FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Hanson, ML Hixon, JA Li, W Felber, BK Anver, MR Stewart, CA Shen, W Steidler, L Durum, SK AF Hanson, M. L. Hixon, J. A. Li, W. Felber, B. K. Anver, M. R. Stewart, C. A. Shen, W. Steidler, L. Durum, S. K. TI LACTOCOCCUS LACTIS EXPRESSING IL-27: A POTENTIAL THERAPEUTIC FOR INFLAMMATORY BOWEL DISEASE SO INFLAMMATION RESEARCH LA English DT Meeting Abstract CT 17th International Conference of the Inflammation-Research-Association CY SEP 09-13, 2012 CL Bolton Landing, NY SP Inflammat Res Assoc C1 [Hanson, M. L.; Hixon, J. A.; Li, W.; Felber, B. K.; Anver, M. R.; Stewart, C. A.; Shen, W.; Durum, S. K.] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Steidler, L.] ActoGenix NV, Zwijnaarde, Belgium. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1023-3830 J9 INFLAMM RES JI Inflamm. Res. PD SEP PY 2012 VL 61 SU 1 BP S15 EP S16 PG 2 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 998FT UT WOS:000308223600022 ER PT J AU Khatami, M AF Khatami, Mahin TI UNRESOLVED INFLAMMATION: 'IMMUNE TSUNAMI' AND CANCER CACHEXIA INDUCED BY "TARGETED" THERAPIES SO INFLAMMATION RESEARCH LA English DT Meeting Abstract CT 17th International Conference of the Inflammation-Research-Association CY SEP 09-13, 2012 CL Bolton Landing, NY SP Inflammat Res Assoc C1 [Khatami, Mahin] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1023-3830 J9 INFLAMM RES JI Inflamm. Res. PD SEP PY 2012 VL 61 SU 1 BP S17 EP S18 PG 2 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 998FT UT WOS:000308223600026 ER PT J AU Yan, HH Pang, YL Yang, L AF Yan, Hannah H. Pang, Yanli Yang, Li TI CCL9 MEDIATES TGF-beta REGULATION OF TUMOR CELL SURVIVAL AND LUNG METASTASIS SO INFLAMMATION RESEARCH LA English DT Meeting Abstract CT 17th International Conference of the Inflammation-Research-Association CY SEP 09-13, 2012 CL Bolton Landing, NY SP Inflammat Res Assoc C1 [Yan, Hannah H.; Pang, Yanli; Yang, Li] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 21892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1023-3830 J9 INFLAMM RES JI Inflamm. Res. PD SEP PY 2012 VL 61 SU 1 BP S28 EP S28 PG 1 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 998FT UT WOS:000308223600054 ER PT J AU Tolea, MI Terracciano, A Milaneschi, Y Metter, EJ Ferrucci, L AF Tolea, Magdalena I. Terracciano, Antonio Milaneschi, Yuri Metter, E. Jeffrey Ferrucci, Luigi TI Personality Typology in Relation to Muscle Strength SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Personality; Muscle strength; Physical activity; Cross-sectional studies ID OLDER-ADULTS; PRIMARY-CARE; PHYSICAL-ACTIVITY; PERCEIVED HEALTH; 5-FACTOR MODEL; AGE; TRAITS; MEN; DISABILITY; WOMEN AB Physical inactivity plays a central role in the age-related decline in muscle strength, an important component in the process leading to disability. Personality, a significant determinant of health behaviors including physical activity, could therefore impact muscle strength throughout adulthood and affect the rate of muscle strength decline with aging. Personality typologies combining "high neuroticism" (N a parts per thousand yenaEuro parts per thousand 55), "low extraversion" (E < 45), and "low conscientiousness" (C < 45) have been associated with multiple risky health behaviors but have not been investigated with regards to muscle strength. The purpose of this study is to investigate associations between individual and combined typologies consisting of high N, low E, and low C and muscle strength, and whether physical activity and body mass index act as mediators. This cross-sectional study includes 1,220 participants from the Baltimore Longitudinal Study of Aging. High N was found among 18%, low E among 31%, and low C among 26% of the sample. High levels of N, particularly when combined with either low E or low C, were associated with lower muscle strength compared with having only one or none of these personality types. Facet analyses suggest an important role for the N components of depression and hostility. Physical activity level appears to partly explain some of these associations. Findings provide support for the notion that the typological approach to personality may be useful in identifying specific personality types at risk of low muscle strength and offer the possibility for more targeted prevention and intervention programs. C1 [Tolea, Magdalena I.; Milaneschi, Yuri; Metter, E. Jeffrey; Ferrucci, Luigi] Natl Inst Aging, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21225 USA. [Terracciano, Antonio] Natl Inst Aging, Intramural Res Program, Lab Personal & Cognit, Baltimore, MD USA. RP Tolea, MI (reprint author), Natl Inst Aging, Clin Res Branch, Longitudinal Studies Sect, 3001 S Hanover St,5th Floor, Baltimore, MD 21225 USA. EM toleam@mail.nih.gov RI terracciano, antonio/B-1884-2008 FU Intramural NIH HHS [ZIA AG000197-04, Z99 AG999999, ZIA AG000183-22, ZIA AG000183-23, ZIA AG000197-03]; NIA NIH HHS [Z01 AG000015-50] NR 47 TC 4 Z9 4 U1 2 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 IS 3 BP 382 EP 390 DI 10.1007/s12529-011-9166-5 PG 9 WC Psychology, Clinical SC Psychology GA 992CT UT WOS:000307753800016 PM 21614452 ER PT J AU Teresi, JA Stewart, AL Stahl, SM AF Teresi, Jeanne A. Stewart, Anita L. Stahl, Sidney M. TI Fifteen Years of Progress in Measurement and Methods at the Resource Centers for Minority Aging Research SO JOURNAL OF AGING AND HEALTH LA English DT Article C1 [Teresi, Jeanne A.] Columbia Univ, Stroud Ctr, Hebrew Home, NY USA. [Teresi, Jeanne A.] Columbia Univ, Div Res, Hebrew Home, NY USA. [Stewart, Anita L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Stahl, Sidney M.] NIA, Individual Behav Proc Branch, Div Behav & Social Res, NIH, Bethesda, MD 20892 USA. RP Teresi, JA (reprint author), Columbia Univ, Stroud Ctr, Fac Med, 5901 Palisade Ave, Riverdale, NY USA. EM jat61@columbia.edu FU NIA NIH HHS [P30 AG 15292, P30 AG 31054, P30 AG015294, P30 AG 21677, P30 AG 31043, P30 AG 15272, P30 AG 21684, P30 AG 15272-12S2, P30 AG 15294, P30 AG 15281]; NIMHD NIH HHS [P60 MD00206, P60 MD000206] NR 9 TC 2 Z9 2 U1 2 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0898-2643 J9 J AGING HEALTH JI J. Aging Health PD SEP PY 2012 VL 24 IS 6 BP 985 EP 991 DI 10.1177/0898264312457750 PG 7 WC Gerontology; Health Policy & Services SC Geriatrics & Gerontology; Health Care Sciences & Services GA 990NY UT WOS:000307638900004 PM 22904184 ER PT J AU Bornstein, MH Hendricks, C AF Bornstein, Marc H. Hendricks, Charlene TI Basic language comprehension and production in > 100,000 young children from sixteen developing nations SO JOURNAL OF CHILD LANGUAGE LA English DT Article ID VOCABULARY COMPETENCE; LEXICAL DEVELOPMENT; ACQUISITION; SUPPORT; INPUT; RISK AB Using the Multiple Indicator Cluster Survey, language comprehension and production were compared in a sample of 101,250 children aged 2; 00 to 9; 11 and a focus subsample of 38,845 children aged 2; 00 to 4; 11 from sixteen under-researched developing nations. In the whole sample, comprehension slightly exceeded production; correlations between comprehension and production by country were positive and significant, but varied in size, and the average correlation was positive, significant, and small to medium. Mean comprehension and production varied with child age, reaching an asymptote at 5; 00, and correlations between comprehension and production by age were positive, significant, and similar at each age. In the focus subsample, comprehension exceeded production; correlations between comprehension and production by country were positive and significant, but varied in size, and the average correlation was positive, significant, and medium in size. Children in countries with lower standards of living were less likely to demonstrate basic language comprehension or production. C1 [Bornstein, Marc H.; Hendricks, Charlene] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 40 TC 7 Z9 8 U1 1 U2 9 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0305-0009 J9 J CHILD LANG JI J. Child Lang. PD SEP PY 2012 VL 39 IS 4 BP 899 EP 918 DI 10.1017/S0305000911000407 PG 20 WC Psychology, Developmental; Linguistics; Psychology, Experimental SC Psychology; Linguistics GA 984IT UT WOS:000307184000009 PM 22129486 ER PT J AU Cousins, MM Ou, SS Wawer, MJ Munshaw, S Swan, D Magaret, CA Mullis, CE Serwadda, D Porcella, SF Gray, RH Quinn, TC Donnell, D Eshleman, SH Redd, AD AF Cousins, Matthew M. Ou, San-San Wawer, Maria J. Munshaw, Supriya Swan, David Magaret, Craig A. Mullis, Caroline E. Serwadda, David Porcella, Stephen F. Gray, Ronald H. Quinn, Thomas C. Donnell, Deborah Eshleman, Susan H. Redd, Andrew D. TI Comparison of a High-Resolution Melting Assay to Next-Generation Sequencing for Analysis of HIV Diversity SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID EVOLUTION; INFECTION; POPULATION; UGANDA; RAKAI; ENV; SUPERINFECTION; SENSITIVITY; PROGRESSION; PREVENTION AB Next-generation sequencing (NGS) has recently been used for analysis of HIV diversity, but this method is labor-intensive, costly, and requires complex protocols for data analysis. We compared diversity measures obtained using NGS data to those obtained using a diversity assay based on high-resolution melting (HRM) of DNA duplexes. The HRM diversity assay provides a single numeric score that reflects the level of diversity in the region analyzed. HIV gag and env from individuals in Rakai, Uganda, were analyzed in a previous study using NGS (n = 220 samples from 110 individuals). Three sequence-based diversity measures were calculated from the NGS sequence data (percent diversity, percent complexity, and Shannon entropy). The amplicon pools used for NGS were analyzed with the HRM diversity assay. HRM scores were significantly associated with sequence-based measures of HIV diversity for both gag and env (P < 0.001 for all measures). The level of diversity measured by the HRM diversity assay and NGS increased over time in both regions analyzed (P < 0.001 for all measures except for percent complexity in gag), and similar amounts of diversification were observed with both methods (P < 0.001 for all measures except for percent complexity in gag). Diversity measures obtained using the HRM diversity assay were significantly associated with those from NGS, and similar increases in diversity over time were detected by both methods. The HRM diversity assay is faster and less expensive than NGS, facilitating rapid analysis of large studies of HIV diversity and evolution. C1 [Quinn, Thomas C.; Redd, Andrew D.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. [Cousins, Matthew M.; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Ou, San-San; Swan, David; Magaret, Craig A.; Donnell, Deborah] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Munshaw, Supriya; Mullis, Caroline E.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Serwadda, David] Rakai Hlth Sci Program, Kalisizo, Uganda. [Porcella, Stephen F.] NIAID, Genom Unit, Res Technol Sect, Rocky Mt Labs,Div Intramural Res,NIH, Hamilton, MT USA. RP Redd, AD (reprint author), NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Baltimore, MD USA. EM aredd2@jhmi.edu OI Donnell, Deborah/0000-0002-0587-7480 FU Bill and Melinda Gates Foundation [22006.03]; National Institutes of Health (NIH), Division of Allergy and Infectious Diseases [U1AI51171, 1UO1AI075115-O1A1]; Department of the Army, U.S. Army Medical Research and Materiel Command [DAMD17-98-2-8007]; Henry M. Jackson Foundation [5D43TW00010]; HIV Prevention Trials Network (HPTN); NIAID, the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health; Office of AIDS Research of the NIH and DHHS [U01AI068613, UM1AI068613]; NIAID [1R01-AI095068, UM1-AI068617]; Division of Intramural Research, NIAID, NIH; Office of AIDS Research, NIH; Idaho Technology FX We thank the participants and the study team of the Rakai Community Cohort Study, which was supported by (i) the Bill and Melinda Gates Foundation (22006.03), (ii) the National Institutes of Health (NIH), Division of Allergy and Infectious Diseases (U1AI51171 and 1UO1AI075115-O1A1), (iii) the Department of the Army, U.S. Army Medical Research and Materiel Command Cooperative Agreement (DAMD17-98-2-8007), and (v) the Henry M. Jackson Foundation (5D43TW00010). This study was supported by (i) the HIV Prevention Trials Network (HPTN) sponsored by the NIAID, the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health, and the Office of AIDS Research of the NIH and DHHS (U01AI068613 and UM1AI068613 to S. H. E.), (ii) NIAID (1R01-AI095068 to S. H. E.), and (iii) NIAID (UM1-AI068617 to D. D.). This study was supported in part by funding from the Division of Intramural Research, NIAID, NIH, and the Office of AIDS Research, NIH.; M.M.C. has given presentations at meetings sponsored by Idaho Technology (marketer of the LightScanner platform and reagents designed specifically for HRM analysis). NR 33 TC 25 Z9 25 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD SEP PY 2012 VL 50 IS 9 BP 3054 EP 3059 DI 10.1128/JCM.01460-12 PG 6 WC Microbiology SC Microbiology GA 994OZ UT WOS:000307941900031 PM 22785188 ER PT J AU Winstona, J Wolf, R AF Winstona, Jason Wolf, Ronald TI Psoriasin (S100A7) promotes migration of a squamous carcinoma cell line SO JOURNAL OF DERMATOLOGICAL SCIENCE LA English DT Letter ID GLYCATION END-PRODUCTS; RAGE; RECEPTOR; INFLAMMATION C1 [Winstona, Jason; Wolf, Ronald] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Wolf, Ronald] Univ Munich, Dept Dermatol, D-8000 Munich, Germany. RP Wolf, R (reprint author), Dept Dermatol & Allergol, Frauenlobstr 9-11, D-80337 Munich, Germany. EM ronald.wolf@med.uni-muenchen.de FU Intramural NIH HHS NR 12 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0923-1811 J9 J DERMATOL SCI JI J. Dermatol. Sci. PD SEP PY 2012 VL 67 IS 3 BP 205 EP 207 DI 10.1016/j.jdermsci.2012.06.009 PG 3 WC Dermatology SC Dermatology GA 990FK UT WOS:000307616200011 PM 22795619 ER PT J AU Odgerel, Z Lee, HS Erdenebileg, N Gandbold, S Luvsanjamba, M Sambuughin, N Sonomtseren, S Sharavdorj, P Jodov, E Altaisaikhan, K Goldfarb, LG AF Odgerel, Zagaa Lee, Hee S. Erdenebileg, Narnygerel Gandbold, Suren Luvsanjamba, Munkhjargal Sambuughin, Nyamkhishig Sonomtseren, Sainbileg Sharavdorj, Purevdulam Jodov, Erdenezul Altaisaikhan, Khasag Goldfarb, Lev G. TI Genetic variants in potassium channels are associated with type 2 diabetes in a Mongolian population SO JOURNAL OF DIABETES LA English DT Article DE ABCC8; genetic association; KCNQ1; Mongolia; potassium channels; type 2 diabetes ID SUBUNITS KIR6.2 KCNJ11; SULFONYLUREA RECEPTOR; SUSCEPTIBILITY LOCI; MELLITUS; KCNQ1; MUTATIONS; DISEASES; ABCC8 AB Background: Recent genome-wide association studies (GWAS) have identified more than 40 common sequence variants associated with type 2 diabetes (T2D). However, the results are not always the same in populations with differing genetic backgrounds. In the present study, we evaluated a hypothesis that a North Asian population living in a geographic area with unusually harsh environmental conditions would develop unique genetic risks. Methods: A population-based association study was performed with 21 single-nucleotide polymorphisms (SNPs) in nine genes selected according to the results of GWAS conducted in other populations. The study participants included 393 full-heritage Mongolian individuals (177 diagnosed with T2D and 216 matched controls). Genotyping was performed by TaqMan methodology. Results: The strongest association was detected with SNPs located within the potassium channel-coding genes KCNQ1 (highest odds ratio [OR] = 1.92; P = 3.4 x 10-5) and ABCC8 (OR = 1.79; P = 5 x 10-4). Genetic variants identified as strongly influencing the risk of T2D in other populations (e.g. KCNJ11 or TCF7L2) did not show significant association in Mongolia. Conclusions: The strongest T2D risk-associated SNPs in Mongolians are located within two of three tested potassium channel-coding genes. Accumulated variations in these genes may be related to the exposure to harsh environmental conditions. C1 [Odgerel, Zagaa; Lee, Hee S.; Goldfarb, Lev G.] NINDS, NIH, Bethesda, MD 20892 USA. [Erdenebileg, Narnygerel] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Gandbold, Suren] Natl Inst Forens Sci, Ulaanbaatar, Mongol Peo Rep. [Luvsanjamba, Munkhjargal; Sharavdorj, Purevdulam] Minist Hlth, Ulaanbaatar, Mongol Peo Rep. [Sambuughin, Nyamkhishig] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Sonomtseren, Sainbileg; Jodov, Erdenezul; Altaisaikhan, Khasag] Hlth Sci Univ Mongolia, Ulaanbaatar, Mongol Peo Rep. RP Goldfarb, LG (reprint author), NINDS, NIH, Room 4S06,5625 Fishers Lane, Bethesda, MD 20892 USA. EM goldfarbl@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke, National Institutes of Health FX The authors thank the patients, their family members, and healthy volunteers for participating in the study. This work was supported, in part, by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 25 TC 8 Z9 9 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1753-0393 J9 J DIABETES JI J. Diabetes PD SEP PY 2012 VL 4 IS 3 BP 238 EP 242 DI 10.1111/j.1753-0407.2011.00177.x PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 994LO UT WOS:000307932500010 PM 22151254 ER PT J AU Zapka, J Klabunde, CN Taplin, S Yuan, GG Ransohoff, D Kobrin, S AF Zapka, Jane Klabunde, Carrie N. Taplin, Stephen Yuan, Gigi Ransohoff, David Kobrin, Sarah TI Screening Colonoscopy in the US: Attitudes and Practices of Primary Care Physicians SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE colorectal cancer screening; primary care physicians; colonoscopy screening practices ID SERVICES TASK-FORCE; COLORECTAL-CANCER; NATIONAL-SURVEY; RECOMMENDATIONS; POPULATION; PREVENTION; BELIEFS; TRENDS AB Rising colorectal cancer (CRC) screening rates in the last decade are attributable almost entirely to increased colonoscopy use. Little is known about factors driving the increase, but primary care physicians (PCPs) play a central role in CRC screening delivery. Explore PCP attitudes toward screening colonoscopy and their associations with CRC screening practice patterns. Cross-sectional analysis of data from a nationally representative survey conducted in 2006-2007. 1,266 family physicians, general practitioners, general internists, and obstetrician-gynecologists. Physician-reported changes in the volume of screening tests ordered, performed or supervised in the past 3 years, attitudes toward colonoscopy, the influence of evidence and perceived norms on their recommendations, challenges to screening, and practice characteristics. The cooperation rate (excludes physicians without valid contact information) was 75%; 28% reported their volume of FOBT ordering had increased substantially or somewhat, and the majority (53%) reported their sigmoidoscopy volume decreased either substantially or somewhat. A majority (73%) reported that colonoscopy volume increased somewhat or substantially. The majority (86%) strongly agreed that colonoscopy was the best of the available CRC screening tests; 69% thought it was readily available for their patients; 59% strongly or somewhat agreed that they might be sued if they did not offer colonoscopy to their patients. All three attitudes were significantly related to substantial increases in colonoscopy ordering. PCPs report greatly increased colonoscopy recommendation relative to other screening tests, and highly favorable attitudes about colonoscopy. Greater emphasis is needed on informed decision-making with patients about preferences for test options. C1 [Zapka, Jane] Med Univ S Carolina, Dept Med, Dept Biostat & Epidemiol, Charleston, SC 29425 USA. [Klabunde, Carrie N.; Taplin, Stephen; Kobrin, Sarah] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Yuan, Gigi] Informat Management Serv Inc, Silver Spring, MD USA. [Ransohoff, David] Univ N Carolina, Chapel Hill, NC USA. RP Zapka, J (reprint author), Med Univ S Carolina, Dept Med, Dept Biostat & Epidemiol, 135 Cannon St, Charleston, SC 29425 USA. EM zapka@musc.edu FU National Cancer Institute [N02-PC-51308]; Agency for Healthcare Research and Quality [Y3-PC-5019-01, Y3-PC-5019-02]; Centers for Disease Control and Prevention [Y3-PC-6017-01] FX Funding support for this study was provided by the National Cancer Institute (contract no. N02-PC-51308); the Agency for Healthcare Research and Quality (inter-agency agreement nos. Y3-PC-5019-01 and Y3-PC-5019-02); and the Centers for Disease Control and Prevention (inter-agency agreement no. Y3-PC-6017-01). The findings and conclusions in this report are those of the authors and do not necessarily represent the views or official position of the National Cancer Institute, the Agency for Healthcare Research and Quality, or the Centers for Disease Control and Prevention. NR 40 TC 20 Z9 20 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2012 VL 27 IS 9 BP 1150 EP 1158 DI 10.1007/s11606-012-2051-3 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 988SP UT WOS:000307511300014 PM 22539065 ER PT J AU Hernandez-Andrade, E Romero, R Ahn, H Hussein, Y Yeo, L Korzeniewski, SJ Chaiworapongsa, T Hassan, SS AF Hernandez-Andrade, Edgar Romero, Roberto Ahn, Hyunyoung Hussein, Youssef Yeo, Lami Korzeniewski, Steven J. Chaiworapongsa, Tinnakorn Hassan, Sonia S. TI Transabdominal evaluation of uterine cervical length during pregnancy fails to identify a substantial number of women with a short cervix SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE ultrasound; agreement; preterm labor; screening; progesterone; progestins ID SPONTANEOUS PRETERM DELIVERY; SONOGRAPHIC SHORT CERVIX; TRANSVAGINAL ULTRASONOGRAPHIC MEASUREMENT; PREVIOUS OBSTETRIC HISTORY; PLACEBO-CONTROLLED TRIAL; BORN EXTREMELY PRETERM; AMNIOTIC-FLUID SLUDGE; CLINICAL-SIGNIFICANCE; VAGINAL PROGESTERONE; WEEKS GESTATION AB Objective: To assess the diagnostic performance of transabdominal sonographic measurement of cervical length in identifying patients with a short cervix. Methods: Cervical length was measured in 220 pregnant women using transabdominal and transvaginal ultrasound (US). Reproducibility and agreement between and within both methods were assessed. The diagnostic accuracy of transabdominal US for identifying cases with a cervical length <25 mm was evaluated. Results: Twenty-one out of 220 cases (9.5%) had a cervical length <25 mm by transvaginal US. Only 43% (n = 9) of patients with a short cervix were correctly identified by transabdominal US. In patients with a cervical length of <25 mm by transvaginal US, transabdominal measurement of the cervix overestimated this parameter by an average of 8 mm (95% LOAs, -26.4 to 10.5 mm). Among women without a short cervix, transabdominal US underestimated cervical length on average (LOA) by 1.1 mm (95% LOAs, -11.0 to 13.2 mm). Transvaginal US was also more reproducible (intra-class correlation coefficient: (ICC) (0.96; 95% CI, 0.94 to 0.97) based on comparisons between 2D images and immediately acquired 3D volume datasets relative to transabdominal US (ICC: 0.71; 95% CI, 0.57 to 0.84). Transvaginal US detected 13 cases with funneling and six cases with sludge whereas only three cases of funneling and one of sludge were detected by transabdominal US. Conclusion: Transabdominal measurement overestimated cervical LOA by 8 mm among women with a short cervix and resulted in the underdiagnosis of 57% of cases. C1 [Hernandez-Andrade, Edgar; Romero, Roberto; Ahn, Hyunyoung; Hussein, Youssef; Yeo, Lami; Korzeniewski, Steven J.; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Hernandez-Andrade, Edgar; Yeo, Lami; Korzeniewski, Steven J.; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM ehernand@med.wayne.edu; prbchiefstaff@med.wayne.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported, in part, by Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 122 TC 29 Z9 32 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD SEP PY 2012 VL 25 IS 9 BP 1682 EP 1689 DI 10.3109/14767058.2012.657278 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 995HU UT WOS:000307999600031 PM 22273078 ER PT J AU Lee, SM Romero, R Park, JW Kim, SM Park, CW Korzeniewski, SJ Chaiworapongsa, T Yoon, BH AF Lee, Seung Mi Romero, Roberto Park, Jeong Woo Kim, Sun Min Park, Chan-Wook Korzeniewski, Steven J. Chaiworapongsa, Tinnakorn Yoon, Bo Hyun TI The clinical significance of a positive Amnisure test in women with preterm labor and intact membranes SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Adverse pregnancy outcome; infection; intact membranes; intra-amniotic inflammation; prematurity; preterm birth ID FLUID MATRIX METALLOPROTEINASE-8; FETAL INFLAMMATORY RESPONSE; RANDOMIZED CONTROLLED-TRIAL; FACTOR BINDING PROTEIN-1; C-REACTIVE PROTEIN; MMP-8 BEDSIDE TEST; PREMATURE RUPTURE; AMNIOTIC-FLUID; INTRAAMNIOTIC INFECTION; ANTENATAL CORTICOSTEROIDS AB Objective: This study was conducted to examine the frequency and clinical significance of a positive Amnisure test in patients with preterm labor and intact membranes by sterile speculum exam. Study design: A retrospective cohort study was performed including 90 patients with preterm labor and intact membranes who underwent Amnisure tests prior to amniocentesis (72 h); most patients (n = 64) also underwent fetal fibronectin (fFN) tests. Amniotic fluid (AF) was cultured for aerobic/anaerobic bacteria and genital mycoplasmas and assayed for matrix metalloproteinase-8. Results: (1) the prevalence of a positive Amnisure test was 19% (17/90); (2) patients with a positive Amnisure test had significantly higher rates of adverse pregnancy and neonatal outcomes (e.g., impending preterm delivery, intra-amniotic infection/inflammation, and neonatal morbidity) than those with a negative Amnisure test; (3) a positive test was associated with significantly increased risk of intra-amniotic infection and/or inflammation, delivery within 7, 14, or 28 days and spontaneous preterm birth (< 35 weeks) among patients with a negative fFN test. Conclusions: A positive Amnisure test in patients with preterm labor and intact membranes is a risk factor for adverse pregnancy outcome, particularly in patients with a negative fFN test. A positive Amnisure test in patients without symptoms or signs of ROM should not be taken as an indicator that membranes have ruptured. C1 [Lee, Seung Mi; Park, Jeong Woo; Kim, Sun Min; Park, Chan-Wook; Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul 110744, South Korea. [Lee, Seung Mi] Seoul Natl Univ, Seoul Metropolitan Govt, Boramae Med Ctr, Dept Obstet & Gynecol, Seoul 110744, South Korea. [Romero, Roberto; Korzeniewski, Steven J.; Chaiworapongsa, Tinnakorn] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto; Korzeniewski, Steven J.; Chaiworapongsa, Tinnakorn] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Korzeniewski, Steven J.; Chaiworapongsa, Tinnakorn] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Yoon, BH (reprint author), Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul 110744, South Korea. EM yoonbh@snu.ac.kr RI Yoon, Bo Hyun/H-6344-2011; Park, Chan-Wook/J-5498-2012; OI Park, Jeong Woo/0000-0001-6499-0814 FU National Research Foundation of Korea (NRF); Korea government (MEST) [2011-0000195]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/DHHS FX This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0000195), and, in part, by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/DHHS. NR 147 TC 13 Z9 16 U1 0 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD SEP PY 2012 VL 25 IS 9 BP 1690 EP 1698 DI 10.3109/14767058.2012.657279 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 995HU UT WOS:000307999600032 PM 22280400 ER PT J AU Shen, JX Yakel, JL AF Shen, Jian-xin Yakel, Jerrel L. TI Functional alpha 7 Nicotinic ACh Receptors on Astrocytes in Rat Hippocampal CA1 Slices SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Nicotinic receptor; Calcium signaling; Patch-clamp ID LONG-TERM POTENTIATION; ACETYLCHOLINE-RECEPTOR; ALZHEIMERS-DISEASE; SYNAPTIC PLASTICITY; CHOLINERGIC MODULATION; COGNITIVE FUNCTION; AMYLOID PLAQUES; GLIAL-CELLS; MOUSE MODEL; CALCIUM AB Although much is known about the functional expression of the neuronal nicotinic acetylcholine receptors (nAChRs) in various neuronal populations in the brain and elsewhere, much less is known about their expression and functional relevance in glial cells. The expression of functional nAChRs has been reported for cultured astrocytes; however, previous work has failed to detect nAChR-mediated responses in astrocytes in acute slices. In the current study, functional alpha 7 nAChRs on astrocytes in the CA1 region of the rat hippocampus were studied in situ using whole-cell patch-clamp recording and two-photon calcium imaging techniques in acute slices. We found that astrocytes and the chondroitin sulfate proteoglycan NG2-expressing (i.e., NG2) cells did express functional alpha 7 nAChRs. Although the amplitudes of the responses were small, they could be enhanced by the alpha 7-selective positive allosteric modulator PNU-120596. Under these conditions, we found that in comparing the properties of these responses between astrocytes, NG2, and interneurons, there were differences in the kinetics and increases in intracellular calcium levels. This is the first demonstration of functional alpha 7 nAChR-mediated current responses in astrocytes in acute hippocampal slices, data which may shed light on the role of alpha 7 nAChRs in neuroprotection. C1 [Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM jxshen@stu.edu.cn; yakel@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences; National Natural Science Foundation of China [31171089] FX We would like to thank C. Erxleben for the advice in preparing the manuscript. Research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Further support was provided to Jian-xin Shen by the National Natural Science Foundation of China (No. 31171089). NR 50 TC 37 Z9 38 U1 1 U2 11 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD SEP PY 2012 VL 48 IS 1 BP 14 EP 21 DI 10.1007/s12031-012-9719-3 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 986HZ UT WOS:000307334000002 PM 22351110 ER PT J AU Purohit, V Rapaka, RS Rutter, J Shurtleff, D AF Purohit, Vishnudutt Rapaka, Rao S. Rutter, Joni Shurtleff, David TI Do Opioids Activate Latent HIV-1 by Down-Regulating Anti-HIV microRNAs? SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Review DE Anti-HIV-1 microRNAs; Morphine; CD4+T cells; Monocytes/macrophages; HIV latency ID BLOOD MONONUCLEAR PHAGOCYTES; INTERFERON-ALPHA EXPRESSION; ANTIRETROVIRAL THERAPY; MEDIATED-ENHANCEMENT; CELLULAR MICRORNAS; MORPHINE TREATMENT; VIRUS-REPLICATION; GENE-EXPRESSION; MESSENGER-RNA; INFECTION AB Researchers have recently demonstrated the presence of anti-HIV-1 microRNAs (miR-28, miR-125b, miR-150, miR-223, and miR-382) in monocytes, macrophages, and CD4+ T cells, which are the primary targets of HIV infection. These miRNAs appear to regulate the level of infectivity of HIV-1 in the target cells, and thus have an impact on HIV-1 latency. The levels of these miRNAs are significantly higher in resting CD4+ T cells than those in active CD4+ T cells, whereas HIV-1 infectivity is greater in active than in resting CD4+ T cells. Similarly, the levels of these miRNAs are significantly higher in monocytes than in macrophages, whereas HIV-1 infectivity is greater in macrophages than in monocytes. Down-regulation or inhibition of the activity of these miRNAs can promote replication of latent HIV-1 in resting CD4+ T cells and in monocytes. Recently, morphine was shown to down regulate the expression of anti-HIV miRNAs (miRNA-28, 125b, 150, and 382) in cultured human monocytes and this effect of morphine was mediated via activation of mu opioid receptors (MOR). In addition, levels of these anti-HIV miRNAs were significantly lower in the peripheral blood mononuclear cells (PBMCs) isolated from heroin-dependent subjects than those from control subjects. These findings raise an important question: Does morphine have potential to activate latent HIV-1 in resting CD4+ T cells and macrophages, including microglia of human subjects maintained on highly active antiretroviral therapy (HAART)? Further research is required to answer this question. C1 [Purohit, Vishnudutt; Rapaka, Rao S.; Rutter, Joni; Shurtleff, David] NIDA, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. RP Purohit, V (reprint author), NIDA, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, 6001 Execut Blvd Room 4275,MSC 9555, Bethesda, MD 20892 USA. EM vpurohit@nida.nih.gov OI Rutter, Joni/0000-0002-6502-2361 NR 34 TC 8 Z9 9 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD SEP PY 2012 VL 7 IS 3 BP 519 EP 523 DI 10.1007/s11481-012-9356-1 PG 5 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 989JL UT WOS:000307556000002 PM 22527633 ER PT J AU Ramadan, E Basselin, M Chang, L