozidis, C Tokatlidis, K AF Chatzi, Afroditi Sideris, Dionisia P. Katrakili, Nitsa Pozidis, Charalampos Tokatlidis, Kostas TI Biogenesis of yeast Mia40-uncoupling folding from import and atypical recognition features SO FEBS JOURNAL LA English DT Article DE biogenesis; mitochondria; Erv1; import; Mia40 ID MITOCHONDRIAL INTERMEMBRANE SPACE; DISULFIDE RELAY SYSTEM; CYTOCHROME-C PEROXIDASE; ELECTRON-TRANSFER; PROTEIN IMPORT; MEMBRANE ORGANIZATION; RECEPTOR MIA40; BOND FORMATION; SUBSTRATE; ERV1 AB The discovery of the mitochondrial intermembrane space assembly (MIA) pathway was followed by studies that focused mainly on the typical small substrates of this disulfide relay system and the interactions between its two central partners: the oxidoreductase Mia40 and the FAD-protein Erv1. Recent studies have revealed that more complex proteins utilize this pathway, including Mia40 itself. In the present study, we dissect the Mia40 biogenesis in distinct stages, supporting a kinetically coordinated sequence of events, starting with (a) import and insertion through the Tim23 translocon, followed by (b) folding of the core of imported Mia40 assisted by the endogenous Mia40 and (c) final interaction with Erv1. The interaction with endogenous Mia40 and the subsequent interaction with Erv1 represent kinetically distinguishable steps that rely on completely different determinants. Interaction with Mia40 proceeds very early (within 30s) and is characterized by no Cys-specificity, an increased tolerance to mutations of the hydrophobic substrate-binding cleft and no apparent dependence on glutathione as a proofreading mechanism. All of these features illustrate a very atypical behaviour for the Mia40 precursor compared to other substrates of the MIA pathway. By contrast, interaction with Erv1 occurs after 5min of import and relies on a more stringent specificity. C1 [Chatzi, Afroditi; Sideris, Dionisia P.; Katrakili, Nitsa; Pozidis, Charalampos; Tokatlidis, Kostas] Fdn Res & Technol Hellas IMBB FORTH, Inst Mol Biol & Biotechnol, Iraklion 71110, Crete, Greece. [Chatzi, Afroditi] Univ Crete, Dept Biol, Iraklion, Greece. [Sideris, Dionisia P.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Tokatlidis, Kostas] Univ Crete, Dept Mat Sci & Technol, Iraklion, Greece. RP Tokatlidis, K (reprint author), Fdn Res & Technol Hellas IMBB FORTH, Inst Mol Biol & Biotechnol, Iraklion 71110, Crete, Greece. EM tokatlid@imbb.forth.gr OI Tokatlidis, Kostas/0000-0001-6295-8183 FU IMBB-FORTH; University of Crete; European Union (European Social Fund); Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework Research Funding Program THALES; Greek General Secretariat for Research and Technology program ARISTEIA FX This work was supported by funds received from IMBB-FORTH, the University of Crete and the European Union (European Social Fund), as well as Greek national funds obtained through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework Research Funding Program THALES and the Greek General Secretariat for Research and Technology program ARISTEIA. NR 38 TC 6 Z9 6 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD OCT PY 2013 VL 280 IS 20 BP 4960 EP 4969 DI 10.1111/febs.12482 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 254AL UT WOS:000327132100005 PM 23937629 ER PT J AU Bharadwaj, AS Schewitz-Bowers, LP Wei, L Lee, RWJ Smith, JR AF Bharadwaj, Arpita S. Schewitz-Bowers, Lauren P. Wei, Lai Lee, Richard W. J. Smith, Justine R. TI Intercellular Adhesion Molecule 1 Mediates Migration of Th1 and Th17 Cells Across Human Retinal Vascular Endothelium SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE uveitis; retina; endothelial cell; Th1 cell; Th17 cell ID EXPERIMENTAL AUTOIMMUNE UVEITIS; CENTRAL-NERVOUS-SYSTEM; ALPHA-4 INTEGRIN EXPRESSION; LEUKOCYTE TRAFFICKING; T(H)17 CELLS; IN-VIVO; MONOCLONAL-ANTIBODIES; T-CELLS; DISEASE; BARRIER AB PURPOSE. Autoimmune inflammation of the retina causes vision loss in the majority of affected individuals. Th1 or Th17 cells initiate the disease on trafficking from the circulation into the eye across the retinal vascular endothelium. We investigated the ability of human Th1- and Th17-polarized cells to cross a simulated human retinal endothelium, and examined the role of IgG superfamily members in this process. METHODS. Th1-and Th17-polarized cell populations were generated from human peripheral blood CD4(+) T cells, using two Th1-and Th17-polarizing protocols. Transendothelial migration assays were performed over 18 hours in Boyden chambers, after seeding the transwell membrane with human retinal endothelial cells. In some assays intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), or activated leukocyte cell adhesion molecule (ALCAM) blocking antibody, or isotype-and concentration-matched control antibody, was added to the upper chambers. RESULTS. Th1-and Th17-polarized cells migrated equally efficiently across the human retinal endothelial monolayer. The percentage of IL-17(+) IFN-gamma(-) Th17-polarized cells was reduced following migration. Blocking ICAM-1, but not VCAM-1 or ALCAM, significantly reduced migration of Th1-and Th17-polarized cells for a majority of human donors. CONCLUSIONS. Taken in the context of other literature on transendothelial migration, our results illustrate the importance of investigating the specific tissue and vascular endothelium when considering helper T cell migration in autoimmune inflammation. Our findings further indicate that while generalizations about involvement of specific adhesion molecules in uveitis and other autoimmune disease may be possible, these may not apply to individual patients universally. The observations are relevant to the use of adhesion blockade for therapeutic purposes. C1 [Bharadwaj, Arpita S.; Smith, Justine R.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Schewitz-Bowers, Lauren P.; Lee, Richard W. J.] Univ Bristol, Sch Clin Sci, Bristol, Avon, England. [Schewitz-Bowers, Lauren P.; Lee, Richard W. J.] Natl Hlth Serv Fdn Trust, Moorfields Eye Hosp, Biomed Res Ctr, Natl Inst Hlth Res, London, England. [Schewitz-Bowers, Lauren P.; Lee, Richard W. J.] UCL, Inst Ophthalmol, London, England. [Wei, Lai] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Smith, Justine R.] Flinders Univ S Australia, Adelaide, SA 5001, Australia. RP Smith, JR (reprint author), Flinders Univ South Australia, Flinders Med Ctr, Flinders Dr, Bedford Pk, SA 5042, Australia. EM justine.smith@flinders.edu.au RI Wei, Lai/D-1088-2014; Lee, Richard/A-3116-2017 OI Lee, Richard/0000-0002-9480-6843 FU National Eye Institute (National Institutes of Health) [R01 EY019875]; Collins Medical Trust; Research to Prevent Blindness (unrestricted grant to Casey Eye Institute) FX Supported by grants from the National Eye Institute (National Institutes of Health; R01 EY019875), Collins Medical Trust, and Research to Prevent Blindness (unrestricted grant to Casey Eye Institute). NR 55 TC 10 Z9 10 U1 1 U2 5 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2013 VL 54 IS 10 BP 6917 EP 6925 DI 10.1167/iovs.13-12058 PG 9 WC Ophthalmology SC Ophthalmology GA 246VI UT WOS:000326567700053 PM 24022011 ER PT J AU Sano, K Nakajima, T Ali, T Bartlett, DW Wu, AM Kim, I Paik, CH Choyke, PL Kobayashi, H AF Sano, Kohei Nakajima, Takahito Ali, Towhid Bartlett, Derek W. Wu, Anna M. Kim, Insook Paik, Chang H. Choyke, Peter L. Kobayashi, Hisataka TI Activatable fluorescent cys-diabody conjugated with indocyanine green derivative: consideration of fluorescent catabolite kinetics on molecular imaging SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE optical probe; activatable imaging; diabody; indocyanine green; polyethylene glycol linker; catabolism ID IN-VIVO; MONOCLONAL-ANTIBODIES; CANCER; BIODISTRIBUTION; PROBES AB Antibody fragments including diabodies have more desirable pharmacokinetic characteristics than whole antibodies. An activatable optical imaging probe based on a cys-diabody targeting prostate-specific membrane antigen conjugated with the near-infrared fluorophore, indocyanine green (ICG), was designed such that it can only be activated when bound to the tumor, leading to high signal-to-background ratios. We employed short polyethylene glycol (PEG) linkers between the ICG and the reactive functional group (Sulfo-OSu group), resulting in covalent conjugation of ICG to the cys-diabody, which led to lower dissociation of ICG from cys-diabody early after injection, reducing hepatic uptake. However, unexpectedly, high and long-term fluorescence was observed in the kidneys, liver, and blood pool more than 1 h after injection of the cys-diabody PEG-ICG conjugate. A biodistribution study using I-125-labeled cys-diabody-ICG showed immediate uptake in the kidneys followed by a rapid decrease, while gastric activity increased due to released radioiodine during rapid cys-diabody-ICG catabolism in the kidneys. To avoid this catabolic pathway, it would be preferable to use antibody fragments large enough not to be filtered through glomerulus or to conjugate the fragments with fluorescent dyes that are readily excreted into urine when cleaved from the cys-diabody to achieve high tumor-specific detection. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI. C1 [Sano, Kohei; Nakajima, Takahito; Ali, Towhid; Choyke, Peter L.; Kobayashi, Hisataka] NCI, NIH, Ctr Canc Res, Mol Imaging Program, Bethesda, MD 20892 USA. [Bartlett, Derek W.] ImaginAb, Inglewood, CA 90301 USA. [Wu, Anna M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Kim, Insook] SAIC Frederick Inc, Appl Dev Res Directorate, Frederick Natl Lab, Frederick, MD 21702 USA. [Paik, Chang H.] NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, NIH, Ctr Canc Res, Mol Imaging Program, Bldg 10,Room B3B69,MSC1088, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. 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. NR 18 TC 6 Z9 6 U1 0 U2 12 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD OCT PY 2013 VL 18 IS 10 AR 101304 DI 10.1117/1.JBO.18.10.101304 PG 6 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 246TW UT WOS:000326563000010 PM 23752742 ER PT J AU Cooper, ID Crum, JA AF Cooper, I. Diane Crum, Janet A. TI New activities and changing roles of health sciences librarians: a systematic review, 1990-2012 SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Review ID INFORMATIONIST; SERVICES; PROGRAM; MODEL; BIOINFORMATIONIST; EDUCATION; OUTREACH; DISASTER; WEB AB Objective: The paper identifies and documents new health sciences librarian activities and roles during the period from 1990-2012. Methods: A systematic review of the literature was conducted using MEDLINE, Library and Information Abstracts, Library Literature, Scopus, and Web of Science. To find new roles that might not yet have been described in the literature, job announcements published in the Medical Library Association email discussion list archives from 2008-2012 were searched. For inclusion, an article needed to contain a substantive description of a new role and/or activity performed by librarians and be in the field of medical or health sciences librarianship. Papers that did not describe an actual (rather than proposed) librarian role were excluded. Results: New roles identified through the literature search were: embedded librarians (such as clinical informationist, bioinformationist, public health informationist, disaster information specialist); systematic review librarian; emerging technologies librarian; continuing medical education librarian; grants development librarian; and data management librarian. New roles identified through job announcements were digital librarian, metadata librarian, scholarly communication librarian, and translational research librarian. New twists to old roles were also identified: clinical medical librarian, instruction librarian, outreach librarian, and consumer health librarian. Conclusions: While the main purposes of health sciences librarianship remain the same, the new roles represent major new activities so that, for many librarians, daily on-the-job work is completely different. C1 [Cooper, I. Diane] NIH, NIH Lib, Off Res Serv, Bethesda, MD 20892 USA. [Crum, Janet A.] City Hope Natl Med Ctr, Lib Serv, Lee Graff Med & Sci Lib, Duarte, CA 91010 USA. RP Cooper, ID (reprint author), NIH, NIH Lib, Off Res Serv, 10 Ctr Dr, Bethesda, MD 20892 USA. EM cooperd@mail.nih.gov; jcrum@coh.org RI Crum, Janet/B-5109-2010 OI Crum, Janet/0000-0003-2722-3645 NR 52 TC 17 Z9 23 U1 6 U2 56 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2013 VL 101 IS 4 BP 268 EP 277 DI 10.3163/1536-5050.101.4.008 PG 10 WC Information Science & Library Science SC Information Science & Library Science GA 244RI UT WOS:000326406700013 PM 24163598 ER PT J AU Crum, JA Cooper, ID AF Crum, Janet A. Cooper, I. Diane TI Emerging roles for biomedical librarians: a survey of current practice, challenges, and changes SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article ID PUBLIC-ACCESS POLICY; HEALTH; TRENDS AB Objective: This study is intended to (1) identify emerging roles for biomedical librarians and determine how common these roles are in a variety of library settings, (2) identify barriers to taking on new roles, and (3) determine how librarians are developing the capacity to take on new roles. Methods: A survey was conducted of librarians in biomedical settings. Results: Most biomedical librarians are taking on new roles. The most common roles selected by survey respondents include analysis and enhancement of user experiences, support for social media, support for systematic reviews, clinical informationist, help for faculty or staff with authorship issues, and implementation of researcher profiling and collaboration tools. Respondents in academic settings are more likely to report new roles than hospital librarians are, but some new roles are common in both settings. Respondents use a variety of methods to free up time for new roles, but predominant methods vary between directors and librarians and between academic and hospital respondents. Lack of time is the biggest barrier that librarians face when trying to adopt new roles. New roles are associated with increased collaboration with individuals and/or groups outside the library. Conclusion and Implications: This survey documents the widespread incorporation of new roles in biomedical libraries in the United States, as well as the barriers to adopting these roles and the means by which librarians are making time for them. The results of the survey can be used to inform strategic planning, succession planning, library education, and career development for biomedical librarians. C1 [Crum, Janet A.] City Hope Natl Med Ctr, Lee Graff Med & Sci Lib, Lib Serv, Duarte, CA 91010 USA. [Cooper, I. Diane] NIH, NIH Lib, Off Res Serv, Bethesda, MD 20892 USA. RP Crum, JA (reprint author), City Hope Natl Med Ctr, Lee Graff Med & Sci Lib, Lib Serv, 1500 East Duarte Rd, Duarte, CA 91010 USA. EM jcrum@coh.org; cooperd@mail.nih.gov RI Crum, Janet/B-5109-2010 OI Crum, Janet/0000-0003-2722-3645 NR 14 TC 6 Z9 7 U1 1 U2 30 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD OCT PY 2013 VL 101 IS 4 BP 278 EP 286 DI 10.3163/1536-5050.101.4.009 PG 9 WC Information Science & Library Science SC Information Science & Library Science GA 244RI UT WOS:000326406700014 PM 24163599 ER PT J AU Li, DQ Pakala, SB Reddy, SDN Peng, SH Balasenthil, S Deng, CX Lee, CC Rea, MA Kumar, R AF Li, Da-Qiang Pakala, Suresh B. Reddy, Sirigiri Divijendra Natha Peng, Shaohua Balasenthil, Seetharaman Deng, Chu-Xia Lee, Cheng Chi Rea, Michael A. Kumar, Rakesh TI Metastasis-associated protein 1 is an integral component of the circadian molecular machinery SO NATURE COMMUNICATIONS LA English DT Article ID MESSENGER-RNA EXPRESSION; DNA-DAMAGE RESPONSE; HISTONE DEACETYLASE; GENE-EXPRESSION; FEEDBACK LOOP; MUTANT MICE; CELL-LINES; CLOCK; COMPLEX; TRANSCRIPTION AB The mammalian circadian clock regulates the daily cycles of many important physiological processes, but its mechanism is not well understood. Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. Knockout of MTA1 in mice disrupts the free-running period of circadian rhythms under constant light and normal entrainment of behaviour to 12-h-light/12-h-dark cycles. The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription. Moreover, MTA1 deacetylates BMAL1 at lysine 538 through regulating deacetylase SIRT1 expression, thus disturbing the CRY1-mediated negative feedback loop. These findings uncover a previously unappreciated role for MTA1 in maintenance of circadian rhythmicity through acting on the positive limb of the clock machinery. C1 [Li, Da-Qiang; Pakala, Suresh B.; Reddy, Sirigiri Divijendra Natha; Kumar, Rakesh] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Med, Washington, DC 20037 USA. [Peng, Shaohua; Balasenthil, Seetharaman; Kumar, Rakesh] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Lee, Cheng Chi] Univ Texas Hlth Sci Ctr Houston, Dept Biochem & Mol Biol, Houston, TX 77225 USA. [Rea, Michael A.] Univ Houston, Dept Biol & Biochem, Circadian Neurobiol Lab, Houston, TX 77204 USA. [Kumar, Rakesh] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. RP Kumar, R (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Med, Washington, DC 20037 USA. EM bcmrxk@gwu.edu RI deng, chuxia/N-6713-2016; sirigiri, divijendra reddy/E-1031-2017 OI sirigiri, divijendra reddy/0000-0003-4657-2285 FU National Institutes of Health [CA98823, MH62490] FX We are very grateful to Drs Kazuhiro Yagita (Nagoya University Graduate School of Science, Nagoya, Japan), Paolo Sassone-Coirsi (University of California, Irvine, CA), Roman V. Kondratov (Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH) for providing plasmid DNAs. We thank all members of the Kumar laboratory for fruitful discussion and technical assistance. This work was initiated at the University of Texas M. D. Anderson Cancer Center (Houston, TX) and mechanistic studies continued at the George Washington University. This work was supported by National Institutes of Health Grants CA98823 (to R. K.) and Grant MH62490 (to M.A.R.). NR 58 TC 6 Z9 10 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD OCT PY 2013 VL 4 AR 2545 DI 10.1038/ncomms3545 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 245MU UT WOS:000326468600003 PM 24089055 ER PT J AU Muller, TA Grundler, R Istvanffy, R Hennighausen, L Illert, AL Duyster, J AF Mueller, T. A. Grundler, R. Istvanffy, R. Hennighausen, L. Illert, A. L. Duyster, J. TI Oncostatin M is an important STAT5 target gene in FLT3-ITD signalling SO ONKOLOGIE LA English DT Meeting Abstract C1 [Mueller, T. A.; Illert, A. L.; Duyster, J.] Univ Freiburg Klinikum, Med Klin 1, Freiburg, Germany. [Grundler, R.; Istvanffy, R.] Tech Univ Munich, Klinikum Rechts Isar, Med Klin 3, Munich, Germany. [Hennighausen, L.] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-584X EI 1423-0240 J9 ONKOLOGIE JI Onkologie PD OCT PY 2013 VL 36 SU 7 BP 42 EP 43 PG 2 GA 244BA UT WOS:000326360900094 ER PT J AU Kleber, M Hock, K Ihorst, G Koch, B Wasch, R Landgren, O Engelhardt, M AF Kleber, M. Hoeck, K. Ihorst, G. Koch, B. Waesch, R. Landgren, O. Engelhardt, M. TI Incidence rate of different neoplasms (DNs) in multiple myeloma (MM) patients (pts): Institutional database of 744 MM pts SO ONKOLOGIE LA English DT Meeting Abstract C1 [Kleber, M.; Hoeck, K.; Waesch, R.; Engelhardt, M.] Univ Freiburg, D-79106 Freiburg, Germany. [Ihorst, G.] Univ Med Ctr, Clin Trials Unit, Freiburg, Germany. [Koch, B.] Univ Freiburg, Med Ctr, Cent Lab, Freiburg, Germany. [Landgren, O.] NCI, Multiple Myeloma Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0378-584X EI 1423-0240 J9 ONKOLOGIE JI Onkologie PD OCT PY 2013 VL 36 SU 7 BP 170 EP 171 PG 2 GA 244BA UT WOS:000326360900422 ER PT J AU Aristotelous, T Ahn, S Shukla, AK Gawron, S Sassano, MF Kahsai, AW Wingler, LM Zhu, X Tripathi-Shukla, P Huang, XP Riley, J Besnard, J Read, KD Roth, BL Gilbert, IH Hopkins, AL Lefkowitz, RJ Navratilova, I AF Aristotelous, Tonia Ahn, Seungkirl Shukla, Arun K. Gawron, Sylwia Sassano, Maria F. Kahsai, Alem W. Wingler, Laura M. Zhu, Xiao Tripathi-Shukla, Prachi Huang, Xi-Ping Riley, Jennifer Besnard, Jeremy Read, Kevin D. Roth, Bryan L. Gilbert, Ian H. Hopkins, Andrew L. Lefkowitz, Robert J. Navratilova, Iva TI Discovery of beta 2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Fragment screening; G-protein coupled receptors; surface plasmon resonance; beta 2 adrenoceptor ID PROTEIN-COUPLED RECEPTOR; SURFACE-PLASMON RESONANCE; ADENOSINE A(2A) RECEPTOR; CRYSTAL-STRUCTURE; ADRENERGIC-RECEPTOR; BIOPHYSICAL METHODS; DRUG DISCOVERY; PURIFICATION; IDENTIFICATION; ADRENOCEPTOR AB G-protein coupled receptors (GPCRs) are the primary target class of currently marketed drugs, accounting for about a quarter of all drug targets of approved medicines. However, almost all the screening efforts for novel ligand discovery rely exclusively on cellular systems overexpressing the receptors. An alternative ligand discovery strategy is a fragment-based drug discovery, where low molecular weight compounds, known as fragments, are screened as initial starting points for optimization. However, the screening of fragment libraries usually employs biophysical screening methods, and as such, it has not been routinely applied to membrane proteins. We present here a surface plasmon resonance biosensor approach that enables, cell-free, label-free, fragment screening that directly measures fragment interactions with wild-type GPCRs. We exemplify the method by the discovery of novel, selective, high affinity antagonists of human beta 2 adrenoceptor. C1 [Aristotelous, Tonia; Gawron, Sylwia; Riley, Jennifer; Besnard, Jeremy; Read, Kevin D.; Gilbert, Ian H.; Hopkins, Andrew L.; Navratilova, Iva] Univ Dundee, Div Biol Chem & Drug Discovery, Coll Life Sci, Dundee DD1 5EH, Scotland. [Ahn, Seungkirl; Shukla, Arun K.; Kahsai, Alem W.; Wingler, Laura M.; Zhu, Xiao; Tripathi-Shukla, Prachi; Lefkowitz, Robert J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Sassano, Maria