Chen, M Ma, KZ Rapoport, SI AF Ramadan, Epolia Basselin, Mireille Chang, Lisa Chen, Mei Ma, Kaizong Rapoport, Stanley I. TI Chronic Lithium Feeding Reduces Upregulated Brain Arachidonic Acid Metabolism in HIV-1 Transgenic Rat SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Article DE HIV-1; Lithium; Arachidonic acid; Brain imaging; Phospholipase A(2); Metabolism ID CENTRAL-NERVOUS-SYSTEM; GLYCOGEN-SYNTHASE KINASE-3; CYCLIN-DEPENDENT KINASE-5; DOCOSAHEXAENOIC ACID; UNANESTHETIZED RATS; MOOD STABILIZERS; NEUROCOGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; PROTEIN EXPRESSION; LIPID-METABOLISM AB HIV-1 transgenic (Tg) rats, a model for human HIV-1 associated neurocognitive disorder (HAND), show upregulated markers of brain arachidonic acid (AA) metabolism with neuroinflammation after 7 months of age. Since lithium decreases AA metabolism in a rat lipopolysaccharide model of neuroinflammation, and may be useful in HAND, we hypothesized that lithium would dampen upregulated brain AA metabolism in HIV-1 Tg rats. Regional brain AA incorporation coefficients k* and rates J (in) , markers of AA signaling and metabolism, were measured in 81 brain regions using quantitative autoradiography, after intravenous [1-(14) C]AA infusion in unanesthetized 10-month-old HIV-1 Tg and age-matched wildtype rats that had been fed a control or LiCl diet for 6 weeks. k* and J (in) for AA were significantly higher in HIV-1 Tg than wildtype rats fed the control diet. Lithium feeding reduced plasma unesterified AA concentration in both groups and J (in) in wildtype rats, and blocked increments in k* (19 of 54 regions) and J (in) (77 of 81 regions) in HIV-1 Tg rats. These in vivo neuroimaging data indicate that lithium treatment dampened upregulated brain AA metabolism in HIV-1 Tg rats. Lithium may improve cognitive dysfunction and be neuroprotective in HIV-1 patients with HAND through a comparable effect. C1 [Ramadan, Epolia; Basselin, Mireille; Chang, Lisa; Chen, Mei; Ma, Kaizong; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Basselin, M (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 9,Rm 1S126 MSC 0947, Bethesda, MD 20892 USA. EM mirvasln@mail.nih.gov FU National Institute on Aging, NIH FX The research was supported entirely by the Intramural Research Program of the National Institute on Aging, NIH. No author has a financial or other conflict of interest related to this work. NR 91 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD SEP PY 2012 VL 7 IS 3 BP 701 EP 713 DI 10.1007/s11481-012-9381-0 PG 13 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 989JL UT WOS:000307556000021 PM 22760927 ER PT J AU Zadeh, S Gamba, N Hudson, C Wiener, L AF Zadeh, Sima Gamba, Nicole Hudson, Caroline Wiener, Lori TI Taking Care of Care Providers: A Wellness Program for Pediatric Nurses SO JOURNAL OF PEDIATRIC ONCOLOGY NURSING LA English DT Article DE staff wellness; oncology nursing; compassion fatigue; education; burnout ID COMPASSION FATIGUE; BURNOUT; STAFF AB The cumulative effect of professional stress and compassion fatigue within the health care profession has been receiving increasing attention. The impact can be especially worrisome for nurses who work with chronic illness populations, such as oncology. While interventions targeted at reducing nurses stress and promoting wellness are cited as necessary, they are often lacking in busy medical environments. In this article, the authors describe a newly developed 10-session wellness program that was offered on 2 occasions to both inpatient and outpatient nursing staff. The nursing staff chose the content areas, and each session used a combined approach of hands on and didactic learning. A description of the activity offered during each session along with the core competency and objectives measured are provided. Overall, staff found the wellness series very helpful to themselves and to their ability to positively change their job performance. C1 [Zadeh, Sima] NCI, NIH, Pediat Clin, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Gamba, Nicole] NIH, Ctr Clin, Pediat Inpatient Unit, Bethesda, MD 20892 USA. [Gamba, Nicole] NIH, Ctr Clin, Day Hosp, Bethesda, MD 20892 USA. [Hudson, Caroline] NIH, Ctr Clin, Pediat Unit, Bethesda, MD 20892 USA. RP Zadeh, S (reprint author), NCI, NIH, Pediat Clin, Pediat Oncol Branch, 10 Ctr Dr,1-5460, Bethesda, MD 20892 USA. EM zadehsl@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 16 TC 7 Z9 9 U1 6 U2 26 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1043-4542 J9 J PEDIATR ONCOL NURS JI J. Pediatr. Oncol. Nurs. PD SEP-OCT PY 2012 VL 29 IS 5 BP 294 EP 299 DI 10.1177/1043454212451793 PG 6 WC Oncology; Nursing SC Oncology; Nursing GA 990OD UT WOS:000307639400007 PM 22907685 ER PT J AU Rotinen, M Villar, J Encio, I AF Rotinen, Mirja Villar, Joaquin Encio, Ignacio TI Regulation of 17 beta-hydroxysteroid dehydrogenases in cancer: regulating steroid receptor at pre-receptor stage SO JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY LA English DT Review DE Endocrine-related cancer; Androgens; Estrogens; Steroid receptor; HSD17Bs; Inhibitor ID NUCLEAR HORMONE-RECEPTORS; SURFACE EPITHELIAL-CELLS; HUMAN PROSTATE-CANCER; BREAST-CANCER; ENDOMETRIAL CANCER; ESTROGEN-RECEPTOR; IN-SITU; ANDROGEN RECEPTOR; 3-ALPHA-HYDROXYSTEROID DEHYDROGENASE; METABOLIZING ENZYMES AB Increased intracelullar hormone concentration levels have been shown to be the cause of several endocrine-related cancers including breast, prostate, endometrial, ovarian, cervix, testicular, thyroid, and osteosarcoma. Deregulated expression of steroidogenic enzymes in these tumors seems to be the source of a positive balance in active steroids that bind to the corresponding nuclear receptor, thus ultimately stimulating cell proliferation. Among these enzymes, 17 beta-hydroxysteroid dehydrogenases catalyze the interconversion between 17-ketosteroids and 17-hydroxysteroids on the last steps of sex hormones biosynthesis and metabolism. To date, 14 isoforms have been identified in vertebrates although only 13 are present in humans. Development and clinical evaluation of specific inhibitors to block their activity is currently under progress especially against the best characterized members 1 to 5. Selectivity and potency of these drugs constitute the main challenge in this new approach to cancer and steroid-dependent diseases treatment at the "pre-receptor level". Here we review the current state of knowledge regarding the deregulation of the expression of some of these enzymes in endocrine-related tumors. C1 [Rotinen, Mirja; Villar, Joaquin; Encio, Ignacio] Univ Publ Navarra, Dept Hlth Sci, Pamplona 31008, Spain. [Villar, Joaquin] NICHD, Sect Mol Endocrinol, PDEGEN, NIH, Bethesda, MD 20892 USA. RP Encio, I (reprint author), Univ Publ Navarra, Dept Hlth Sci, Avda Baranain, Pamplona 31008, Spain. EM ignacio.encio@unavarra.es NR 129 TC 4 Z9 4 U1 1 U2 18 PU SERVICIO PUBLICACIONES UNIVERSIDAD NAVARRA PI PAMPLONA PA CAMPUS UNIV, CARRETERA DEL SADAR S-N, APARTADO 177, 31080 PAMPLONA, SPAIN SN 1138-7548 EI 1877-8755 J9 J PHYSIOL BIOCHEM JI J. Physiol. Biochem. PD SEP PY 2012 VL 68 IS 3 BP 461 EP 473 DI 10.1007/s13105-012-0155-1 PG 13 WC Biochemistry & Molecular Biology; Physiology SC Biochemistry & Molecular Biology; Physiology GA 988TL UT WOS:000307513500016 PM 22374586 ER PT J AU Orlov, NV Eckley, DM Shamir, L Goldberg, IG AF Orlov, Nikita V. Eckley, D. Mark Shamir, Lior Goldberg, Ilya G. TI Improving class separability using extended pixel planes: a comparative study SO MACHINE VISION AND APPLICATIONS LA English DT Article DE Multi-scale representations; Transforms; Spectral features ID IMAGE-ANALYSIS; SUBCELLULAR STRUCTURES; PATTERN-RECOGNITION; MICROSCOPIC IMAGES; GLOBAL FEATURES; CLASSIFICATION; SCALE AB In this work we explored class separability in feature spaces built on extended representations of pixel planes (EPP) produced using scale pyramid, subband pyramid, and image transforms. The image transforms included Chebyshev, Fourier, wavelets, gradient, and Laplacian; we also utilized transform combinations, including Fourier, Chebyshev, and wavelets of the gradient transform, as well as Fourier of the Laplacian transform. We demonstrate that all three types of EPP promote class separation. We also explored the effect of EPP on suboptimal feature libraries, using only textural features in one case and only Haralick features in another. The effect of EPP was especially clear for these suboptimal libraries, where the transform-based representations were found to increase separability to a greater extent than scale or subband pyramids. EPP can be particularly useful in new applications where optimal features have not yet been developed. C1 [Orlov, Nikita V.; Eckley, D. Mark; Shamir, Lior; Goldberg, Ilya G.] NIA, NIH, Baltimore, MD 21224 USA. [Shamir, Lior] Lawrence Technol Univ, Dept Math & Comp Sci, Southfield, MI 48075 USA. RP Orlov, NV (reprint author), NIA, NIH, 251 Bayview Blvd,Bayview Res Ctr Bld,Suite 100, Baltimore, MD 21224 USA. EM norlov@nih.gov; dme@nih.gov; Ishamir@ltu.edu; igg@nih.gov RI Eckley, Mark/M-3526-2014 OI Eckley, Mark/0000-0003-2296-5164 FU NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 42 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0932-8092 J9 MACH VISION APPL JI Mach. Vis. Appl. PD SEP PY 2012 VL 23 IS 5 BP 1047 EP 1058 DI 10.1007/s00138-011-0349-5 PG 12 WC Computer Science, Artificial Intelligence; Computer Science, Cybernetics; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 989DB UT WOS:000307539300015 PM 23074356 ER PT J AU Sandler, NG Douek, DC AF Sandler, Netanya G. Douek, Daniel C. TI Microbial translocation in HIV infection: causes, consequences and treatment opportunities SO NATURE REVIEWS MICROBIOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; INFLAMMATORY-BOWEL-DISEASE; T-CELL-ACTIVATION; INTESTINAL EPITHELIAL-CELLS; TOLL-LIKE RECEPTORS; NONCIRRHOTIC PORTAL-HYPERTENSION; MUCOSAL IMMUNE RECONSTITUTION; TISSUE FACTOR EXPRESSION; TUMOR-NECROSIS-FACTOR AB Systemic immune activation is increased in HIV-infected individuals, even in the setting of virus suppression with antiretroviral therapy. Although numerous factors may contribute, microbial products have recently emerged as potential drivers of this immune activation. In this Review, we describe the intestinal damage that occurs in HIV infection, the evidence for translocation of microbial products into the systemic circulation and the pathways by which these products activate the immune system. We also discuss novel therapies that disrupt the translocation of microbial products and the downstream effects of microbial translocation. C1 [Sandler, Netanya G.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Douek, DC (reprint author), NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ddouek@mail.nih.gov OI Utay, Netanya/0000-0002-6407-8670 FU NIAID NIH HHS [AI-76174] NR 167 TC 151 Z9 151 U1 0 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD SEP PY 2012 VL 10 IS 9 BP 655 EP 666 DI 10.1038/nrmicro2848 PG 12 WC Microbiology SC Microbiology GA 993PE UT WOS:000307871000016 PM 22886237 ER PT J AU Banerjee, A Tognoli, E Kelso, JAS Jirsa, VK AF Banerjee, Arpan Tognoli, Emmanuelle Kelso, J. A. Scott Jirsa, Viktor K. TI Spatiotemporal re-organization of large-scale neural assemblies underlies bimanual coordination SO NEUROIMAGE LA English DT Article DE Unimanual; Bimanual; Coordination; Recruitment; Temporal modulation; EEG; MEG; Mode level cognitive subtraction; Event related potentials ID SUPPLEMENTARY MOTOR AREA; TRANSCRANIAL MAGNETIC STIMULATION; IN-PHASE MOVEMENTS; HUMAN BRAIN; FINGER MOVEMENTS; INTERHEMISPHERIC INHIBITION; SENSORIMOTOR CORTEX; HAND MOVEMENTS; FUNCTIONAL MRI; ACTIVATION AB Bimanual coordination engages a distributed network of brain areas, the spatiotemporal organization of which has given rise to intense debates. Do bimanual movements require information processing in the same set of brain areas that are engaged by movements of the individual components (left and right hands)? Or is it necessary that other brain areas are recruited to help in the act of coordination? These two possibilities are often considered as mutually exclusive, with studies yielding support for one or the other depending on techniques and hypotheses. However, as yet there is no account of how the two views may work together dynamically. Using the method of Mode-Level Cognitive Subtraction (MLCS) on high density EEG recorded during unimanual and bimanual movements, we expose spatiotemporal reorganization of large-scale cortical networks during stable inphase and antiphase coordination and transitions between them. During execution of stable bimanual coordination patterns, neural dynamics were dominated by temporal modulation of unimanual networks. At instability and transition, there was evidence for recruitment of additional areas. Our study provides a framework to quantify large-scale network mechanisms underlying complex cognitive tasks often studied with macroscopic neurophysiological recordings. (c) 2012 Elsevier Inc. All rights C1 [Banerjee, Arpan; Tognoli, Emmanuelle; Kelso, J. A. Scott] Florida Atlantic Univ, Ctr Complex Syst & Brain Sci, Boca Raton, FL 33431 USA. [Kelso, J. A. Scott] Univ Ulster, Intelligent Syst Res Ctr, Coleraine BT52 1SA, Londonderry, North Ireland. [Jirsa, Viktor K.] Aix Marseille Univ, UMR Inserm 1106, Fac Med, Inst Neurosci Syst, F-13005 Marseille, France. RP Banerjee, A (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 10 Ctr Dr,5D39,Bldg 10, Bethesda, MD 20892 USA. EM banerjeea2@mail.nih.gov RI Jirsa, Viktor/M-4630-2016; OI Jirsa, Viktor/0000-0002-8251-8860; Tognoli, Emmanuelle/0000-0003-3674-504X FU Brain Network Recovery Group through the James S. McDonnell Foundation; FP7-ICT Brain Scales; NIMH [MH080838]; NSF [BCS0826897]; US Office of Naval Research [N000140510117]; Chaire d'Excellence Pierre de Fermat; Davimos Family Endowment for Excellence in Science FX This work was supported by the grants Brain Network Recovery Group through the James S. McDonnell Foundation and the FP7-ICT Brain Scales to VKJ. ET and JASK were supported by NIMH grant MH080838, NSF grant BCS0826897, US Office of Naval Research Contract N000140510117, the Chaire d'Excellence Pierre de Fermat (JASK) and the Davimos Family Endowment for Excellence in Science (ET). We thank Allison De Larosiere for her contribution to data collection. AB acknowledges Dr. Bijan Pesaran for helpful discussions and Dr. Ajay Pillai for useful comments. NR 76 TC 12 Z9 12 U1 5 U2 29 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1582 EP 1592 DI 10.1016/j.neuroimage.2012.05.046 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000026 PM 22634864 ER PT J AU Banerjee, A Pillai, AS Sperling, JR Smith, JF Horwitz, B AF Banerjee, Arpan Pillai, Ajay S. Sperling, Justin R. Smith, Jason F. Horwitz, Barry TI Temporal microstructure of cortical networks (TMCN) underlying task-related differences SO NEUROIMAGE LA English DT Article DE EEG; MEG; Network timing; Decoding; Event related potential; Event related field; Multivariate; SAM; Source analysis; Forward solution ID POSITRON-EMISSION-TOMOGRAPHY; REALISTIC VOLUME CONDUCTORS; PARTIAL LEAST-SQUARES; SHORT-TERM-MEMORY; PREFRONTAL CORTEX; WORKING-MEMORY; HUMAN BRAIN; SPATIOTEMPORAL ANALYSIS; STRUCTURAL DESCRIPTIONS; FIELD POTENTIALS AB Neuro-electromagnetic recording techniques (EEG. MEG, iEEG) provide high temporal resolution data to study the dynamics of neurocognitive networks: large scale neural assemblies involved in task-specific information processing. How does a neurocognitive network reorganize spatiotemporally on the order of a few milliseconds to process specific aspects of the task? At what times do networks segregate for task processing, and at what time scales does integration of information occur via changes in functional connectivity? Here, we propose a data analysis framework-Temporal microstructure of cortical networks (TMCN)-that answers these questions for EEG/MEG recordings in the signal space. Method validation is established on simulated MEG data from a delayed-match to-sample (DMS) task. We then provide an example application on MEG recordings during a paired associate task (modified from the simpler DMS paradigm) designed to study modality specific long term memory recall. Our analysis identified the times at which network segregation occurs for processing the memory recall of an auditory object paired to a visual stimulus (visual-auditory) in comparison to an analogous visual-visual pair. Across all subjects, onset times for first network divergence appeared within a range of 0.08-0.47 s after initial visual stimulus onset. This indicates that visual-visual and visual auditory memory recollection involves equivalent network components without any additional recruitment during an initial period of the sensory processing stage which is then followed by recruitment of additional network components for modality specific memory recollection. Therefore, we propose TMCN as a viable computational tool for extracting network timing in various cognitive tasks. Published by Elsevier Inc. C1 [Banerjee, Arpan; Pillai, Ajay S.; Sperling, Justin R.; Smith, Jason F.; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, NIH, Bethesda, MD 20892 USA. RP Banerjee, A (reprint author), Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, NIH, 10 Ctr Dr,Room 5D39, Bethesda, MD 20892 USA. EM Arpan.Banerjee@nih.gov FU NIDCD intramural research program FX This research was supported by the NIDCD intramural research program. NR 80 TC 4 Z9 4 U1 2 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1643 EP 1657 DI 10.1016/j.neuroimage.2012.06.014 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000032 PM 22728151 ER PT J AU Yang, X Lauzon, CB Crainiceanu, C Caffo, B Resnick, SM Landman, BA AF Yang, Xue Lauzon, Carolyn B. Crainiceanu, Ciprian Caffo, Brian Resnick, Susan M. Landman, Bennett A. TI Biological parametric mapping accounting for random regressors with regression calibration and model II regression SO NEUROIMAGE LA English DT Article DE Structure-function relationships; Random regressors; Regression calibration; Model II regression; General linear model ID BAYESIAN-INFERENCE AB Massively univariate regression and inference in the form of statistical parametric mapping have transformed the way in which multi-dimensional imaging data are studied. In functional and structural neuroimaging, the de facto standard "design matrix"-based general linear regression model and its multi-level cousins have enabled investigation of the biological basis of the human brain. With modem study designs, it is possible to acquire multi-modal three-dimensional assessments of the same individuals-e.g., structural, functional and quantitative magnetic resonance imaging, alongside functional and ligand binding maps with positron emission tomography. Largely, current statistical methods in the imaging community assume that the regressors are non-random. For more realistic multi-parametric assessment (e.g., voxel-wise modeling), distributional consideration of all observations is appropriate. Herein, we discuss two unified regression and inference approaches, model II regression and regression calibration, for use in massively univariate inference with imaging data. These methods use the design matrix paradigm and account for both random and non-random imaging regressors. We characterize these methods in simulation and illustrate their use on an empirical dataset. Both methods have been made readily available as a toolbox plug-in for the SPM software. (c) 2012 Elsevier Inc. All rights reserved. C1 [Yang, Xue; Lauzon, Carolyn B.; Landman, Bennett A.] Vanderbilt Univ, Nashville, TN 37235 USA. [Resnick, Susan M.] NIA, NIH, Baltimore, MD 21224 USA. [Crainiceanu, Ciprian; Caffo, Brian] Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD 21218 USA. [Landman, Bennett A.] Johns Hopkins Univ, Baltimore, MD 21205 USA. RP Landman, BA (reprint author), Vanderbilt Univ EECS, 2301 Vanderbilt Pl,POB 351679 Stn B, Nashville, TN 37235 USA. EM bennett.landman@vanderbilt.edu FU NIH [N01-AG-4-0012, T32EB003817, R01EB012547, R01NS060910, P41 EB015909] FX This project was supported in part by grants NIH N01-AG-4-0012, NIH T32EB003817, NIH R01EB012547, NIH R01NS060910, and NIH P41 EB015909. This work represents the opinions of the researchers and not necessarily that of the granting organizations. We are especially grateful for the valuable contributions of the anonymous reviewers. NR 20 TC 2 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1761 EP 1768 DI 10.1016/j.neuroimage.2012.05.020 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000043 PM 22609453 ER PT J AU Lu, HB Chefer, S Kurup, PK Guillem, K Vaupel, DB Ross, TJ Moore, A Yang, YH Peoples, LL Stein, EA AF Lu, Hanbing Chefer, Svetlana Kurup, Pradeep K. Guillem, Karine Vaupel, D. Bruce Ross, Thomas J. Moore, Anna Yang, Yihong Peoples, Laura L. Stein, Elliot A. TI fMRI response in the medial prefrontal cortex predicts cocaine but not sucrose self-administration history SO NEUROIMAGE LA English DT Article DE Neuroadaptation; Self-administration; Abstinence; Pharmacological MRI ID CEREBRAL BLOOD-VOLUME; NUCLEUS-ACCUMBENS; DRUG-SEEKING; FUNCTIONAL CONNECTIVITY; GLUTAMATE TRANSMISSION; INDUCED REINSTATEMENT; MEDIODORSAL NUCLEUS; REWARD REGIONS; IN-VIVO; ADDICTION AB Repeated cocaine exposure induces long-lasting neuroadaptations that alter subsequent responsiveness to the drug. However, systems-level investigation of these neuroplastic consequences is limited. We employed a rodent model of drug addiction to investigate neuroadaptations associated with prolonged forced abstinence after long-term cocaine self-administration (SA). Since natural rewards also activate the mesolimbic reward system in a partially overlapping fashion as cocaine, our design also included a sucrose SA group. Rats were trained to self-administer cocaine or sucrose using a fixed-ratio one, long-access schedule (6 h/day for 20 days). A third group of naive, sedentary rats served as a negative control. After 30 days of abstinence, the reactivity of the reward system was assessed with functional magnetic resonance imaging (fMRI) following an intravenous cocaine injection challenge. A strong positive fMRI response, as measured by fractional cerebral blood volume changes relative to baseline (CBV%), was seen in the sedentary control group in such cortico-limbic regions as medial prefrontal cortex and anterior cingulate cortex. In contrast, both the cocaine and sucrose SA groups demonstrated a very similar initial negative fMRI response followed by an attenuated positive response. The magnitude of the mPFC response was significantly correlated with the total amount of reinforcer intake during the training sessions for the cocaine SA but not for the sucrose SA group. Given that the two SA groups had identical histories of operant training and handling, this region-specific group difference revealed by regression analysis may reflect the development of neuroadaptive mechanisms specifically related to the emergence of addiction-like behavior that occurs only in cocaine SA animals. Published by Elsevier Inc. C1 [Lu, Hanbing; Chefer, Svetlana; Kurup, Pradeep K.; Vaupel, D. Bruce; Ross, Thomas J.; Yang, Yihong; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. [Guillem, Karine; Peoples, Laura L.] Univ Penn, Dept Psychiat, TRL, Philadelphia, PA 19104 USA. [Moore, Anna] Massachusetts Gen Hosp, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Dept Radiol, Mol Imaging Lab, Boston, MA 02129 USA. [Peoples, Laura L.] Univ Penn, Neurosci Grad Grp, Philadelphia, PA 19104 USA. [Guillem, Karine] Univ Bordeaux, Inst Malad Neurodegenerat, UMR 5293, F-33000 Bordeaux, France. [Peoples, Laura L.] Drexel Univ, Dept Physiol & Pharmacol, Coll Med, Philadelphia, PA 19102 USA. [Guillem, Karine] CNRS, Inst Malad Neurodegenerat, UMR 5293, F-33000 Bordeaux, France. RP Stein, EA (reprint author), NIDA, Neuroimaging Res Branch, NIH, 251 Bayview Blvd,Suite 200,RM7A711, Baltimore, MD 21224 USA. EM estein@mail.nih.gov RI Ross, Thomas/B-7469-2008 OI Ross, Thomas/0000-0002-7745-3572 FU Intramural Research Program of the National Institute on Drug Abuse (NIDA); NIH Director's Bench-to-Bedside grant; Institute for Translational Medicine and Therapeutics of the University of Pennsylvania; National Center for Research Resources [UL1RR024134]; [P50DA012756]; [R01 552981] FX We thank William Rea for his excellent technical assistance. This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA) and by an NIH Director's Bench-to-Bedside grant to L. L. Peoples and E. A Stein. It was also partially supported by P50DA012756, and R01 552981 (L.L.P.), Institute for Translational Medicine and Therapeutics of the University of Pennsylvania, and grant UL1RR024134 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. NR 70 TC 8 Z9 10 U1 2 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1857 EP 1866 DI 10.1016/j.neuroimage.2012.05.076 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000054 PM 22664568 ER PT J AU Podell, JE Sambataro, F Murty, VP Emery, MR Tong, YX Das, S Goldberg, TE Weinberger, DR Mattay, VS AF Podell, Jamie E. Sambataro, Fabio Murty, Vishnu P. Emery, Matthew R. Tong, Yunxia Das, Saumitra Goldberg, Terry E. Weinberger, Daniel R. Mattay, Venkata S. TI Neurophysiological correlates of age-related changes in working memory updating SO NEUROIMAGE LA English DT Article DE Working memory; Aging; fMRI; Functional connectivity; Caudate; Prefrontal cortex ID BASAL-GANGLIA; CONVERGING EVIDENCE; BRAIN ACTIVATION; OLDER-ADULTS; COGNITION; DOPAMINE; CONNECTIVITY; INHIBITION; CEREBELLUM; MODULATION AB Normal aging is associated with a gradual decline in executive functions such as set-shifting, inhibition, and updating, along with a progressive decline of neurotransmitter systems including the dopamine system. Modulation from the dopamine system is thought to be critical for the gating of information during working memory. Given the known relationships between executive aging, cognition, and dopamine, this study aims to explore the neurobiology underlying age-related changes in working memory updating using fMRI with healthy subjects from across the adult age spectrum. Our results indicate that older age is associated with poorer performance, reduced meso-cortico-striatal activation, and reduced functional coupling between the caudate and the VLPFC during the updating task. Additionally, caudate activation is associated with improved accuracy and VLPFC activation with faster reaction times in the full sample. Thus, older subjects' under-recruitment of and reduced functional coupling between these regions may specifically underlie age-related changes in working memory updating. These results are consistent with computational models of executive cognition and dopamine-mediated age-related cognitive decline. (c) 2012 Elsevier Inc. All rights reserved. C1 [Weinberger, Daniel R.; Mattay, Venkata S.] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Sambataro, Fabio] Ist Italiano Tecnol UNIPr, Brain Ctr Motor & Social Cognit, Parma, Italy. [Podell, Jamie E.; Sambataro, Fabio; Murty, Vishnu P.; Emery, Matthew R.; Tong, Yunxia; Das, Saumitra; Goldberg, Terry E.; Weinberger, Daniel R.; Mattay, Venkata S.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program,NIH, Bethesda, MD 20892 USA. RP Mattay, VS (reprint author), Lieber Inst Brain Dev, Johns Hopkins Med Campus,855 N Wolfe St, Baltimore, MD 21205 USA. EM anand.mattay@libd.org RI Sambataro, Fabio/E-3426-2010 OI Sambataro, Fabio/0000-0003-2102-416X FU National Institute of Mental Health Intramural Research Program FX We would like to thank Martin Safrin and Kristina Thurin for their assistance with fMRI data collection and Bradley Zoltick for his help with performance data parsing. This work was supported by the National Institute of Mental Health Intramural Research Program, and the study protocol was approved by the Intramural Review Board of the National Institute of Mental Health. NR 54 TC 14 Z9 14 U1 2 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 2151 EP 2160 DI 10.1016/j.neuroimage.2012.05.066 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000079 PM 22659476 ER PT J AU Yao, B Li, TQ van Gelderen, P Shmueli, K de Zwart, JA Duyn, JH AF Yao, Bing Li, Tie-Qiang van Gelderen, Peter Shmueli, Karin de Zwart, Jacco A. Duyn, Jeff H. TI Susceptibility contrast in high field MRI of human brain as a function of tissue iron content (vol 44, pg 1259, 2009) SO NEUROIMAGE LA English DT Correction C1 [Yao, Bing; Li, Tie-Qiang; van Gelderen, Peter; Shmueli, Karin; de Zwart, Jacco A.; Duyn, Jeff H.] NINDS, Adv MRI Sect, Lab Funct Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Yao, B (reprint author), NINDS, Adv MRI Sect, Lab Funct Mol Imaging, NIH, 10 Ctr Dr,Bldg 10,Room B1D728, Bethesda, MD 20892 USA. EM yaob@mail.nih.gov RI Shmueli, Karin/B-9432-2017 NR 1 TC 0 Z9 0 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 2173 EP 2173 DI 10.1016/j.nueroimage.2012.03.055 PG 1 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000083 ER PT J AU Rothman, SM Mattson, MP AF Rothman, Sarah M. Mattson, Mark P. TI Sleep Disturbances in Alzheimer's and Parkinson's Diseases SO NEUROMOLECULAR MEDICINE LA English DT Review DE Alzheimer's disease; Parkinson's disease; Sleep; Circadian ID EYE-MOVEMENT SLEEP; TRANSGENIC MOUSE MODEL; SLOW-WAVE SLEEP; BEHAVIOR DISORDER; REM-SLEEP; DOPAMINERGIC-NEURONS; PARADOXICAL SLEEP; BASAL FOREBRAIN; LEWY BODIES; VOLUNTARY EXERCISE AB Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders and exact a burden on our society greater than cardiovascular disease and cancer combined. While cognitive and motor symptoms are used to define AD and PD, respectively, patients with both disorders exhibit sleep disturbances including insomnia, hypersomnia and excessive daytime napping. The molecular basis of perturbed sleep in AD and PD may involve damage to hypothalamic and brainstem nuclei that control sleep-wake cycles. Perturbations in neurotransmitter and hormone signaling (e.g., serotonin, norepinephrine and melatonin) and the neurotrophic factor BDNF likely contribute to the disease process. Abnormal accumulations of neurotoxic forms of amyloid beta-peptide, tau and alpha-synuclein occur in brain regions involved in the regulation of sleep in AD and PD patients, and are sufficient to cause sleep disturbances in animal models of these neurodegenerative disorders. Disturbed regulation of sleep often occurs early in the course of AD and PD, and may contribute to the cognitive and motor symptoms. Treatments that target signaling pathways that control sleep have been shown to retard the disease process in animal models of AD and PD, suggesting a potential for such interventions in humans at risk for or in the early stages of these disorders. C1 [Rothman, Sarah M.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Rothman, SM (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM rothmansm@mail.nih.gov FU NIH, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. NR 134 TC 30 Z9 34 U1 4 U2 54 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 EI 1559-1174 J9 NEUROMOL MED JI Neuromol. Med. PD SEP PY 2012 VL 14 IS 3 BP 194 EP 204 DI 10.1007/s12017-012-8181-2 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 988WJ UT WOS:000307521200005 PM 22552887 ER PT J AU Rianon, NJ Lang, TF Sigurdsson, G Eiriksdottir, G Sigurdsson, S Garcia, M Pajala, S Koster, A Yu, B Selwyn, BJ Taylor, WC Kapadia, AS Gudnason, V Launer, LJ Harris, TB AF Rianon, N. J. Lang, T. F. Sigurdsson, G. Eiriksdottir, G. Sigurdsson, S. Garcia, M. Pajala, S. Koster, A. Yu, B. Selwyn, B. J. Taylor, W. C. Kapadia, A. S. Gudnason, V. Launer, L. J. Harris, T. B. TI Lifelong physical activity in maintaining bone strength in older men and women of the Age, Gene/Environment Susceptibility-Reykjavik Study SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE AGES-Reykjavik Study; Bone mineral density; Older men and women; Osteoporosis; Physical activity; QCT bone measures ID MINERAL DENSITY; POSTMENOPAUSAL WOMEN; VOLUMETRIC BMD; EXERCISE; PARTICIPATION; HIP; PREDICTION; FRACTURE; SPORT; SPINE AB We examined if lifelong physical activity is important for maintaining bone strength in the elderly. Associations of quantitative computerized tomography-acquired bone measures (vertebral and femoral) and self-reported physical activity in mid-life (mean age, 50 years), in old age (a parts per thousand yen65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. Results conclude lifelong physical activity with continuation into old age (a parts per thousand yen65 years) best maintains better bone health later in life. Skeletal loading is thought to modulate the loss of bone in later life, and physical activity is a chief means of affecting bone strength by skeletal loading. Despite much discussion regarding lifelong versus early adulthood physical activity for preventing bone loss later in life, inconsistency still exists regarding how to maintain bone mass later in life (a parts per thousand yen65 years). We examined if lifelong physical activity is important for maintaining bone strength in the elderly. The associations of quantitative computerized tomography-acquired vertebral and femoral bone measures and self-reported physical activity in mid-life (mean age, 50 years), in old age (a parts per thousand yen65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. Our findings conclude that lifelong physical activity with continuation into old age (a parts per thousand yen65 years) best maintains better bone health in the elderly. C1 [Rianon, N. J.] UTHSC Med Sch, Houston, TX 77030 USA. [Lang, T. F.] UCSF Sch Med, San Francisco, CA USA. [Sigurdsson, G.] Landspitali Univ Hosp, Dept Internal Med, Div Endocrinol & Metab, Reykjavik, Iceland. [Eiriksdottir, G.; Sigurdsson, S.