F.; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, NIMH Psychoact Drug Screening Program, Dept Pharmacol, Chapel Hill, NC 27759 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27759 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC 27759 USA. [Lefkowitz, Robert J.] Duke Univ, Howard Hughes Med Inst, Med Ctr, Durham, NC 27710 USA. [Lefkowitz, Robert J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Hopkins, AL (reprint author), Univ Dundee, Div Biol Chem & Drug Discovery, Coll Life Sci, Dow St, Dundee DD1 5EH, Scotland. EM i.hopkinsnavratilova@dundee.ac.uk; lefko001@receptor-biol.duke.edu; a.hopkins@dundee.ac.uk RI Roth, Bryan/F-3928-2010 FU Michael Hooker Chair of Pharmacology; Innovative Medicines Initiative's K4DD consortium [115366]; Wellcome Trust Strategic Awards [WT083481, 100476/Z/12/Z] FX This work is funded by the MSD Scottish Life Sciences Fund (to I.N. and I.H.G), in part by grants HL16037 and HL70631 from the National Institutes of Health (to R.J.L.) and NIH contracts and grants supporting drug discovery and receptor pharmacology (to B.L.R.). R.J.L. is an Investigator of the Howard Hughes Medical Institute. B.L.R. also received support from the Michael Hooker Chair of Pharmacology. The work is funded in part by the Innovative Medicines Initiative's K4DD consortium under grant agreement no 115366 (I.N. and A.L.H.) and benefits from the Wellcome Trust Strategic Awards to the University of Dundee (WT083481 and 100476/Z/12/Z). NR 25 TC 23 Z9 23 U1 2 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD OCT PY 2013 VL 4 IS 10 BP 1005 EP 1010 DI 10.1021/ml400312j PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 244DL UT WOS:000326367200025 PM 24454993 ER PT J AU Jones, G Arthurs, B Kaya, H MacDonald, K Qin, R Fairbanks, RK Lamoreaux, WT Jawed, I Tward, JD Martincic, D Shivnani, AT Lee, CM AF Jones, Guy Arthurs, Benjamin Kaya, Hakan MacDonald, Kenneth Qin, Rui Fairbanks, Robert K. Lamoreaux, Wayne T. Jawed, Irfan Tward, Jonathan D. Martincic, Danko Shivnani, Anand T. Lee, Christopher M. TI Overall Survival Analysis of Adjuvant Radiation Versus Observation in Stage I Testicular Seminoma A Surveillance, Epidemiology, and End Results (SEER) Analysis SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE seminoma; adjuvant radiotherapy; radiation; observation ID LONG-TERM SURVIVORS; RANDOMIZED-TRIAL; PROGNOSTIC-FACTORS; POOLED ANALYSIS; CANCER; TESTIS; RADIOTHERAPY; ORCHIECTOMY; IRRADIATION; MANAGEMENT AB Objective:The standard adjuvant treatment for men with stage I testicular seminoma remains controversial within the literature. We analyzed survival rates in men with stage I seminoma who underwent adjuvant radiation therapy (RT) or observation (OB) after orchiectomy. Methods:Data were obtained from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute from 1973 to 2003. The primary end points were overall survival (OS) and cause-specific survival (CSS). Multivariate Cox regression models were used to study the significance of clinical variables: age at diagnosis, laterality of primary disease, race, and radiation group. Results:Of 6764 patients eligible for analysis, 5265 were treated with RT and 1499 with OB. After a median follow-up of 7.6 years, the 5-, 10-, and 20-year OS rates for the RT versus OB were 97.9 versus 95.0, 94.8 versus 92.2, and 83.5 versus 84.1 (P=0.0047), respectively. The CSS rates for the same time periods were 99.6 versus 98.7, 99.4 versus 98.7, and 99.2 versus 98.7 (P=0.0015), respectively. Adjuvant RT was associated with improved CSS on multivariate analysis with hazard ratio of 0.37 (confidence interval, 0.20-0.70; P=0.0023). Conclusions:Within this large US population analysis, adjuvant RT was associated with improved OS and CSS compared with OB for men with stage I testicular seminoma. Further studies are needed to determine whether modern RT techniques and field-size reductions may lead to greater improvements in the therapeutic ratio, in light of the trend toward chemotherapy as primary treatment. C1 [Jones, Guy] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Kaya, Hakan; Martincic, Danko] Canc Care Northwest, Dept Med Oncol, Spokane, WA 99202 USA. [Fairbanks, Robert K.; Lamoreaux, Wayne T.; Jawed, Irfan; Lee, Christopher M.] Canc Care Northwest, Dept Radiat Oncol, Spokane, WA 99202 USA. [Arthurs, Benjamin] Univ Washington, Sch Med, Seattle, WA USA. [MacDonald, Kenneth] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA. [Qin, Rui] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Tward, Jonathan D.] Univ Utah, Med Ctr, Huntsman Canc Inst, Dept Radiat Oncol, Salt Lake City, UT USA. [Shivnani, Anand T.] Texas Oncol, Baylor Irving Canc Ctr, Irving, TX USA. RP Lee, CM (reprint author), Canc Care Northwest, 601 S Sherman, Spokane, WA 99202 USA. EM lee@ccnw.net NR 35 TC 6 Z9 6 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD OCT PY 2013 VL 36 IS 5 BP 500 EP 504 DI 10.1097/COC.0b013e318254950a PG 5 WC Oncology SC Oncology GA 244NL UT WOS:000326395900014 PM 22781383 ER PT J AU Jimenez-Gomez, Y Mattison, JA Pearson, KJ Martin-Montalvo, A Palacios, HH Sossong, AM Ward, TM Younts, CM Lewis, K Allard, JS Longo, DL Belman, JP Malagon, MM Navas, P Sanghvi, M Moaddel, R Tilmont, EM Herbert, RL Morrell, CH Egan, JM Baur, JA Ferrucci, L Bogan, JS Bernier, M de Cabo, R AF Jimenez-Gomez, Yolanda Mattison, Julie A. Pearson, Kevin J. Martin-Montalvo, Alejandro Palacios, Hector H. Sossong, Alex M. Ward, Theresa M. Younts, Caitlin M. Lewis, Kaitlyn Allard, Joanne S. Longo, Dan L. Belman, Jonathan P. Malagon, Maria M. Navas, Placido Sanghvi, Mitesh Moaddel, Ruin Tilmont, Edward M. Herbert, Richard L. Morrell, Christopher H. Egan, Josephine M. Baur, Joseph A. Ferrucci, Luigi Bogan, Jonathan S. Bernier, Michel de Cabo, Rafael TI Resveratrol Improves Adipose Insulin Signaling and Reduces the Inflammatory Response in Adipose Tissue of Rhesus Monkeys on High-Fat, High-Sugar Diet SO CELL METABOLISM LA English DT Article ID NF-KAPPA-B; NUCLEAR FACTOR-KAPPAB; NECROSIS-FACTOR-ALPHA; GLUCOSE-TOLERANCE; RECEPTOR SUBSTRATE-1; DIABETES-MELLITUS; GENE-EXPRESSION; SIRT1; RESISTANCE; ADIPOCYTES AB Obesity is associated with a chronic, low-grade, systemic inflammation that may contribute to the development of insulin resistance and type 2 diabetes. Resveratrol, a natural compound with anti-inflammatory properties, is shown to improve glucose tolerance and insulin sensitivity in obese mice and humans. Here, we tested the effect of a 2-year resveratrol administration on proinflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Resveratrol supplementation (80 and 480 mg/day for the first and second year, respectively) decreased adipocyte size, increased sirtuin 1 expression, decreased NF-kappa B activation, and improved insulin sensitivity in visceral, but not subcutaneous, WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS +/- resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys. C1 [Jimenez-Gomez, Yolanda; Mattison, Julie A.; Pearson, Kevin J.; Martin-Montalvo, Alejandro; Palacios, Hector H.; Sossong, Alex M.; Ward, Theresa M.; Younts, Caitlin M.; Lewis, Kaitlyn; Allard, Joanne S.; Tilmont, Edward M.; Bernier, Michel; de Cabo, Rafael] NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Sanghvi, Mitesh; Moaddel, Ruin; Egan, Josephine M.] NIA, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Pearson, Kevin J.] Univ Kentucky, Grad Ctr Nutr Sci, Lexington, KY 40536 USA. [Allard, Joanne S.] Howard Univ Coll Med, Dept Physiol & Biophys, Washington, DC 20059 USA. [Longo, Dan L.] NIA, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Belman, Jonathan P.; Bogan, Jonathan S.] Yale Univ Sch Med, Dept Internal Med, Sect Endocrinol, New Haven, CT 06520 USA. [Belman, Jonathan P.; Bogan, Jonathan S.] Yale Univ Sch Med, Dept Cell Biol, New Haven, CT 06520 USA. [Malagon, Maria M.] Univ Cordoba, Dept Cell Biol Physiol & Immunol, IMIBIC, Reina Sofia Univ Hosp, Cordoba 14014, Spain. [Malagon, Maria M.] CIBERobn, Cordoba 14014, Spain. [Navas, Placido] Univ Pablo Olavide CSIC, Inst Salud Carlos III, Ctr Andaluz Biol Desarrollo, Seville 41013, Spain. [Navas, Placido] Univ Pablo Olavide CSIC, Inst Salud Carlos III, CIBERER, Seville 41013, Spain. [Herbert, Richard L.] NIAID, Clin Med Branch, NIH, Poolesvile, MD 20837 USA. [Morrell, Christopher H.] Loyola Univ Maryland, Dept Math & Stat, Baltimore, MD 21210 USA. [Baur, Joseph A.] Univ Penn, Inst Diabet Obes & Metab, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21225 USA. RP Bernier, M (reprint author), NIA, Translat Gerontol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM bernierm@mail.nih.gov; decabora@mail.nih.gov RI Bogan, Jonathan/A-1575-2010; de Cabo, Rafael/J-5230-2016; Martin-Montalvo, Alejandro/C-2031-2017; Malagon, Maria/L-5386-2014; OI Bogan, Jonathan/0000-0001-6463-8466; de Cabo, Rafael/0000-0002-3354-2442; Martin-Montalvo, Alejandro/0000-0002-3886-5355; Baur, Joseph/0000-0001-8262-6549; Bernier, Michel/0000-0002-5948-368X; , rafael/0000-0003-2830-5693 FU National Institute on Aging, NIH; Office of Dietary Supplements, NIH; NIH [R01 DK075772, F30 DK093198]; Institute de Salud Carlos III [CD07/00208]; Consejeria de Salud, Junta de Andalucia, Spain [EF-0122/2010] FX This work was funded by the Intramural Research Program of the National Institute on Aging, NIH; the Office of Dietary Supplements, NIH; and by the NIH R01 DK075772 (to J.S.B.) and F30 DK093198 (to J.P.B.). Y.J.-G. was supported by a Sara Borrell fellowship of the Institute de Salud Carlos III (CD07/00208) and by a grant for actividades y estancias formativas of the Consejeria de Salud, Junta de Andalucia (EF-0122/2010), Spain. The authors would like to thank DSM Nutritional Products for providing the resveratrol (resVida). None of the authors have any conflict of interest that could affect the performance of the work or the interpretation of the data. NR 52 TC 66 Z9 68 U1 1 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD OCT 1 PY 2013 VL 18 IS 4 BP 533 EP 545 DI 10.1016/j.cmet.2013.09.004 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242UI UT WOS:000326267700011 PM 24093677 ER PT J AU Nabi, RL Prestin, A So, J AF Nabi, Robin L. Prestin, Abby So, Jiyeon TI Facebook Friends with (Health) Benefits? Exploring Social Network Site Use and Perceptions of Social Support, Stress, and Well-Being SO CYBERPSYCHOLOGY BEHAVIOR AND SOCIAL NETWORKING LA English DT Article ID HOST-RESISTANCE; PHYSICAL HEALTH; COMMUNICATION; MORTALITY; SCALE; PERSONALITY; SURVIVAL; SHYNESS; CANCER; ME AB There is clear evidence that interpersonal social support impacts stress levels and, in turn, degree of physical illness and psychological well-being. This study examines whether mediated social networks serve the same palliative function. A survey of 401 undergraduate Facebook users revealed that, as predicted, number of Facebook friends associated with stronger perceptions of social support, which in turn associated with reduced stress, and in turn less physical illness and greater well-being. This effect was minimized when interpersonal network size was taken into consideration. However, for those who have experienced many objective life stressors, the number of Facebook friends emerged as the stronger predictor of perceived social support. The more-friends-the-better heuristic is proposed as the most likely explanation for these findings. C1 [Nabi, Robin L.] Univ Calif Santa Barbara, Dept Commun, Santa Barbara, CA 93106 USA. [Prestin, Abby] NCI, Rockville, MD USA. [So, Jiyeon] Univ Georgia, Dept Commun Studies, Athens, GA 30602 USA. RP Nabi, RL (reprint author), Univ Calif Santa Barbara, Dept Commun, 4137 SSMS Bldg, Santa Barbara, CA 93106 USA. EM nabi@comm.ucsb.edu NR 34 TC 49 Z9 51 U1 7 U2 105 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2152-2715 EI 2152-2723 J9 CYBERPSYCH BEH SOC N JI Cyberpsychology Behav. Soc. Netw. PD OCT 1 PY 2013 VL 16 IS 10 BP 721 EP 727 DI 10.1089/cyber.2012.0521 PG 7 WC Psychology, Social SC Psychology GA 242XG UT WOS:000326278500002 PM 23790356 ER PT J AU Crish, J Conti, MA Sakai, T Adelstein, RS Egelhoff, TT AF Crish, James Conti, Mary Anne Sakai, Takao Adelstein, Robert S. Egelhoff, Thomas T. TI Keratin 5-Cre-driven excision of nonmuscle myosin IIA in early embryo trophectoderm leads to placenta defects and embryonic lethality SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Myosin; MYH9; Trophoblast; Placenta; Keratin 5; Keratinocyte ID CELL-ADHESION; MOUSE PLACENTA; STEM-CELLS; TROPHOBLAST DIFFERENTIATION; EPIDERMAL HOMEOSTASIS; RESTRICTED DELETION; GENE-EXPRESSION; HEAVY-CHAIN; SKIN; ABLATION AB In studies initially focused on roles of nonmuscle myosin IIA (NMIIA) in the developing mouse epidermis, we have discovered that a previously described cytokeratin 5 (K5)-Cre gene construct is expressed in early embryo development. Mice carrying foxed alleles of the nonmuscle myosin II heavy chain gene (NMHC IIA(flox/flox)) were crossed with the K5-Cre line. The progeny of newborn pups did not show a Mendelian genotype distribution, suggesting embryonic lethality. Analysis of post-implantation conceptuses from embryonic day (E)9.5 to E13.5 revealed poorly developed embryos and defective placentas, with significantly reduced labyrinth surface area and blood vessel vascularization. These results suggested the novel possibility that the bovine K5 promoter-driven Cre-recombinase was active early in trophoblast-lineage cells that give rise to the placenta. To test this possibility, K5-Cre transgenic mice were crossed with the mT/mG reporter mouse in which activation of GFP expression indicates Cre transgene expression. We observed activation of K5-Cre-driven GFP expression in the ectoplacental cone, in the extraembryonic ectoderm, and in trophoblast giant cells in the E6.5 embryo. In addition, we observed GFP expression at E11.5 to E13.5 in both the labyrinth of the placenta and the yolk sac. NMIIA expression was detected in these same cell types in normal embryos, as well as in E13.5 yolk sac and labyrinth. These findings taken together suggest that NMHC IIA may play critical roles in the early trophoblast-derived ectoplacental cone and extraembryonic ectoderm, as well as in the yolk sac and labyrinth tissues that form later. Our findings are consistent with phenotypes of constitutive NMIIA knockout mice made earlier, that displayed labyrinth and yolk sac-specific defects, but our findings extend those observations by suggesting possible NMIIA roles in trophoblast lineages as well. These results furthermore demonstrate that K5-Cre gene constructs, previously reported to be activated starting at approximately E12.5 in the forming epidermis, may be widely useful as drivers for activation of cre/lox based gene excision in early embryo extraembronic trophoblast tissues as well. (C) 2013 Elsevier Inc. All rights reserved. C1 [Crish, James; Egelhoff, Thomas T.] Cleveland Clin Fdn, Lerner Res Inst, Dept Cellular & Mol Med NC10, Cleveland, OH 44195 USA. [Conti, Mary Anne; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Sakai, Takao] Cleveland Clin Fdn, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44195 USA. RP Egelhoff, TT (reprint author), Cleveland Clin Fdn, Lerner Res Inst, Dept Cellular & Mol Med NC10, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM egelhot@ccf.org OI Adelstein, Robert/0000-0002-8683-2144 FU NIGMS NIH HHS [R01 GM050009] NR 55 TC 3 Z9 3 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD OCT 1 PY 2013 VL 382 IS 1 BP 136 EP 148 DI 10.1016/j.ydbio.2013.07.017 PG 13 WC Developmental Biology SC Developmental Biology GA 243JH UT WOS:000326312200012 PM 23911870 ER PT J AU Beard, JD Hoppin, JA Richards, M Alayanja, MCR Blair, A Sandler, DP Kamel, F AF Beard, John D. Hoppin, Jane A. Richards, Marie Alayanja, Michael C. R. Blair, Aaron Sandler, Dale P. Kamel, Freya TI Pesticide exposure and self-reported incident depression among wives in the Agricultural Health Study SO ENVIRONMENTAL RESEARCH LA English DT Article DE Depression; Female; Incidence; Pesticides; Spouses ID MARGINAL STRUCTURAL MODELS; FARM RESIDENTS; ORGANOPHOSPHATE PESTICIDES; EPIDEMIOLOGIC RESEARCH; MENTAL-HEALTH; UNITED-STATES; SYMPTOMS; WORKERS; RISK; APPLICATORS AB Background: Depression in women is a public health problem. Studies have reported positive associations between pesticides and depression, but few studies were prospective or presented results for women separately. Objectives: We evaluated associations between pesticide exposure and incident depression among farmers' wives in the Agricultural Health Study, a prospective cohort study in Iowa and North Carolina. Methods: We used data on 16,893 wives who did not report physician-diagnosed depression at enrollment (1993-1997) and who completed a follow-up telephone interview (2005-2010). Among these wives, 1054 reported physician diagnoses of depression at follow-up. We collected information on potential confounders and on ever use of any pesticide, 11 functional and chemical classes of pesticides, and 50 specific pesticides by wives and their husbands via self-administered questionnaires at enrollment. We used inverse probability weighting to adjust for potential confounders and to account for possible selection bias induced by the death or loss of 10,639 wives during follow-up. We used log-binomial regression models to estimate risk ratios and 95% confidence intervals. Results: After weighting for age at enrollment, state of residence, education level, diabetes diagnosis, and drop out, wives' incident depression was positively associated with diagnosed pesticide poisoning, but was not associated with ever using any pesticide. Use of individual pesticides or functional or chemical classes of pesticides was generally not associated with wives' depression. Among wives who never used pesticides, husbands' ever use of individual pesticides or functional or chemical classes of pesticides was generally not associated with wives' incident depression. Conclusions: Our study adds further evidence that high level pesticide exposure, such as pesticide poisoning, is associated with increased risk of depression and sets a lower bound on the level of exposure related to depression, thereby providing reassurance that the moderate levels of pesticide exposure experienced by farmers' wives likely do not increase risk. Published by Elsevier Inc. C1 [Beard, John D.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Beard, John D.; Hoppin, Jane A.; Sandler, Dale P.; Kamel, Freya] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Richards, Marie] Westat Corp, Durham, NC USA. [Alayanja, Michael C. R.; Blair, Aaron] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Kamel, F (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. EM kamel@niehs.nih.gov OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS) [Z01 ES049030]; National Cancer Institute [Z01 CP044008]; NIEHS [T32ES007018] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS) (Z01 ES049030), the National Cancer Institute (Z01 CP044008), and NIEHS Training Grant T32ES007018. The Agricultural Health Study was approved by the Institutional Review Boards of the National Institutes of Health and its contractors; the current analysis involving coded data was exempted from review by the Institutional Review Board of the University of North Carolina at Chapel Hill. All participants provided implied informed consent by completing and returning the enrollment questionnaires after the study was explained to them. NR 49 TC 8 Z9 9 U1 1 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD OCT PY 2013 VL 126 BP 31 EP 42 DI 10.1016/j.envres.2013.06.001 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 240ZC UT WOS:000326135200005 PM 23916637 ER PT J AU Longnecker, MP Harbak, K Kissling, GE Hoppin, JA Eggesbo, M Jusko, TA Eide, J Koch, HM AF Longnecker, M. P. Harbak, K. Kissling, G. E. Hoppin, J. A. Eggesbo, M. Jusko, T. A. Eide, J. Koch, H. M. TI The concentration of bisphenol A in urine is affected by specimen collection, a preservative, and handling SO ENVIRONMENTAL RESEARCH LA English DT Article DE Bisphenol A; Urine specimen collection; Contamination ID TANDEM MASS-SPECTROMETRY; LIQUID-CHROMATOGRAPHY; NORWEGIAN MOTHER; CHILD COHORT; QUANTIFICATION; CONTAMINATION; EXPOSURE; SAMPLES AB In urine specimens that were collected from pregnant women in a large cohort, 24% contained more than 10 ng/ml of total bisphenol A (BPA), suggesting external contamination. Therefore, we conducted an investigation of the source(s) of extraneous BPA in the specimens. We found that under the conditions' used to collect urine specimens in the epidemiologic study, contamination with BPA occurred, and by two separate mechanisms. Published by Elsevier Inc. C1 [Longnecker, M. P.; Hoppin, J. A.; Jusko, T. A.] NIH DHHS USA, Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Harbak, K.] Norwegian Inst Publ Hlth, Div Publ Relat, N-0403 Oslo, Norway. [Harbak, K.] Norwegian Inst Publ Hlth, Inst Resources, N-0403 Oslo, Norway. [Kissling, G. E.] NIH DHHS USA, Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Eggesbo, M.] Norwegian Inst Publ Hlth, Dept Genes & Environm, Div Epidemiol, N-0403 Oslo, Norway. [Eide, J.] Oslo Univ HE, N-0424 Oslo, Norway. [Koch, H. M.] Ruhr Univ Bochum IPA, Inst Prevent, D-44789 Bochum, Germany. [Koch, H. M.] Ruhr Univ Bochum IPA, Occupat Med German Social Accid Insurance Inst, Bochum, Germany. RP Longnecker, MP (reprint author), NIH DHHS USA, Natl Inst Environm Hlth Sci, Epidemiol Branch, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. EM Longnec1@niehs.nih.gov; Kari.Harbak@fhi.no; Kissling@niehs.nih.gov; Hoppin1@niehs.nih.gov; Merete.eggesbo@fhi.no; todd_jusko@urmc.rochester.edu; joeide@ous-hf.no; koch@ipa-dguv.de RI Koch, Holger/B-3277-2011; OI Koch, Holger/0000-0002-8328-2837; Longnecker, Matthew/0000-0001-6073-5322; Eggesbo, Merete/0000-0002-0006-5336 FU National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS). NR 14 TC 10 Z9 11 U1 0 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD OCT PY 2013 VL 126 BP 211 EP 214 DI 10.1016/j.envres.2013.07.002 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 