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Garcia, M.; Koster, A.; Yu, B.; Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Pajala, S.] Natl Inst Hlth & Welf, Helsinki, Finland. [Selwyn, B. J.; Taylor, W. C.; Kapadia, A. S.] UTHSC Sch Publ Hlth, Houston, TX USA. [Gudnason, V.] Univ Iceland, Reykjavik, Iceland. [Launer, L. J.] NIA, Neuroepidemiol Sect, Bethesda, MD 20892 USA. RP Rianon, NJ (reprint author), UTHSC Med Sch, 6431 Fannin JJL324, Houston, TX 77030 USA. EM Nahid.J.Rianon@uth.tmc.edu RI Koster, Annemarie/E-7438-2010; Lang, Thomas/B-2685-2012; Gudnason, Vilmundur/K-6885-2015 OI Lang, Thomas/0000-0002-3720-8038; Gudnason, Vilmundur/0000-0001-5696-0084 FU NIH [N01-AG-12100]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX The Age, Gene/Environment Susceptibility-Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Genotyping was conducted at the NIA IRP Laboratory of Neurogenetics. NR 27 TC 4 Z9 4 U1 0 U2 13 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD SEP PY 2012 VL 23 IS 9 BP 2303 EP 2312 DI 10.1007/s00198-011-1874-9 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 991RA UT WOS:000307717700006 PM 22234811 ER PT J AU Sarangi, PP Hyun, YM Lerman, YV Pietropaoli, AP Kim, M AF Sarangi, Pranita P. Hyun, Young-Min Lerman, Yelena V. Pietropaoli, Anthony P. Kim, Minsoo TI ROLE OF beta(1) INTEGRIN IN TISSUE HOMING OF NEUTROPHILS DURING SEPSIS SO SHOCK LA English DT Article DE Neutrophils; integrin beta(1); sepsis; infiltration ID PULMONARY INFLAMMATION; ACTIVATION; EXPRESSION; MICE; INTERLEUKIN-8; RECRUITMENT; INHIBITION; MIGRATION; PATHWAYS; ELASTASE AB Aberrant activation of neutrophils during sepsis results in the widespread release of proinflammatory mediators, leading to multiorgan system failure and death. However, aberrant activation of neutrophils during sepsis results in the widespread release of harmful inflammatory mediators causing host tissue injuries that can lead to multiorgan system failure and death. One of the pivotal components of neutrophil migration during inflammation is the expression of surface integrins. In this study, we show that administration of a cyclic analog of RGD peptide (Arg-Gly-Asp) significantly reduced the number of tissue-invading neutrophils and the degree of sepsis-induced lethality in mice as compared with control peptide. Second, beta(1) integrin (CD29) was highly upregulated on the neutrophils isolated from both septic patients and animals. Finally, conditional genetic ablation of beta(1) integrin from granulocytes also improved survival and bacterial clearance in septic animals Thus, our results indicate that expression of beta(1) integrin is important for modulating neutrophil trafficking during sepsis and that therapeutics designed against beta(1) integrins may be beneficial. C1 [Kim, Minsoo] Univ Rochester, Dept Microbiol & Immunol, David H Smith Ctr Vaccine Biol & Immunol, Med Ctr, Rochester, NY 14642 USA. [Lerman, Yelena V.] Univ Rochester, Dept Physiol & Pharmacol, Rochester, NY 14642 USA. [Pietropaoli, Anthony P.] Univ Rochester, Pulm & Crit Care Med Div, Rochester, NY 14642 USA. RP Sarangi, PP (reprint author), NIDCR, Lab Cell & Dev Biol, NIH, 30 Convent Dr,Room 432, Bethesda, MD 20892 USA. EM sarangipp@mail.nih.gov; Minsoo_Kim@urmc.rochester.edu FU NIH [HL087088, HL018208, HL094797, DA007232] FX This project was supported by NIH HL087088 (M.K.), NIH HL018208 (M.K.), NIH HL094797 (M.K.), and NIH DA007232 (Y.V.L.). NR 34 TC 5 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1073-2322 EI 1540-0514 J9 SHOCK JI Shock PD SEP PY 2012 VL 38 IS 3 BP 281 EP 287 DI 10.1097/SHK.0b013e31826136f8 PG 7 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 990KC UT WOS:000307628400008 PM 22683734 ER PT J AU Lampl, M Lee, W Koo, W Frongillo, EA Barker, DJP Romero, R AF Lampl, Michelle Lee, Wesley Koo, Winston Frongillo, Edward A. Barker, David J. P. Romero, Roberto TI Ethnic differences in the accumulation of fat and lean mass in late gestation SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Article ID RESTING ENERGY-EXPENDITURE; CORONARY-HEART-DISEASE; AIR-DISPLACEMENT PLETHYSMOGRAPHY; SOUTHEASTERN UNITED-STATES; STAGE RENAL-DISEASE; BODY-COMPOSITION; AFRICAN-AMERICANS; PRETERM BIRTH; IN-UTERO; METABOLIC-RATE AB Objectives: Lower birth weight within the normal range predicts adult chronic diseases, but the same birth weight in different ethnic groups may reflect different patterns of tissue development. Neonatal body composition was investigated among non-Hispanic Caucasians and African Americans, taking advantage of variability in gestational duration to understand growth during late gestation. Methods: Air displacement plethysmography assessed fat and lean body mass among 220 non-Hispanic Caucasian and 93 non-Hispanic African American neonates. The two ethnic groups were compared using linear regression. Results: At 36 weeks of gestation, the average lean mass of Caucasian neonates was 2,515 g vs. that of 2,319 g of African American neonates (difference, P = 0.02). The corresponding figures for fat mass were 231 and 278 g, respectively (difference, P = 0.24). At 41 weeks, the Caucasians were 319 g heavier in lean body mass (P < 0.001) but were also 123 g heavier in fat mass (P = 0.001). The slopes for lean mass vs. gestational week were similar, but the slope of fat mass was 5.8 times greater (P = 0.009) for Caucasian (41.0 g/week) than for African American neonates (7.0 g/week). Conclusions: By 36 weeks of gestation, the African American fetus developed similar fat mass and less lean mass compared with the Caucasian fetus. Thereafter, changes in lean mass among the African American fetus with increasing gestational age at birth were similar to the Caucasian fetus, but fat accumulated more slowly. We hypothesize that different ethnic fetal growth strategies involving body composition may contribute to ethnic health disparities in later life. Am. J. Hum. Biol. 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Lampl, Michelle] Emory Univ, Dept Anthropol, Ctr Study Human Hlth, Atlanta, GA 30322 USA. [Lee, Wesley] Oakland Univ, William Beaumont Sch Med, Dept Obstet & Gynecol, Rochester, MI USA. [Lee, Wesley; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Perinatol Res Branch, NIH, DHHS Bethesda, Bethesda, MD USA. [Koo, Winston] Wayne State Univ, Sch Med, Carman & Ann Adams Dept Pediat, Detroit, MI USA. [Frongillo, Edward A.] Univ S Carolna, Dept Hlth Promot Educ & Behav, Columbia, SC USA. [Barker, David J. P.] Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England. [Romero, Roberto] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. RP Lampl, M (reprint author), Emory Univ, Dept Anthropol, Ctr Study Human Hlth, 107 Candler Lib, Atlanta, GA 30322 USA. EM mlampl@emory.edu RI Lampl, Michelle/B-1619-2013 FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX Contract grant sponsor: Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 69 TC 8 Z9 8 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD SEP-OCT PY 2012 VL 24 IS 5 BP 640 EP 647 DI 10.1002/ajhb.22285 PG 8 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 986WV UT WOS:000307377800009 PM 22565933 ER PT J AU Collin, N Assumpcao, TCF Mizurini, DM Gilmore, DC Dutra-Oliveira, A Kotsyfakis, M Sa-Nunes, A Teixeira, C Ribeiro, JMC Monteiro, RQ Valenzuela, JG Francischetti, IMB AF Collin, Nicolas Assumpcao, Teresa C. F. Mizurini, Daniella M. Gilmore, Dana C. Dutra-Oliveira, Angelica Kotsyfakis, Michalis Sa-Nunes, Anderson Teixeira, Clarissa Ribeiro, Jose M. C. Monteiro, Robson Q. Valenzuela, Jesus G. Francischetti, Ivo M. B. TI Lufaxin, a Novel Factor Xa Inhibitor From the Salivary Gland of the Sand Fly Lutzomyia longipalpis Blocks Protease-Activated Receptor 2 Activation and Inhibits Inflammation and Thrombosis In Vivo SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE hematophagy; leishmaniasis; microcirculation; thrombosis; vector biology ID COAGULATION-FACTOR-XA; ANTICOAGULANT PEPTIDE; PLATELET-AGGREGATION; BLOOD-COAGULATION; TISSUE FACTOR; HEMATOPHAGOUS ANIMALS; ANCYLOSTOMA-CANINUM; IXODES-SCAPULARIS; ARTHROPOD SALIVA; BREAST-CANCER AB Objective-Blood-sucking arthropods' salivary glands contain a remarkable diversity of antihemostatics. The aim of the present study was to identify the unique salivary anticoagulant of the sand fly Lutzomyia longipalpis, which remained elusive for decades. Methods and Results-Several L. longipalpis salivary proteins were expressed in human embryonic kidney 293 cells and screened for inhibition of blood coagulation. A novel 32.4-kDa molecule, named Lufaxin, was identified as a slow, tight, noncompetitive, and reversible inhibitor of factor Xa (FXa). Notably, Lufaxin's primary sequence does not share similarity to any physiological or salivary inhibitors of coagulation reported to date. Lufaxin is specific for FXa and does not interact with FX, Dansyl-Glu-Gly-Arg-FXa, or 15 other enzymes. In addition, Lufaxin blocks prothrombinase and increases both prothrombin time and activated partial thromboplastin time. Surface plasmon resonance experiments revealed that FXa binds Lufaxin with an equilibrium constant approximate to 3 nM, and isothermal titration calorimetry determined a stoichiometry of 1:1. Lufaxin also prevents protease-activated receptor 2 activation by FXa in the MDA-MB-231 cell line and abrogates edema formation triggered by injection of FXa in the paw of mice. Moreover, Lufaxin prevents FeCl3-induced carotid artery thrombus formation and prolongs activated partial thromboplastin time ex vivo, implying that it works as an anticoagulant in vivo. Finally, salivary gland of sand flies was found to inhibit FXa and to interact with the enzyme. Conclusion-Lufaxin belongs to a novel family of slow-tight FXa inhibitors, which display antithrombotic and anti-inflammatory activities. It is a useful tool to understand FXa structural features and its role in prohemostatic and proinflammatory events. (Arterioscler Thromb Vasc Biol. 2012;32:2185-2196.) C1 [Collin, Nicolas; Gilmore, Dana C.; Teixeira, Clarissa; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Collin, Nicolas] Univ Lausanne, Dept Biochem, Vaccine Formulat Lab, CH-1066 Epalinges, Switzerland. [Assumpcao, Teresa C. F.; Ribeiro, Jose M. C.; Francischetti, Ivo M. B.] NIAID, Vector Biol Sect, LMVR, NIH, Bethesda, MD 20892 USA. [Mizurini, Daniella M.; Dutra-Oliveira, Angelica; Monteiro, Robson Q.] Univ Fed Rio de Janeiro, Inst Bioquim Med, Rio De Janeiro, Brazil. [Kotsyfakis, Michalis] Acad Sci Czech Republic, Inst Parasitol, Ctr Biol, CR-37005 Ceske Budejovice, Czech Republic. [Sa-Nunes, Anderson] Univ Sao Paulo, Inst Ciencias Biomed, Dept Imunol, BR-05508 Sao Paulo, Brazil. RP Francischetti, IMB (reprint author), NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jvalenzuela@niaid.nih.gov; ifrancischetti@niaid.nih.gov RI Sa-Nunes, Anderson/D-8667-2012; Inbeb, Inct/K-2317-2013; Monteiro, Robson/B-8007-2014; Kotsyfakis, Michail/G-9525-2014; Ribeiro, Jose/J-7011-2015; OI Sa-Nunes, Anderson/0000-0002-1859-4973; Kotsyfakis, Michail/0000-0002-7526-1876; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH; Bethesda, MD); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro Carlos Chagas Filho (FAPERJ); Fundacao do Cancer and Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Grant Agency of the Czech Republic [P502/12/2409]; National Academy of Sciences of the Czech Republic; Marie Curie Reintegration grant of the EU-FP7 [PIRG07-GA-2010-268177] FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH; Bethesda, MD). R.Q. Monteiro received a grant from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro Carlos Chagas Filho (FAPERJ), Fundacao do Cancer and Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES). M. Kotsyfakis received support from grant number P502/12/2409 of the Grant Agency of the Czech Republic, from a Jan Evangelista Purkyne fellowship of the National Academy of Sciences of the Czech Republic, and from a Marie Curie Reintegration grant of the EU-FP7 (PIRG07-GA-2010-268177). Because Drs Francischetti, Valenzuela, and Ribeiro are government employees, and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the United States subject to a government use license. NR 50 TC 28 Z9 28 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD SEP PY 2012 VL 32 IS 9 BP 2185 EP + DI 10.1161/ATVBAHA.112.253906 PG 28 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 992JZ UT WOS:000307773100021 PM 22796577 ER PT J AU Little, AC Paukner, A Woodward, RA Suomi, SJ AF Little, Anthony C. Paukner, Annika Woodward, Ruth A. Suomi, Stephen J. TI Facial asymmetry is negatively related to condition in female macaque monkeys SO BEHAVIORAL ECOLOGY AND SOCIOBIOLOGY LA English DT Article DE Health; Asymmetry; Sexual selection; Quality; Measurements ID CONDITION SCORING SYSTEM; FLUCTUATING ASYMMETRY; DEVELOPMENTAL STABILITY; SEXUAL-DIMORPHISM; MACACA-MULATTA; RHESUS MACAQUES; HUMAN FACES; GOOD GENES; SYMMETRY; ATTRACTIVENESS AB The face is an important visual trait in social communication across many species. In evolutionary terms, there are large and obvious selective advantages in detecting healthy partners, both in terms of avoiding individuals with poor health to minimise contagion and in mating with individuals with high health to help ensure healthy offspring. Many models of sexual selection suggest that an individual's phenotype provides cues to their quality. Fluctuating asymmetry is a trait that is proposed to be an honest indicator of quality, and previous studies have demonstrated that rhesus monkeys gaze longer at symmetric faces, suggesting preferences for such faces. The current study examined the relationship between measured facial symmetry and measures of health in a captive population of female rhesus macaque monkeys. We measured asymmetry from landmarks marked on front-on facial photographs and computed measures of health based on veterinary health and condition ratings, number of minor and major wounds sustained and gain in weight over the first 4 years of life. Analysis revealed that facial asymmetry was negatively related to condition-related health measures, with symmetric individuals being healthier than more asymmetric individuals. Facial asymmetry appears to be an honest indicator of health in rhesus macaques, and asymmetry may then be used by conspecifics in mate-choice situations. More broadly, our data support the notion that faces are valuable sources of information in non-human primates and that sexual selection based on facial information is potentially important across the primate lineage. C1 [Little, Anthony C.] Univ Stirling, Sch Nat Sci, Stirling FK9 4LA, Scotland. [Paukner, Annika; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Comparat Ethol Lab, US Dept HHS, NIH, Poolesville, MD USA. [Woodward, Ruth A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, US Dept HHS, Res Anim Management Branch, NIH, Poolesville, MD USA. RP Little, AC (reprint author), Univ Stirling, Sch Nat Sci, Stirling FK9 4LA, Scotland. EM anthony.little@stir.ac.uk RI Little, Anthony/B-8497-2009 OI Little, Anthony/0000-0001-9100-1903 FU Royal Society University Research Fellowship; Division of Intramural Research, NICHD FX Anthony Little is supported by a Royal Society University Research Fellowship. This research was supported by the Division of Intramural Research, NICHD. NR 38 TC 4 Z9 4 U1 1 U2 42 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-5443 J9 BEHAV ECOL SOCIOBIOL JI Behav. Ecol. Sociobiol. PD SEP PY 2012 VL 66 IS 9 BP 1311 EP 1318 DI 10.1007/s00265-012-1386-4 PG 8 WC Behavioral Sciences; Ecology; Zoology SC Behavioral Sciences; Environmental Sciences & Ecology; Zoology GA 988SI UT WOS:000307510600013 PM 23667290 ER PT J AU Saporito, RA Donnelly, MA Spande, TF Garraffo, HM AF Saporito, Ralph A. Donnelly, Maureen A. Spande, Thomas F. Garraffo, H. Martin TI A review of chemical ecology in poison frogs SO CHEMOECOLOGY LA English DT Review DE Ants; Bufonids; Chemical defense; Dendrobatids; Mantellids; Melanophryniscus; Oribatid mites; Pseudophryne; Sequestration ID BUFONID TOADS MELANOPHRYNISCUS; DENDROBATES-PUMILIO; GEOGRAPHIC-VARIATION; SKIN ALKALOIDS; DART FROGS; PYRROLIZIDINE ALKALOIDS; CONVERGENT EVOLUTION; DIET SPECIALIZATION; ARTHROPOD SOURCE; OOPHAGA-PUMILIO AB Herein we review what is known about the chemical ecology of poison frogs with a focus on dendrobatid poison frogs. While five anuran families are known to have an alkaloid-derived chemical defense, the dendrobatids have been studied in greatest detail and provides chemical ecologists with a complex model system for understanding how chemical defenses operate in real time and may have evolved through evolutionary time. We describe the diversity of alkaloid defenses known from frogs, alkaloid sequestration, biosynthesis and modification, and we review what is known concerning arthropod sources for alkaloids. There is variation in nearly every attribute of the system and we try to describe some of the challenges associated with unraveling the complexities of this model system. C1 [Saporito, Ralph A.] John Carroll Univ, Dept Biol, University Hts, OH 44118 USA. [Donnelly, Maureen A.] Florida Int Univ, Coll Arts & Sci, Miami, FL 33199 USA. [Spande, Thomas F.; Garraffo, H. Martin] NIDDK, Bioorgan Chem Lab, DHHS, NIH, Bethesda, MD 20892 USA. RP Saporito, RA (reprint author), John Carroll Univ, Dept Biol, University Hts, OH 44118 USA. EM ralph.saporito@gmail.com FU Environmental Protection Agency; Florida International University; National Geographic Society; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health; Organization for Tropical Studies; Smithsonian Tropical Research Institute; National Science Foundation [IOS-0813842] FX This paper is dedicated to the memory of our friend and colleague John W. Daly, whose pioneering research founded and continues to inspire the study of poison frog chemical ecology. We would also like to acknowledge his life-long colleague, C. W. Myers (Curator Emeritus, Department of Herpetology, American Museum of Natural History), who collaborated extensively with John over the past 40 years on the study of poison frogs. We thank Tappey H. Jones (Virginia Military Institute), who collaborated with John in the identification and synthesis of ant alkaloids. We also thank Richard L. Hoffman (Virginia Museum of Natural History), John T. Longino (Evergreen State College), and Roy A. Norton (State University of New York, Syracuse) for their assistance in identifying many of the alkaloid-containing arthropods. We are grateful to Alan H. Savitzky and Jenise M. Snyder for providing valuable comments that improved the quality of this manuscript. We would like to thank the Environmental Protection Agency, Florida International University, National Geographic Society, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Organization for Tropical Studies, and Smithsonian Tropical Research Institute for their generous funding. A National Science Foundation Postdoctoral Research Fellowship partially supported R. A. S. This work is derived from a presentation in the symposium "Sequestered Defensive Compounds in Tetrapod Vertebrates: A Symposium in Memory of John W. Daly," held at the Sixth World Congress of Herpetology in Manaus, Brazil, on 21 August 2008 and supported by NSF IOS-0813842. NR 84 TC 48 Z9 49 U1 13 U2 128 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 0937-7409 EI 1423-0445 J9 CHEMOECOLOGY JI Chemoecology PD SEP PY 2012 VL 22 IS 3 BP 159 EP 168 DI 10.1007/s00049-011-0088-0 PG 10 WC Biochemistry & Molecular Biology; Ecology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology GA 988TB UT WOS:000307512500003 ER PT J AU Abnet, C AF Abnet, C. TI Linxian China: A Population with High Incidence of Esophageal Cancer and Multiple Adverse Exposures SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 43rd Annual Meeting of the Environmental-Mutagen-Society (EMS) CY SEP 08-12, 2012 CL Bellevue, WA SP Environm Mutagen Soc (EMS) C1 [Abnet, C.] 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2012 VL 53 SU 1 BP S23 EP S23 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 993YM UT WOS:000307896300045 ER PT J AU Attene-Ramos, M Huang, R Sakamuru, S Witt, K Tice, R Austin, C Xia, M AF Attene-Ramos, M. Huang, R. Sakamuru, S. Witt, K. Tice, R. Austin, C. Xia, M. TI Toxicity Assessment of Environmental Chemicals Using a Quantitative High-Throughput Screening Approach SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 43rd Annual Meeting of the Environmental-Mutagen-Society (EMS) CY SEP 08-12, 2012 CL Bellevue, WA SP Environm Mutagen Soc (EMS) C1 [Attene-Ramos, M.; Huang, R.; Sakamuru, S.; Austin, C.; Xia, M.] NIH, Chem Genom Ctr, NCATS, Bethesda, MD 20892 USA. [Witt, K.; Tice, R.] NIEHS, DNTP, Res Triangle Pk, NC 27709 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2012 VL 53 SU 1 BP S29 EP S29 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 993YM UT WOS:000307896300069 ER PT J AU Butler, K Rajani, A Elespuru, R AF Butler, K. Rajani, A. Elespuru, R. TI Genotoxicity and Uptake of Titanium Dioxide Nanoparticles in Salmonella typhimurium SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 43rd Annual Meeting of the Environmental-Mutagen-Society (EMS) CY SEP 08-12, 2012 CL Bellevue, WA SP Environm Mutagen Soc (EMS) C1 [Butler, K.] NCI, Bethesda, MD 20892 USA. [Butler, K.; Rajani, A.; Elespuru, R.] US FDA, Silver Spring, 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2012 VL 53 SU 1 BP S58 EP S58 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 993YM UT WOS:000307896300184 ER PT J AU Gorospe, M AF Gorospe, M. TI Regulation of HuR Function by Stress-Response Kinases SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 43rd Annual Meeting of the Environmental-Mutagen-Society (EMS) CY SEP 08-12, 2012 CL Bellevue, WA SP Environm Mutagen Soc (EMS) C1 [Gorospe, M.] NIH, NIA IRP, Baltimore, MD USA. 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2012 VL 53 SU 1 BP S19 EP S19 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 993YM UT WOS:000307896300029 ER PT J AU Hobbs, CA Morgan, DL Shepard, K Price, HC Kissling, GE Shockley, KR Recio, L Witt, KL French, JE AF Hobbs, C. A. Morgan, D. L. Shepard, K. Price, H. C. Kissling, G. E. Shockley, K. R. Recio, L. Witt, K. L. French, J. E. TI Population Variation in Micronucleus Response to Inhaled Benzene in Diversity Outbred (J:DO) Mice SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 43rd Annual Meeting of the Environmental-Mutagen-Society (EMS) CY SEP 08-12, 2012 CL Bellevue, WA SP Environm Mutagen Soc (EMS) C1 [Hobbs, C. A.; Shepard, K.; Recio, L.] Integrated Lab Syst Inc, Genet & Mol Toxicol Div, Res Triangle Pk, NC USA. [Price, H. C.] Alion Sci & Technol, Life Sci & Inhalat Toxicol Lab, Res Triangle Pk, NC USA. [Morgan, D. L.; Kissling, G. E.; Shockley, K. R.; Witt, K. L.; French, J. E.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2012 VL 53 SU 1 BP S26 EP S26 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 993YM UT WOS:000307896300057 ER PT J AU Martin, WJ AF Martin, W. J., II TI Household Air Pollution: A Preventable Cause of Two Million Deaths Annually SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 43rd Annual Meeting of the Environmental-Mutagen-Society (EMS) CY SEP 08-12, 2012 CL Bellevue, WA SP Environm Mutagen Soc (EMS) C1 [Martin, W. J., II] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2012 VL 53 SU 1 BP S14 EP S14 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 993YM UT WOS:000307896300006 ER PT J AU Morita, T Uno, Y Kojima, H Hayashi, M Tice, R Corvi, R Schectman, L AF Morita, T. Uno, Y. Kojima, H. Hayashi, M. Tice, R. Corvi, R. Schectman, L. TI The JaCVAM Validation Study of the In Vivo Comet Assay: Selection of Test Chemicals SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 43rd Annual Meeting of the Environmental-Mutagen-Society (EMS) CY SEP 08-12, 2012 CL Bellevue, WA SP Environm Mutagen Soc (EMS) C1 [Morita, T.; Kojima, H.] Natl Inst Hlth Sci, Tokyo, Japan. [Uno, Y.] Mitsubishi Tanabe Pharma, Chiba, Japan. [Kojima, H.] Japanese Ctr Validat Alternat Methods, Tokyo, Japan. [Hayashi, M.] Biosafety Res Ctr, Shizuoka, Japan. [Tice, R.] NIEHS, Div Natl Toxicol Program, Hillsborough, NC USA. [Corvi, R.] European Union Reference Lab Alternat Methods Ani, Ispra, Italy. [Schectman, L.] Innovat Toxicol Consulting LLC, Lake Worth, FL 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2012 VL 53 SU 1 BP S50 EP S50 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 993YM UT WOS:000307896300152 ER PT J AU Olanbiwonnu, T Brooks, P Tamblyn, L Laposa, R AF Olanbiwonnu, T. Brooks, P. Tamblyn, L. Laposa, R. TI Transcriptional Mutagenesis from 8-oxoguanine or 8,5 '-cyclo-2 '-deoxyadenosine in Adult Neural Stem Cells SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 43rd Annual Meeting of the Environmental-Mutagen-Society (EMS) CY SEP 08-12, 2012 CL Bellevue, WA SP Environm Mutagen Soc (EMS) C1 [Olanbiwonnu, T.; Tamblyn, L.; Laposa, R.] Univ Toronto, Toronto, ON, Canada. [Brooks, P.] NIAAA, Lab Neurogenet, 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2012 VL 53 SU 1 BP S64 EP S64 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 993YM UT WOS:000307896300209 ER PT J AU Olivero, O AF Olivero, O. TI Chromosomal Instability and Aneuploidy Induced by Nucleoside Analogs SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 43rd Annual Meeting of the Environmental-Mutagen-Society (EMS) CY SEP 08-12, 2012 CL Bellevue, WA SP Environm Mutagen Soc (EMS) C1 [Olivero, O.] NCI, 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2012 VL 53 SU 1 BP S33 EP S33 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 993YM UT WOS:000307896300082 ER PT J AU Schaaper, RM Ahluwalia, D Bienstock, RJ AF Schaaper, R. M. Ahluwalia, D. Bienstock, R. J. TI Mutational Consequences of Altered DNA Precursor Pools SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 43rd Annual Meeting of the Environmental-Mutagen-Society (EMS) CY SEP 08-12, 2012 CL Bellevue, WA SP Environm Mutagen Soc (EMS) C1 [Schaaper, R. M.; Ahluwalia, D.; Bienstock, R. J.] NIEHS, Res Triangle Pk, NC 27709 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2012 VL 53 SU 1 BP S31 EP S31 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 993YM UT WOS:000307896300077 ER PT J AU Swartz, CD Hobbs, CA Lentz, C Garibaldi, P Green, A Recio, L Witt, KL AF Swartz, C. D. Hobbs, C. A. Lentz, C. Garibaldi, P. Green, A. Recio, L. Witt, K. L. TI 2-Nitroethanol, but Not Related Nitroalcohols, Is Weakly Mutagenic in Bacteria and Negative for Chromosomal and DNA Damage SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 43rd Annual Meeting of the Environmental-Mutagen-Society (EMS) CY SEP 08-12, 2012 CL Bellevue, WA SP Environm Mutagen Soc (EMS) C1 [Swartz, C. D.; Hobbs, C. A.; Lentz, C.; Garibaldi, P.; Green, A.; Recio, L.] Integrated Syst Lab, Res Triangle Pk, NC USA. [Witt, K. L.] NIEHS, Res Triangle Pk, NC 27709 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD SEP PY 2012 VL 53 SU 1 BP S57 EP S57 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 993YM UT WOS:000307896300178 ER PT J AU Simonsen, L Viboud, C AF Simonsen, Lone Viboud, Cecile TI The Art of Modeling the Mortality Impact of Winter-Seasonal Pathogens SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID RESPIRATORY SYNCYTIAL VIRUS; UNITED-STATES; INFLUENZA; HOSPITALIZATIONS; BURDEN; INFECTIONS; ENGLAND; DEATHS; WALES C1 [Simonsen, Lone] George Washington Univ, Dept Global Hlth, Washington, DC 20037 USA. [Simonsen, Lone; Viboud, Cecile] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Simonsen, L (reprint author), George Washington Univ, Dept Publ Hlth, 2175 K St, Washington, DC 20037 USA. EM lone@gwu.edu OI Simonsen, Lone/0000-0003-1535-8526 NR 22 TC 5 Z9 5 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 SEP 1 PY 2012 VL 206 IS 5 BP 625 EP 627 DI 10.1093/infdis/jis419 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 988PA UT WOS:000307501800001 PM 22723644 ER PT J AU Allison, RD Conry-Cantilena, C Koziol, D Schechterly, C Ness, P Gibble, J Kleiner, DE Ghany, MG Alter, HJ AF Allison, Robert D. Conry-Cantilena, Cathy Koziol, Deloris Schechterly, Cathy Ness, Paul Gibble, Joan Kleiner, David E. Ghany, Marc G. Alter, Harvey J. TI A 25-Year Study of the Clinical and Histologic Outcomes of Hepatitis C Virus Infection and Its Modes of Transmission in a Cohort of Initially Asymptomatic Blood Donors SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID NON-A; NON-B; TRANSFUSION; ROUTES AB Background. A total of 738 volunteer blood donors who were positive for anti-hepatitis C virus (HCV) were assessed for risk factors and outcomes for up to 15 years within the study and up to 54 years from the estimated onset of infection. Methods.A third-generation recombinant immunoblot assay (RIBA) was performed to distinguish true from false anti-HCV reactivity. Findings of HCV polymerase chain reaction classified subjects as having chronic HCV infection or as having recovered. Liver biopsy specimens were staged by Ishak fibrosis score and graded by histologic activity index. Results.Of 738 anti-HCV-positive subjects, 469 (64%) had positive RIBA results, 217 (29%) had negative results, and 52 (7%) had indeterminate results. Primary independent risk factors were injection drug use (odds ratio [OR], 35.0; P < .0001), blood transfusion (OR, 9.9; P < .0001), and intranasal cocaine use, including 79 "snorters" who repeatedly denied injection drug use or blood transfusion (OR, 8.5; P < .0001). Classification and regression tree and random forest analyses confirmed these risk factors. A total of 384 RIBA-positive donors (82%) were HCV RNA positive; of these, liver biopsy specimens from 185 (48%) showed no fibrosis in 33%, mild fibrosis in 52%, bridging fibrosis in 12%, and cirrhosis in 2% a mean duration of 25 years after infection. Analysis of 63 repeat biopsy specimens showed that 8% progressed >= 2 Ishak stages over 5 years (mean progression, 0.06 Ishak stages/year). Conclusions.Injection drug use and blood transfusion before 1990 are dominant risk factors for HCV acquisition; intranasal cocaine use may be a surreptitious route of parenteral spread. After a mean of 25 years of HCV infection, histologic outcomes were relatively mild: 85% had no or mild fibrosis, and only 2% had cirrhosis. Nearly one-fifth spontaneously recovered. C1 [Allison, Robert D.; Conry-Cantilena, Cathy; Schechterly, Cathy; Alter, Harvey J.] NCI, Dept Transfus Med, Bethesda, MD 20892 USA. [Koziol, Deloris] NCI, Biostat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Ghany, Marc G.] NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Ness, Paul] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Ness, Paul] Johns Hopkins Med Inst, Dept Oncol, Baltimore, MD 21205 USA. [Gibble, Joan] Amer Red Cross, Greater Chesapeake & Potomac Reg, Baltimore, MD USA. RP Alter, HJ (reprint author), NIH, Clin Studies Sect, 10 Ctr Dr,Bldg 10,Rm 1C711, Bethesda, MD 20892 USA. EM halter@cc.nih.gov OI Allison, Robert/0000-0001-8458-5250; Kleiner, David/0000-0003-3442-4453 FU Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute, National Institutes of Health. NR 22 TC 12 Z9 15 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 SEP 1 PY 2012 VL 206 IS 5 BP 654 EP 661 DI 10.1093/infdis/jis410 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 988PA UT WOS:000307501800005 PM 22740714 ER PT J AU Blazkova, J Chun, TW Belay, BW Murray, D Justement, JS Funk, EK Nelson, A Hallahan, CW Moir, S Wender, PA Fauci, AS AF Blazkova, Jana Chun, Tae-Wook Belay, Bietel W. Murray, Danielle Justement, J. Shawn Funk, Emily K. Nelson, Amy Hallahan, Claire W. Moir, Susan Wender, Paul A. Fauci, Anthony S. TI Effect of Histone Deacetylase Inhibitors on HIV Production in Latently Infected, Resting CD4(+) T Cells From Infected Individuals Receiving Effective Antiretroviral Therapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID VALPROIC ACID; RESERVOIR; PROSTRATIN; EXPRESSION; AIDS AB Persistence of the latent viral reservoir has been recognized as a major obstacle to eradicating human immunodeficiency virus (HIV) in infected individuals receiving antiretroviral therapy. It has been suggested that histone deacetylase inhibitors (HDACis) may purge HIV in the latent viral reservoir. However, the effect of HDACis on the degree and extent of HIV expression in the latent viral reservoir has not been fully delineated. Here we demonstrate that HDACis do not induce HIV production in the latent viral reservoir of aviremic individuals. Therefore, alternative therapeutic strategies may be necessary to eliminate HIV in the latent viral reservoir. C1 [Chun, Tae-Wook] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Wender, Paul A.] Stanford Univ, Dept Chem, Stanford, CA 94305 USA. RP Chun, TW (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Rm 6A32,9000 Rockville Pike, Bethesda, MD 20892 USA. EM twchun@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 15 TC 52 Z9 53 U1 3 U2 8 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 SEP 1 PY 2012 VL 206 IS 5 BP 765 EP 769 DI 10.1093/infdis/jis412 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 988PA UT WOS:000307501800018 PM 22732922 ER PT J AU Caterino, M Chandler, RJ Venditti, CP Ruoppolo, M AF Caterino, M. Chandler, R. J. Venditti, C. P. Ruoppolo, M. TI IDENTIFICATION OF DEREGULATED PROTEINS IN METHYLMALONIC ACIDEMIA (MMA) SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Meeting Abstract C1 [Caterino, M.] Fdn SDN, Naples, Italy. [Chandler, R. J.; Venditti, C. P.] NHGRI, NIH, Bethesda, MD 20892 USA. [Ruoppolo, M.] Univ Naples Federico II, DBBM, Naples, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD SEP PY 2012 VL 35 SU 1 BP S60 EP S60 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 988TH UT WOS:000307513100202 ER PT J AU Huppke, P Brendel, C Kalscheuer, V Korenke, GC Freisinger, P Pitelet, G Wilson, C Moller, LB Kaler, SG Gartner, J AF Huppke, P. Brendel, C. Kalscheuer, V Korenke, G. C. Freisinger, P. Pitelet, G. Wilson, C. Moller, L. B. Kaler, S. G. Gaertner, J. TI MUTATIONS IN SLC33A1 CAUSE AN AUTOSOMAL RECESSIVE LETHAL DISORDER WITH CONGENITAL CATARACTS, BILATERAL HEARING LOSS, DEVELOPMENTAL DELAY AND REDUCED COPPER AND CERULOPLASMIN IN SERUM SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Meeting Abstract C1 [Huppke, P.; Brendel, C.] Univ Med Gottingen, Gottingen, Germany. [Kalscheuer, V] Max Planck Inst Mol Genet, D-14195 Berlin, Germany. [Korenke, G. C.] Childrens Hosp, Dep Neuroped, Oldenburg, Germany. [Freisinger, P.] Klinikum Steinenberg, Reutlingen, Germany. [Pitelet, G.] CHU Nice, Serv Neuropediat, Nice, France. [Wilson, C.] Starship Childrens Hosp, Auckland, New Zealand. [Moller, L. B.] Kennedy Ctr, Glostrup, Denmark. [Kaler, S. G.; Gaertner, J.] NIH, Bethesda, MD 20892 USA. RI Freisinger, Peter/F-2325-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD SEP PY 2012 VL 35 SU 1 BP S17 EP S17 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 988TH UT WOS:000307513100052 ER PT J AU Pandraud, A Clayton, P Foley, AR Muntoni, F Johnson, JO Singleton, AB Reilly, MM Houlden, H AF Pandraud, A. Clayton, P. Foley, A. R. Muntoni, F. Johnson, J. O. Singleton, A. B. Reilly, M. M. Houlden, H. TI INVESTIGATION OF RIBOFLAVIN TRANSPORTER MUTATIONS IN BROWN-VIALETTO-VAN LAERE SYNDROME, A POTENTIALLY TREATABLE METABOLIC DISEASE SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Meeting Abstract C1 [Pandraud, A.; Reilly, M. M.; Houlden, H.] UCL, MRC Ctr Neuromusc Dis, NHNN, ION, London, England. [Clayton, P.] UCL, Dpt Clin Molec Genet, ICH, London, England. [Foley, A. R.; Muntoni, F.] UCL, Dubowitz Neuromusc Ctr, ICH, GOSH, London, England. [Johnson, J. O.; Singleton, A. B.] NIA, Lab Neurogen, NIH, Bethesda, MD 20892 USA. RI Reilly, Mary/C-8482-2013; Houlden, Henry/C-1532-2008; Singleton, Andrew/C-3010-2009 OI Houlden, Henry/0000-0002-2866-7777; NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD SEP PY 2012 VL 35 SU 1 BP S18 EP S18 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 988TH UT WOS:000307513100053 ER PT J AU Schreiber, J Theodore, WH Pearl, PL Gibson, KM AF Schreiber, J. Theodore, W. H. Pearl, P. L. Gibson, K. M. TI PHYSIOLOGICAL MARKERS OF TAURINE THERAPY IN SUCCINIC SEMIALDEHYDE DEHYDROGENASE (SSADH) DEFICIENCY SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Meeting Abstract C1 [Schreiber, J.; Theodore, W. H.] NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. [Pearl, P. L.