240ZC UT WOS:000326135200029 PM 23899777 ER PT J AU Chan, EC Bai, Y Bandara, G Simakova, O Brittain, E Scott, L Dyer, KD Klion, AD Maric, I Gilfillan, AM Metcalfe, DD Wilson, TM AF Chan, Eunice Ching Bai, Yun Bandara, Geethani Simakova, Olga Brittain, Erica Scott, Linda Dyer, Kimberly D. Klion, Amy D. Maric, Irina Gilfillan, Alasdair M. Metcalfe, Dean D. Wilson, Todd M. TI KIT GNNK splice variants: Expression in systemic mastocytosis and influence on the activating potential of the D816V mutation in mast cells SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; C-KIT; TYROSINE KINASE; SIGNAL-TRANSDUCTION; MULTIPLE-MYELOMA; CATALYTIC DOMAIN; ISOFORMS; GROWTH; DIFFERENTIATION; RECEPTOR AB Stem cell factor-dependent KIT activation is an essential process for mast cell homeostasis. The two major splice variants of KIT differ by the presence or absence of four amino acids (GNNK) at the juxta-membrane region of the extracellular domain. We hypothesized that the expression pattern of these variants differs in systemic mastocytosis and that transcripts containing the KIT D816V mutation segregate preferentially to one GNNK variant. A quantitative real-time PCR assay to assess GNNK(-) and GNNK(+) transcripts from bone marrow mononuclear cells was developed. The GNNK(-)/GNNK(+) copy number ratio showed a trend toward a positive correlation with the percentage of neoplastic mast cell involvement, and KIT D816V containing transcripts displayed a significantly elevated GNNK(-)/GNNK(+) copy number ratio. Relative expression of only the GNNK(-) variant correlated with increasing percentage of neoplastic mast cell involvement. A mast cell transfection system revealed that the GNNK(-) isoform of wild type KIT was associated with increased granule formation, histamine content, and growth. When accompanying the KIT D816V mutation, the GNNK(-) isoform enhanced cytokine-free metabolism and moderately reduced sensitivity to the tyrosine kinase inhibitor, PKC412. These data suggest that neoplastic mast cells favor a GNNK(-) variant predominance, which in turn enhances the activating potential of the KIT D816V mutation and thus could influence therapeutic sensitivity in systemic mastocytosis. Published by Elsevier Inc. on behalf of ISEH -Society for Hematology and Stem Cells. C1 [Chan, Eunice Ching; Bai, Yun; Bandara, Geethani; Scott, Linda; Gilfillan, Alasdair M.; Metcalfe, Dean D.; Wilson, Todd M.] Mast Cell Biol Sect, Lab Allerg Dis, Bethesda, MD USA. [Simakova, Olga; Maric, Irina] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Brittain, Erica] NIAID, Bethesda, MD 20892 USA. [Dyer, Kimberly D.] NIAID, Inflammat & Immunobiol Sect, Lab Allerg Dis Branch, Bethesda, MD 20892 USA. [Klion, Amy D.] NIAID, Eosinophil Biol Unit, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Wilson, TM (reprint author), NIH, Bldg 10,Room 9N214-D1, Bethesda, MD 20892 USA. EM twilson@niaid.nih.gov OI Klion, Amy/0000-0002-4986-5326 FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) FX This study was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). We thank Dr. Helene Rosenberg (Inflammation Immunobiology Section, Laboratory of Allergic Diseases, NIH) for critical review of this manuscript and all the subjects and LAD clinical research staff for their contributions. NR 35 TC 7 Z9 7 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD OCT PY 2013 VL 41 IS 10 BP 870 EP 881 DI 10.1016/j.exphem.2013.05.005 PG 12 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 245AQ UT WOS:000326431700005 PM 23743299 ER PT J AU Liu, J Huang, J Zhang, YW Lan, Q Rothman, N Zheng, TZ Ma, SG AF Liu, Jin Huang, Jian Zhang, Yawei Lan, Qing Rothman, Nathaniel Zheng, Tongzhang Ma, Shuangge TI Identification of gene-environment interactions in cancer studies using penalization SO GENOMICS LA English DT Article DE Gene-environment interaction; Penalized marker identification; Cancer prognosis ID NON-HODGKIN-LYMPHOMA; RISK; POLYMORPHISMS; DISEASES; PATHWAY AB High-throughput cancer studies have been extensively conducted, searching for genetic markers associated with outcomes beyond clinical and environmental risk factors. Gene-environment interactions can have important implications beyond main effects. The commonly-adopted single-marker analysis cannot accommodate the joint effects of a large number of markers. The existing joint-effects methods also have limitations. Specifically, they may suffer from high computational cost, do not respect the "main effect, interaction" hierarchical structure, or use ineffective techniques. We develop a penalization method for the identification of important G x E interactions and main effects. It has an intuitive formulation, respects the hierarchical structure, accommodates the joint effects of multiple markers, and is computationally affordable. In numerical study, we analyze prognosis data under the AFT (accelerated failure time) model. Simulation shows satisfactory performance of the proposed method. Analysis of an NHL (non-Hodgkin lymphoma) study with SNP measurements shows that the proposed method identifies markers with important implications and satisfactory prediction performance. (C) 2013 Elsevier Inc. All rights reserved. C1 [Liu, Jin] UIC Sch Publ Hlth, Div Epidemiol & Biostat MC 923, Chicago, IL 60612 USA. [Huang, Jian] Univ Iowa, Dept Biostat, Dept Stat & Actuarial Sci, Iowa City, IA 52242 USA. [Zhang, Yawei; Zheng, Tongzhang; Ma, Shuangge] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [Lan, Qing; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Ma, SG (reprint author), 60 Coll ST LEPH 206, New Haven, CT 06520 USA. EM shuangge.ma@yale.edu FU NIH [CA142774, CA165923]; Yale Comprehensive Cancer Center; National Bureau of Statistics of China [2012LD001] FX We thank the editor, associate editor, and three reviewers for very careful review and insightful comments, which have led to a significant improvement of the article. This study was supported by CA142774 and CA165923 from NIH, a pilot grant from the Yale Comprehensive Cancer Center, and 2012LD001 from National Bureau of Statistics of China. NR 20 TC 7 Z9 7 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 EI 1089-8646 J9 GENOMICS JI Genomics PD OCT PY 2013 VL 102 IS 4 BP 189 EP 194 DI 10.1016/j.ygeno.2013.08.006 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 244YE UT WOS:000326425300001 PM 23994599 ER PT J AU Yuan, M Fang, HY Zhang, H AF Yuan, Min Fang, Hongyan Zhang, Han TI Correcting for differential genotyping error in genetic association analysis SO JOURNAL OF HUMAN GENETICS LA English DT Article DE Cochran-Armitage's trend test; differential error; genomic control; Pearson's chi-square test ID GENOMIC CONTROL; POPULATION STRATIFICATION; PROBABILITY; PHENOTYPE; TESTS; MODEL; POWER AB Differential genotype error in case-control association studies occurs when cases and controls are genotyped under different conditions. Existence of differential errors can considerably bias the association test, resulting in inflation of type I error and spurious significance. With the availability of high-throughput genotyping technologies such as the SNPchip, null markers that are unlinked with the disease can be used to correct for the bias caused by differential errors. A similar method, known as the genomic control, had been used to correct for population stratification in association studies. In this paper, we show that the same idea can be used to correct for the bias caused by differential errors, under the assumption that the null markers and the candidate marker are subject to the same or similar genotyping error model. The variance inflation is shown to be minor and the bias in the association test is the major source of type I error inflation in the presence of differential errors. Our method centralizes the test statistic by deducting the bias estimated from null markers through a quadratic regression method, which adjusts for the variability of null marker allele frequencies. Simulation results show that the proposed method performs very well in correcting for the type I error inflations. C1 [Yuan, Min] Univ Sci & Technol China, Sch Math, Dept Probabil & Stat, Hefei 230026, Anhui, Peoples R China. [Fang, Hongyan] Univ Sci & Technol China, Dept Stat & Finance, Hefei 230026, Anhui, Peoples R China. [Zhang, Han] Natl Canc Inst, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD USA. RP Yuan, M (reprint author), Univ Sci & Technol China, Sch Math, Dept Probabil & Stat, 96 JinZhai Rd, Hefei 230026, Anhui, Peoples R China. EM myuan@ustc.edu.cn RI Zhang, Han/K-2118-2016 OI Zhang, Han/0000-0001-7977-9616 FU National Science Foundation of China (NSFC) [11201452, 11271346] FX This work is partially supported by the National Science Foundation of China (NSFC), grant no. 11201452 and no. 11271346. NR 27 TC 1 Z9 1 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1434-5161 EI 1435-232X J9 J HUM GENET JI J. Hum. Genet. PD OCT PY 2013 VL 58 IS 10 BP 657 EP 666 DI 10.1038/jhg.2013.74 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 241HM UT WOS:000326157100002 PM 23863749 ER PT J AU Nugent, AC Carlson, PJ Bain, EE Eckelman, W Herscovitch, P Manji, H Zarate, CA Drevets, WC AF Nugent, Allison C. Carlson, Paul J. Bain, Earle E. Eckelman, William Herscovitch, Peter Manji, Husseini Zarate, Carlos A., Jr. Drevets, Wayne C. TI Mood stabilizer treatment increases serotonin type 1A receptor binding in bipolar depression SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; TEMPORAL-LOBE EPILEPSY; DORSAL RAPHE NUCLEUS; 5-HT1A RECEPTOR; MESSENGER-RNA; MINERALOCORTICOID RECEPTOR; TRANSCRIPTIONAL REGULATION; ANTIDEPRESSANT TREATMENTS; RESISTANT DEPRESSION; MAJOR DEPRESSION C1 [Nugent, Allison C.