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Gibson, K. M.] Wash State Univ, Spokane, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD SEP PY 2012 VL 35 SU 1 BP S140 EP S140 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 988TH UT WOS:000307513100489 ER PT J AU DeKlotz, CC Cardin, E Maglione, J Ried, T DeWitt, CA AF DeKlotz, C. C. Cardin, E. Maglione, J. Ried, T. DeWitt, C. A. TI All-Trans-Retinoic Acid and Cetuximab: Effects on Colon Adenocarcinoma Cell Viability SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 42nd Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 07-10, 2012 CL Venice, ITALY SP European Soc Dermatol Res (ESDR) C1 [DeKlotz, C. C.; DeWitt, C. A.] Georgetown Univ Hosp, Washington Hosp Ctr, Washington, DC 20007 USA. [Cardin, E.; Ried, T.] NCI, NIH, Bethesda, MD 20892 USA. [Maglione, J.] Georgetown Univ, Sch Med, Washington, DC USA. 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 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2012 VL 132 SU 2 MA 239 BP S42 EP S42 PG 1 WC Dermatology SC Dermatology GA 992XM UT WOS:000307814000239 ER PT J AU Elentner, A Schmuth, M Hermann, M Gonzalez, F Dubrac, S AF Elentner, A. Schmuth, M. Hermann, M. Gonzalez, F. Dubrac, S. TI Pregnane X Receptor (PXR) modulates CCR7 and Langerhans cell migration via TGF-beta1 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 42nd Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 07-10, 2012 CL Venice, ITALY SP European Soc Dermatol Res (ESDR) C1 [Elentner, A.; Schmuth, M.; Dubrac, S.] Innsbruck Med Univ, Dept Dermatol, Innsbruck, Austria. [Hermann, M.] Dept Gen & Transplant Surg, KTM ZIT Lab, Innsbruck, Austria. [Gonzalez, F.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. 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 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2012 VL 132 SU 2 MA 010 BP S2 EP S2 PG 1 WC Dermatology SC Dermatology GA 992XM UT WOS:000307814000011 ER PT J AU Mascia, F Keith, C Lam, G Yuspa, SH AF Mascia, F. Keith, C. Lam, G. Yuspa, S. H. TI Epidermal ablation of EGFR impairs skin immuno-homeostasis and epithelial differentiation: implication in the pathogenesis of the rash in patients treated with anti EGFR drugs SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 42nd Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 07-10, 2012 CL Venice, ITALY SP European Soc Dermatol Res (ESDR) C1 [Mascia, F.; Keith, C.; Lam, G.; Yuspa, S. H.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2012 VL 132 SU 2 MA 279 BP S50 EP S50 PG 1 WC Dermatology SC Dermatology GA 992XM UT WOS:000307814000279 ER PT J AU Motegi, S Uchiyama, A Yamada, K Ogino, S Takeuchi, Y Udey, MC Ishikawa, O AF Motegi, S. Uchiyama, A. Yamada, K. Ogino, S. Takeuchi, Y. Udey, M. C. Ishikawa, O. TI MFG-E8 promotes wound healing in murine skin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 42nd Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 07-10, 2012 CL Venice, ITALY SP European Soc Dermatol Res (ESDR) C1 [Motegi, S.; Uchiyama, A.; Yamada, K.; Ogino, S.; Takeuchi, Y.; Ishikawa, O.] Gunma Univ, Dept Dermatol, Grad Sch Med, Maebashi, Gumma 371, Japan. [Udey, M. C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2012 VL 132 SU 2 MA 040 BP S8 EP S8 PG 1 WC Dermatology SC Dermatology GA 992XM UT WOS:000307814000041 ER PT J AU Nagao, K Kobayashi, T Kabashima, K Ohyama, M Clausen, BE Udey, MC Amagai, M AF Nagao, K. Kobayashi, T. Kabashima, K. Ohyama, M. Clausen, B. E. Udey, M. C. Amagai, M. TI Stress-induced chemokine production by hair follicles recruit Langerhans cell precursors to skin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 42nd Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 07-10, 2012 CL Venice, ITALY SP European Soc Dermatol Res (ESDR) C1 [Nagao, K.; Kobayashi, T.; Ohyama, M.; Amagai, M.] Keio Univ, Sch Med, Tokyo, Japan. [Kabashima, K.] Kyoto Univ, Kyoto, Japan. [Clausen, B. E.] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Udey, M. C.] NIH, Bethesda, MD 20892 USA. RI Kabashima, Kenji/G-2521-2014; Nagao, Keisuke/J-5116-2013 OI Kabashima, Kenji/0000-0002-0773-0554; Nagao, Keisuke/0000-0002-7005-3138 NR 0 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2012 VL 132 SU 2 MA 639 BP S112 EP S112 PG 1 WC Dermatology SC Dermatology GA 992XM UT WOS:000307814000636 ER PT J AU Nakamura, Y Franchi, L Kambe, N Meng, G Strober, W Nunez, G AF Nakamura, Y. Franchi, L. Kambe, N. Meng, G. Strober, W. Nunez, G. TI Critical Role for Mast Cells in IL-1 beta-Driven Skin Inflammation Accompanying a Disease-Associated Nlrp3 Mutation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 42nd Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 07-10, 2012 CL Venice, ITALY SP European Soc Dermatol Res (ESDR) C1 [Nakamura, Y.; Franchi, L.; Nunez, G.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA. [Nakamura, Y.; Franchi, L.; Nunez, G.] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI USA. [Kambe, N.] Chiba Univ, Grad Sch Med, Dept Dermatol, Chiba, Japan. [Meng, G.] Shanghai Inst Biol Sci, Inst Pasteur Shanghai, Key Lab Mol Virol & Immunol, Unit Innate Immun, Shanghai, Peoples R China. [Strober, W.] NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2012 VL 132 SU 2 MA 632 BP S111 EP S111 PG 1 WC Dermatology SC Dermatology GA 992XM UT WOS:000307814000629 ER PT J AU Wu, C Udey, MC AF Wu, C. Udey, M. C. TI Regulation of Tight Junction Composition and Function by the Claudin-associating Protein EpCAM (CD326) SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 42nd Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 07-10, 2012 CL Venice, ITALY SP European Soc Dermatol Res (ESDR) C1 [Wu, C.; Udey, M. C.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2012 VL 132 SU 2 MA 252 BP S45 EP S45 PG 1 WC Dermatology SC Dermatology GA 992XM UT WOS:000307814000252 ER PT J AU Zhang, XZ Daucher, M Baeza, J Kim, CW Russell, R Kottilil, S AF Zhang, Xiaozhen Daucher, Marybeth Baeza, Josue Kim, Cheol-Woo Russell, Rodney Kottilil, Shyamasundaran TI Human immunodeficiency virus enhances hepatitis C virus replication by differential regulation of IFN and TGF family genes SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE CD4; HIV; HCV; co-infection; pathogenesis ID HCV/HIV COINFECTION; CELL-CULTURE; CYTOKINE EXPRESSION; INDUCED APOPTOSIS; INFECTION; LIVER; HIV-1; BETA; HEPATOCYTES; TIME AB HIV co-infection significantly impacts the natural history of hepatitis C virus (HCV) by increasing plasma HCV viral load, accelerating liver disease progression, and reducing rates of HCV clearance. Cytokines play an important role in regulating hepatic inflammation and fibrogenesis during chronic HCV infection, yet the impact of HIV on cytokine expression is unknown. In this study, an HCV continuous infection cell culture system was modified to permit co-infection with HIV to test the hypothesis that virus-induced disregulation of immune-response genes, particularly interferons and TGF-beta, may create a permissive environment for the initial establishment of HIV/HCV co-infection in the host. CCR5-expressing Huh-7.5 hepatoma cells were transduced with human CD4 antigen to allow HIV infection in vitro. Co-infection of CD4+ Huh-7.5 cells with HIV and HCV or co-culture of HIV-infected CD4+ Huh-7.5 cells and HCV-infected Huh-7.5 cells increased the level of HCV RNA compared to HCV mono-infection. Quantitative gene expression analysis revealed HIV-induced up regulation of most tested IFN family genes when compared to HCV or co-infection. HCV infection induced up regulation of many TGF family genes that were subsequently down-regulated in the presence of HIV or HIV/HCV. Interestingly, co-infection resulted in down regulation of several IFN genes and significant up regulation of TGF-beta genes leading to an overall enhancement of HCV replication. These data suggest that HIV infection may influence HCV replication in vitro by increasing levels of HCV RNA, possibly through the differential regulation of endogenous IFN and TGF family genes. J. Med. Virol. 84:1344-1352, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Zhang, Xiaozhen; Daucher, Marybeth; Baeza, Josue; Kim, Cheol-Woo; Kottilil, Shyamasundaran] NIAID, Immunoregulat Lab, Immunopathogenesis Sect, NIH, Bethesda, MD 20892 USA. [Russell, Rodney] Mem Univ Newfoundland, Fac Med, Hlth Sci Ctr, St John, NF, Canada. RP Kottilil, S (reprint author), Magnuson Clin Ctr, Bldg 10,Room 11N204,10 Ctr Dr, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov FU NIH; National Institute of Allergy and Infectious Diseases FX Grant sponsor: NIH; Grant sponsor: National Institute of Allergy and Infectious Diseases. NR 42 TC 6 Z9 6 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD SEP PY 2012 VL 84 IS 9 BP 1344 EP 1352 DI 10.1002/jmv.23315 PG 9 WC Virology SC Virology GA 977IA UT WOS:000306648800004 PM 22825812 ER PT J AU Stojilkovic, SS Kretschmannova, K Tomic, M Stratakis, CA AF Stojilkovic, S. S. Kretschmannova, K. Tomic, M. Stratakis, C. A. TI Dependence of the Excitability of Pituitary Cells on Cyclic Nucleotides SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Review DE cAMP; cGMP; protein kinase A; protein kinase G; voltage-gated channels ID CYCLASE-ACTIVATING POLYPEPTIDE; RAT ANTERIOR-PITUITARY; CORTICOTROPIN-RELEASING HORMONE; PROTEIN-KINASE-A; INTRACELLULAR CA2+ CONCENTRATION; SECRETING ADENOMA CELLS; GATED SODIUM-CHANNELS; RECTIFYING K+ CURRENT; RECTIFIER POTASSIUM CURRENT; SOLUBLE ADENYLYL-CYCLASE AB Cyclic 3',5'-adenosine monophosphate and cyclic 3',5'-guanosine monophosphate are intracellular (second) messengers that are produced from the nucleotide triphosphates by a family of enzymes consisting of adenylyl and guanylyl cyclases. These enzymes are involved in a broad array of signal transduction pathways mediated by the cyclic nucleotide monophosphates and their kinases, which control multiple aspects of cell function through the phosphorylation of protein substrates. We review the findings and working hypotheses on the role of the cyclic nucleotides and their kinases in the control of electrical activity of the endocrine pituitary cells and the plasma membrane channels involved in this process. C1 Eunice Kennedy Shiver Natl Inst Child Hlth & Huma, Sect Cellular Signalling, NIH, Bethesda, MD USA. Eunice Kennedy Shiver Natl Inst Child Hlth & Huma, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. RP Stojilkovic, SS (reprint author), NICHD, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stankos@helix.nih.gov RI Tomic, Melanija/C-3371-2016 FU National Institute of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The authors are thankful to all past and present members of their laboratories who have contributed to the understanding of the role of cyclic nucleotides and pituitary cells. This work is supported by the National Institute of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural grants. NR 207 TC 1 Z9 1 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD SEP PY 2012 VL 24 IS 9 BP 1183 EP 1200 DI 10.1111/j.1365-2826.2012.02335.x PG 18 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 989FE UT WOS:000307544900001 PM 22564128 ER PT J AU Abramzon, Y Johnson, JO Scholz, SW Taylor, JP Brunetti, M Calvo, A Mandrioli, J Benatar, M Mora, G Restagno, G Chio, A Traynor, BJ AF Abramzon, Yevgeniya Johnson, Janel O. Scholz, Sonja W. Taylor, J. P. Brunetti, Maura Calvo, Andrea Mandrioli, Jessica Benatar, Michael Mora, Gabriele Restagno, Gabriella Chio, Adriano Traynor, Bryan J. TI Valosin-containing protein (VCP) mutations in sporadic amyotrophic lateral sclerosis SO NEUROBIOLOGY OF AGING LA English DT Article DE Amyotrophic lateral sclerosis; Valosin-containing protein; Mutations; Sporadic disease ID INCLUSION-BODY MYOPATHY; FRONTOTEMPORAL DEMENTIA; PAGET-DISEASE; ALS; BONE; FUS; POPULATION; TDP-43 AB We recently reported that mutations in the valosin-containing protein (VCP) gene are a cause of 1%-2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three U. S. cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS but account for <1% of this form of disease. (C) 2012 Elsevier Inc. All rights reserved. C1 [Abramzon, Yevgeniya; Johnson, Janel O.; Traynor, Bryan J.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Scholz, Sonja W.] NIA, Mol Genet Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Scholz, Sonja W.] Georgetown Univ, Dept Neurosci, Washington, DC USA. [Taylor, J. P.] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. [Brunetti, Maura; Restagno, Gabriella] ASO OIRM S, Dept Clin Pathol, Mol Genet Unit, Turin, Italy. [Calvo, Andrea; Chio, Adriano] Univ Turin, Dept Neurosci, Turin, Italy. [Mandrioli, Jessica] S Agostino Estense Hosp, Dept Neurosci, Modena, Italy. [Mandrioli, Jessica] Univ Modena, I-41100 Modena, Italy. [Benatar, Michael] Univ Miami, Dept Neurol, Miami, FL USA. [Mora, Gabriele] ALS Ctr, Salvatore Maugeri Fdn, Milan, Italy. [Traynor, Bryan J.] Johns Hopkins Univ, Dept Neurol, Brain Sci Inst, Baltimore, MD 21218 USA. RP Traynor, BJ (reprint author), NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, 35 Convent Dr,Room 1A-1000, Bethesda, MD 20892 USA. EM traynorb@mail.nih.gov RI Traynor, Bryan/G-5690-2010; Calvo, Andrea/K-4141-2016; MANDRIOLI, JESSICA/K-7235-2016; OI Calvo, Andrea/0000-0002-5122-7243; MANDRIOLI, JESSICA/0000-0002-9244-9782; Chio, Adriano/0000-0001-9579-5341; Scholz, Sonja/0000-0002-6623-0429 FU National Institutes of Health, National Institute on Aging [Z01-AG000949-02]; Packard Center for ALS Research at Hopkins; ALS Association; Fondazione Vialli e Mauro for ALS Research Onlus; Federazione Italiana Giuoco Calcio (FICG); Ministero della Salute (Ricerca Sanitaria Finalizzata) FX This work was supported in part by the Intramural Research Programs of the National Institutes of Health, National Institute on Aging (Z01-AG000949-02). The work was also funded by the Packard Center for ALS Research at Hopkins, the ALS Association, the Fondazione Vialli e Mauro for ALS Research Onlus, Federazione Italiana Giuoco Calcio (FICG), and the Ministero della Salute (Ricerca Sanitaria Finalizzata 2007). DNA samples for this study were obtained in part from the NINDS Human Genetics DNA and Cell Line Repository at Coriell (www.coriell.org). NR 22 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD SEP PY 2012 VL 33 IS 9 AR 2231.e1 DI 10.1016/j.neurobiolaging.2012.04.005 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 981TW UT WOS:000306994600041 PM 22572540 ER PT J AU Zanotti-Fregonara, P Liow, JS Comtat, C Zoghbi, SS Zhang, Y Pike, VW Fujita, M Innis, RB AF Zanotti-Fregonara, Paolo Liow, Jeih-San Comtat, Claude Zoghbi, Sami S. Zhang, Yi Pike, Victor W. Fujita, Masahiro Innis, Robert B. TI Image-derived input function in PET brain studies: blood-based methods are resistant to motion artifacts SO NUCLEAR MEDICINE COMMUNICATIONS LA English DT Article DE image-derived input function; neuroreceptor tracers; PET ID POSITRON-EMISSION-TOMOGRAPHY; QUANTIFICATION; PHOSPHODIESTERASE-4; RECONSTRUCTION; RADIOLIGAND AB Background Image-derived input function (IDIF) from carotid arteries is an elegant alternative to full arterial blood sampling for brain PET studies. However, a recent study using blood-free IDIFs found that this method is particularly vulnerable to patient motion. The present study used both simulated and clinical [C-11](R)-rolipram data to assess the robustness of a blood-based IDIF method (a method that is ultimately normalized with blood samples) with regard to motion artifacts. Methods The impact of motion on the accuracy of IDIF was first assessed with an analytical simulation of a high-resolution research tomograph using a numerical phantom of the human brain, equipped with internal carotids. Different degrees of translational (from 1 to 20 mm) and rotational (from 1 to 15 degrees) motions were tested. The impact of motion was then tested on the high-resolution research tomograph dynamic scans of three healthy volunteers, reconstructed with and without an online motion correction system. IDIFs and Logan-distribution volume (V-T) values derived from simulated and clinical scans with motion were compared with those obtained from the scans with motion correction. Results In the phantom scans, the difference in the area under the curve (AUC) for the carotid time-activity curves was up to 19% for rotations and up to 66% for translations compared with the motionless simulation. However, for the final IDIFs, which were fitted to blood samples, the AUC difference was 11% for rotations and 8% for translations. Logan-V-T errors were always less than 10%, except for the maximum translation of 20 mm, in which the error was 18%. Errors in the clinical scans without motion correction appeared to be minor, with differences in AUC and Logan-V-T always less than 10% compared with scans with motion correction. Conclusion When a blood-based IDIF method is used for neurological PET studies, the motion of the patient affects IDIF estimation and kinetic modeling only minimally. Nucl Med Commun 33:982-989 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Zanotti-Fregonara, Paolo; Liow, Jeih-San; Zoghbi, Sami S.; Zhang, Yi; Pike, Victor W.; Fujita, Masahiro; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Comtat, Claude] CEA SHFJ, Orsay, France. RP Innis, RB (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B1 D43,Ctr Dr,MSC 1026, Bethesda, MD 20892 USA. EM innisr@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX The authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). The authors thank Thada Shantalaxmi for help with the HRRT scan reconstructions. Ioline Henter provided invaluable editorial assistance. NR 23 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0143-3636 J9 NUCL MED COMMUN JI Nucl. Med. Commun. PD SEP PY 2012 VL 33 IS 9 BP 982 EP 989 DI 10.1097/MNM.0b013e328356185c PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 988ZX UT WOS:000307531100012 PM 22760300 ER PT J AU Kessler, RC Avenevoli, S McLaughlin, KA Green, JG Lakoma, MD Petukhova, M Pine, DS Sampson, NA Zaslavsky, AM Merikangas, KR AF Kessler, R. C. Avenevoli, S. McLaughlin, K. A. Green, J. Greif Lakoma, M. D. Petukhova, M. Pine, D. S. Sampson, N. A. Zaslavsky, A. M. Merikangas, K. Ries TI Lifetime co-morbidity of DSM-IV disorders in the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A) SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Adolescence; epidemiology; lifetime co-morbidity; lifetime prevalence; mental disorders; NCS-A ID COMMON MENTAL-DISORDERS; EARLY DEVELOPMENTAL-STAGES; SOCIAL-ANXIETY-DISORDER; AGE-OF-ONSET; DEPRESSIVE-DISORDERS; SUBSTANCE USE; PSYCHIATRIC-DISORDERS; HEALTH SURVEYS; YOUNG-ADULTS; BIRTH COHORT AB Background. Research on the structure of co-morbidity among common mental disorders has largely focused on current prevalence rather than on the development of co-morbidity. This report presents preliminary results of the latter type of analysis based on the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A). Method. A national survey was carried out of adolescent mental disorders. DSM-IV diagnoses were based on the Composite International Diagnostic Interview (CIDI) administered to adolescents and questionnaires self-administered to parents. Factor analysis examined co-morbidity among 15 lifetime DSM-IV disorders. Discrete-time survival analysis was used to predict first onset of each disorder from information about prior history of the other 14 disorders. Results. Factor analysis found four factors representing fear, distress, behavior and substance disorders. Associations of temporally primary disorders with the subsequent onset of other disorders, dated using retrospective age-of-onset (AOO) reports, were almost entirely positive. Within-class associations (e. g. distress disorders predicting subsequent onset of other distress disorders) were more consistently significant (63.2%) than between-class associations (33.0%). Strength of associations decreased as co-morbidity among disorders increased. The percentage of lifetime disorders explained (in a predictive rather than a causal sense) by temporally prior disorders was in the range 3.7-6.9% for earliest-onset disorders [specific phobia and attention deficit hyperactivity disorder (ADHD)] and much higher (23.1-64.3%) for later-onset disorders. Fear disorders were the strongest predictors of most other subsequent disorders. Conclusions. Adolescent mental disorders are highly co-morbid. The strong associations of temporally primary fear disorders with many other later-onset disorders suggest that fear disorders might be promising targets for early interventions. C1 [Kessler, R. C.; Petukhova, M.; Sampson, N. A.; Zaslavsky, A. M.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Avenevoli, S.] NIMH, Div Dev Translat Res, Bethesda, MD 20892 USA. [McLaughlin, K. A.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Gen Pediat, Boston, MA 02115 USA. [Green, J. Greif] Boston Univ, Sch Educ, Boston, MA 02215 USA. [Lakoma, M. D.] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02115 USA. [Pine, D. S.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Merikangas, K. Ries] NIMH, Div Intramural Res Programs, Bethesda, MD 20892 USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM ncs@hcp.med.harvard.edu OI McLaughlin, Katie/0000-0002-1362-2410 FU National Institute of Mental Health (NIMH) [U01-MH60220, R01-MH66627, U01MH060220-09S1, R01-MH070884, R13-MH066849, R01-MH069864, R01-MH077883]; National Institute on Drug Abuse (NIDA) [R01-DA016558]; Substance Abuse and Mental Health Services Administration (SAMHSA); Robert Wood Johnson Foundation (RWJF) [044780]; John W. Alden Trust; NIMH Intramural Research Program; NIMH [R01-MH66627]; Fogarty International Center of the National Institutes of Health [FIRCA R03-TW006481]; John D. and Catherine T. MacArthur Foundation; Pfizer Foundation; Pan American Health Organization; AstraZeneca; Bristol-Myers Squibb; Eli Lilly Company; GlaxoSmithKline; Ortho-McNeil; Pfizer; Sanofi-Aventis; Wyeth; Analysis Group Inc.; EPI-Q; Johnson & Johnson Pharmaceuticals; Ortho-McNeil Janssen Scientific Affairs; Pfizer Inc.; Sanofi-Aventis Groupe; Shire US, Inc. FX The NCS-A is supported by the National Institute of Mental Health (NIMH; U01-MH60220, R01-MH66627 and U01MH060220-09S1) with supplemental support from the National Institute on Drug Abuse (NIDA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; Grant 044780), and the John W. Alden Trust. The work of Dr Merikangas is supported by the NIMH Intramural Research Program. The work of Dr Zaslavsky is supported by NIMH Grant R01-MH66627. A complete list of NCS-A publications can be found at www.hcp.med.harvard.edu/ncs. A public use version of the NCS-A dataset is available for secondary analysis. Instructions for accessing the dataset can be found at www.hcp.med.harvard.edu/ncs/index.php. The NCS-A is carried out in conjunction with the World Health Organization World Mental Health (WMH) Survey Initiative. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation, fieldwork and consultation on data analysis. The WMH Data Coordination Centres have received support from NIMH (R01-MH070884, R13-MH066849, R01-MH069864, R01-MH077883), NIDA (R01-DA016558), the Fogarty International Center of the National Institutes of Health (FIRCA R03-TW006481), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, and the Pan American Health Organization. The WMH Data Coordination Centres have also received unrestricted educational grants from AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Company, GlaxoSmithKline, Ortho-McNeil, Pfizer, Sanofi-Aventis, and Wyeth. A complete list of WMH publications can be found at www.hcp.med.harvard.edu/wmh/. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies, or the US Government. All authors had full access to the survey data. Dr Kessler takes responsibility for the integrity of the data and the accuracy of the data analysis.; R. C. Kessler has been a consultant for AstraZeneca, Analysis Group, Bristol-Myers Squibb, Cerner-Galt Associates, Eli Lilly & Company, GlaxoSmithKline Inc., HealthCore Inc., Health Dialog, Integrated Benefits Institute, John Snow Inc., Kaiser Permanente, Matria Inc., Mensante, Merck & Co., Inc., Ortho-McNeil Janssen Scientific Affairs, Pfizer Inc., Primary Care Network, Research Triangle Institute, Sanofi-Aventis Groupe, Shire US Inc., SRA International, Inc., Takeda Global Research & Development, Transcept Pharmaceuticals Inc., and Wyeth-Ayerst; has served on advisory boards for Appliance Computing II, Eli Lilly & Company, Mindsite, Ortho-McNeil Janssen Scientific Affairs, and Wyeth-Ayerst; and has had research support for his epidemiological studies from Analysis Group Inc., Bristol-Myers Squibb, Eli Lilly & Company, EPI-Q, GlaxoSmithKline, Johnson & Johnson Pharmaceuticals, Ortho-McNeil Janssen Scientific Affairs., Pfizer Inc., Sanofi-Aventis Groupe, and Shire US, Inc. NR 58 TC 71 Z9 72 U1 4 U2 48 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD SEP PY 2012 VL 42 IS 9 BP 1997 EP 2010 DI 10.1017/S0033291712000025 PG 14 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 984LE UT WOS:000307190400021 PM 22273480 ER PT J AU Jiang, CC Zhao, ML Waters, KM Diaz, M AF Jiang, Chuancang Zhao, Ming-Lang Waters, Katherine M. Diaz, Marilyn TI Activation-induced deaminase contributes to the antibody-independent role of B cells in the development of autoimmunity SO AUTOIMMUNITY LA English DT Article DE Somatic hypermutation; AID; B cells; T cells; lupus ID SOMATIC MUTATION; IMMUNE-RESPONSE; STRANDED-DNA; SYSTEMIC AUTOIMMUNITY; GERMINAL-CENTERS; LUPUS NEPHRITIS; DEFICIENT MICE; MRL/LPR MICE; AUTOANTIBODIES; HYPERMUTATION AB B cells contribute to autoimmunity both as secretors of pathogenic antibodies and through the activation of autoreactive T cells. B cells and antibodies acquire higher affinity to self-antigen through a process known as immunoglobulin hypermutation or SHM. The contribution of SHM to pathogenic antibody development in lupus has been established in various autoimmune mouse models and by examining antibodies from patients. However, its role in the antibody-independent contribution of B cells to autoimmunity has not been examined. Herein, we generate lupus-prone MRL/lpr mice with a limited IgM-only B cell repertoire, no secreted antibodies and no SHM. This enabled us to isolate the role of somatic hypermutation in B cell-mediated autoimmunity. We found that SHM-deficiency correlated with a reduction in autoreactive B cells, a decrease in T cell activation and a decrease in kidney lymphocytic infiltration. These data establish AID as an important contributor to the antibody-independent role of B cells in autoimmunity. C1 [Jiang, Chuancang; Zhao, Ming-Lang; Waters, Katherine M.; Diaz, Marilyn] NIEHS, Somat Hypermutat Grp, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Diaz, M (reprint author), NIEHS, Somat Hypermutat Grp, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM diaz@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences [Z01 ES101603] FX The authors declare no conflict of interest. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Project Z01 ES101603. NR 38 TC 6 Z9 6 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0891-6934 J9 AUTOIMMUNITY JI Autoimmunity PD SEP PY 2012 VL 45 IS 6 BP 440 EP 448 DI 10.3109/08916934.2012.682668 PG 9 WC Immunology SC Immunology GA 985VT UT WOS:000307299300002 PM 22559231 ER PT J AU Igarashi, M Kim, HW Gao, F Chang, L Ma, KZ Rapoport, SI AF Igarashi, Miki Kim, Hyung-Wook Gao, Fei Chang, Lisa Ma, Kaizong Rapoport, Stanley I. TI Fifteen weeks of dietary n-3 polyunsaturated fatty acid deprivation increase turnover of n-6 docosapentaenoic acid in rat-brain phospholipids SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article DE Docosapentaenoic; Docosahexaenoic; Turnover; Brain; Diet; PUFA ID ALPHA-LINOLENIC ACID; THIN-LAYER CHROMATOGRAPHY; AIN-93 PURIFIED DIETS; DOCOSAHEXAENOIC ACID; ARACHIDONIC-ACID; PUFA DEPRIVATION; NUTRITIONAL DEPRIVATION; ADULT-RATS; LIVER CONVERSION; BIPOLAR DISORDER AB Docosapentaenoic acid (DPAn-6, 22:5n-6) is an n-6 polyunsaturated fatty acid (PUFA) whose brain concentration can be increased in rodents by dietary n-3 PUPA deficiency, which may contribute to their behavioral dysfunction. We used our in vivo intravenous infusion method to see if brain DPAn-6 turnover and metabolism also were altered with deprivation. We studied male rats that had been fed for 15 weeks post-weaning an n-3 PUFA adequate diet containing 4.6% alpha-linolenic acid (alpha-LNA, 18:3n-3) or a deficient diet (0.2% alpha-LNA), each lacking docosahexaenoic acid (22:6n-3) and arachidonic acid (AA, 20:4n-6). [1-C-14]DPAn-6 was infused intravenously for 5 min in unanesthetized rats, after which the brain underwent high-energy micro-waving, and then was analyzed. The n-3 PUFA deficient compared with adequate diet increased DPAn-6 and decreased DHA concentrations in plasma and brain, while minimally changing brain AA concentration. Incorporation rates of unesterified DPAn-6 from plasma into individual brain phospholipids were increased 5.2-7.7 fold, while turnover rates were increased 2.1-4.7 fold. The observations suggest that increased metabolism and brain concentrations of DPAn-6 and its metabolites, together with a reduced brain DHA concentration, contribute to behavioral and functional abnormalities reported with dietary n-3 PUFA deprivation in rodents. (196 words) Published by Elsevier B.V. C1 [Igarashi, Miki; Kim, Hyung-Wook; Gao, Fei; Chang, Lisa; Ma, Kaizong; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Igarashi, M (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room 1S126, Bethesda, MD 20892 USA. EM miki.i@uci.edu FU National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the National Institute on Aging. The authors thank the NIH Fellows' Editorial Board for editorial assistance. NR 80 TC 7 Z9 8 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 EI 0006-3002 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD SEP PY 2012 VL 1821 IS 9 BP 1235 EP 1243 DI 10.1016/j.bbalip.2011.11.002 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 984NX UT WOS:000307198800007 PM 22142872 ER PT J AU Cheon, Y Kim, HW Igarashi, M Modi, HR Chang, L Ma, KZ Greenstein, D Wohltmann, M Turk, J Rapoport, SI Taha, AY AF Cheon, Yewon Kim, Hyung-Wook Igarashi, Miki Modi, Hiren R. Chang, Lisa Ma, Kaizong Greenstein, Deanna Wohltmann, Mary Turk, John Rapoport, Stanley I. Taha, Ameer Y. TI Disturbed brain phospholipid and docosahexaenoic acid metabolism in calcium-independent phospholipase A(2)-VIA (iPLA(2)beta)-knockout mice SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article DE Mouse; DHA; Turnover; Incorporation; Lipid; PLA2G6 ID POLYUNSATURATED FATTY-ACIDS; INFANTILE NEUROAXONAL DYSTROPHY; CYCLOOXYGENASE-2 KNOCKOUT MOUSE; GROUP-SPECIFIC ASSAYS; N-3 PUFA DEPRIVATION; ALPHA-LINOLENIC ACID; RAT-BRAIN; ARACHIDONIC-ACID; NUTRITIONAL DEPRIVATION; DENDRITIC PATHOLOGY AB Calcium-independent phospholipase A(2) group VIA (iPLA(2)beta) releases docosahexaenoic acid (DNA) from phospholipids in vitro. Mutations in the iPLA(2)beta gene, PLA2G6, are associated with dystonia-parkinsonism and infantile neuroaxonal dystrophy. To understand the role of iPLA(2)beta in brain, we applied our in vivo kinetic method using radiolabeled DHA in 4 to 5-month-old wild type (iPLA(2)beta(+/+)) and knockout (iPLA(2)beta(-/-)) mice, and measured brain DHA kinetics, lipid concentrations, and expression of PLA(2), cyclooxygenase (COX), and lipoxygenase (LOX) enzymes. Compared to iPLA(2)beta(+/+) mice, iPLA(2)beta(-/-) mice showed decreased rates of incorporation of unesterified DHA from plasma into brain phospholipids, reduced concentrations of several fatty acids (including DHA) esterified in ethanolamine- and serine-glycerophospholipids, and increased lysophospholipid fatty acid concentrations. DHA turnover in brain phospholipids did not differ between genotypes. In iPLA(2)beta(-/-) mice, brain levels of iPLA(2)beta mRNA, protein, and activity were decreased, as was the iPLA(2)gamma (Group VIB PLA(2)) mRNA level, while levels of secretory sPLA(2)-V mRNA, protein, and activity and cytosolic cPLA(2)-IVA mRNA were increased. Levels of COX-1 protein were decreased in brain, while COX-2 protein and mRNA were increased. Levels of 5-, 12-, and 15-LOX proteins did not differ significantly between genotypes. Thus, a genetic iPLA(2)beta deficiency in mice is associated with reduced DHA metabolism, profound changes in lipid-metabolizing enzyme expression (demonstrating lack of redundancy) and of phospholipid fatty acid content of brain (particularly of DHA), which may be relevant to neurologic abnormalities in humans with PLA2G6 mutations. Published by Elsevier B.V. C1 [Cheon, Yewon; Kim, Hyung-Wook; Igarashi, Miki; Modi, Hiren R.; Chang, Lisa; Ma, Kaizong; Rapoport, Stanley I.; Taha, Ameer Y.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Greenstein, Deanna] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Wohltmann, Mary; Turk, John] Washington Univ, Sch Med, Dept Med, Mass Spectrometry Facil, St Louis, MO 63110 USA. [Wohltmann, Mary; Turk, John] Washington Univ, Sch Med, Div Endocrinol Metab & Lipid Res, St Louis, MO 63110 USA. RP Cheon, Y (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 9,1S126, Bethesda, MD 20892 USA. EM cheony@mail.nih.gov FU National Institute on Aging; National Institute of Mental Health, National Institutes of Health; NIH [R37-DK34388, P41-RR00954, P60-DK20579, P30-DK56341] FX The work conducted by Y. Cheon, H-W. Kim, M. Igarashi, H. R. Modi, L. Chang, K. Ma, S. I. Rapoport and A. Y. Taha was supported by the Intramural Research Program of the National Institute on Aging and that by D. Greenstein by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. The work conducted by M. Wohltmann and J. Turk was supported by NIH grants R37-DK34388, P41-RR00954, P60-DK20579, and P30-DK56341. We appreciate the editorial assistance of the NIH Fellows Editorial Board. NR 68 TC 17 Z9 18 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD SEP PY 2012 VL 1821 IS 9 BP 1278 EP 1286 DI 10.1016/j.bbalip.2012.02.003 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 984NX UT WOS:000307198800011 PM 22349267 ER PT J AU Agochukwu, NB Solomon, BD Muenke, M AF Agochukwu, Nneamaka B. Solomon, Benjamin D. Muenke, Maximilian TI Impact of genetics on the diagnosis and clinical management of syndromic craniosynostoses SO CHILDS NERVOUS SYSTEM LA English DT Article DE Syndromic craniosynostoses; Craniosynostosis syndromes; Management craniosynostosis; Craniosynostosis; Diagnosis craniosynostosis; FGFR craniosynostosis ID SAETHRE-CHOTZEN-SYNDROME; JACKSON-WEISS-SYNDROME; AUTOSOMAL-DOMINANT CRANIOSYNOSTOSIS; FRONTO-ORBITAL ADVANCEMENT; GROWTH-FACTOR RECEPTOR-2; FGFR1 P252R MUTATION; APERT-SYNDROME; PFEIFFER-SYNDROME; CROUZON-SYNDROME; MUENKE-SYNDROME AB More than 60 different mutations have been identified to be causal in syndromic forms of craniosynostosis. The majority of these mutations occur in the fibroblast growth factor receptor 2 gene (FGFR2). The clinical management of syndromic craniosynostosis varies based on the particular causal mutation. Additionally, the diagnosis of a patient with syndromic craniosynostosis is based on the clinical presentation, signs, and symptoms. The understanding of the hallmark features of particular syndromic forms of craniosynostosis leads to efficient diagnosis, management, and long-term prognosis of patients with syndromic craniosynostoses. A comprehensive literature review was done with respect to the major forms of syndromic craniosynostosis and additional less common FGFR-related forms of syndromic craniosynostosis. Additionally, information and data gathered from studies performed in our own investigative lab (lab of Dr. Muenke) were further analyzed and reviewed. A literature review was also performed with regard to the genetic workup and diagnosis of patients with craniosynostosis. Patients with Apert syndrome (craniosynostosis syndrome due to mutations in FGFR2) are most severely affected in terms of intellectual disability, developmental delay, central nervous system anomalies, and limb anomalies. All patients with FGFR-related syndromic craniosynostosis have some degree of hearing loss that requires thorough initial evaluations and subsequent follow-up. Patients with syndromic craniosynostosis require management and treatment of issues involving multiple organ systems which span beyond craniosynostosis. Thus, effective care of these patients requires a multidisciplinary approach. C1 [Agochukwu, Nneamaka B.; Muenke, Maximilian] NIH, Clin Res Training Program, Bethesda, MD 20892 USA. [Agochukwu, Nneamaka B.; Solomon, Benjamin D.; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Muenke, M (reprint author), NIH, Clin Res Training Program, MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 109 TC 14 Z9 14 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0256-7040 EI 1433-0350 J9 CHILD NERV SYST JI Childs Nerv. Syst. PD SEP PY 2012 VL 28 IS 9 BP 1447 EP 1463 DI 10.1007/s00381-012-1756-2 PG 17 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA 987IS UT WOS:000307411000026 PM 22872262 ER PT J AU Nah, HD Koyama, E Agochukwu, NB Bartlett, SP Muenke, M AF Nah, Hyun-Duck Koyama, Eiki Agochukwu, Nneamaka B. Bartlett, Scott P. Muenke, Maximilian TI Phenotype profile of a genetic mouse model for Muenke syndrome SO CHILDS NERVOUS SYSTEM LA English DT Article DE Muenke syndrome; Genetic mouse model; FGFR3 ID GROWTH-FACTOR RECEPTOR-3; CORONAL CRANIOSYNOSTOSIS; PRO250ARG MUTATION; CRANIAL BASE; HEARING-LOSS; INNER-EAR; CELL FATE; FIBROBLAST; FGFR3; ACHONDROPLASIA AB The Muenke syndrome mutation (FGFR3 (P250R) ), which was discovered 15 years ago, represents the single most common craniosynostosis mutation. Muenke syndrome is characterized by coronal suture synostosis, midface hypoplasia, subtle limb anomalies, and hearing loss. However, the spectrum of clinical presentation continues to expand. To better understand the pathophysiology of the Muenke syndrome, we present collective findings from several recent studies that have characterized a genetically equivalent mouse model for Muenke syndrome (FgfR3 (P244R) ) and compare them with human phenotypes. FgfR3 (P244R) mutant mice show premature fusion of facial sutures, premaxillary and/or zygomatic sutures, but rarely the coronal suture. The mice also lack the typical limb phenotype. On the other hand, the mutant mice display maxillary retrusion in association with a shortening of the anterior cranial base and a premature closure of intersphenoidal and spheno-occipital synchondroses, resembling human midface hypoplasia. In addition, sensorineural hearing loss is detected in all FgfR3 (P244R) mutant mice as in the majority of Muenke syndrome patients. It is caused by a defect in the mechanism of cell fate determination in the organ of Corti. The mice also express phenotypes that have not been previously described in humans, such as reduced cortical bone thickness, hypoplastic trabecular bone, and defective temporomandibular joint structure. Therefore, the FgfR3 (P244R) mouse provides an excellent opportunity to study disease mechanisms of some classical phenotypes of Muenke syndrome and to test novel therapeutic strategies. The mouse model can also be further explored to discover previously unreported yet potentially significant phenotypes of Muenke syndrome. C1 [Nah, Hyun-Duck; Koyama, Eiki] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. [Nah, Hyun-Duck; Bartlett, Scott P.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Agochukwu, Nneamaka B.; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Agochukwu, Nneamaka B.] NIH, Clin Res Training Program, Bethesda, MD 20892 USA. RP Nah, HD (reprint author), Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, 1116G ARC,3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM nah@email.chop.edu FU NIH/NIAMS; Mary Downs Endowment Chair Fund; Division of Intramural Research at the National Human Genome Research Institute (National Institutes of Health, Department of Health and Human Services, United States of America) FX We thank Drs. Steven R. Twigg and Andrew O. Wilkie (Oxford University, Cambridge, UK) for sharing the FgfR3P244R mice with us. The studies on the basicranial synchondrosis and the temporomandibular joint were supported by a grant from NIH/NIAMS to H-D.N. and Mary Downs Endowment Chair Fund to S. P. B. We would like to express our gratitude to our patients for their willingness to take part in ongoing studies at the NIH on Muenke syndrome. These studies were supported in part by the Division of Intramural Research at the National Human Genome Research Institute (National Institutes of Health, Department of Health and Human Services, United States of America). NR 57 TC 5 Z9 5 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0256-7040 J9 CHILD NERV SYST JI Childs Nerv. Syst. PD SEP PY 2012 VL 28 IS 9 BP 1483 EP 1493 DI 10.1007/s00381-012-1778-9 PG 11 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA 987IS UT WOS:000307411000029 PM 22872265 ER PT J AU Shen, YN Cooper, GF AF Shen, Yanna Cooper, Gregory F. TI Multivariate Bayesian modeling of known and unknown causes of events-An application to biosurveillance SO COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE LA English DT Article DE Bayesian modeling; Unknown causes of events; Disease outbreak detection ID OUTBREAKS; ALGORITHM AB This paper investigates Bayesian modeling of known and unknown causes of events in the context of disease-outbreak detection. We introduce a multivariate Bayesian approach that models multiple evidential features of every person in the population. This approach models and detects (1) known diseases (e.g., influenza and anthrax) by using informative prior probabilities and (2) unknown diseases (e.g., a new, highly contagious respiratory virus that has never been seen before) by using relatively non-informative prior probabilities. We report the results of simulation experiments which support that this modeling method can improve the detection of new disease outbreaks in a population. A contribution of this paper is that it introduces a multivariate Bayesian approach for jointly modeling both known and unknown causes of events. Such modeling has general applicability in domains where the space of known causes is incomplete. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Cooper, Gregory F.] Univ Pittsburgh, Dept Biomed Informat, Pittsburgh, PA USA. [Shen, Yanna] Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. [Shen, Yanna] Univ Pittsburgh, Intelligent Syst Program, Pittsburgh, PA USA. RP Shen, YN (reprint author), US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun 38A 9N912A, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM yanna.shen@nih.gov FU National Science Foundation [IIS-0325581, IIS-0911032]; Centers for Disease Control and Prevention [P01-HK000086] FX This research was funded by grants IIS-0325581 and IIS-0911032 from the National Science Foundation and by grant P01-HK000086 from the Centers for Disease Control and Prevention. NR 33 TC 1 Z9 1 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-2607 J9 COMPUT METH PROG BIO JI Comput. Meth. Programs Biomed. PD SEP PY 2012 VL 107 IS 3 BP 436 EP 446 DI 10.1016/j.cmpb.2010.11.015 PG 11 WC Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods; Engineering, Biomedical; Medical Informatics SC Computer Science; Engineering; Medical Informatics GA 983CI UT WOS:000307093400008 PM 21195503 ER PT J AU He, L Long, LR Antani, S Thoma, GR AF He, Lei Long, L. Rodney Antani, Sameer Thoma, George R. TI Histology image analysis for carcinoma detection and grading SO COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE LA English DT Article DE Histopathology; Carcinoma; Histology image analysis; Image segmentation; Feature extraction; Computed assisted diagnosis ID NONLINEAR DIMENSIONALITY REDUCTION; ACTIVE CONTOUR MODELS; BREAST-CANCER; LUNG-CANCER; FLUORESCENCE MICROSCOPY; THRESHOLDING TECHNIQUES; ANISOTROPIC DIFFUSION; TEXTURE FEATURES; TISSUE-SECTIONS; SEGMENTATION AB This paper presents an overview of the image analysis techniques in the domain of histopathology, specifically, for the objective of automated carcinoma detection and classification. As in other biomedical imaging areas such as radiology, many computer assisted diagnosis (CAD) systems have been implemented to aid histopathologists and clinicians in cancer diagnosis and research, which have been attempted to significantly reduce the labor and subjectivity of traditional manual intervention with histology images. The task of automated histology image analysis is usually not simple due to the unique characteristics of histology imaging, including the variability in image preparation techniques, clinical interpretation protocols, and the complex structures and very large size of the images themselves. In this paper we discuss those characteristics, provide relevant background information about slide preparation and interpretation, and review the application of digital image processing techniques to the field of histology image analysis. In particular, emphasis is given to state-of-the-art image segmentation methods for feature extraction and disease classification. Four major carcinomas of cervix, prostate, breast, and lung are selected to illustrate the functions and capabilities of existing CAD systems. Published by Elsevier Ireland Ltd. C1 [He, Lei; Long, L. Rodney; Antani, Sameer; Thoma, George R.] NIH, Natl Lib Med, Bethesda, MD USA. RP He, L (reprint author), NIH, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD USA. EM leihe2005@gmail.com OI Antani, Sameer/0000-0002-0040-1387 FU Intramural Research Program of the National Institutes of Health (NIH); National Library of Medicine (NLM); Lister Hill National Center for Biomedical Communications (LHNCBC) FX This research was supported 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). NR 161 TC 47 Z9 48 U1 1 U2 34 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-2607 EI 1872-7565 J9 COMPUT METH PROG BIO JI Comput. Meth. Programs Biomed. PD SEP PY 2012 VL 107 IS 3 BP 538 EP 556 DI 10.1016/j.cmpb.2011.12.007 PG 19 WC Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods; Engineering, Biomedical; Medical Informatics SC Computer Science; Engineering; Medical Informatics GA 983CI UT WOS:000307093400017 PM 22436890 ER PT J AU Li, H Spencer, SD Lian, L Zhang, Z Lu, P AF Li, H. Spencer, S. D. Lian, L. Zhang, Z. Lu, P. TI Phylogenetic analysis of the nucleoprotein gene of measles viruses prevalent in Nantong, Jiangsu Province, China, during 2010 SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE Measles (rubeola) ID MOLECULAR EPIDEMIOLOGY AB Measles control in China is monitored in part by surveillance of circulating wild-type viruses. The objective of this study was genetic characterization and phylogenetic analysis of measles strains in the Nantong City region of Jiangsu province, China, during 2010. Sera from suspected cases were tested for IgM antibodies and measles virus isolated by inoculation of transport medium onto Vero/SLAM cells. Isolated strains were phylogenetically analysed according to the nucleotide sequence of the C-terminal region of the nucleoprotein gene amplified by RT-PCR. The results revealed 34 cases confirmed by positive IgM, for an incidence of 0.45/100 000. Six isolates identified were all clustered within genotype H1. The findings reported here support continued endemic transmission of measles virus in China. C1 [Li, H.] Nantong Ctr Dis Control & Prevent, Dept Microbiol, Nantong 226007, Jiangsu, Peoples R China. [Spencer, S. D.] NCI, SAIC Frederick Inc, Bethesda, MD 20892 USA. [Lian, L.; Zhang, Z.] Nantong Ctr Dis Control & Prevent, Dept Immunizat Program, Nantong 226007, Jiangsu, Peoples R China. [Lu, P.] Jiangsu Ctr Dis Control & Prevent, Dept Immunizat Program, Nanjing, Jiangsu, Peoples R China. RP Li, H (reprint author), Nantong Ctr Dis Control & Prevent, Dept Microbiol, 99 Hongxing Rd, Nantong 226007, Jiangsu, Peoples R China. EM ntlihaibo@gmail.com FU Jiangsu Prevention Medicine Foundation [YZ201014] FX This study was supported by the financial grants from Jiangsu Prevention Medicine Foundation (YZ201014). NR 8 TC 0 Z9 1 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD SEP PY 2012 VL 140 IS 9 BP 1607 EP 1611 DI 10.1017/S0950268811002433 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 985QR UT WOS:000307283700009 PM 22117136 ER PT J AU Salvadore, G van der Veen, JW Zhang, Y Marenco, S Machado-Vieira, R Baumann, J Ibrahim, LA Luckenbaugh, DA Shen, J Drevets, WC Zarate, CA AF Salvadore, Giacomo van der Veen, Jan Willem Zhang, Yan Marenco, Stefano Machado-Vieira, Rodrigo Baumann, Jacqueline Ibrahim, Lobna A. Luckenbaugh, David A. Shen, Jun Drevets, Wayne C. Zarate, Carlos A., Jr. TI An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE biomarkers; glutamate; glutamine; magnetic resonance spectroscopy (MRS); major depressive disorder (MDD) ID MAGNETIC-RESONANCE-SPECTROSCOPY; D-ASPARTATE ANTAGONIST; RAPID ANTIDEPRESSANT RESPONSE; RESISTANT MAJOR DEPRESSION; ANTERIOR CINGULATE; GLUTAMATERGIC SYSTEM; GABA CONCENTRATIONS; PREFRONTAL CORTEX; OCCIPITAL CORTEX; MOOD DISORDERS AB Amino-acid neurotransmitter system dysfunction plays a major role in the pathophysiology of major depressive disorder (MDD). We used proton magnetic resonance spectroscopy (H-1-MRS) to investigate whether prefrontal levels of amino-acid neurotransmitters predict antidepressant response to a single intravenous infusion of the N-methyl-D-aspartate (NMDA) antagonist ketamine in MDD patients. Fourteen drug-free patients with MDD were scanned 1-3 d before receiving a single intravenous infusion of ketamine (0.5 mg/kg). We measured gamma aminobutyric acid (GABA), glutamate, and Glx/glutamate ratio (a surrogate marker of glutamine) in the ventromedial prefrontal cortex (VM-PFC) and the dorsomedial/dorsal anterolateral prefrontal cortex (DM/DA-PFC). Correlation analyses were conducted to determine whether pretreatment GABA, glutamate, or Glx/glutamate ratio predicted change in depressive and anxiety symptoms 230 min after ketamine administration. Pretreatment GABA or glutamate did not correlate with improved depressive symptoms in either of the two regions of interest (p > 0.1); pretreatment Glx/glutamate ratio in the DM/DA-PFC was negatively correlated with improvement in depressive symptoms [r(s)(11) = -0.57, p < 0.05]. Pretreatment glutamate levels in the VM-PFC were positively correlated with improvement in anxiety symptoms [r(s)(11) = 0.57, p < 0.05]. The findings suggest an association between lower Glx/glutamate ratio and greater improvement in response to ketamine treatment. Because glutamine is mainly contained in glia, the decreased Glx/glutamate ratio observed in this study may reflect the reduction in glial cells found in the same regions in post-mortem studies of individuals with MDD, and suggests that the presence of this neuropathological construct may be associated with antidepressant responsiveness to ketamine. C1 [Salvadore, Giacomo; Machado-Vieira, Rodrigo; Baumann, Jacqueline; Ibrahim, Lobna A.; Luckenbaugh, David A.; Zarate, Carlos A., Jr.] NIMH, Dept Hlth & Human Serv, Expt Therapeut & Pathophysiol Branch, Div Intramural Res Program,NIH, Bethesda, MD 20892 USA. [van der Veen, Jan Willem; Zhang, Yan; Shen, Jun] NIMH, Magnet Resonance Spect Core, NIH, Bethesda, MD 20892 USA. [Marenco, Stefano] NIMH, Gene Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. [Drevets, Wayne C.] Univ Oklahoma, Coll Med, Laureate Inst Brain Res, Dept Psychiat, Tulsa, OK USA. [Machado-Vieira, Rodrigo] Inst & Dept Sao Paulo, LIM27, Sao Paulo, Brazil. RP Salvadore, G (reprint author), Johnson & Johnson PRD, 1125 Trenton Harbourton Rd, Titusville, NJ 08560 USA. EM gsalvado@its.jnj.com RI Marenco, Stefano/A-2409-2008; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI Marenco, Stefano/0000-0002-2488-2365; MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). Ioline Henter (NIMH) provided invaluable editorial assistance. NR 44 TC 27 Z9 27 U1 2 U2 20 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 EI 1469-5111 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD SEP PY 2012 VL 15 IS 8 BP 1063 EP 1072 DI 10.1017/S1461145711001593 PG 10 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 984KH UT WOS:000307188000005 PM 22040773 ER PT J AU Malkesman, O Austin, DR Tragon, T Wang, G Rompala, G Hamidi, AB Cui, ZZ Young, WS Nakazawa, K Zarate, CA Manji, HK Chen, G AF Malkesman, Oz Austin, Daniel R. Tragon, Tyson Wang, Gang Rompala, Gregory Hamidi, Anahita B. Cui, Zhenzhong Young, W. Scott Nakazawa, Kazu Zarate, Carlos A., Jr. Manji, Husseini K. Chen, Guang TI Acute D-serine treatment produces antidepressant-like effects in rodents SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Antidepressant; D-serine; glutamate; N-methyl-D-aspartate receptor (NMDAR); NR1 knockout ID MAJOR DEPRESSIVE DISORDER; D-ASPARTATE ANTAGONIST; STAR-ASTERISK-D; MOOD-DISORDERS; MESSENGER-RNA; ANIMAL-MODELS; RAT-BRAIN; SYNAPTIC PLASTICITY; PREFRONTAL CORTEX; BIPOLAR DISORDER AB Research suggests that dysfunctional glutamatergic signalling may contribute to depression, a debilitating mood disorder affecting millions of individuals worldwide. Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects in approximately 70% of patients. Glutamate evokes the release of D-serine from astrocytes and neurons, which then acts as a co-agonist and binds at the glycine site on the NR1 subunit of NMDA receptors. Several studies have implicated glial deficits as one of the underlying facets of the neurobiology of depression. The present study tested the hypothesis that D-serine modulates behaviours related to depression. The behavioural effects of a single, acute D-serine administration were examined in several rodent tests of antidepressant-like effects, including the forced swim test (FST), the female urine sniffing test (FUST) following serotonin depletion, and the learned helplessness (LH) paradigm. D-serine significantly reduced immobility in the FST without affecting general motor function. Both D-serine and ketamine significantly rescued sexual reward-seeking deficits caused by serotonin depletion in the FUST. Finally, D-serine reversed LH behaviour, as measured by escape latency, number of escapes, and percentage of mice developing LH. Mice lacking NR1 expression in forebrain excitatory neurons exhibited a depression-like phenotype in the same behavioural tests, and did not respond to D-serine treatment. These findings suggest that D-serine produces antidepressant-like effects and support the notion of complex glutamatergic dysfunction in depression. It is unclear whether D-serine has a convergent influence on downstream synaptic plasticity cascades that may yield a similar therapeutic profile to NMDA antagonists like ketamine. C1 [Malkesman, Oz; Austin, Daniel R.; Tragon, Tyson; Wang, Gang; Rompala, Gregory; Hamidi, Anahita B.; Manji, Husseini K.; Chen, Guang] NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. [Cui, Zhenzhong; Young, W. Scott] NIMH, Sect Neural Gene Express, NIH, Bethesda, MD 20892 USA. [Nakazawa, Kazu] NIMH, Unit Genet Cognit & Behav, NIH, Bethesda, MD 20892 USA. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Manji, Husseini K.; Chen, Guang] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. RP Chen, G (reprint author), J&J Pharmaceut Res & Dev LLC, 3210 Merryfield Row, San Diego, CA 92121 USA. EM GChen13@its.jnj.com RI Young, W Scott/A-9333-2009; Nakazawa, Kazutoshi/J-6195-2015; Chen, Guang/A-2570-2017 OI Young, W Scott/0000-0001-6614-5112; Nakazawa, Kazutoshi/0000-0001-5699-9093; FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) FX All authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). H. K. M. and G. C. are currently full-time employees of Johnson and Johnson Pharmaceutical Research and Development (USA); all of this work was initiated and most was conducted while they were employees of the NIMH. A patent application for the use of ketamine in depression has been submitted listing Dr Manji and Dr Zarate among the inventors; they have assigned their rights on the patent to the U.S. Government. NR 73 TC 27 Z9 28 U1 0 U2 15 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD SEP PY 2012 VL 15 IS 8 BP 1135 EP 1148 DI 10.1017/S1461145711001386 PG 14 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 984KH UT WOS:000307188000011 PM 21906419 ER PT J AU Wadiwala, MF Kamal, AK AF Wadiwala, Muhammad Faisal Kamal, Ayeesha Kamran TI What is better antiplatelet agent to prevent recurrent stroke? SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Kamal, Ayeesha Kamran] Aga Khan Univ Hosp, Stroke Serv, Karachi, Pakistan. Aga Khan Univ Hosp, Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. Aga Khan Univ Hosp, Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ Hosp, Stroke Serv, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [D43TW008660, D43 TW008660] NR 1 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2012 VL 62 IS 9 BP 976 EP 977 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 983UJ UT WOS:000307143900028 PM 23139991 ER PT J AU Kron, MA Wang, C Vodanovic-Jankovic, S Howard, OMZ Kuhn, LA AF Kron, Michael A. Wang, Cheng Vodanovic-Jankovic, Sanja Howard, O. M. Zack Kuhn, Leslie A. TI Interleukin-8-like activity in a filarial asparaginyl-tRNA synthetase SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Aminoacyl-tRNA synthetase; Chemokine; Interleukin-8 (IL-8); Filaria; Immunoregulation; Receptors ID N-TERMINAL DOMAIN; BRUGIA-MALAYI; CHEMOKINE RECEPTORS; PROTEIN; CXCR1 AB A wide range of secondary biological functions have been documented for eukaryotic aminoacyl-tRNA synthetases including roles in transcriptional regulation, mitochondrial RNA splicing, cell growth, and chemokine-like activities. The asparaginyl-tRNA synthetase (AsnRS) of the filarial nematode, Brugia malayi, is a highly expressed excretory-secretory molecule which activates interleukin 8 (IL-8) receptors via extracellular domains that are different from those used by IL-8. Recent success in determining the complete atomic structure of the B. malayi AsnRS provided the opportunity to map its chemokine-like activity. Chemotaxis assays demonstrated that IL-8-like activity is localized in a novel 80 amino acid amino terminal substructure. Structural homology searches revealed similarities between that domain in B. malayi AsnRS and substructures involved in receptor binding by human IL-8. These observations provide important new insights into how parasite-derived molecules may play a role in the modulation of immune cell function. (C) 2012 Published by Elsevier B.V. C1 [Kron, Michael A.; Wang, Cheng; Vodanovic-Jankovic, Sanja] Med Coll Wisconsin, Dept Med, Biotechnol & Bioengn Ctr, Milwaukee, WI 53092 USA. [Howard, O. M. Zack] NCI, Mol Immunoregulat Lab, Frederick, MD 21701 USA. [Kuhn, Leslie A.] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. [Kuhn, Leslie A.] Michigan State Univ, Dept Comp Sci & Engn, E Lansing, MI 48824 USA. RP Kron, MA (reprint author), Med Coll Wisconsin, Dept Med, Biotechnol & Bioengn Ctr, C2805 Clin Translat Sci Bldg,8701 Watertown Pk Rd, Milwaukee, WI 53092 USA. EM mkron@mcw.edu RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 FU U.S. National Institutes of Health [NIAID UO1 A153877] FX This work was supported in part by a grant from the U.S. National Institutes of Health (NIAID UO1 A153877) to M.K. and LK. We thank Sai Chetan Sukuru for his early analysis of the AsnRS catalytic and anticodon binding domains for IL-8-like sequence and structural motifs. NR 20 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD SEP PY 2012 VL 185 IS 1 BP 66 EP 69 DI 10.1016/j.molbiopara.2012.06.003 PG 4 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 987MH UT WOS:000307420700009 PM 22710390 ER PT J AU Lerman, BJ Hoffman, EP Sutherland, ML Bouri, K Hsu, DK Liu, FT Rothstein, JD Knoblach, SM AF Lerman, Bruce J. Hoffman, Eric P. Sutherland, Margaret L. Bouri, Khaled Hsu, Daniel K. Liu, Fu-Tong Rothstein, Jeffrey D. Knoblach, Susan M. TI Deletion of galectin-3 exacerbates microglial activation and accelerates disease progression and demise in a SOD1(G93A) mouse model of amyotrophic lateral sclerosis SO BRAIN AND BEHAVIOR LA English DT Article DE Alternative activation; amyotrophic lateral sclerosis; microglia; motor neuron disease; SOD1 AB Galectins are pleiotropic carbohydrate-binding lectins involved in inflammation, growth/differentiation, and tissue remodeling. The functional role of galectins in amyotrophic lateral sclerosis (ALS) is unknown. Expression studies revealed increases in galectin-1 mRNA and protein in spinal cords from SOD1(G93A) mice, and in galectin-3 and -9 mRNAs and proteins in spinal cords of both SOD1(G93A) mice and sporadic ALS patients. As the increase in galectin-3 appeared in early presymptomatic stages and increased progressively through to end stage of disease in the mouse, it was selected for additional study, where it was found to be mainly expressed by microglia. Galectin-3 antagonists are not selective and do not readily cross the blood-brain barrier; therefore, we generated SOD1(G93A)/Gal-3(-/-) transgenic mice to evaluate galectin-3 deletion in a widely used mouse model of ALS. Disease progression, neurological symptoms, survival, and inflammation were assessed to determine the effect of galectin-3 deletion on the SOD1(G93A) disease phenotype. Galectin-3 deletion did not change disease onset, but resulted in more rapid progression through functionally defined disease stages, more severely impaired neurological symptoms at all stages of disease, and expiration, on average, 25 days earlier than SOD1(G93A)/Gal-3(+/+) cohorts. In addition, microglial staining, as well as TNF-alpha, and oxidative injury were increased in SOD1(G93A)/Gal-3(-/-) mice compared with SOD1(G93A)/Gal-3(+/+) cohorts. These data support an important functional role for microglial galectin-3 in neuroinflammation during chronic neurodegenerative disease. We suggest that elevations in galectin-3 by microglia as disease progresses may represent a protective, anti-inflammatory innate immune response to chronic motor neuron degeneration. C1 [Lerman, Bruce J.] George Washington Univ, Sch Med & Hlth Sci, Dept Pharmacol, Washington, DC 20052 USA. [Hoffman, Eric P.; Knoblach, Susan M.] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20052 USA. [Hoffman, Eric P.; Bouri, Khaled; Knoblach, Susan M.] Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. [Hoffman, Eric P.; Bouri, Khaled; Knoblach, Susan M.] Childrens Natl Med Ctr, Ctr Genet Med, Washington, DC 20010 USA. [Sutherland, Margaret L.] NINDS, Neurodegenerat Cluster, NIH, Rockville, MD USA. [Hsu, Daniel K.; Liu, Fu-Tong] Univ Calif Davis, Sch Med, Dept Dermatol, Sacramento, CA 95817 USA. [Rothstein, Jeffrey D.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. RP Knoblach, SM (reprint author), Childrens Natl Med Ctr, Med Genet Res Ctr, 111 Michigan Ave NE, Washington, DC 20010 USA. EM sknoblach@cnmcresearch.org FU NIH/NINDS [NS041679]; NIH NCMRR/NINDS (NCMRR-DC Core Molecular and Functional Outcome Measures in Rehabilitation Medicine) [2R24HD050846-06]; NIH NINDS (Intellectual and Developmental Disabilities Research Center) [5R01NS029525, 1P30HD40677-06] FX This work was partially supported by NIH/NINDS NS041679, NIH NCMRR/NINDS 2R24HD050846-06 (NCMRR-DC Core Molecular and Functional Outcome Measures in Rehabilitation Medicine), and by NIH NINDS 5R01NS029525 (Intellectual and Developmental Disabilities Research Center 1P30HD40677-06). NR 59 TC 19 Z9 19 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2162-3279 J9 BRAIN BEHAV JI Brain Behav. PD SEP PY 2012 VL 2 IS 5 BP 563 EP 575 DI 10.1002/brb3.75 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA V35UT UT WOS:000209174200005 PM 23139902 ER PT J AU Armstrong, AY Eltoukhi, H Segars, JH AF Armstrong, A. Y. Eltoukhi, H. Segars, J. H. TI THE IMPACT OF HEALTH CARE REFORM ON ACCESS TO ART IN THE US SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Armstrong, A. Y.; Eltoukhi, H.; Segars, J. H.] NICHD, Program Reprod & Adult Endocrinol, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-481 BP S254 EP S254 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700845 ER PT J AU Beall, S Moon, K Widra, E DeCherney, A Chang, F Richter, K AF Beall, S. Moon, K. Widra, E. DeCherney, A. Chang, F. Richter, K. TI CHARACTERISTICS PREDICTIVE OF FAILED LEUPROLIDE ACETATE (LA) TRIGGER AMONG PATIENTS UNDERGOING GONADOTROPIN-RELEASING HORMONE (GNRH) ANTAGONIST SUPPRESSION FOR VITRO FERTILIZATION (IVF). SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Beall, S.; Moon, K.; DeCherney, A.; Richter, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Widra, E.; Chang, F.] Shady Grove Fertil Reprod Sci Ctr, Rockville, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-207 BP S172 EP S172 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700575 ER PT J AU Beall, S Moon, K Widra, E DeCherney, A Chang, F Richter, K AF Beall, S. Moon, K. Widra, E. DeCherney, A. Chang, F. Richter, K. TI MATCHED SAMPLES COMPARISON OF IN VITRO FERTILIZATION (IVF) CLINICAL OUTCOMES ASSOCIATED WITH LEUPROLIDE ACETATE ( LA) VERSUS HUMAN CHORIONIC GONADOTROPIN (hCG) TRIGGER FOR OOCYTE MATURATION SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Beall, S.; Moon, K.; DeCherney, A.; Richter, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Widra, E.; Chang, F.] Shady Grove Fertil Reprod Sci Ctr, Rockville, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-175 BP S53 EP S53 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700174 ER PT J AU Beall, S Betz, G Segars, J Chang, F Richter, K AF Beall, S. Betz, G. Segars, J. Chang, F. Richter, K. TI DRAMATIC PROGRAM-WIDE REDUCTION IN THE INCIDENCE OF SEVERE OVARIAN HYPERSTIMULATION SYNDROME (OHSS) REQUIRING PARACENTESIS WITH SELECTIVE USE OF GONADOTROPIN-RELEASING HORMONE (GNRH) AGONIST TRIGGER. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Beall, S.; Segars, J.; Chang, F.; Richter, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Betz, G.] Shady Grove Fertil Reprod Sci Ctr, Rockville, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-204 BP S171 EP S171 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700572 ER PT J AU Beall, S Moon, K Widra, E Segars, J Chang, F Richter, K AF Beall, S. Moon, K. Widra, E. Segars, J. Chang, F. Richter, K. TI HUMAN CHORIONIC GONADOTROPIN (hCG) RE-TRIGGER FOLLOWING A POOR RESPONSE TO LEUPROLIDE ACETATE (LA) TRIGGER IS NOT ASSOCIATED WITH POOR IN VITRO FERTILIZATION (IVF) TREATMENT OUTCOMES SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Beall, S.; Moon, K.; Segars, J.; Richter, K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Widra, E.; Chang, F.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-170 BP S52 EP S52 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700169 ER PT J AU Bolnick, JM Kilburn, BA Bajpayee, S Reddy, N Diamond, MP Armant, DR AF Bolnick, J. M. Kilburn, B. A. Bajpayee, S. Reddy, N. Diamond, M. P. Armant, D. R. TI ISOLATION OF TROPHOBLAST CELLS FROM TRANSCERVICAL SPECIMENS FOR PRENATAL DETERMINATION OF FETAL SEX BY SINGLE-CELL ANALYSIS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Bolnick, J. M.; Kilburn, B. A.; Bajpayee, S.; Reddy, N.; Diamond, M. P.; Armant, D. R.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Armant, D. R.] NICHD, Program Reprod & Adult Endocrinol, NIH, DHHS, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-72 BP S133 EP S133 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700442 ER PT J AU Broomfield, DP Kulak, D Plowden, TC Mumford, S Armstrong, AY AF Broomfield, D. P. Kulak, D. Plowden, T. C. Mumford, S. Armstrong, A. Y. TI SALPINGECTOMY IS COST EFFECTIVE WHEN THE POST SURGICAL PREGNANCY RATE IS TWICE THE PREGNANCY RATE OF PATIENTS WITH HYDROSALPINGES: A DECISION TREE MATHEMATICAL MODEL WITH SENSITIVITY ANALYSIS SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Broomfield, D. P.] Howard Univ Hosp, Obstet & Gynecol, Washington, DC USA. [Kulak, D.] Montefiore Med Ctr, Obstet & Gynecol, Bronx, NY 10467 USA. [Plowden, T. C.] Bayne Jones Army Community Hosp, Obstet & Gynecol, Ft Polk, LA USA. [Mumford, S.] NICHD, Epidemiol & Populat Stat, NIH, Bethesda, MD USA. [Armstrong, A. Y.] NICHD, Clin Serv Program Reprod & Adult Endocrinol, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-595 BP S288 EP S288 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700951 ER PT J AU Brzyski, RG Barnhart, K Santoro, N Eisenberg, E AF Brzyski, R. G. Barnhart, K. Santoro, N. Eisenberg, E. TI IS PARTNER CONSENT FOR A WOMAN'S PARTICIPATION IN FERTILITY CLINICAL TRIALS JUSTIFIED? THE REPRODUCTIVE MEDICINE NETWORK EXPERIENCE. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Brzyski, R. G.] Univ Texas HSC San Antonio, San Antonio, TX USA. [Barnhart, K.] Univ Penn, Med Ctr, Philadelphia, PA 19104 USA. [Santoro, N.] Univ Colorado, Anschutz Med Campus, Aurora, CO USA. [Eisenberg, E.] NICHHD, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-250 BP S74 EP S74 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700247 ER PT J AU Calhoun, K Padilla-Banks, E VandeVoort, C Hunt, P Williams, CJ AF Calhoun, K. Padilla-Banks, E. VandeVoort, C. Hunt, P. Williams, C. J. TI IN THE FETAL RHESUS MONKEY UTERUS, IN UTERO EXPOSURE TO WHOM IT MAY CONCERN: BISPHENOL A (BPA) IS ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND ACCELERATED ADENOGENESIS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Calhoun, K.] Univ N Carolina, Div Reprod Endocrinol, Ob Gyn, Chapel Hill, NC USA. [Padilla-Banks, E.; Williams, C. J.] NIEHS, Reprod Med Grp, Res Triangle Pk, NC 27709 USA. [Hunt, P.] Washington State Univ, Mol BioSci, Pullman, WA 99164 USA. [VandeVoort, C.] Univ Calif Davis, Ob Gyn, Davis, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-106 BP S32 EP S33 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700107 ER PT J AU Catherino, WH Malik, M Britten, J Levy, G Gilden, M AF Catherino, W. H. Malik, M. Britten, J. Levy, G. Gilden, M. TI MIFEPRISTONE, A CLINICALLY EFFECTIVE LEIOMYOMA THERAPY, DIRECTLY REGULATES FIBROSIS IN HUMAN 3-DIMENSIONAL CULTURES. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Catherino, W. H.; Malik, M.; Britten, J.; Levy, G.; Gilden, M.] Uniformed Serv Univ Hlth Sci, Obstet & Gynecol, Bethesda, MD 20814 USA. [Catherino, W. H.; Levy, G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-408 BP S233 EP S233 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700772 ER PT J AU Catherino, WH Malik, M Britten, J Gilden, M AF Catherino, W. H. Malik, M. Britten, J. Gilden, M. TI RAPAMYCIN, WHICH INHIBITS ESTRADIOL-MEDIATED LEIOMYOMA CELL PROLIERATION, HAS MINIMAL IMPACT ON FIBROSIS IN HUMAN 3-DIMENSIONAL CULTURES. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Catherino, W. H.; Malik, M.; Britten, J.; Gilden, M.] Uniformed Serv Univ Hlth Sci, Obstet & Gynecol, Bethesda, MD 20814 USA. [Catherino, W. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-407 BP S232 EP S233 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700771 ER PT J AU Chang, S Driggers, PH Malik, M Wei, Q Segars, JH AF Chang, S. Driggers, P. H. Malik, M. Wei, Q. Segars, J. H. TI EXPRESSION AND PHOSPHORYLATION OF KEY FOCAL ADHESION PROTEINS DIFFERS IN UTERINE LEIOMYOMATA AND MYOMETRIUM, AND IS ALTERED BY TREATMENT WITH ULIPRISTAL ACETATE SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Chang, S.; Driggers, P. H.; Wei, Q.; Segars, J. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Malik, M.] Uniformed Serv Univ Hlth Sci, Obstet & Gynecol, Bethesda, MD 20814 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-396 BP S229 EP S229 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700760 ER PT J AU Chason, RJ Leung, PK DeCherney, AH Segars, JH Catt, KJ AF Chason, R. J. Leung, P. K. DeCherney, A. H. Segars, J. H. Catt, K. J. TI GONADOTROPIN RELEASING HORMONE (GnRH) REDUCES LIGAND-INDUCED ESTROGEN RECEPTOR (ER) DIMERIZATION IN GT1-7 CELLS SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Chason, R. J.; Leung, P. K.; DeCherney, A. H.; Segars, J. H.; Catt, K. J.] NICHD, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-304 BP S202 EP S202 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700670 ER PT J AU Cox, JM Maquire, M DeCherney, AH Richter, KS Levy, M Henne, MB AF Cox, J. M. Maquire, M. DeCherney, A. H. Richter, K. S. Levy, M. Henne, M. B. TI CLOMID-GONADOTROPIN OVARIAN HYPERSTIMULATION AND INTRAUTERINE INSEMINATION: EFFICACY WITH MULTIPLE CYCLES. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Maquire, M.; DeCherney, A. H.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Richter, K. S.; Levy, M.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Cox, J. M.; Henne, M. B.] Walter Reed Natl Mil Med Ctr, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-8 BP S3 EP S3 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700009 ER PT J AU Devine, K Mumford, S Segars, J Armstrong, AY AF Devine, K. Mumford, S. Segars, J. Armstrong, A. Y. TI IS PRE-ART HYSTEROSCOPIC MYOMECTOMY COST-EFFECTIVE IN WOMEN WITH SUBMUCOUS (SM) FIBROIDS SEEKING ART? SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Devine, K.; Segars, J.; Armstrong, A. Y.] NICHD, Program Adult & Reprod Endocrinol, NIH, Bethesda, MD USA. [Mumford, S.] NICHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-397 BP S229 EP S229 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700761 ER PT J AU Devine, K Mumford, S Hodes-Wertz, B Druckenmiller, S Propst, A Noyes, NN AF Devine, K. Mumford, S. Hodes-Wertz, B. Druckenmiller, S. Propst, A. Noyes, N. N. TI BABY BUDGETING: A COST-EFFECTIVENESS ANALYSIS (CEA) OF ELECTIVE OOCYTE CRYOPRESERVATION (EOC) AS A MEANS TO INCREASE LIVE BIRTH RATES (LBR) IN WOMEN DELAYING REPRODUCTION. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Devine, K.] NICHD, Program Adult & Reprod Endocrinol, NIH, Bethesda, MD USA. [Mumford, S.] NICHD, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Hodes-Wertz, B.; Druckenmiller, S.; Noyes, N. N.] NYU Sch Med, NYU Fertil Ctr, New York, NY USA. [Propst, A.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-24 BP S7 EP S8 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700025 ER PT J AU Duke, CMP Khachikyan, I Rosenberg, AZ Guo, XC Segars, JH Armstrong, AY AF Duke, C. M. P. Khachikyan, I. Rosenberg, A. Z. Guo, X. C. Segars, J. H. Armstrong, A. Y. TI THE PROTECTIVE MECHANISM OF CETRORELIX ACETATE IN A CHEMOTHERAPY-INDUCED MURINE MODEL OF OVARIAN DAMAGE. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Duke, C. M. P.] Johns Hopkins Univ, Sch Med, Gynecol & Obstet, Baltimore, MD USA. [Khachikyan, I.; Guo, X. C.; Segars, J. H.; Armstrong, A. Y.] NICHHD, Program Reprod & Adult Endocrinol, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Rosenberg, A. Z.] NIH, Pathol Lab, Ctr Clin, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-236 BP S70 EP S70 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700233 ER PT J AU Gemmill, JAL Sinaii, N Shanis, D Chrousos, G Khachikyan, I Stratton, P AF Gemmill, J. A. L. Sinaii, N. Shanis, D. Chrousos, G. Khachikyan, I. Stratton, P. TI ASSESSMENT OF THE RELATIONSHIP AMONG MULTIFOCAL PAIN, PAIN SEVERITY, DISTURBED SLEEP, AND PSYCHOLOGICAL SYMPTOMS IN WOMEN WITH CHRONIC PELVIC PAIN ASSOCIATED WITH ENDOMETRIOSIS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Gemmill, J. A. L.; Shanis, D.; Chrousos, G.; Khachikyan, I.; Stratton, P.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Sinaii, N.] NIH, Biostat & Clin Epidemiol Serv, CC, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-225 BP S67 EP S67 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700222 ER PT J AU Green, LJ Levy, G Wesley, R Nieman, L Armstrong, A AF Green, L. J. Levy, G. Wesley, R. Nieman, L. Armstrong, A. TI EFFICACY OF ULIPRISTAL ACETATE FOR THE TREATMENT OF SYMPTOMATIC UTERINE LEIOMYOMAS IN AFRICAN AMERICANS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Green, L. J.] Howard Univ Hosp, Obstet & Gynecol, Washington, DC USA. [Levy, G.; Wesley, R.; Nieman, L.; Armstrong, A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-323 BP S96 EP S96 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700319 ER PT J AU Hammoud, AO Schliep, KC Mumford, SL Stanford, JB Porucznik, CA Schisterman, EF AF Hammoud, A. O. Schliep, K. C. Mumford, S. L. Stanford, J. B. Porucznik, C. A. Schisterman, E. F. TI LUTEAL PHASE DEFICIENCY IN NORMAL CYCLING WOMEN. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Hammoud, A. O.] Univ Utah, Obstet & Gynecol, Salt Lake City, UT USA. [Schliep, K. C.; Stanford, J. B.; Porucznik, C. A.] Univ Utah, Family & Prevent Med, Salt Lake City, UT USA. [Mumford, S. L.; Schisterman, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Rockville, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-82 BP S25 EP S26 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700083 ER PT J AU Hill, MJ Heitmann, RJ Richter, K Graham, JR DeCherney, AH Levy, MJ AF Hill, M. J. Heitmann, R. J. Richter, K. Graham, J. R. DeCherney, A. H. Levy, M. J. TI THE NUMBER OF SUPERNUMERARY VITRIFIED BLASTOCYSTS IS POSITIVELY CORRELATED TO IMPLANTATION IN SINGLE BLASTOCYST TRANSFERS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Hill, M. J.; Heitmann, R. J.; Richter, K.; Graham, J. R.; Levy, M. J.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Hill, M. J.; Heitmann, R. J.; DeCherney, A. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-346 BP S102 EP S103 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700341 ER PT J AU Hill, MJ Heitmann, RJ Richter, K Graham, JR DeCherney, AH Widra, E AF Hill, M. J. Heitmann, R. J. Richter, K. Graham, J. R. DeCherney, A. H. Widra, E. TI THE SIMPLIFIED SART EMBRYO SCORING SYSTEM IS HIGHLY CORRELATED TO IMPLANTATION AND LIVE BIRTH IN SINGLE BLASTOCYST TRANSFERS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Hill, M. J.; Heitmann, R. J.; Richter, K.; Graham, J. R.; Widra, E.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Hill, M. J.; Heitmann, R. J.; DeCherney, A. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-533 BP S269 EP S269 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700891 ER PT J AU Hill, MJ Levens, ED Richter, K Graham, JR DeCherney, AH Browne, PE AF Hill, M. J. Levens, E. D. Richter, K. Graham, J. R. DeCherney, A. H. Browne, P. E. TI TROPHECTODERM GRADE, BUT NOT INNER CELL MASS GRADE, IS PREDICTIVE OF OUTCOMES IN SINGLE BLASTOCYST TRANSFERS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Hill, M. J.; Levens, E. D.; Richter, K.; Graham, J. R.; Browne, P. E.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Hill, M. J.; Levens, E. D.; DeCherney, A. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-331 BP S98 EP S98 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700327 ER PT J AU Hill, MJ Levy, G Richter, K DeCherney, A Suthar, G Levy, MJ AF Hill, M. J. Levy, G. Richter, K. DeCherney, A. Suthar, G. Levy, M. J. TI ELEVATED SERUM PROGESTERONE ON THE DAY OF HUMAN CHORIONIC GONADOTROPIN (hCG) TRIGGER NEGATIVELY IMPACTS IMPLANTATION IN BOTH CLEAVAGE AND BLASTOCYST EMBRYO TRANSFERS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Hill, M. J.; Levy, G.; Richter, K.; Suthar, G.; Levy, M. J.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. [Hill, M. J.; Levy, G.; DeCherney, A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-281 BP S83 EP S84 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700277 ER PT J AU Jorge, S Driggers, PH Malik, M Segars, JH AF Jorge, S. Driggers, P. H. Malik, M. Segars, J. H. TI AKAP13 AUGMENTS PROGESTERONE-DEPENDENT GENE ACTIVATION IN FIBROID CELLS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Jorge, S.; Driggers, P. H.; Segars, J. H.] NICHD, Program Adult & Reprod Endocrinol, NIH, Bethesda, MD USA. [Malik, M.] USUHS, Dept ObGyn, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-238 BP S71 EP S71 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700235 ER PT J AU Levy, G Malik, M Britten, J Gilden, M Segars, JH Catherino, WH AF Levy, G. Malik, M. Britten, J. Gilden, M. Segars, J. H. Catherino, W. H. TI LIAROZOLE REDUCES TGF-beta 3 MEDIATED FIBROSIS IN 2-DIMENSIONAL AND 3-DIMENSIONAL LEIOMYOMA CULTURES. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Levy, G.; Segars, J. H.; Catherino, W. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Levy, G.; Malik, M.; Britten, J.; Gilden, M.; Catherino, W. H.] Uniformed Serv Univ Hlth Sci, Dept Ob Gyn, Bethesda, MD 20814 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-401 BP S230 EP S231 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700765 ER PT J AU Levy, G Hill, MJ Comeaux, T Beall, S Segars, JH Csokmay, J AF Levy, G. Hill, M. J. Comeaux, T. Beall, S. Segars, J. H. Csokmay, J. TI SERUM HUMAN CHORIONIC GONADOTROPIN DOES NOT CORRELATE WITH OOCYTE MATURITY SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Levy, G.; Hill, M. J.; Beall, S.; Segars, J. H.; Csokmay, J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Comeaux, T.; Csokmay, J.] Bayne Jones Army Community Hosp, Dept Ob Gyn, Ft Polk, LA 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-567 BP S279 EP S279 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700924 ER PT J AU Libfraind, LL Richter, KS Wolff, EF Geddes, K Levy, MJ AF Libfraind, L. L. Richter, K. S. Wolff, E. F. Geddes, K. Levy, M. J. TI A SHARED RISK (SR) REFUND PROGRAM FOR IN VITRO FERTILIZATION (IVF) TREATMENT RECEIVES STRONG ENDORSEMENT FROM PARTICIPANTS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Libfraind, L. L.; Wolff, E. F.] NIH, Bethesda, MD 20892 USA. [Richter, K. S.; Geddes, K.; Levy, M. J.] Shady Grove Fertil Reprod Sci Ctr, Rockville, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-423 BP S237 EP S237 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700787 ER PT J AU Malik, M Britten-Webb, J Catherino, WH AF Malik, M. Britten-Webb, J. Catherino, W. H. TI LEIOMYOMA CELL REGULATION VIA THE PROFIBROBLASTIC PROTEIN LAMININ, RESULTS IN SPATIAL ORGANIZATION SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Malik, M.; Britten-Webb, J.; Catherino, W. H.] USUHS, Obstet & Gynecol, Bethesda, MD USA. [Catherino, W. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-237 BP S71 EP S71 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700234 ER PT J AU Malik, M Britten-Webb, J Levy, G Gilden, M Catherino, WH AF Malik, M. Britten-Webb, J. Levy, G. Gilden, M. Catherino, W. H. TI TGFBETA MEDIATED FIBROSIS IN LEIOMYOMA CELLS WORKS THROUGH THE SMAD DEPENDENT SIGNALING AND NOT THROUGH MAPK/ERK PATHWAY SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Malik, M.; Britten-Webb, J.; Levy, G.; Gilden, M.; Catherino, W. H.] USUHS, Obstet & Gynecol, Bethesda, MD USA. [Levy, G.; Catherino, W. H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-243 BP S72 EP S72 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700240 ER PT J AU Muneyyirci-Delale, O Charles, C Sinaii, N Anopa, J Dalloul, M Stratton, P AF Muneyyirci-Delale, O. Charles, C. Sinaii, N. Anopa, J. Dalloul, M. Stratton, P. TI CHANGES IN SELF-REPORTED SYMPTOMS OF WOMEN WITH ENDOMETRIOSIS DURING TREATMENT. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Muneyyirci-Delale, O.; Charles, C.; Anopa, J.; Dalloul, M.] Suny Downstate Med Ctr, Obstet & Gynecol, Brooklyn, NY 11203 USA. [Muneyyirci-Delale, O.] Kings Cty Hosp Ctr, Obstet & Gynecol, Brooklyn, NY USA. [Sinaii, N.] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. [Stratton, P.] NICHD, Program Reprod & Adult Endocrinol, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-346 BP S215 EP S215 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700712 ER PT J AU Pal, L Williams, J AF Pal, L. Williams, J. CA Reprod Med Network Investigators TI VITAMIN D (VitD) STATUS PREDICTS PCOS RELATED INFERTILITY TREATMENT SUCCESS: RETROSPECTIVE COHORT ANALYSIS OF 25OHD LEVELS IN STORED SERA FROM A RCT OF CLOMID (CC) VS. METFORMIN (M) VS. (CC plus M) IN PCOS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Pal, L.; Williams, J.] Yale Univ, Obstet Gynecol & Reprod Sci, New Haven, CT USA. [Reprod Med Network Investigators] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S BP S62 EP S62 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700206 ER PT J AU Stanford, JB Schliep, KC Chen, Z Xie, Y Louis, GMB Peterson, CM AF Stanford, J. B. Schliep, K. C. Chen, Z. Xie, Y. Louis, G. M. Buck Peterson, C. M. TI COMPARABILITY OF ENDOMETRIOSIS DIAGNOSIS AND STAGING BY OPERATING SURGEON AND EXPERT REVIEWER DURING REAL-TIME LAPAROSCOPY IN THE ENDO STUDY. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Stanford, J. B.; Schliep, K. C.] Univ Utah, Family & Prevent Med, Salt Lake City, UT USA. [Chen, Z.; Xie, Y.; Louis, G. M. Buck] NICHHD, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. [Peterson, C. M.] Univ Utah, Obstet & Gynecol, Salt Lake City, UT 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-352 BP S216 EP S216 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700718 ER PT J AU Yu, B DeCherney, A Segars, J Ignaszewski, A Russanova, V Howard, B AF Yu, B. DeCherney, A. Segars, J., Jr. Ignaszewski, A. Russanova, V. Howard, B. TI DIMINISHED OVARIAN FUNCTION IS ASSOCIATED WITH DISTINCTIVE DNA METHYLOME CHANGES IN HUMAN OVARIAN GRANULOSA CELLS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Yu, B.; DeCherney, A.; Segars, J., Jr.] NICHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Ignaszewski, A.] Shady Grove Fertil Reprod Sci Ctr, Embryol Lab, Rockville, MD USA. [Russanova, V.; Howard, B.] NICHD, Program Genom Differentiat, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-197 BP S59 EP S59 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700195 ER PT J AU Ariza, J Jodar, L Mercken, EM Carboneau, B de Cabo, R Villalba, JM AF Ariza, J. Jodar, L. Mercken, E. M. Carboneau, B. de Cabo, R. Villalba, J. M. TI Hormetic response via Nrf2 in mice with a genetic deletion of the antioxidant enzyme NQO1 SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract DE Nrf2; NQO1; Oxidative stress; Hormesis C1 [Ariza, J.; Jodar, L.; Villalba, J. M.] Univ Cordoba, E-14071 Cordoba, Spain. [Mercken, E. M.; Carboneau, B.; de Cabo, R.] NIA, Lab Expt Gerontol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 SEP PY 2012 VL 53 SU 1 MA 0524 BP S126 EP S127 DI 10.1016/j.freeradbiomed.2012.08.264 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40LT UT WOS:000209480800261 ER PT J AU Finkel, T AF Finkel, T. TI Oxidants, DNA damage and stem cell function SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract C1 [Finkel, T.] NIH, New York, NY 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 SEP PY 2012 VL 53 SU 1 MA 6.4 BP S15 EP S15 DI 10.1016/j.freeradbiomed.2012.08.102 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40LT UT WOS:000209480800031 ER PT J AU Nagababu, E AF Nagababu, E. TI Glutathione-hemin complex catalyzes S-nitrosothiol formation under hypoxia conditions SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract DE S-nitrosothiols; Nitric oxide; hemin; Glutathione C1 [Nagababu, E.] NIA, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD SEP PY 2012 VL 53 SU 1 MA 0650 BP S189 EP S189 DI 10.1016/j.freeradbiomed.2012.08.397 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40LT UT WOS:000209480800393 ER PT J AU Scott, I Webster, BR Sack, MN AF Scott, I. Webster, B. R. Sack, M. N. TI A conserved prokaryotic region of GCN5L1 is required for mitochondrial acetyltransferase function SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract DE Mitochondria; Acetyltransferase; GCN5L1; SIRT3 C1 [Scott, I.; Webster, B. R.; Sack, M. N.] NHLBI, 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 SEP PY 2012 VL 53 SU 1 MA 6 BP S37 EP S38 DI 10.1016/j.freeradbiomed.2012.08.500 PG 2 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40LT UT WOS:000209480800078 ER PT J AU Summers, FA Mason, RP Ehrenshaft, M AF Summers, F. A. Mason, R. P. Ehrenshaft, M. TI DNA radical detection using immunoblotting SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Meeting Abstract DE DNA; oxidation; immuno-spin trapping; peroxiredoxin C1 [Summers, F. A.; Mason, R. P.; Ehrenshaft, M.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 1 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 SEP PY 2012 VL 53 SU 1 MA 0223 BP S218 EP S218 DI 10.1016/j.freeradbiomed.2012.08.457 PG 1 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA V40LT UT WOS:000209480800453 ER PT J AU Koonin, EV Wolf, YI AF Koonin, Eugene V. Wolf, Yuri I. TI Evolution of microbes and viruses: a paradigm shift in evolutionary biology? SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Review DE Darwin; modern synthesis; comparative genomics; tree of life; horizontal gene transfer ID HORIZONTAL GENE-TRANSFER; DIVERSITY-GENERATING RETROELEMENTS; ESCHERICHIA-COLI O157-H7; TRANSFER-RNA SYNTHETASES; GENOME EVOLUTION; TRANSPOSABLE ELEMENTS; PHYLOGENETIC TREES; MULLERS RATCHET; NEISSERIA-GONORRHOEAE; BACTERIAL EVOLUTION AB When Charles Darwin formulated the central principles of evolutionary biology in the Origin of Species in 1859 and the architects of the Modern Synthesis integrated these principles with population genetics almost a century later, the principal if not the sole objects of evolutionary biology were multicellular eukaryotes, primarily animals and plants. Before the advent of efficient gene sequencing, all attempts to extend evolutionary studies to bacteria have been futile. Sequencing of the r-RNA genes in thousands of microbes allowed the construction of the three- domain "ribosomal Tree of Life" that was widely thought to have resolved the evolutionary relationships between the cellular life forms. However, subsequent massive sequencing of numerous, complete microbial genomes revealed novel evolutionary phenomena, the most fundamental of these being: (1) pervasive horizontal gene transfer (HGT), in large part mediated by viruses and plasmids, that shapes the genomes of archaea and bacteria and call for a radical revision (if not abandonment) of the Tree of Life concept, (2) Lamarckian-type inheritance that appears to be critical for antivirus defense and other forms of adaptation in prokaryotes, and (3) evolution of evolvability, i.e., dedicated mechanisms for evolution such as vehicles for HGT and stress-induced mutagenesis systems. In the non-cellular part of the microbial world, phylogenomics and metagenomics of viruses and related selfish genetic elements revealed enormous genetic and molecular diversity and extremely high abundance of viruses that come across as the dominant biological entities on earth. Furthermore, the perennial arms race between viruses and their hosts is one of the defining factors of evolution. Thus, microbial phylogenomics adds new dimensions to the fundamental picture of evolution even as the principle of descent with modification discovered by Darwin and the laws of population genetics remain at the core of evolutionary biology. C1 [Koonin, Eugene V.; Wolf, Yuri I.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike,NIH Bldg 38a, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services FX The authors research is supported by intramural funds of the US Department of Health and Human Services (to National Library of Medicine, NIH). NR 202 TC 40 Z9 43 U1 4 U2 88 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD SEP PY 2012 VL 2 AR UNSP 119 DI 10.3389/fcimb.2012.00119 PG 15 WC Immunology; Microbiology SC Immunology; Microbiology GA 221BI UT WOS:000324631800005 PM 22993722 ER PT J AU Gomez, J AF Gomez, J. TI MOLECULAR PROFILING OF STAGE II AND III BREAST CANCER IN LATIN AMERICAN WOMEN RECEIVING STANDARD-OF-CARE TREATMENT SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract DE cancer genetics C1 [Gomez, J.] NCI, Off Latin Amer Canc Program Dev US LACRN, Washington, DC USA. EM gallion@uthscsa.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA S187 BP S75 EP S75 PG 1 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000183 ER PT J AU Groffen, DAI Bosma, H Koster, A Von Bonsdorff, MB Eiriksdottir, G Aspelund, T Penninx, BW Kempen, GI Kirschbaum, C Harris, TB Gudnason, V AF Groffen, D. A. I. Bosma, H. Koster, A. Von Bonsdorff, M. B. Eiriksdottir, G. Aspelund, T. Penninx, B. W. Kempen, G. I. Kirschbaum, C. Harris, T. B. Gudnason, V. TI EDUCATIONAL LEVEL, SALIVARY CORTISOL, AND ALL CAUSE MORTALITY IN AN OLDER POPULATION. RESULTS FROM THE AGES-REYKJAVIK STUDY SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Groffen, D. A. I.; Bosma, H.; Koster, A.] Maastricht Univ, Dept Social Med, CAPHRI Sch Publ Hlth & Primary Care, Maastricht, Netherlands. [Von Bonsdorff, M. B.] Gerontol Res Ctr, Dept Hlth Sci, Jyvaskyla, Finland. [Eiriksdottir, G.; Aspelund, T.; Gudnason, V.] Iceland Heart Assoc, Reykjavik, Iceland. [Penninx, B. W.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Kempen, G. I.] Maastricht Univ, Dept Hlth Serv Res, CAPHRI Sch Publ Hlth & Primary Care, Maastricht, Netherlands. [Kirschbaum, C.] Tech Univ Dresden, Biol Psychol, Dresden, Germany. [Harris, T. B.] NIA, NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. EM d.groffen@maastrichtuniversity.nl NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA O785 BP S316 EP S316 PG 1 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000757 ER PT J AU Kaufmann, PG Powell, LH Freedland, KE AF Kaufmann, P. G. Powell, L. H. Freedland, K. E. TI DESIGN AND EXECUTION OF RANDOMIZED CLINICAL TRIALS INVOLVING BEHAVIORAL INTERVENTIONS - Part I. SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Kaufmann, P. G.] NHLBI, Bethesda, MD 20892 USA. [Powell, L. H.