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Bethesda, MD 20892 USA. [Carlson, Paul J.] Univ Utah, Sch Med, Dept Psychiat, Salt Lake City, UT 84112 USA. [Bain, Earle E.] Abbott Labs, Abbott Pk, IL 60064 USA. [Eckelman, William] Univ Calif San Diego, San Diego Med Ctr, San Diego, CA 92103 USA. [Herscovitch, Peter] NIH, PET Dept, Bethesda, MD 20892 USA. [Manji, Husseini; Drevets, Wayne C.] Johnson & Johnson Pharmaceut Res & Dev, Titusville, FL USA. [Drevets, Wayne C.] Laureate Inst Brain Res, Tulsa, OK USA. [Drevets, Wayne C.] Univ Oklahoma, Coll Med, Dept Psychiat, Tulsa, OK USA. RP Nugent, AC (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Sect Neuroimaging Mood Disorders, 10 Ctr Dr,Room B1D43S, Bethesda, MD 20892 USA. EM nugenta@mail.nih.gov OI Nugent, Allison/0000-0003-2569-2480 FU IRP of the National Institute of the NIMH; NIH FX This work was supported in part by the IRP of the National Institute of the NIMH and NIH. NR 73 TC 5 Z9 5 U1 0 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 EI 1461-7285 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD OCT PY 2013 VL 27 IS 10 BP 894 EP 902 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 217RU UT WOS:000324378600003 PM 23926239 ER PT J AU Lubitz, SA Moser, C Sullivan, L Rienstra, M Fontes, JD Villalon, ML Pai, M McManus, DD Schnabel, RB Magnani, JW Yin, XY Levy, D Pencina, MJ Larson, MG Ellinor, PT Benjamin, EJ AF Lubitz, Steven A. Moser, Carlee Sullivan, Lisa Rienstra, Michiel Fontes, Joao D. Villalon, Mark L. Pai, Manju McManus, David D. Schnabel, Renate B. Magnani, Jared W. Yin, Xiaoyan Levy, Daniel Pencina, Michael J. Larson, Martin G. Ellinor, Patrick T. Benjamin, Emelia J. TI Atrial Fibrillation Patterns and Risks of Subsequent Stroke, Heart Failure, or Death in the Community SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE atrial fibrillation; heart failure; mortality; pattern; risk; stroke ID FOLLOW-UP; PROGRESSION; MANAGEMENT; INTERMITTENT; DIAGNOSIS; PROGNOSIS; SURVIVAL; FEATURES; OUTCOMES; COHORT AB Background-Atrial fibrillation (AF) patterns and their relations with long-term prognosis are uncertain, partly because pattern definitions are challenging to implement in longitudinal data sets. We developed a novel AF classification algorithm and examined AF patterns and outcomes in the community. Methods and Results-We characterized AF patterns between 1980 and 2005 among Framingham Heart Study participants who survived >= 1 year after diagnosis. We classified participants based on their pattern within the first 2 years after detection as having AF without recurrence, recurrent AF, or sustained AF. We examined associations between AF patterns and 10-year survival using proportional hazards regression. Among 612 individuals with AF, mean age was 72.5 +/- 10.8 years, and 53% were men. Of these, 478 participants had >= 2 electrocardiograms (median, 3; limits 2 to 23) within 2 years after initial AF and were classified as having AF without 2-year recurrence (n=63, 10%), recurrent AF (n=162, 26%) or sustained AF (n=207, 34%), although some (n=46, 8%) were indeterminate. Of 432 classified participants, 363 died, 75 had strokes, and 110 were diagnosed with heart failure during the next 10 years. Relative to individuals without AF recurrence, the multivariable-adjusted mortality was higher among people with recurrent AF (hazard ratio [HR], 2.04; 95% confidence interval [CI], 1.26 to 3.29) and sustained AF (HR, 2.36; 95% CI, 1.49 to 3.75). Conclusions-In our community-based AF sample, only 10% had AF without early-term (2-year) recurrence. Compared with individuals without 2-year AF recurrences, the 10-year prognosis was worse for individuals with either sustained or recurrent AF. Our proposed AF classification algorithm may be applicable in longitudinal datas ets. C1 [Lubitz, Steven A.; Rienstra, Michiel; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Moser, Carlee; Sullivan, Lisa; Pencina, Michael J.; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Fontes, Joao D.; Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Sch Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [Villalon, Mark L.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Fontes, Joao D.; Schnabel, Renate B.; Magnani, Jared W.; Yin, Xiaoyan; Levy, Daniel; Pencina, Michael J.; Larson, Martin G.; Benjamin, Emelia J.] Boston Univ, Framingham, MA USA. [Fontes, Joao D.; Schnabel, Renate B.; Magnani, Jared W.; Yin, Xiaoyan; Levy, Daniel; Pencina, Michael J.; Larson, Martin G.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Pai, Manju] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [McManus, David D.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Schnabel, Renate B.] Univ Heart Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD USA. RP Lubitz, SA (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St,GRB 109, Boston, MA 02114 USA. EM slubitz@partners.org OI Larson, Martin/0000-0002-9631-1254; Sullivan, Lisa/0000-0003-0726-7149; Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation at Boston University; AHA [13EIA14220013]; [N01-HC 25195]; [6R01-NS 17950]; [1RC1HL101056]; [1R01HL102214]; [1R01AG028321]; [1RO1HL092577]; [5R21DA027021]; [1RO1HL104156]; [1K24HL105780]; [1K23HL114724]; [U01HL105268]; [KL2RR031981]; [12FTF11350014]; [09FTF2190028] FX This work was funded by N01-HC 25195, 6R01-NS 17950, grants to Dr Benjamin (1RC1HL101056; 1R01HL102214, 1R01AG028321), Drs Benjamin and Ellinor (1RO1HL092577), Dr Ellinor (5R21DA027021, 1RO1HL104156, 1K24HL105780), Dr Lubitz (1K23HL114724), and Dr McManus (U01HL105268, KL2RR031981), and in part by the Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation at Boston University (http://www.bumc.bu.edu/evanscenteribr/). Dr Lubitz (12FTF11350014), Dr Magnani (09FTF2190028), and Dr Ellinor (13EIA14220013) were supported by AHA awards. NR 28 TC 9 Z9 9 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD OCT PY 2013 VL 2 IS 5 AR UNSP e000126 DI 10.1161/JAHA.113.000126 PG 18 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 243UL UT WOS:000326343200024 PM 24002369 ER PT J AU Oster, ME Riehle-Colarusso, T Simeone, RM Gurvitz, M Kaltman, JR McConnell, M Rosenthal, GL Honein, MA AF Oster, Matthew E. Riehle-Colarusso, Tiffany Simeone, Regina M. Gurvitz, Michelle Kaltman, Jonathan R. McConnell, Michael Rosenthal, Geoffrey L. Honein, Margaret A. TI Public Health Science Agenda for Congenital Heart Defects: Report From a Centers for Disease Control and Prevention Experts Meeting SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article ID PEDIATRIC CARDIAC-DISEASE; 2ND NATURAL-HISTORY; BALTIMORE-WASHINGTON INFANT; UNITED-STATES; SCIENTIFIC STATEMENT; BIRTH-DEFECTS; TASK-FORCE; CARDIOVASCULAR-DISEASE; CURRENT KNOWLEDGE; VALVAR STENOSIS C1 [Oster, Matthew E.; Riehle-Colarusso, Tiffany; Simeone, Regina M.; Honein, Margaret A.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [Oster, Matthew E.; McConnell, Michael] Emory Univ, Sch Med, Childrens Healthcare Atlanta, Atlanta, GA 30322 USA. [Simeone, Regina M.] Oak Ridge Inst Sci & Educ, Oak Ridge, TN 37831 USA. [Gurvitz, Michelle] Harvard Univ, Sch Med, Boston Childrens Hosp, Cambridge, MA 02138 USA. [Kaltman, Jonathan R.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20824 USA. [Rosenthal, Geoffrey L.] Univ Maryland, Sch Med, Childrens Hosp, Baltimore, MD 21201 USA. RP Oster, ME (reprint author), Childrens Healthcare Atlanta, Div Pediat Cardiol, 1405 Clifton Rd NE, Atlanta, GA 30322 USA. EM osterm@kidsheart.com FU Centers for Disease Control and Prevention FX This work was supported in part by an appointment to the Research Participation Program at the Centers for Disease Control and Prevention administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the Centers for Disease Control and Prevention. NR 56 TC 20 Z9 21 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD OCT PY 2013 VL 2 IS 5 AR UNSP e000256 DI 10.1161/JAHA.113.000256 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 243UL UT WOS:000326343200031 PM 23985376 ER PT J AU Degtyareva, NP Heyburn, L Sterling, J Resnick, MA Gordenin, DA Doetsch, PW AF Degtyareva, Natalya P. Heyburn, Lanier Sterling, Joan Resnick, Michael A. Gordenin, Dmitry A. Doetsch, Paul W. TI Oxidative stress-induced mutagenesis in single-strand DNA occurs primarily at cytosines and is DNA polymerase zeta-dependent only for adenines and guanines SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BASE EXCISION-REPAIR; SACCHAROMYCES-CEREVISIAE; ESCHERICHIA-COLI; BREAK-REPAIR; CANCER-CELLS; IN-VIVO; DAMAGE; MUTATIONS; YEAST; INSTABILITY AB Localized hyper-mutability caused by accumulation of lesions in persistent single-stranded (ss) DNA has been recently found in several types of cancers. An increase in endogenous levels of reactive oxygen species (ROS) is considered to be one of the hallmarks of cancers. Employing a yeast model system, we addressed the role of oxidative stress as a potential source of hyper-mutability in ssDNA by modulation of the endogenous ROS levels and by exposing cells to oxidative DNA-damaging agents. We report here that under oxidative stress conditions the majority of base substitution mutations in ssDNA are caused by erroneous, DNA polymerase (Pol) zeta-independent bypass of cytosines, resulting in C to T transitions. For all other DNA bases Pol zeta is essential for ROS-induced mutagenesis. The density of ROS-induced mutations in ssDNA is lower, compared to that caused by UV and MMS, which suggests that ssDNA could be actively protected from oxidative damage. These findings have important implications for understanding mechanisms of oxidative mutagenesis, and could be applied to development of anticancer therapies and cancer prevention. C1 [Degtyareva, Natalya P.; Heyburn, Lanier; Doetsch, Paul W.] Emory Univ, Sch Med, Dept Biochem, Rollins Res Ctr 4013, Atlanta, GA 30322 USA. [Degtyareva, Natalya P.; Doetsch, Paul W.] Emory Univ, Sch Med, Winship Canc Inst, Rollins Res Ctr 4013, Atlanta, GA 30322 USA. [Sterling, Joan; Resnick, Michael A.; Gordenin, Dmitry A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Doetsch, Paul W.] Emory Univ, Sch Med, Dept Radiat Oncol, Rollins Res Ctr 4013, Atlanta, GA 30322 USA. RP Doetsch, PW (reprint author), Emory Univ, Sch Med, Dept Biochem, Rollins Res Ctr 4013, Atlanta, GA 30322 USA. EM medpwd@emory.edu OI Gordenin, Dmitry/0000-0002-8399-1836 FU National Institute of Environmental Health Sciences [ES011163]; Intramural Research Program of the National Institute of Environmental Health Sciences [ES065073] FX Funding for open access charge: National Institute of Environmental Health Sciences [ES011163 to P. W. D.]; Intramural Research Program of the National Institute of Environmental Health Sciences [ES065073 to M.A.R.]