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Freedland, K. E.] Washington Univ, St Louis, MO USA. EM kaufmann@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA 1 BP S1 EP S1 PG 1 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000002 ER PT J AU Kaufmann, PG Powell, LH Freedland, KE AF Kaufmann, P. G. Powell, L. H. Freedland, K. E. TI DESIGN AND EXECUTION OF RANDOMIZED CLINICAL TRIALS INVOLVING BEHAVIORAL INTERVENTIONS - PART II. SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract C1 [Kaufmann, P. G.] NHLBI, Bethesda, MD 20892 USA. [Powell, L. H.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Freedland, K. E.] Washington Univ, St Louis, MO USA. EM kaufmann@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA 6 BP S2 EP S2 PG 1 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000006 ER PT J AU McBride, M Persky Wagner, K Faith, S Ward, S AF McBride, M. Persky Wagner, K. Faith, S. Ward, S. TI USING A VIRTUAL REALITY BUFFET TO ASSESS MOTHERS' BEHAVIORAL RESPONSES TO FAMILY HISTORY ASSESSMENT OF THEIR CHILDREN'S RISK FOR OBESITY SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract DE eating behaviors; children's health; genetics C1 [McBride, M.; Persky] NIH, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Wagner, K.] Univ North Carolina Chapel Hill, Hlth Behav & Hlth Educ, Chapel Hill, NC USA. [Faith, S.; Ward, S.] Univ North Carolina Chapel Hill, Nutr, Chapel Hill, NC USA. EM cmcbride@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA O549 BP S219 EP S219 PG 1 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000529 ER PT J AU Evans, S Almahdi, B Sultan, P Sohanpal, I Brandner, B Collier, T Shergill, SS Cregg, R Averbeck, BB AF Evans, Simon Almahdi, Basil Sultan, Pervez Sohanpal, Imrat Brandner, Brigitta Collier, Tracey Shergill, Sukhi S. Cregg, Roman Averbeck, Bruno B. TI Performance on a probabilistic inference task in healthy subjects receiving ketamine compared with patients with schizophrenia SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE Ketamine; decision making; schizophrenia ID STRIATAL DOPAMINE; REASONING BIASES; THOUGHT-DISORDER; LINKING BIOLOGY; WORKING-MEMORY; PSYCHOSIS; DELUSIONS; VOLUNTEERS; CONCLUSIONS; COGNITION AB Evidence suggests that some aspects of schizophrenia can be induced in healthy volunteers through acute administration of the non-competitive NMDA-receptor antagonist, ketamine. In probabilistic inference tasks, patients with schizophrenia have been shown to 'jump to conclusions' (JTC) when asked to make a decision. We aimed to test whether healthy participants receiving ketamine would adopt a JTC response pattern resembling that of patients. The paradigmatic task used to investigate JTC has been the 'urn' task, where participants are shown a sequence of beads drawn from one of two 'urns', each containing coloured beads in different proportions. Participants make a decision when they think they know the urn from which beads are being drawn. We compared performance on the urn task between controls receiving acute ketamine or placebo with that of patients with schizophrenia and another group of controls matched to the patient group. Patients were shown to exhibit a JTC response pattern relative to their matched controls, whereas JTC was not evident in controls receiving ketamine relative to placebo. Ketamine does not appear to promote JTC in healthy controls, suggesting that ketamine does not affect probabilistic inferences. C1 [Evans, Simon; Averbeck, Bruno B.] UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. [Almahdi, Basil; Sultan, Pervez; Sohanpal, Imrat; Brandner, Brigitta; Cregg, Roman] Univ Coll Hosp, London, England. [Shergill, Sukhi S.] Kings Coll London, Inst Psychiat, Dept Psychiat, Cognit Schizophrenia & Imaging Lab, London, England. [Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Evans, S (reprint author), UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. EM sle27@sussex.ac.uk FU MRC; Wellcome Trust FX This work was supported by an MRC studentship to SE and a Wellcome Trust grant to BA. NR 51 TC 8 Z9 8 U1 3 U2 7 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 SEP PY 2012 VL 26 IS 9 BP 1211 EP 1217 DI 10.1177/0269881111435252 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 982CE UT WOS:000307018500006 PM 22389244 ER PT J AU Kong, A Beresford, SAA Alfano, CM Schubert, KEF Neuhouser, ML Johnson, DB Duggan, C Wang, CY Xiao, LR Jeffery, RW Bain, CE McTiernan, A AF Kong, Angela Beresford, Shirley A. A. Alfano, Catherine M. Schubert, Karen E. Foster Neuhouser, Marian L. Johnson, Donna B. Duggan, Catherine Wang, Ching-Yun Xiao, Liren Jeffery, Robert W. Bain, Carolyn E. McTiernan, Anne TI Self-Monitoring and Eating-Related Behaviors Are Associated with 12-Month Weight Loss in Postmenopausal Overweight-to-Obese Women SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Women; Behavioral strategies; Eating behaviors; Weight loss AB Lifestyle-based interventions, which typically promote various behavior modification strategies, can serve as a setting for evaluating specific behaviors and strategies thought to promote or hinder weight loss. The aim of our study was to test the associations of self-monitoring (ie, self-weighing and food journal completion) and eating-related (ie, dietary intake, diet-related weight-control strategies, and meal patterns) behaviors with weight loss in a sample of postmenopausal overweight-to-obese women enrolled in a 12-month dietary weight loss intervention. Changes in body weight and adoption of self-monitoring and eating-related behaviors were assessed in 123 participants. Generalized linear models tested associations of these behaviors with 12-month weight change after adjusting for potential confounders. Mean percent weight loss was 10.7%. In the final model, completing more food journals was associated with a greater percent weight loss (interquartile range 3.7% greater weight loss; P<0.0001), whereas skipping meals (4.3% lower weight loss; P<0.05) and eating out for lunch (at least once a week, 2.5% lower weight loss; P<0.01) were associated with a lower amount of weight loss. These findings suggest that a greater focus on dietary self-monitoring, home-prepared meals, and consuming meals at regular intervals may improve 12-month weight loss among postmenopausal women enrolled in a dietary weight loss intervention. C1 [Kong, Angela] Univ Illinois, Inst Hlth Res & Policy, Canc Educ & Career Dev Program, Chicago, IL USA. [Beresford, Shirley A. A.; Schubert, Karen E. Foster; Johnson, Donna B.] Univ Washington, Ctr Publ Hlth Nutr, Seattle, WA 98195 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98109 USA. [Duggan, Catherine; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Prevent Ctr, Seattle, WA 98109 USA. [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98109 USA. [Xiao, Liren; Bain, Carolyn E.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Jeffery, Robert W.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. RP McTiernan, A (reprint author), Fred Hutchinson Canc Res Ctr, Prevent Ctr, M4-B874,POB 19024, Seattle, WA 98109 USA. EM amctiern@fhcrc.org RI Duggan, Catherine/F-9414-2015 OI Duggan, Catherine/0000-0001-7369-4021 FU National Cancer Institute [R01 CA105204-01A1, U54-CA116847, R25CA094880, 2R25CA057699]; National Center for Research Resources [5KL2RR025015-03] FX This work was supported by grant nos. R01 CA105204-01A1, U54-CA116847, R25CA094880, and 2R25CA057699 from the National Cancer Institute and no. 5KL2RR025015-03 from the National Center for Research Resources. NR 54 TC 14 Z9 14 U1 1 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD SEP PY 2012 VL 112 IS 9 BP 1428 EP 1435 DI 10.1016/j.jand.2012.05.014 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA V33ZV UT WOS:000209057600019 PM 22795495 ER PT J AU Glasgow, RE Kurz, D Dickman, JM Osuna, D Strycker, L King, DK AF Glasgow, Russell E. Kurz, Deanna Dickman, Jennifer M. Osuna, Diego Strycker, Lisa King, Diane K. TI Linking internet-based diabetes self-management to primary care: lessons learned and implications for research translation and practice implementation SO TRANSLATIONAL BEHAVIORAL MEDICINE LA English DT Article DE Implementation; Primary care; Chronic disease self-management; Integration; Health technology AB There has been little discussion of or research on the key translational issue of how to integrate patient self-management programs across multiple primary care clinics within an HMO. The purpose of this study was to summarize our experiences and lessons learned in trying to integrate information from a web-based diabetes self-management program into primary care and the electronic health record (EHR). We describe plans, implementation, adaptations made, and data on patient and physician reactions to the My Path diabetes self-management program provided to 331 adult primary care patients. Mixed methods results revealed that, despite the availability of a state-of-the-art EHR, the intervention was not well integrated into primary care. Information from health-promotion and disease management programs, even within the same organization and with advanced EHR systems, is challenging to integrate into busy primary care. C1 [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Kurz, Deanna; Dickman, Jennifer M.; Osuna, Diego] Kaiser Permanente Colorado, Denver, CO USA. [Strycker, Lisa] Oregon Res Inst, Eugene, OR 97403 USA. [King, Diane K.] Univ Alaska, Fairbanks, AK 99701 USA. RP Glasgow, RE (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 6144, Rockville, MD 20852 USA. EM glasgowre@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases [DK35524] FX This paper is dedicated to the memory of Dr. Osuna, whose commitment to reducing health disparities and to integrating research and practice was an inspiration to us. This study was supported by grant DK35524 from the National Institute of Diabetes and Digestive and Kidney Diseases. All authors declare no conflicts of interest. Dr. Glasgow is now Deputy Director for Implementation Science, Division of Cancer Control and Population Sciences, National Cancer Institute. The opinions in this article do not necessarily represent those of the National Cancer Institute or any other body. NR 33 TC 1 Z9 1 U1 2 U2 4 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1869-6716 EI 1613-9860 J9 TRANSL BEHAV MED JI Transl. Behav. Med. PD SEP PY 2012 VL 2 IS 3 BP 313 EP 321 DI 10.1007/s13142-012-0109-8 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V39LM UT WOS:000209412500013 PM 24073131 ER PT J AU Nagpal, R Kumar, A Kumar, M Behare, PV Jain, S Yadav, H AF Nagpal, Ravinder Kumar, Ashwani Kumar, Manoj Behare, Pradip V. Jain, Shalini Yadav, Hariom TI Probiotics, their health benefits and applications for developing healthier foods: a review SO FEMS MICROBIOLOGY LETTERS LA English DT Review DE dairy foods; functional foods; gut microbial communities; lactic acid bacteria; lactobacillus; probiotics ID LACTIC-ACID-BACTERIA; LACTOBACILLUS-ACIDOPHILUS NCFM; RHAMNOSUS STRAIN GG; COLON CARCINOGENESIS; HUMAN GUT; IN-VITRO; BIFIDOBACTERIUM-LONGUM; GASTROINTESTINAL-TRACT; GROWTH-CHARACTERISTICS; INTESTINAL MICROFLORA AB In the industrialized world, functional foods have become a part of an everyday diet and are demonstrated to offer potential health benefits beyond the widely accepted nutritional effects. Currently, the most important and frequently used functional food compounds are probiotics and prebiotics, or they are collectively known as synbiotics. Moreover, with an already healthy image, dairy products appear to be an excellent mean for inventing nutritious foods. Such probiotic dairy foods beneficially affect the host by improving survival and implantation of live microbial dietary supplements in the gastrointestinal flora, by selectively stimulating the growth or activating the catabolism of one or a limited number of health-promoting bacteria in the intestinal tract, and by improving the gastrointestinal tract's microbial balance. Hence, the paper reviews the current scenario of probiotics and their prospective potential applications for functional foods for better health and nutrition of the society. C1 [Nagpal, Ravinder] Shaheed Udham Singh Coll Res & Technol, Dept Microbiol & Biotechnol, Mohali, Punjab, India. [Kumar, Ashwani] Seth Jai Parkash Mukand Lal Inst Engn & Technol, Dept Biotechnol, Radaur, Haryana, India. [Kumar, Manoj] Natl Inst Nutr, Dept Microbiol & Immunol, Hyderabad 500007, Andhra Pradesh, India. [Behare, Pradip V.] Natl Dairy Res Inst, Dairy Microbiol Div, Karnal 132001, Haryana, India. [Jain, Shalini; Yadav, Hariom] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Kumar, A (reprint author), JMIT, Dept Biotechnol, Radaur 135133, Haryana, India. EM ashwanindri@rediffmail.com OI Yadav, Hariom/0000-0003-4504-1597 NR 119 TC 53 Z9 61 U1 12 U2 133 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0378-1097 EI 1574-6968 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD SEP PY 2012 VL 334 IS 1 BP 1 EP 15 DI 10.1111/j.1574-6968.2012.02593.x PG 15 WC Microbiology SC Microbiology GA 981XX UT WOS:000307007200001 PM 22568660 ER PT J AU Beydoun, HA Beydoun, MA Kaufman, JS Lo, B Zonderman, AB AF Beydoun, Hind A. Beydoun, May A. Kaufman, Jay S. Lo, Bruce Zonderman, Alan B. TI Intimate partner violence against adult women and its association with major depressive disorder, depressive symptoms and postpartum depression: A systematic review and meta-analysis SO SOCIAL SCIENCE & MEDICINE LA English DT Review DE USA; Women; Intimate partner violence; Major depressive disorder; Elevated depressive symptoms; Postpartum depression; Meta-analysis ID ATTENDING GENERAL-PRACTICE; AFRICAN-AMERICAN WOMEN; MENTAL-HEALTH; SUBSTANCE-ABUSE; SOCIAL SUPPORT; CARE SETTINGS; LATINA WOMEN; RISK-FACTOR; LOW-INCOME; PREVALENCE AB To date, few systematic reviews of observational studies have been conducted to comprehensively evaluate the co-morbidity of intimate partner violence (IPV) and specific depression outcomes in women. In this systematic review and meta-analysis, we summarize the extant literature and estimate the magnitude of the association between IPV and key depressive outcomes (elevated depressive symptoms, diagnosed major depressive disorder and postpartum depression). PubMed (January 1, 1980-December 31, 2010) searches of English-language observational studies were conducted. Most of the selected 37 studies had cross-sectional population-based designs, focused on elevated depressive symptoms and were conducted in the United States. Most studies suggested moderate or strong positive associations between IPV and depression. Our meta-analysis suggested two to three-fold increased risk of major depressive disorder and 1.5-2-fold increased risk of elevated depressive symptoms and postpartum depression among women exposed to intimate partner violence relative to non-exposed women. A sizable proportion (9%-28%) of major depressive disorder, elevated depressive symptoms, and postpartum depression can be attributed to lifetime exposure to IPV. In an effort to reduce the burden of depression, continued research is recommended for evaluating IPV preventive strategies. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Beydoun, May A.; Zonderman, Alan B.] NIA, Lab Behav Neurosci, NIH, IRP, Baltimore, MD 21224 USA. [Kaufman, Jay S.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Lo, Bruce] Eastern Virginia Med Sch, Dept Emergency Med, Norfolk, VA 23501 USA. RP Beydoun, HA (reprint author), Eastern Virginia Med Sch, Grad Program Publ Hlth, POB 1980, Norfolk, VA 23501 USA. EM baydouha@evms.edu OI Kaufman, Jay/0000-0003-1606-401X; Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS [Z01 AG000513-08] NR 100 TC 75 Z9 77 U1 12 U2 65 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD SEP PY 2012 VL 75 IS 6 BP 959 EP 975 DI 10.1016/j.socscimed.2012.04.025 PG 17 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 979LQ UT WOS:000306821900002 PM 22694991 ER PT J AU Choi, KY Jeon, EJ Yoon, HY Lee, BS Na, JH Min, KH Kim, SY Myung, SJ Lee, S Chen, XY Kwon, IC Choi, K Jeong, SY Kim, K Park, JH AF Choi, Ki Young Jeon, Eun Jung Yoon, Hong Yeol Lee, Beom Suk Na, Jin Hee Min, Kyung Hyun Kim, Sang Yoon Myung, Seung-Jae Lee, Seulki Chen, Xiaoyuan Kwon, Ick Chan Choi, Kuiwon Jeong, Seo Young Kim, Kwangmeyung Park, Jae Hyung TI Theranostic nanoparticles based on PEGylated hyaluronic acid for the diagnosis, therapy and monitoring of colon cancer SO BIOMATERIALS LA English DT Article DE Hyaluronic acid; Nanoparticle; Theranostics; Irinotecan; Colon cancer; Tumor targeting ID METASTATIC COLORECTAL-CANCER; 1ST-LINE TREATMENT; FLUOROURACIL; LEUCOVORIN; CARCINOMA; COLONOSCOPIES; NEOPLASIA; TUMORS; AGENT; TRIAL AB Colon cancer is the second leading cause of cancer-related death in the United States. The considerable mortality from colon cancer is due to metastasis to other organs, mainly the liver. In the management of colon cancer, early detection and targeted therapy are crucial. In this study, we aimed to establish a versatile theranostic system for early tumor detection and targeted tumor therapy by using poly(ethylene glycol)-conjugated hyaluronic acid nanoparticles (P-HA-NPs) which can selectively accumulate in tumor tissue. For the diagnostic application, a near-infrared fluorescence (NIRF) imaging dye (Cy 5.5) was chemically conjugated onto the HA backbone of P-HA-NPs. After intravenous injection of Cy5.5-P-HA-NPs into the tumor-bearing mice, small-sized colon tumors as well as liver-implanted colon tumors were effectively visualized using the NIRF imaging technique. For targeted therapy, we physically encapsulated the anticancer drug, irinotecan (IRT), into the hydrophobic cores of P-HA-NPs. Owing to their notable tumor targeting capability, IRT-P-HA-NPs exhibited an excellent antitumor activity while showing a reduction in undesirable systemic toxicity. Importantly, we demonstrated the theranostic application using Cy5.5-P-HA-NPs and IRT-P-HA-NPs in orthotopic colon cancer models. Following the systemic administration of Cy5.5-P-HA-NPs, neoplasia was clearly visualized, and the tumor growth was effectively suppressed by intravenous injection of IRT-P-HA-NPs. It should be emphasized that the therapeutic responses could be simultaneously monitored by Cy5.5-P-HA-NPs. Our results suggest that P-HA-NPs can be used as a versatile theranostic system for the early detection, targeted therapy, and therapeutic monitoring of colon cancer. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Park, Jae Hyung] Sungkyunkwan Univ, Dept Polymer Sci & Engn, Theranost Macromol Res Ctr, Suwon 440746, South Korea. [Choi, Ki Young; Yoon, Hong Yeol; Lee, Beom Suk; Na, Jin Hee; Min, Kyung Hyun; Kim, Sang Yoon; Kwon, Ick Chan; Choi, Kuiwon; Kim, Kwangmeyung] Korea Inst Sci & Technol, Biomed Res Inst, Seoul 136791, South Korea. [Choi, Ki Young; Lee, Seulki; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Jeon, Eun Jung] Catholic Univ Korea, Sch Med, Dept Internal Med, Seoul, South Korea. [Lee, Beom Suk; Kim, Sang Yoon] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Otolaryngol, Seoul 138736, South Korea. [Na, Jin Hee; Min, Kyung Hyun; Jeong, Seo Young] Kyung Hee Univ, Dept Life & Nanopharmaceut Sci, Seoul 130701, South Korea. [Myung, Seung-Jae] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Internal Med, Seoul 138736, South Korea. [Myung, Seung-Jae] Univ Ulsan, Coll Med, Asan Med Ctr, Asan Digest Dis Res Inst, Seoul 138736, South Korea. RP Park, JH (reprint author), Sungkyunkwan Univ, Dept Polymer Sci & Engn, Theranost Macromol Res Ctr, 300 Sheoncheon Dong, Suwon 440746, South Korea. EM kim@kist.re.kr; jhpark1@skku.edu RI byun, jaehyun/G-5584-2014; Yoon, Hong Yeol/A-2413-2016; CHOI, KI YOUNG/Q-7177-2016; Yoon, Hong Yeol/D-4005-2017; OI Yoon, Hong Yeol/0000-0003-3242-3633; Myung, Seung-Jae/0000-0003-0585-4016 FU Korea Healthcare Technology RD Project [A101706-1001-0000200]; Global Research Laboratory (GRL) Project; Converging Research Program [20090081876]; Basic Science Research Programs of MEST [20100027955, 2012012827] FX This work was financially supported by the Korea Healthcare Technology R&D Project (A101706-1001-0000200) of MW, the Global Research Laboratory (GRL) Project, the Converging Research Program (20090081876), and the Basic Science Research Programs (20100027955 & 2012012827) of MEST. NR 35 TC 61 Z9 64 U1 19 U2 105 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 SEP PY 2012 VL 33 IS 26 BP 6186 EP 6193 DI 10.1016/j.biomaterials.2012.05.029 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 978DI UT WOS:000306720400022 PM 22687759 ER PT J AU Chauvet, C Goldberg, SR Jaber, M Solinas, M AF Chauvet, Claudia Goldberg, Steven R. Jaber, Mohamed Solinas, Marcello TI Effects of environmental enrichment on the incubation of cocaine craving SO NEUROPHARMACOLOGY LA English DT Article DE Addiction; Treatment; Relapse; Neuroadaptation; Stress; Withdrawal ID DRUG-ABUSE; RATS; REINSTATEMENT; EXPRESSION; WITHDRAWAL; SEEKING; STRESS; SENSITIZATION; ADDICTION; RELAPSE AB Recent studies have demonstrated that exposure to environmental enrichment (EE) during withdrawal periods reduces the risks of relapse to drug-seeking behavior. In this study, we investigated whether EE could prevent the development of time-dependent increases in cocaine-seeking behavior (incubation of craving). In addition, we investigated whether EE could eliminate already developed incubation and whether the effects of EE would last when enrichment is discontinued. For this, we allowed rats to self-administer cocaine for 10 daily 6 h sessions and measured cocaine-seeking 1,30 and 60 days after the last self-administration session. In between these tests, rats were kept in forced abstinence and housed either in EE or standard environments (SE). Between day 30 and 60 of withdrawal, half of the rats in each group were maintained in their original environmental condition and the other half was switched to the other environmental condition. We found that exposure to EE prevents development of incubation of cocaine craving and eliminates already developed incubation. In addition, contrary to our expectations, when EE was discontinued, its positive effects on incubation of craving disappeared. These results indicate that EE can reduce cocaine seeking but only temporarily and questions the hypothesis that EE can permanently eliminate the neural consequences of exposure to drugs of abuse. Therefore, stimulating environments could have positive effects on the treatment of cocaine addiction only if they are maintained for long periods of abstinence that encompass the time-frame during which addicts are most vulnerable to relapse. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Solinas, Marcello] Univ Poitiers, Neurobiol & Neuropharmacol Addict Grp, Expt & Clin Neurosci Lab, INSERM,U1084, F-86022 Poitiers, France. [Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Solinas, M (reprint author), Univ Poitiers, Neurobiol & Neuropharmacol Addict Grp, Expt & Clin Neurosci Lab, INSERM,U1084, 1 Rue George Bonnet, F-86022 Poitiers, France. EM marcello.solinas@univ-poitiers.fr RI Solinas, Marcello/M-3500-2016 OI Solinas, Marcello/0000-0002-0664-5964 FU Centre National pour la Recherche Scientifique; University of Poitiers; Mission Interministerielle de la Lutte contre les Drogues et la Toxicomanie; Region Poitou Charentes; CPER 5 (Contrat de Projet Etat-Region); Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services; French Ministry of Research FX We thank N Thiriet and J Nader for their helpful discussion and C Nicolas and J. Vejoux for help with the experiments. This work was supported by Centre National pour la Recherche Scientifique, University of Poitiers, Mission Interministerielle de la Lutte contre les Drogues et la Toxicomanie (MILDT-INSERM, 2006-2007 and MILDT-INSERM-INCA 2007-2009), Region Poitou Charentes, CPER 5 (Contrat de Projet Etat-Region) and the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. C Chauvet was a recipient of a PhD fellowship from the French Ministry of Research. NR 37 TC 23 Z9 23 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2012 VL 63 IS 4 BP 635 EP 641 DI 10.1016/j.neuropharm.2012.05.014 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 977DX UT WOS:000306637700015 PM 22634364 ER PT J AU Tranah, GJ Lam, ET Katzman, SM Nalls, MA Zhao, YQ Evans, DS Yokoyama, JS Pawlikowska, L Kwok, PY Mooney, S Kritchevsky, S Goodpaster, BH Newman, AB Harris, TB Manini, TM Cummings, SR AF Tranah, Gregory J. Lam, Ernest T. Katzman, Shana M. Nalls, Michael A. Zhao, Yiqiang Evans, Daniel S. Yokoyama, Jennifer S. Pawlikowska, Ludmila Kwok, Pui-Yan Mooney, Sean Kritchevsky, Stephen Goodpaster, Bret H. Newman, Anne B. Harris, Tamara B. Manini, Todd M. Cummings, Steven R. CA Hlth Aging Body Composition Study TI Mitochondrial DNA sequence variation is associated with free-living activity energy expenditure in the elderly SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Article DE Metabolic rate; Energy expenditure; Mitochondria; mtDNA; Oxidative phosphorylation; DNA sequencing ID HEREDITARY OPTIC NEUROPATHY; HUMAN SKELETAL-MUSCLE; CYTOCHROME-C-OXIDASE; GENOME-WIDE ASSOCIATION; RESPIRATORY-CHAIN FUNCTION; AMINO-ACID SUBSTITUTIONS; AGE-DEPENDENT INCREASE; RESTING METABOLIC-RATE; AGING HUMAN TISSUES; PHYSICAL-ACTIVITY AB The decline in activity energy expenditure underlies a range of age-associated pathological conditions, neuromuscular and neurological impairments, disability, and mortality. The majority (90%) of the energy needs of the human body are met by mitochondrial oxidative phosphorylation (OXPHOS). OXPHOS is dependent on the coordinated expression and interaction of genes encoded in the nuclear and mitochondria! genomes. We examined the role of mitochondrial genomic variation in free-living activity energy expenditure (AEE) and physical activity levels (PAL) by sequencing the entire (similar to 16.5 kilobases) mtDNA from 138 Health. Aging, and Body Composition Study participants. Among the common mtDNA variants, the hypervariable region 2 m.185G>A variant was significantly associated with AEE (p = 0.001) and PAL (p = 0.0005) after adjustment for multiple comparisons. Several unique nonsynonymous variants were identified in the extremes of AEE with some occurring at highly conserved sites predicted to affect protein structure and function. Of interest is the p.T194M, CytB substitution in the lower extreme of AEE occurring at a residue in the Qi site of complex III. Among participants with low activity levels, the burden of singleton variants was 30% higher across the entire mtDNA and OXPHOS complex I when compared to those having moderate to high activity levels. A significant pooled variant association across the hypervariable 2 region was observed for AEE and PAL These results suggest that mtDNA variation is associated with free-living AEE in older persons and may generate new hypotheses by which specific mtDNA complexes, genes, and variants may contribute to the maintenance of activity levels in late life. Published by Elsevier B.V. C1 [Tranah, Gregory J.] UCSF, San Francisco Coordinating Ctr, Calif Pacific Med Ctr Res Inst, San Francisco, CA 94107 USA. [Lam, Ernest T.; Kwok, Pui-Yan] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Katzman, Shana M.; Zhao, Yiqiang; Mooney, Sean] Buck Inst Res Aging, Novato, CA 94945 USA. [Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Yokoyama, Jennifer S.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA. [Pawlikowska, Ludmila] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Kritchevsky, Stephen] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC 27157 USA. [Goodpaster, Bret H.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. [Manini, Todd M.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL 32601 USA. RP Tranah, GJ (reprint author), UCSF, San Francisco Coordinating Ctr, Calif Pacific Med Ctr Res Inst, 185 Berry St,Lobby 5,Suite 5700, San Francisco, CA 94107 USA. EM gtranah@sfcc-cpmc.edu RI Kwok, Pui-Yan/F-7725-2014; Newman, Anne/C-6408-2013; OI Kwok, Pui-Yan/0000-0002-5087-3059; Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, R03-AG032498]; NINR [R01-NR012459]; NIH [T32 GM007175]; NLM [LM009722]; [Z01A6000932] FX This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; and N01-AG-6-2106; NIA grants R01-AG028050 and R03-AG032498, NINR grant R01-NR012459; and Z01A6000932. E.T.L. was supported in part by NIH Training Grant T32 GM007175 and Y.Z. by NLM grant LM009722. Data analyses for this study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland (http://biowulf.nih.gov). NR 151 TC 6 Z9 6 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD SEP PY 2012 VL 1817 IS 9 BP 1691 EP 1700 DI 10.1016/j.bbabio.2012.05.012 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 975UG UT WOS:000306536400017 PM 22659402 ER PT J AU Shiba, Y Randazzo, PA AF Shiba, Yoko Randazzo, Paul A. TI ArfGAP1 function in COPI mediated membrane traffic: Currently debated models and comparison to other coat-binding ArfGAPs SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Review DE ArfGAP1; Arf1; Golgi apparatus; Retrograde traffic; Coatomer; COPI ID ADP-RIBOSYLATION FACTOR; GTPASE-ACTIVATING PROTEIN; NUCLEOTIDE-EXCHANGE FACTORS; TRANS-GOLGI NETWORK; CELL-FREE SYSTEM; SACCHAROMYCES-CEREVISIAE; ARF GAPS; FACTOR-I; SORTING SIGNALS; SUCCESSIVE COMPARTMENTS AB The ArfGAPs are a family of proteins containing an ArfGAP catalytic domain that induces the hydrolysis of GTP bound to the small guanine nucleotide binding-protein ADP-ribosylation factor (Arf). Functional models for Arfs, which are regulators of membrane traffic, are based on the idea that guanine nucleotide-binding proteins function as switches: Arf with GTP bound is active and binds to effector proteins; the conversion of GTP to GDP inactivates Arf. The cellular activities of ArfGAPs have been examined primarily as regulatory proteins that inactivate Arf; however, Arf function in membrane traffic does not strictly adhere to the concept of a simple switch, adding complexity to models explaining the role of ArfGAPs. Here, we review the literature addressing the function Arf and ArfGAP1 in COPI mediated transport, focusing on two critical and integrated functions of membrane traffic, cargo sorting and vesicle coat polymerization. We briefly discuss other ArfGAPs that may have similar function in Arf-dependent membrane traffic outside the ER-Golgi. C1 [Shiba, Yoko; Randazzo, Paul A.] NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. RP Randazzo, PA (reprint author), NCI, Lab Cellular & Mol Biol, Bldg 37,Room 2042, Bethesda, MD 20892 USA. EM randazzp@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX The authors thank Julie Donaldson for critically reading the manuscript. The work was supported by the Intramural Program of the National Cancer Institute, National Institutes of Health. NR 100 TC 4 Z9 4 U1 2 U2 15 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 EI 1699-5848 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD SEP PY 2012 VL 27 IS 9 BP 1143 EP 1153 PG 11 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 975OU UT WOS:000306521400003 PM 22806901 ER PT J AU Walters, AD Bommakanti, A Cohen-Fix, O AF Walters, Alison D. Bommakanti, Ananth Cohen-Fix, Orna TI Shaping the nucleus: Factors and forces SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE NUCLEAR SHAPE; ENDOPLASMIC RETICULUM; MITOSIS; NUCLEAR ENVELOPE; LAMINOPATHIES ID SPINDLE POLE BODY; ENDOPLASMIC-RETICULUM; MEMBRANE-PROTEINS; SACCHAROMYCES-CEREVISIAE; PORE COMPLEXES; ENVELOPE ENVIRONMENT; MAMMALIAN-CELLS; FISSION YEAST; GENOME; SIZE AB Take a look at a textbook illustration of a cell and you will immediately be able to locate the nucleus, which is often drawn as a spherical or ovoid shaped structure. But not all cells have such nuclei. In fact, some disease states are diagnosed by the presence of nuclei that have an abnormal shape or size. What defines nuclear shape and nuclear size, and how does nuclear geometry affect nuclear function? While the answer to the latter question remains largely unknown, significant progress has been made towards understanding the former. In this review, we provide an overview of the factors and forces that affect nuclear shape and size, discuss the relationship between ER structure and nuclear morphology, and speculate on the possible connection between nuclear size and its shape. We also note the many interesting questions that remain to be explored. J. Cell. Biochem. 