. NR 48 TC 8 Z9 8 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2013 VL 41 IS 19 BP 8995 EP 9005 DI 10.1093/nar/gkt671 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 239SC UT WOS:000326044700023 PM 23925127 ER PT J AU Imashimizu, M Oshima, T Lubkowska, L Kashlev, M AF Imashimizu, Masahiko Oshima, Taku Lubkowska, Lucyna Kashlev, Mikhail TI Direct assessment of transcription fidelity by high-resolution RNA sequencing SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ESCHERICHIA-COLI; POLYMERASE-II; WIDESPREAD RNA; IN-VIVO; CLEAVAGE FACTORS; RARE MUTATIONS; ACTIVE-CENTER; TRIGGER LOOP; ELONGATION; TRANSLOCATION AB Cancerous and aging cells have long been thought to be impacted by transcription errors that cause genetic and epigenetic changes. Until now, a lack of methodology for directly assessing such errors hindered evaluation of their impact to the cells. We report a high-resolution Illumina RNA-seq method that can assess noncoded base substitutions in mRNA at 10(-4)-10(-5) per base frequencies in vitro and in vivo. Statistically reliable detection of changes in transcription fidelity through similar to 10(3) nt DNA sites assures that the RNA-seq can analyze the fidelity in a large number of the sites where errors occur. A combination of the RNA-seq and biochemical analyses of the positions for the errors revealed two sequence-specific mechanisms that increase transcription fidelity by Escherichia coli RNA polymerase: (i) enhanced suppression of nucleotide misincorporation that improves selectivity for the cognate substrate, and (ii) increased backtracking of the RNA polymerase that decreases a chance of error propagation to the full-length transcript after misincorporation and provides an opportunity to proofread the error. This method is adoptable to a genome-wide assessment of transcription fidelity. C1 [Imashimizu, Masahiko; Lubkowska, Lucyna; Kashlev, Mikhail] NCI, Gene Regulat & Chromosome Biol Lab, Frederick Natl Lab Canc Res, NIH, Frederick, MD 21702 USA. [Oshima, Taku] Nara Inst Sci & Technol, Grad Sch Biol Sci, Nara 6300192, Japan. RP Kashlev, M (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Frederick Natl Lab Canc Res, NIH, Frederick, MD 21702 USA. EM kashlevm@mail.nih.gov FU JSPS; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Fellowship from JSPS (to M. I. in part); Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (to M. K). Funding for open access charge: The Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 70 TC 22 Z9 22 U1 1 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2013 VL 41 IS 19 BP 9090 EP 9104 DI 10.1093/nar/gkt698 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 239SC UT WOS:000326044700030 PM 23925128 ER PT J AU Chee, CE Krishnamurthi, S Nock, CJ Meropol, NJ Gibbons, J Fu, PF Bokar, J Teston, L O'Brien, T Gudena, V Reese, A Bergman, A Saltzman, J Wright, JJ Dowlati, A Brell, J AF Chee, Cheng Ean Krishnamurthi, Smitha Nock, Charles J. Meropol, Neal J. Gibbons, Joseph Fu, Pingfu Bokar, Joseph Teston, Lois O'Brien, Timothy Gudena, Vinay Reese, Amy Bergman, Amark Saltzman, Joel Wright, John J. Dowlati, Afshin Brell, Joanna TI Phase II Study of Dasatinib (BMS-354825) in Patients With Metastatic Adenocarcinoma of the Pancreas SO ONCOLOGIST LA English DT Article AB Background. Src, EphA2, and platelet-derived growth factor receptors alpha and beta are dysregulated in pancreatic ductal adenocarcinoma (PDAC). Dasatinib is an oral multitarget tyrosine kinase inhibitor that targets BCR-ABL, c-Src, c-KIT, plateletderived growth factor receptor beta, and EphA2. We conducted a phase II, single-arm study of dasatinib as first-line therapy in patients with metastatic PDAC. Methods. Dasatinib (100 mg twice a day, later reduced to 70 mg twice a day because of toxicities) was orally administered continuously on a 28-day cycle. The primary endpoint was overall survival (OS). Response was measured using the Response Evaluation Criteria in Solid Tumors. Circulating tumor cells (CTCs) were also collected. Results. Fifty-one patients enrolled in this study. The median OS was 4.7 months (95% confidence interval [CI]: 2.8-6.9 months). Median progression-free survival was 2.1 months (95% CI: 1.6-3.2 months). In 34 evaluable patients, the best response achieved was stable disease in 10 patients (29.4%). One patient had stable disease while on treatment for 20 months. The most common nonhematologic toxicities were fatigue and nausea. Edema and pleural effusions occurred in 29% and 6% of patients, respectively. The number of CTCs did not correlate with survival. Conclusion. Single-agent dasatinib does not have clinical activity in metastatic PDAC. C1 [Chee, Cheng Ean; Krishnamurthi, Smitha; Nock, Charles J.; Meropol, Neal J.; Gibbons, Joseph; Bokar, Joseph; Teston, Lois; Gudena, Vinay; Reese, Amy; Bergman, Amark; Saltzman, Joel; Dowlati, Afshin] Case Western Reserve Univ, Case Comprehens Canc Ctr, Univ Hosp Seidman Canc Ctr, Cleveland, OH 44106 USA. [Fu, Pingfu] Case Western Reserve Univ, Case Comprehens Canc Ctr, Biostat & Bioinformat Core Facil, Cleveland, OH 44106 USA. [O'Brien, Timothy] Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Wright, John J.] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Brell, Joanna] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Chee, CE (reprint author), Case Western Reserve Univ, Case Comprehens Canc Ctr, Div Hematol Oncol, Univ Hosp Seidman Canc Ctr, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM cheng.chee@uhhospitals.org FU NCI NIH HHS [P30 CA043703, U01 CA062502] NR 0 TC 13 Z9 13 U1 0 U2 0 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD OCT PY 2013 VL 18 IS 10 BP 1091 EP 1092 DI 10.1634/theoncologist.2013-0255 PG 2 WC Oncology SC Oncology GA 243NK UT WOS:000326322900006 PM 24072218 ER PT J AU Chow, MZY Geng, L Kong, CW Keung, W Fung, JCK Boheler, KR Li, RA AF Chow, Maggie Zi Ying Geng, Lin Kong, Chi-Wing Keung, Wendy Fung, Jacky Chun-Kit Boheler, Kenneth R. Li, Ronald A. TI Epigenetic Regulation of the Electrophysiological Phenotype of Human Embryonic Stem Cell-Derived Ventricular Cardiomyocytes: Insights for Driven Maturation and Hypertrophic Growth SO STEM CELLS AND DEVELOPMENT LA English DT Article ID HISTONE DEACETYLASES; CARDIAC-HYPERTROPHY; FACILITATED MATURATION; PLURIPOTENT; CHROMATIN; EXPRESSION; GENES; DIFFERENTIATION; METHYLATION; INHIBITORS AB Epigenetic regulation is implicated in embryonic development and the control of gene expression in a cell-specific manner. However, little is known about the role of histone methylation changes on human cardiac differentiation and maturation. Using human embryonic stem cells (hESCs) and their derived ventricular (V) cardiomyocytes (CMs) as a model, we examined trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) on promoters of genes associated with cardiac electrophysiology, contraction, and Ca2+ handling. To avoid ambiguities due to heterogeneous chamber-specific types, hESC-derived ventricular cardiomyocytes (VCMs) were selected by dual zeocin-GFP expression under the transcriptional control of the MLC2v promoter and confirmed electrophysiologically by its signature action potential phenotype. High levels of H3K4me3 are present on pluripotency genes in hESCs with an absence of H3K27me3. Human ESC-VCMS, relative to hESCs, were characterized by a profound loss of H3K27me3 and an enrichment of H3K4me3 marks on cardiac-specific genes, including MYH6, MYH7, MYL2, cTNT, and ANF. Gene transcripts encoding key voltage-gated ion channels and Ca2+-handling proteins in hESC-VCMs were significantly increased, which could be attributed to a distinct pattern of differential H3K4me3 and H3K27me3 profiles. Treatment of hESC-VCMs with the histone deacetylase inhibitor valproic acid increased H3K4me3 on gene promoters, induced hypertrophic growth (as gauged by cell volume and capacitance), and augmented cardiac gene expression, but it did not affect electrophysiological properties of these cells. Hence, cardiac differentiation of hESCs involves a dynamic shift in histone methylation, which differentially affects VCM gene expression and function. We conclude that the epigenetic state of hESC-VCMs is dynamic and primed to promote growth and developmental maturation, but that proper environmental stimuli with chromatin remodeling will be required to synergistically trigger global CM maturation to a more adult-like phenotype. C1 [Chow, Maggie Zi Ying; Kong, Chi-Wing; Keung, Wendy; Boheler, Kenneth R.; Li, Ronald A.] Univ Hong Kong, Stem Cell & Regenerat Med Consortium, Pok Fu Lam, Hong Kong, Peoples R China. [Chow, Maggie Zi Ying; Geng, Lin; Kong, Chi-Wing; Keung, Wendy; Fung, Jacky Chun-Kit; Li, Ronald A.] Univ Hong Kong, Dept Physiol, Pok Fu Lam, Hong Kong, Peoples R China. [Boheler, Kenneth R.] NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. [Li, Ronald A.] Icahn Sch Med Mt Sinai, Ctr Cardiovasc Res, New York, NY USA. RP Li, RA (reprint author), Univ Hong Kong, Stem Cell & Regenerat Med Consortium, Hong Kong Jockey Club Bldg Interdisciplinary Res,, Pok Fu Lam, Hong Kong, Peoples R China. EM ronaldli@hkucc.hku.hk OI Keung, Wendy/0000-0002-6827-6754 FU Research Grant Council [TBRS T13-706/11, GRF 103544] FX This work was supported by grants from the Research Grant Council (TBRS T13-706/11 and GRF 103544). NR 58 TC 9 Z9 10 U1 1 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 EI 1557-8534 J9 STEM CELLS DEV JI Stem Cells Dev. PD OCT 1 PY 2013 VL 22 IS 19 BP 2678 EP 2690 DI 10.1089/scd.2013.0125 PG 13 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 245EO UT WOS:000326443700010 PM 23656529 ER PT J AU Shen, J Xu, L Fang, H Richard, AM Bray, JD Judson, RS Zhou, GX Colatsky, TJ Aungst, JL Teng, C Harris, SC Ge, WG Dai, SY Su, ZQ Jacobs, AC Harrouk, W Perkins, R Tong, WD Hong, HX AF Shen, Jie Xu, Lei Fang, Hong Richard, Ann M. Bray, Jeffrey D. Judson, Richard S. Zhou, Guangxu Colatsky, Thomas J. Aungst, Jason L. Teng, Christina Harris, Steve C. Ge, Weigong Dai, Susie Y. Su, Zhenqiang Jacobs, Abigail C. Harrouk, Wafa Perkins, Roger Tong, Weida Hong, Huixiao TI EADB: An Estrogenic Activity Database for Assessing Potential Endocrine Activity SO TOXICOLOGICAL SCIENCES LA English DT Article DE endocrine disruptor; estrogen receptor; estrogenic activity; database ID DISRUPTING CHEMICALS; RECEPTOR MODULATORS; BINDING AFFINITIES; SIGNALING PATHWAYS; UPDATE; INFORMATION; MECHANISMS; DISCOVERY; TOXICITY; LIGANDS AB Endocrine-active chemicals can potentially have adverse effects on both humans and wildlife. They can interfere with the bodys endocrine system through direct or indirect interactions with many protein targets. Estrogen receptors (ERs) are one of the major targets, and many endocrine disruptors are estrogenic and affect the normal estrogen signaling pathways. However, ERs can also serve as therapeutic targets for various medical conditions, such as menopausal symptoms, osteoporosis, and ER-positive breast cancer. Because of the decades-long interest in the safety and therapeutic utility of estrogenic chemicals, a large number of chemicals have been assayed for estrogenic activity, but these data exist in various sources and different formats that restrict the ability of regulatory and industry scientists to utilize them fully for assessing risk-benefit. To address this issue, we have developed an Estrogenic Activity Database (EADB; ) and made it freely available to the public. EADB contains 18,114 estrogenic activity data points collected for 8212 chemicals tested in 1284 binding, reporter gene, cell proliferation, and in vivo assays in 11 different species. The chemicals cover a broad chemical structure space and the data span a wide range of activities. A set of tools allow users to access EADB and evaluate potential endocrine activity of chemicals. As a case study, a classification model was developed using EADB for predicting ER binding of chemicals. C1 [Shen, Jie; Zhou, Guangxu; Harris, Steve C.; Ge, Weigong; Su, Zhenqiang; Perkins, Roger; Tong, Weida; Hong, Huixiao] US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Xu, Lei] Changan Univ, Sch Mat Sci & Engn, Xian 710064, Peoples R China. [Fang, Hong] US FDA, Off Sci Coordinat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Richard, Ann M.; Judson, Richard S.] US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Bray, Jeffrey D.] US FDA, Div Reprod & Urol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Colatsky, Thomas J.] US FDA, Div Drug Safety Res, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Aungst, Jason L.] US FDA, Div Food Contact Notificat, Off Food Addit Safety, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Teng, Christina] NIEHS, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Dai, Susie Y.] Texas A&M Univ, Off Texas State Chem & Vet Pathobiol, College Stn, TX 77843 USA. [Jacobs, Abigail C.] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Harrouk, Wafa] US FDA, Div Nonprescript Clin Evaluat, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Hong, HX (reprint author), US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM huixiao.hong@fda.hhs.gov OI Judson, Richard/0000-0002-2348-9633 FU Research Participation Program at the National Center for Toxicological Research FX Research Participation Program at the National Center for Toxicological Research (J.S.) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. NR 39 TC 25 Z9 25 U1 2 U2 24 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2013 VL 135 IS 2 BP 277 EP 291 DI 10.1093/toxsci/kft164 PG 15 WC Toxicology SC Toxicology GA 244JM UT WOS:000326384200004 PM 23897986 ER PT J AU Gwinn, WM Qu, W Shines, CJ Bousquet, RW Taylor, GJ Waalkes, MP Morgan, DL AF Gwinn, William M. Qu, Wei Shines, Cassandra J. Bousquet, Ronald W. Taylor, Genie J. Waalkes, Michael P. Morgan, Daniel L. TI Macrophage Solubilization and Cytotoxicity of Indium-Containing Particles In Vitro SO TOXICOLOGICAL SCIENCES LA English DT Article DE indium; InP; ITO; solubilization; macrophage cytotoxicity ID PULMONARY ALVEOLAR PROTEINOSIS; TIN-OXIDE; INTRATRACHEAL INSTILLATIONS; EPITHELIAL-CELLS; TOXICITY; LUNG; WORKERS; PHOSPHIDE; FIBROSIS; ACIDIFICATION AB Indium-containing particles (ICPs) are used extensively in the microelectronics industry. Pulmonary toxicity is observed after inhalation exposure to ICPs; however, the mechanism(s) of pathogenesis is unclear. ICPs are insoluble at physiological pH and are initially engulfed by alveolar macrophages (and likely airway epithelial cells). We hypothesized that uptake of ICPs by macrophages followed by phagolysosomal acidification results in the solubilization of ICPs into cytotoxic indium ions. To address this, we characterized the in vitro cytotoxicity of indium phosphide (InP) or indium tin oxide (ITO) particles with macrophages (RAW cells) and lung-derived epithelial (LA-4) cells at 24h using metabolic (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) and membrane integrity (lactate dehydrogenase) assays. InP and ITO were readily phagocytosed by RAW and LA-4 cells; however, the particles were much more cytotoxic to RAW cells and cytotoxicity was dose dependent. Treatment of RAW cells with cytochalasin D (CytoD) blocked particle phagocytosis and reduced cytotoxicity. Treatment of RAW cells with bafilomycin A1, a specific inhibitor of phagolysosomal acidification, also reduced cytotoxicity but did not block particle uptake. Based on direct indium measurements, the concentration of ionic indium was increased in culture medium from RAW but not LA-4 cells following 24-h treatment with particles. Ionic indium derived from RAW cells was significantly reduced by treatment with CytoD. These data implicate macrophage uptake and solubilization of InP and ITO via phagolysosomal acidification as requisite for particle-induced cytotoxicity and the release of indium ions. This may apply to other ICPs and strongly supports the notion that ICPs require solubilization in order to be toxic. C1 [Gwinn, William M.; Qu, Wei; Shines, Cassandra J.; Waalkes, Michael P.; Morgan, Daniel L.] NIEHS, NTP Lab, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Bousquet, Ronald W.; Taylor, Genie J.] Alion Sci & Technol Corp, Res Triangle Pk, NC 27709 USA. RP Morgan, DL (reprint author), NIEHS, DNTP, MD IF 00,POB 12233, Res Triangle Pk, NC 27709 USA. EM morgan3@niehs.nih.gov FU National Toxicology Program; National Institute of Environmental Health Sciences; National Institutes of Health FX National Toxicology Program; National Institute of Environmental Health Sciences; National Institutes of Health. NR 30 TC 12 Z9 16 U1 2 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2013 VL 135 IS 2 BP 414 EP 424 DI 10.1093/toxsci/kft154 PG 11 WC Toxicology SC Toxicology GA 244JM UT WOS:000326384200016 PM 23872580 ER PT J AU Nomura, W Aikawa, H Ohashi, N Urano, E Metifiot, M Fujino, M Maddali, K Ozaki, T Nozue, A Narumi, T Hashimoto, C Tanaka, T Pommier, Y Yamamoto, N Komano, JA Murakami, T Tamamura, H AF Nomura, Wataru Aikawa, Haruo Ohashi, Nami Urano, Emiko Metifiot, Mathieu Fujino, Masayuki Maddali, Kasthuraiah Ozaki, Taro Nozue, Ami Narumi, Tetsuo Hashimoto, Chie Tanaka, Tomohiro Pommier, Yves Yamamoto, Naoki Komano, Jun A. Murakami, Tsutomu Tamamura, Hirokazu TI Cell-Permeable Stapled Peptides Based on HIV-1 Integrase Inhibitors Derived from HIV-1 Gene Products SO ACS CHEMICAL BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RING-CLOSING METATHESIS; IN-VITRO; PREINTEGRATION COMPLEXES; REVERSE-TRANSCRIPTASE; STRAND TRANSFER; PROTEIN; RALTEGRAVIR; DETERMINANTS; RESISTANT AB HIV-1 integrase (IN) is an enzyme which is indispensable for the stable infection of host cells because it catalyzes the insertion of viral DNA into the genome and thus is an attractive target for the development of anti-HIV agents. Earlier, we found Vpr-derived peptides with inhibitory activity against HIV-1 IN. These Vpr-derived peptides are originally located in an alpha-helical region of the parent Vpr protein. Addition of an octa-arginyl group to the inhibitory peptides caused significant inhibition against HIV replication associated with an increase in cell permeability but also relatively high cytotoxicity. In the current study, stapled peptides, a new class of stabilized alpha-helical peptidomimetics were adopted to enhance the cell permeability of the above lead peptides. A series of stapled peptides, which have a hydrocarbon link formed by a ruthenium-catalyzed ring-closing metathesis reaction between successive turns of alpha-helix, were designed, synthesized, and evaluated for biological activity. In cell-based assays some of the stapled peptides showed potent anti-HIV activity comparable with that of the original octa-arginine-containing peptide (2) but with lower cytotoxicity. Fluorescent imaging experiments revealed that these stapled peptides are significantly cell permeable, and CD analysis showed they form alpha-helical structures, whereas the unstapled congeners form beta-sheet structures. The application of this stapling strategy to Vpr-derived IN inhibitory peptides led to a remarkable increase in their potency in cells and a significant reduction of their cytotoxicity. C1 [Nomura, Wataru; Aikawa, Haruo; Ohashi, Nami; Ozaki, Taro; Nozue, Ami; Narumi, Tetsuo; Hashimoto, Chie; Tanaka, Tomohiro; Tamamura, Hirokazu] Tokyo Med & Dent Univ, Dept Med Chem, Inst Biomat & Bioengn, Chiyoda Ku, Tokyo 1010062, Japan. [Urano, Emiko; Fujino, Masayuki; Komano, Jun A.; Murakami, Tsutomu] Natl Inst Infect Dis, AIDS Res Ctr, Shinjuku Ku, Tokyo 1628640, Japan. [Metifiot, Mathieu; Maddali, Kasthuraiah; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yamamoto, Naoki] Natl Univ Singapore, Dept Microbiol, Yong Loo Lin Sch Med, Singapore 117597, Singapore. [Komano, Jun A.] Osaka Prefectural Inst Publ Hlth, Dept Infect Dis, Higashinari Ku, Osaka 5370025, Japan. RP Tamamura, H (reprint author), Tokyo Med & Dent Univ, Dept Med Chem, Inst Biomat & Bioengn, Chiyoda Ku, 2-3-10 Kandasurugadai, Tokyo 1010062, Japan. EM tamamura.mr@tmd.ac.jp RI Nomura, Wataru/F-5812-2015; OI Nomura, Wataru/0000-0001-8348-7544 FU JSPS; Ministry of Education, Culture, Sports, Science, and Technology of Japan; Japanese Ministry of Health, Labor, and Welfare FX We thank T. Koide and C. Yamazaki, Department of Chemistry and Biochemistry, Waseda University, for allowing access to a CD spectropolarimeter. N.O., C.H., and T.T. are supported by JSPS research fellowships for young scientists. This work was supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Health and Labour Sciences Research Grants from Japanese Ministry of Health, Labor, and Welfare. NR 30 TC 22 Z9 23 U1 1 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD OCT PY 2013 VL 8 IS 10 BP 2235 EP 2244 DI 10.1021/cb400495h PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 240TU UT WOS:000326121400018 PM 23898787 ER PT J AU Abdelmohsen, K Panda, A Kang, MJ Xu, J Selimyan, R Yoon, JH Martindale, JL De, S Wood, WH Becker, KG Gorospe, M AF Abdelmohsen, Kotb Panda, Amaresh Kang, Min-Ju Xu, Jason Selimyan, Roza Yoon, Je-Hyun Martindale, Jennifer L. De, Supriyo Wood, William H., III Becker, Kevin G. Gorospe, Myriam TI Senescence-associated lncRNAs: senescence-associated long noncoding RNAs SO AGING CELL LA English DT Article DE senescence-associated gene expression patterns; proliferation; post-transcriptional gene regulation; noncoding; transcriptome ID REPLICATIVE SENESCENCE; CELLULAR SENESCENCE; HUMAN-DISEASE; EXPRESSION; CELLS; SEQ; DIFFERENTIATION; FIBROBLASTS; TRANSLATION; TRANSCRIPTS AB Noncoding RNAs include small transcripts, such as microRNAs and piwi-interacting RNAs, and a wide range of long noncoding RNAs (lncRNAs). Although many lncRNAs have been identified, only a small number of lncRNAs have been characterized functionally. Here, we sought to identify lncRNAs differentially expressed during replicative senescence. We compared lncRNAs expressed in proliferating, early-passage, 'young' human diploid WI-38 fibroblasts [population doubling (PDL) 20] with those expressed in senescent, late-passage, 'old' fibroblasts (PDL 52) by RNA sequencing (RNA-Seq). Numerous transcripts in all lncRNA groups (antisense lncRNAs, pseudogene-encoded lncRNAs, previously described lncRNAs and novel lncRNAs) were validated using reverse transcription (RT) and real-time, quantitative (q)PCR. Among the novel senescence-associated lncRNAs (SAL-RNAs) showing lower abundance in senescent cells, SAL-RNA1 (XLOC_023166) was found to delay senescence, because reducing SAL-RNA1 levels enhanced the appearance of phenotypic traits of senescence, including an enlarged morphology, positive beta-galactosidase activity, and heightened p53 levels. Our results reveal that the expression of known and novel lncRNAs changes with senescence and suggests that SAL-RNAs play direct regulatory roles in this important cellular process. C1 [Abdelmohsen, Kotb; Panda, Amaresh; Kang, Min-Ju; Xu, Jason; Selimyan, Roza; Yoon, Je-Hyun; Martindale, Jennifer L.; De, Supriyo; Wood, William H., III; Becker, Kevin G.; Gorospe, Myriam] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Abdelmohsen, K (reprint author), NIA, Genet Lab, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM abdelmohsenk@mail.nih.gov; myriam-gorospe@nih.gov OI PANDA, AMARESH/0000-0003-3189-8995; De, Supriyo/0000-0002-2075-7655; Becker, Kevin/0000-0002-6794-6656 FU NIA-IRP, NIH FX This work was supported in its entirety by the NIA-IRP, NIH. NR 37 TC 47 Z9 53 U1 2 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD OCT PY 2013 VL 12 IS 5 BP 890 EP 900 DI 10.1111/acel.12115 PG 11 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 217RA UT WOS:000324376300017 PM 23758631 ER EF