113: 28132821, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Walters, Alison D.; Bommakanti, Ananth; Cohen-Fix, Orna] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Cohen-Fix, O (reprint author), 8 Ctr Dr,Bldg 8,Room 319, Bethesda, MD 20892 USA. EM ornacf@helix.nih.gov FU National Institutes of Diabetes and Digestive and Kidney Diseases FX Grant sponsor: National Institutes of Diabetes and Digestive and Kidney Diseases. NR 90 TC 28 Z9 29 U1 3 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD SEP PY 2012 VL 113 IS 9 BP 2813 EP 2821 DI 10.1002/jcb.24178 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 972QQ UT WOS:000306292700003 PM 22566057 ER PT J AU Light, AC Zhu, YL Shi, J Saszik, S Lindstrom, S Davidson, L Li, XY Chiodo, VA Hauswirth, WW Li, W DeVries, SH AF Light, Adam C. Zhu, Yongling Shi, Jun Saszik, Shannon Lindstrom, Sarah Davidson, Laura Li, Xiaoyu Chiodo, Vince A. Hauswirth, William W. Li, Wei DeVries, Steven H. TI Organizational motifs for ground squirrel cone bipolar cells SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE ground squirrel; adeno-associated virus; inner plexiform layer; retina ID RETINAL GANGLION-CELLS; MACAQUE MONKEY RETINA; INNER PLEXIFORM LAYER; AII AMACRINE CELLS; MAMMALIAN RETINA; MOUSE RETINA; RABBIT RETINA; PRIMATE RETINA; IMMUNOCYTOCHEMICAL ANALYSIS; CHOLINE-ACETYLTRANSFERASE AB In daylight vision, parallel processing starts at the cone synapse. Cone signals flow to On and Off bipolar cells, which are further divided into types according to morphology, immunocytochemistry, and function. The axons of the bipolar cell types stratify at different levels in the inner plexiform layer (IPL) and can interact with costratifying amacrine and ganglion cells. These interactions endow the ganglion cell types with unique functional properties. The wiring that underlies the interactions among bipolar, amacrine, and ganglion cells is poorly understood. It may be easier to elucidate this wiring if organizational rules can be established. We identify 13 types of cone bipolar cells in the ground squirrel, 11 of which contact contiguous cones, with the possible exception of short-wavelength-sensitive cones. Cells were identified by antibody labeling, tracer filling, and Golgi-like filling following transduction with an adeno-associated virus encoding for green fluorescent protein. The 11 bipolar cell types displayed two organizational patterns. In the first pattern, eight to 10 of the 11 types came in pairs with partially overlapping axonal stratification. Pairs shared morphological, immunocytochemical, and functional properties. The existence of similar pairs is a new motif that might have implications for how signals first diverge from a cone to bipolar cells and then reconverge onto a costratifying ganglion cell. The second pattern is a mirror symmetric organization about the middle of the IPL involving at least seven bipolar cell types. This anatomical symmetry may be associated with a functional symmetry in On and Off ganglion cell responses. J. Comp. Neurol. 520:28642887, 2012. (c) 2012 Wiley Periodicals Inc. C1 [Light, Adam C.; Zhu, Yongling; Shi, Jun; Saszik, Shannon; Lindstrom, Sarah; Davidson, Laura; Li, Xiaoyu; DeVries, Steven H.] Northwestern Univ, Dept Ophthalmol, Feinberg Sch Med, Chicago, IL 60611 USA. [Chiodo, Vince A.; Hauswirth, William W.] Univ Florida, Dept Ophthalmol, Gainesville, FL 32610 USA. [Li, Wei] NEI, Unit Retinal Neurophysiol, NIH, Bethesda, MD 20892 USA. RP DeVries, SH (reprint author), Northwestern Univ, Dept Ophthalmol, Feinberg Sch Med, Tarry 5-715,300 E Super St, Chicago, IL 60611 USA. EM s-devries@northwestern.edu RI shi, jun/C-2389-2011; OI Lindstrom, Sarah H./0000-0001-7952-8120 FU National Institutes of Health [R01EY018204, R01EY012141, R01EY11123, P30EY021721]; Research to Prevent Blindness; Macular Vision Research Foundation; Foundation Fighting Blindness; Eldon Family Foundation; Vision for Children FX Grant sponsor: National Institutes of Health; Grant numbers: R01EY018204, R01EY012141 (to S. H. D.), R01EY11123 (to W. W. H.), P30EY021721 (to W. W. H.); Grant sponsors: Research to Prevent Blindness (to S. H. D., W. W. H.), Macular Vision Research Foundation (to W. W. H.), Foundation Fighting Blindness (to W. W. H.), Eldon Family Foundation (to W. W. H.), Vision for Children (to W.W.H.). NR 82 TC 17 Z9 17 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD SEP 1 PY 2012 VL 520 IS 13 BP 2864 EP 2887 DI 10.1002/cne.23068 PG 24 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 970LF UT WOS:000306129500004 PM 22778006 ER PT J AU Gorlick, R Maris, JM Houghton, PJ Lock, R Carol, H Kurmasheva, RT Kolb, EA Keir, ST Reynolds, CP Kang, MH Billups, CA Smith, MA AF Gorlick, Richard Maris, John M. Houghton, Peter J. Lock, Richard Carol, Hernan Kurmasheva, Raushan T. Kolb, E. Anders Keir, Stephen T. Reynolds, C. Patrick Kang, Min H. Billups, Catherine A. Smith, Malcolm A. TI Testing of the Akt/PKB inhibitor MK-2206 by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; MK-2206; preclinical testing ID ACUTE LYMPHOBLASTIC-LEUKEMIA; HUMAN NEUROBLASTOMA-CELLS; GROWTH-FACTOR; 3-KINASE PATHWAY; AKT INHIBITOR; IN-VITRO; CANCER; CHEMOTHERAPY; ACTIVATION; SURVIVAL AB Background MK-2206 is a small molecule allosteric inhibitor of Akt/PKB that is undergoing clinical trials for treatment of cancer. Procedures MK-2206 was tested against the PPTP in vitro panel using a 96-hour exposure (1.0?nM10?mu M), and in vivo using thrice weekly dosing for a planned 4 weeks at its maximum tolerated dose (MTD) of 180?mg/kg. Results In vitro, the median relative IC50 value for MK-2206 was 2.2?mu M. Four cell lines with IC50 values?30 cigarettes had ORs of 103.5 (95% confidence interval (CI): 74.8143.2) for SqCC, 111.3 (95% CI: 69.8177.5) for SCLC and 21.9 (95% CI: 16.629.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI: 31.5124.6), 108.6 (95% CI: 50.7232.8) and 16.8 (95% CI: 9.230.6), respectively. Although ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development. C1 [Pesch, Beate; Kendzia, Benjamin; Johnen, Georg; Gross, Isabelle Mercedes; Bruening, Thomas] Inst Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med, German Social Accid Insurance, Bochum, Germany. [Gustavsson, Per; Olsson, Ann] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Joeckel, Karl-Heinz] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Pohlabeln, Hermann; Ahrens, Wolfgang] Univ Bremen, Bremen Inst Prevent Res & Social Med, D-28359 Bremen, Germany. [Olsson, Ann; Brennan, Paul; Straif, Kurt] Int Agcy Res Canc, F-69372 Lyon, France. [Brueske, Irene; Wichmann, Heinz-Erich] HelmholtzZentrum Munchen, Inst Epidemiol, Munich, Germany. [Merletti, Franco; Richiardi, Lorenzo] Univ Turin, Canc Epidemiol Unit, Turin, Italy. [Merletti, Franco; Richiardi, Lorenzo] Univ Turin, CPO Piemonte, Turin, Italy. [Richiardi, Lorenzo] Univ Padua, Dept Environm Med & Publ Hlth, Padua, Italy. [Fortes, Cristina] IDI IRCCS, Clin Epidemiol Unit, Rome, Italy. [Siemiatycki, Jack; Parent, Marie-Elise] Univ Montreal Hosp Res Ctr CRCHUM, Montreal, PQ, Canada. [Siemiatycki, Jack; Parent, Marie-Elise] Sch Publ Hlth, Montreal, PQ, Canada. [Parent, Marie-Elise] Univ Quebec, Inst Armand Frappier, INRS, Laval, PQ, Canada. [Consonni, Dario] Osped Maggiore Policlin, Fdn IRCCS Ca Granda, Epidemiol Unit, Milan, Italy. [Landi, Maria Teresa; Caporaso, Neil] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Zaridze, David] Russian Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Cassidy, Adrian] Univ Liverpool, Canc Res Ctr, Roy Castle Lung Canc Res Programme, Liverpool L69 3BX, Merseyside, England. [Szeszenia-Dabrowska, Neonila] Nofer Inst Occupat Med, Lodz, Poland. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Warsaw, Poland. [Stuecker, Isabelle] INSERM, U 754 IFR69, Villejuif, France. [Fabianova, Eleonora] Reg Author Publ Hlth, Specialized State Hlth Inst, Dept Occupat Hlth, Banska Bystrica, Slovakia. [Dumitru, Rodica Stanescu] Natl Inst Publ Hlth, Bucharest, Romania. [Bencko, Vladimir] Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic. [Foretova, Lenka] Masaryk Mem Canc Inst, Brno, Czech Republic. [Janout, Vladimir] Palacky Univ, Dept Prevent Med, Fac Med, CR-77147 Olomouc, Czech Republic. [Rudin, Charles M.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Boffetta, Paolo] Mt Sinai Hosp, Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. RP Pesch, B (reprint author), Inst Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med, German Social Accid Insurance, Burkle de la Camp Pl 1, Bochum, Germany. EM pesch@ipa-dguv.de RI Zaridze, David/K-5605-2013; Bruske, Irene/N-3125-2013; Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; Bruning, Thomas/G-8120-2015; Consonni, Dario/K-7943-2016 OI Bruning, Thomas/0000-0001-9560-5464; Consonni, Dario/0000-0002-8935-3843 FU German Social Accident Insurance [FP 271]; Canadian Institutes of Health Research; Guzzo-SRC Chair in Environment and Cancer; Fondation de France; German Federal Ministry of Education, Science, Research, and Technology; Ministry of Labour and Social Affairs; EC's INCO-COPERNICUS Program; Polish State Committee for Science Research; Roy Castle Foundation; NIH/NCI/DCEG; Lombardy Region; INAIL; European Union; Italian Association for Cancer Research; Region Piedmont; Compagnia di San Paolo; Europe Against Cancer Program; Swedish Council for Work Life Research; Swedish EPA FX Grant sponsor: German Social Accident Insurance; Grant number: FP 271; Grant sponsors: Canadian Institutes of Health Research and Guzzo-SRC Chair in Environment and Cancer, the Fondation de France, the German Federal Ministry of Education, Science, Research, and Technology and the Ministry of Labour and Social Affairs, EC's INCO-COPERNICUS Program, Polish State Committee for Science Research, Roy Castle Foundation, NIH/NCI/DCEG Intramural Research Program, Lombardy Region, INAIL and the European Union Nuclear Fission Safety Program, Italian Association for Cancer Research, Region Piedmont, Compagnia di San Paolo, Europe Against Cancer Program, the Swedish Council for Work Life Research and the Swedish EPA NR 46 TC 91 Z9 92 U1 1 U2 11 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 SEP 1 PY 2012 VL 131 IS 5 BP 1210 EP 1219 DI 10.1002/ijc.27339 PG 10 WC Oncology SC Oncology GA 965GZ UT WOS:000305756900049 PM 22052329 ER PT J AU Cardwell, CR Abnet, CC Veal, P Hughes, CM Cantwell, MM Murray, LJ AF Cardwell, Chris R. Abnet, Christian C. Veal, Philip Hughes, Carmel M. Cantwell, Marie M. Murray, Liam J. TI Exposure to oral bisphosphonates and risk of cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cancer; risk; bisphosphonates; cohort; epidemiology ID ADJUVANT CLODRONATE TREATMENT; VITAMIN-D SUPPLEMENTATION; BONE-MINERAL DENSITY; BREAST-CANCER; POSTMENOPAUSAL WOMEN; ZOLEDRONIC ACID; FOLLOW-UP; COLORECTAL-CANCER; SUBSEQUENT RISK; COLON-CANCER AB Recently, oral bisphosphonate use has increased markedly in the United States and elsewhere. Little is known about cancer risks associated with these drugs. A few studies have observed associations between bisphosphonates and the risk of breast, colorectal and esophageal cancer. However, the risk of all cancer and the risk of other cancers have not been investigated. In our study, we examined the risk of all cancer and site specific cancers in individuals taking bisphosphonates. Data were extracted from the UK General Practice Research Database to compare site-specific cancer incidence in a cohort of oral bisphosphonate users and a control cohort. Hazard ratios (HRs) were calculated using Cox regression modeling. The bisphosphonate and control cohort contained 41,826 participants (mean age 70, 81% female). Overall, the bisphosphonate cohort compared with the control cohort had a reduced risk of all cancer after any bisphosphonate usage [HR = 0.87, 95% confidence interval (CI) 0.82, 0.92]. In the bisphosphonate cohort, compared with the control cohort, there was no evidence of a difference in the risk of lung (HR = 1.03, 95% CI 0.88, 1.20) or prostate cancer (HR = 0.86, 95% CI 0.67, 1.09) but breast (HR = 0.71, 95% CI 0.62, 0.81) and colorectal cancer (HR = 0.74, 95% CI, 0.600.91) were both reduced. Our findings indicate that bisphosphonates do not appear to increase cancer risk. Although reductions in breast and colorectal cancer incidence were observed in bisphosphonate users it is unclear, particularly for breast cancer, to what extent confounding by low bone density may explain the association. C1 [Cardwell, Chris R.; Veal, Philip; Cantwell, Marie M.; Murray, Liam J.] Queens Univ Belfast, Ctr Publ Hlth, Sch Med Dent & Biomed Sci, Belfast BT12 6BJ, Antrim, North Ireland. [Abnet, Christian C.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Hughes, Carmel M.] Queens Univ Belfast, Sch Pharm, Belfast BT12 6BJ, Antrim, North Ireland. RP Cardwell, CR (reprint author), Queens Univ Belfast, Ctr Publ Hlth, Sch Med Dent & Biomed Sci, Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. EM c.cardwell@qub.ac.uk RI Research Datalink, Clinical Practice/H-2477-2013; Abnet, Christian/C-4111-2015; CPRD, CPRD/B-9594-2017; OI Abnet, Christian/0000-0002-3008-7843; Cardwell, Chris/0000-0002-2689-4335 FU Medical Research Council; MHRA; UK Medicines and Healthcare Products Regulatory Agency FX Grant sponsor: Medical Research Council's License Agreement with MHRA; We thank Maciej Domanski, MSc (Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom) for data management. This study is based in part on data from the Full Feature General Practice Research Database obtained under license from the UK Medicines and Healthcare Products Regulatory Agency. Access to the GPRD database was funded through the Medical Research Council's license agreement with the UK Medicines and Healthcare Products Regulatory Agency. However, the interpretation and conclusions contained in this study are those of the authors alone. NR 35 TC 26 Z9 26 U1 0 U2 5 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 SEP 1 PY 2012 VL 131 IS 5 BP E717 EP E725 DI 10.1002/ijc.27389 PG 9 WC Oncology SC Oncology GA 965GZ UT WOS:000305756900013 PM 22161552 ER PT J AU Sun, HM Xia, MH Austin, CP Huang, RL AF Sun, Hongmao Xia, Menghang Austin, Christopher P. Huang, Ruili TI Paradigm Shift in Toxicity Testing and Modeling SO AAPS JOURNAL LA English DT Review DE computational toxicology; qHTS; risk assessment; Tox21 ID NATIONAL-TOXICOLOGY-PROGRAM; RODENT CARCINOGENICITY BIOASSAYS; THROUGHPUT SCREENING DATA; SUPPORT VECTOR MACHINE; COMPUTATIONAL TOXICOLOGY; PREDICTIVE-TOXICOLOGY; DRUG DISCOVERY; ANIMAL-MODELS; IMMUNOTOXICITY ASSESSMENT; ENVIRONMENTAL CHEMICALS AB The limitations of traditional toxicity testing characterized by high-cost animal models with low-throughput readouts, inconsistent responses, ethical issues, and extrapolability to humans call for alternative strategies for chemical risk assessment. A new strategy using in vitro human cell-based assays has been designed to identify key toxicity pathways and molecular mechanisms leading to the prediction of an in vivo response. The emergence of quantitative high-throughput screening (qHTS) technology has proved to be an efficient way to decompose complex toxicological end points to specific pathways of targeted organs. In addition, qHTS has made a significant impact on computational toxicology in two aspects. First, the ease of mechanism of action identification brought about by in vitro assays has enhanced the simplicity and effectiveness of machine learning, and second, the high-throughput nature and high reproducibility of qHTS have greatly improved the data quality and increased the quantity of training datasets available for predictive model construction. In this review, the benefits of qHTS routinely used in the US Tox21 program will be highlighted. Quantitative structure-activity relationships models built on traditional in vivo data and new qHTS data will be compared and analyzed. In conjunction with the transition from the pilot phase to the production phase of the Tox21 program, more qHTS data will be made available that will enrich the data pool for predictive toxicology. It is perceivable that new in silico toxicity models based on high-quality qHTS data will achieve unprecedented reliability and robustness, thus becoming a valuable tool for risk assessment and drug discovery. C1 [Sun, Hongmao; Xia, Menghang; Austin, Christopher P.; Huang, Ruili] NIH, Dept Hlth & Human Serv, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Sun, HM (reprint author), NIH, Dept Hlth & Human Serv, Chem Genom Ctr, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM hongmao.sun@nih.gov; huangru@mail.nih.gov FU Intramural Research Programs of the National Toxicology Program [Y2-ES-7020-01]; National Institute of Environmental Health Sciences (NIEHS); National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) FX This work was supported by the Intramural Research Programs (Interagency agreement #Y2-ES-7020-01) of the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), and the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH). The statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS, or NCATS, NIH, or the US government. We thank in particular Anna Rossoshek for helpful comments and suggestions during the preparation of this manuscript. NR 97 TC 26 Z9 26 U1 1 U2 31 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PD SEP PY 2012 VL 14 IS 3 BP 473 EP 480 DI 10.1208/s12248-012-9358-1 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 962DO UT WOS:000305519900012 PM 22528508 ER PT J AU Fleg, JL Strait, J AF Fleg, Jerome L. Strait, James TI Age-associated changes in cardiovascular structure and function: a fertile milieu for future disease SO HEART FAILURE REVIEWS LA English DT Article DE Cardiovascular; Aging; Arterial; Ventricular function; Exercise; beta adrenergic ID SUBCLINICAL ARTERIAL-DISEASE; HEALTHY-MEN; HUMAN HEART; ECHOCARDIOGRAPHIC-ASSESSMENT; DIASTOLIC DYSFUNCTION; CONTRACTION DURATION; MYOCARDIAL-ISCHEMIA; AEROBIC CAPACITY; DYNAMIC EXERCISE; CYCLE EXERCISE AB Important changes occur in the cardiovascular system with advancing age, even in apparently healthy individuals. Thickening and stiffening of the large arteries develop due to collagen and calcium deposition and loss of elastic fibers in the medial layer. These arterial changes cause systolic blood pressure to rise with age, while diastolic blood pressure generally declines after the sixth decade. In the left ventricle, modest concentric wall thickening occurs due to cellular hypertrophy, but cavity size does not change. Although left ventricular systolic function is preserved across the age span, early diastolic filling rate declines 30-50% between the third and ninth decades. Conversely, an age-associated increase in late diastolic filling due to atrial contraction preserves end-diastolic volume. Aerobic exercise capacity declines approximately 10% per decade in cross-sectional studies; in longitudinal studies, however, this decline is accelerated in the elderly. Reductions in peak heart rate and peripheral oxygen utilization but not stroke volume appear to mediate the age-associated decline in aerobic capacity. Deficits in both cardiac beta-adrenergic receptor density and in the efficiency of postsynaptic beta-adrenergic signaling contribute significantly to the reduced cardiovascular performance during exercise in older adults. Although these cardiovascular aging changes are considered "normative", they lower the threshold for the development of cardiovascular disease, which affects the majority of older adults. C1 [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Strait, James] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Fleg, JL (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8150, Bethesda, MD 20892 USA. EM flegj@nhlbi.nih.gov; strait.j@nia.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 51 TC 31 Z9 34 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1382-4147 J9 HEART FAIL REV JI Heart Fail. Rev. PD SEP PY 2012 VL 17 IS 4-5 SI SI BP 545 EP 554 DI 10.1007/s10741-011-9270-2 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 957AC UT WOS:000305129800003 PM 21809160 ER PT J AU Jacobson, KA Balasubramanian, R Deflorian, F Gao, ZG AF Jacobson, Kenneth A. Balasubramanian, Ramachandran Deflorian, Francesca Gao, Zhan-Guo TI G protein-coupled adenosine (P1) and P2Y receptors: ligand design and receptor interactions SO PURINERGIC SIGNALLING LA English DT Article DE GPCR structure; Adenosine receptors; P2Y receptors; Agonists; Antagonists; Clinical trials, nucleosides; Nucleotides ID SITE-DIRECTED MUTAGENESIS; AMINO-ACID-RESIDUES; HUMAN MAST-CELLS; A(2B) ADENOSINE; NUCLEOTIDE RECEPTORS; MUTATIONAL ANALYSIS; THERAPEUTIC APPLICATIONS; ANTAGONIST RECOGNITION; MOLECULAR RECOGNITION; PHYLOGENETIC ANALYSIS AB The medicinal chemistry and pharmacology of the four subtypes of adenosine receptors (ARs) and the eight subtypes of P2Y receptors (P2YRs, activated by a range of purine and pyrimidine mono- and dinucleotides) has recently advanced significantly leading to selective ligands. X-ray crystallographic structures of both agonist- and antagonist-bound forms of the A(2A)AR have provided unprecedented three-dimensional detail concerning molecular recognition in the binding site and the conformational changes in receptor activation. It is apparent that this ubiquitous cell signaling system has implications for understanding and treating many diseases. ATP and other nucleotides are readily released from intracellular sources under conditions of injury and organ stress, such as hypoxia, ischemia, or mechanical stress, and through channels and vesicular release. Adenosine may be generated extracellularly or by cellular release. Therefore, depending on pathophysiological factors, in a given tissue, there is often a tonic activation of one or more of the ARs or P2YRs that can be modulated by exogenous agents for a beneficial effect. Thus, this field has provided fertile ground for pharmaceutical development, leading to clinical trials of selective receptor ligands as imaging agents or for conditions including cardiac arrhythmias, ischemia/reperfusion injury, diabetes, pain, thrombosis, Parkinson's disease, rheumatoid arthritis, psoriasis, dry eye disease, pulmonary diseases such as cystic fibrosis, glaucoma, cancer, chronic hepatitis C, and other diseases. C1 [Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIDDK, National Institutes of Health FX Supported by the NIDDK Intramural Research Program, National Institutes of Health. NR 119 TC 33 Z9 34 U1 1 U2 21 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 EI 1573-9546 J9 PURINERG SIGNAL JI Purinergic Signal. PD SEP PY 2012 VL 8 IS 3 SI SI BP 419 EP 436 DI 10.1007/s11302-012-9294-7 PG 18 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 949QO UT WOS:000304591000005 PM 22371149 ER PT J AU Goldberg, RN Lang, BE Coxon, B Decker, SR AF Goldberg, Robert N. Lang, Brian E. Coxon, Bruce Decker, Stephen R. TI Saturation molalities and standard molar enthalpies of solution of alpha-D-xylose(cr) in H2O(l); standard molar enthalpies of solution of 1,4-beta-D-xylobiose(am), and 1,4-beta-D-xylotriose(am) in H2O(l) SO JOURNAL OF CHEMICAL THERMODYNAMICS LA English DT Article DE Enthalpy of solution; Saturation molality; Solubility; Standard formation properties; 1,4-beta-D-Xylobiose; 1,4-beta-D-Xylotriose; alpha-D-Xylose ID AQUEOUS-SOLUTION; WATER; THERMODYNAMICS; HYDROLYSIS; SOLUBILITY; PENTOSES; HEXOSES; POLYOLS; MALTOSE; XYLOSE AB The saturation molality of alpha-D-xylose(cr) in water was measured by using HPLC and is m(sat) = (8.43 +/- 0.42) mol . kg(-1) at T = 298.15 K. It was also established that the anhydrous form of alpha-D-xylose(cr) is the crystalline form that is in equilibrium with the aqueous solution at T = 298.15 K. Solution calorimetry was used to measure the following standard molar enthalpies of solution at T = 298.15 K: Delta H-sol(m)degrees = (12.10 +/- 0.12) kJ . mol(-1) for alpha-D-xylose(cr); Delta H-sol(m)degrees = -(8.1 +/- 2.7) kJ . mol(-1) for 1,4-beta-D-xylobiose(am); and Delta H-sol(m)degrees = -(24.1 +/- 6.4) kJ . mol(-1) for 1,4-beta-D-xylotriose(am). It was observed that both 1,4-beta-D-xylobiose(am) and 1,4-beta-D-xylotriose(am) were amorphous substances and that they form thick gels in water in which no solid phase is present. Consequently, it is not possible to measure m(sat) for these two substances. All substances were carefully characterized by using both HPLC and Karl Fischer analysis. NMR was used to measure the anomeric purity of the alpha-D-xylose(cr). Thermodynamic network calculations were used to calculate standard molar formation properties for the aforementioned substances. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Goldberg, Robert N.; Lang, Brian E.] Natl Inst Stand & Technol, Div Biochem Sci, Gaithersburg, MD 20876 USA. [Goldberg, Robert N.] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. [Coxon, Bruce] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Decker, Stephen R.] Natl Renewable Energy Lab, Biosci Ctr, Golden, CO 80401 USA. RP Goldberg, RN (reprint author), Natl Inst Stand & Technol, Div Biochem Sci, Gaithersburg, MD 20876 USA. EM robert.goldberg@nist.gov; brian.lang@nist.gov; coxonb@mail.nih.gov; steve.decker@nrel.gov FU Department of Energy Office of the Biomass Program; US Department of Energy [DE-AC36-08-GO28308]; National Renewable Energy Laboratory FX We thank Dr. Alan Mighell for his literature search on possible crystalline forms of 1,4-beta-D-xylobiose and 1,4-beta-D-xylotriose. This work was funded, in part, by the Department of Energy Office of the Biomass Program and by the US Department of Energy under Contract No. DE-AC36-08-GO28308 with the National Renewable Energy Laboratory. NR 32 TC 6 Z9 6 U1 1 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0021-9614 J9 J CHEM THERMODYN JI J. Chem. Thermodyn. PD SEP PY 2012 VL 52 BP 2 EP 10 DI 10.1016/j.jct.2011.07.004 PG 9 WC Thermodynamics; Chemistry, Physical SC Thermodynamics; Chemistry GA 942OZ UT WOS:000304056300002 ER PT J AU Coussens, NP Schuck, P Zhao, HY AF Coussens, Nathan P. Schuck, Peter Zhao, Huaying TI Strategies for assessing proton linkage to bimolecular interactions by global analysis of isothermal titration calorimetry data SO JOURNAL OF CHEMICAL THERMODYNAMICS LA English DT Article DE Protein interactions; Thermodynamics; Proton linkage; Isothermal titration calorimetry; Global analysis; SEDPHAT ID ASPARTIC PROTEASE; DRUG DISCOVERY; LEAST-SQUARES; BINDING; ENERGETICS; COMPLEXES; DOMAIN; SITE; THERMODYNAMICS; COOPERATIVITY AB Isothermal titration calorimetry (ITC) is a traditional and powerful method for studying the linkage of ligand binding to proton uptake or release. The theoretical framework has been developed for more than two decades and numerous applications have appeared. In the current work, we explored strategic aspects of experimental design. To this end, we simulated families of ITC data sets that embed different strategies with regard to the number of experiments, range of experimental pH, buffer ionization enthalpy, and temperature. We then re-analyzed the families of data sets in the context of global analysis, employing a proton linkage binding model implemented in the global data analysis platform SEDPHAT, and examined the information content of all data sets by a detailed statistical error analysis of the parameter estimates. In particular, we studied the impact of different assumptions about the knowledge of the exact concentrations of the components, which in practice presents an experimental limitation for many systems. For example, the uncertainty in concentration may reflect imperfectly known extinction coefficients and stock concentrations or may account for different extents of partial inactivation when working with proteins at different pH values. Our results show that the global analysis can yield reliable estimates of the thermodynamic parameters for intrinsic binding and protonation, and that in the context of the global analysis the exact molecular component concentrations may not be required. Additionally, a comparison of data from different experimental strategies illustrates the benefit of conducting experiments at a range of temperatures. Published by Elsevier Ltd. C1 [Schuck, Peter; Zhao, Huaying] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Coussens, Nathan P.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Zhao, HY (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bldg 13,Rm 3N17,13 S Dr, Bethesda, MD 20892 USA. EM zhaoh3@mail.nih.gov RI Zhao, Huaying/F-5716-2012; OI Schuck, Peter/0000-0002-8859-6966 FU NCI; NIBIB, National Institutes of Health FX We thank Dr. Lawrence E. Samelson for his encouragement and critical reading of the manuscript. This work was supported by the Intramural Research Programs of NCI and NIBIB, National Institutes of Health. NR 43 TC 9 Z9 9 U1 1 U2 14 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0021-9614 J9 J CHEM THERMODYN JI J. Chem. Thermodyn. PD SEP PY 2012 VL 52 BP 95 EP 107 DI 10.1016/j.jct.2012.02.008 PG 13 WC Thermodynamics; Chemistry, Physical SC Thermodynamics; Chemistry GA 942OZ UT WOS:000304056300014 PM 22773848 ER PT J AU Kirschenbaum, LJ Riesz, P AF Kirschenbaum, Louis J. Riesz, Peter TI Sonochemical degradation of cyclic nitroxides in aqueous solution SO ULTRASONICS SONOCHEMISTRY LA English DT Article DE Nitroxides; Sonochemical decomposition; Hydrophobicity; EPR; Ultrasonics ID SONOLYTIC DESTRUCTION; ORGANIC-COMPOUNDS; KINETICS MODEL; OH RADICALS; REDUCTION; ANTIOXIDANTS; CAVITATION; ULTRASOUND; MECHANISM; DECOMPOSITION AB The sonochemical degradation of eight five- and six-membered nitroxides has been studied by EPR spectroscopy after exposure to ultrasound at a frequency of 354 kHz in argon-saturated aqueous solution. Concentration vs. time profiles do not follow a simple rate law. Octanol/water partition functions have been determined for all eight nitroxides, and an excellent linear correlation has been found between initial decomposition rates and hydrophobicity (log K-octanol/water). Variation of initial rate with concentration was investigated for one compound (TEMPONE) and is largely consistent with an equilibrium distribution of substrate between bulk solution and the gas/liquid interface. (C) 2012 Elsevier B.V. All rights reserved. C1 [Kirschenbaum, Louis J.] Univ Rhode Isl, Dept Chem, Kingston, RI 02881 USA. [Kirschenbaum, Louis J.; Riesz, Peter] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Kirschenbaum, LJ (reprint author), Univ Rhode Isl, Dept Chem, Kingston, RI 02881 USA. EM Kirschenbaum@chm.uri.edu NR 40 TC 5 Z9 5 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1350-4177 J9 ULTRASON SONOCHEM JI Ultrason. Sonochem. PD SEP PY 2012 VL 19 IS 5 BP 1114 EP 1119 DI 10.1016/j.ultsonch.2012.01.014 PG 6 WC Acoustics; Chemistry, Multidisciplinary SC Acoustics; Chemistry GA 942VA UT WOS:000304076900021 PM 22361491 ER PT J AU Liu, MM Chan, CC Tuo, JS AF Liu, Melissa M. Chan, Chi-Chao Tuo, Jingsheng TI Genetic mechanisms and age-related macular degeneration: common variants, rare variants, copy number variations, epigenetics, and mitochondrial genetics SO HUMAN GENOMICS LA English DT Review DE Age-related macular degeneration; Copy number variation; Genetics; Epigenetics; Mitochondria ID COMPLEMENT FACTOR-H; GENOME-WIDE ASSOCIATION; S-TRANSFERASE M1; PIGMENT EPITHELIAL-CELLS; REAL-TIME PCR; DNA-DAMAGE; OXIDATIVE STRESS; HUMAN-DISEASE; POLYMORPHISM; RISK AB Age-related macular degeneration (AMD) is a complex and multifaceted disease involving contributions from both genetic and environmental influences. Previous work exploring the genetic contributions of AMD has implicated numerous genomic regions and a variety of candidate genes as modulators of AMD susceptibility. Nevertheless, much of this work has revolved around single-nucleotide polymorphisms (SNPs), and it is apparent that a significant portion of the heritability of AMD cannot be explained through these mechanisms. In this review, we consider the role of common variants, rare variants, copy number variations, epigenetics, microRNAs, and mitochondrial genetics in AMD. Copy number variations in regulators of complement activation genes (CFHR1 and CFHR3) and glutathione S transferase genes (GSTM1 and GSTT1) have been associated with AMD, and several additional loci have been identified as regions of potential interest but require further evaluation. MicroRNA dysregulation has been linked to the retinal pigment epithelium degeneration in geographic atrophy, ocular neovascularization, and oxidative stress, all of which are hallmarks in the pathogenesis of AMD. Certain mitochondrial DNA haplogroups and SNPs in mitochondrially encoded NADH dehydrogenase genes have also been associated with AMD. The role of these additional mechanisms remains only partly understood, but the importance of their further investigation is clear to elucidate more completely the genetic basis of AMD. C1 [Liu, Melissa M.; Chan, Chi-Chao; Tuo, Jingsheng] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Liu, Melissa M.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. RP Tuo, JS (reprint author), NEI, Immunol Lab, NIH, 10-10 N103,10 Ctr Dr, Bethesda, MD 20892 USA. EM tuoj@nei.nih.gov OI Tuo, Jingsheng/0000-0002-1372-7810 FU NEI NIH HHS [T32 EY007143] NR 92 TC 32 Z9 32 U1 1 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 J9 HUM GENOMICS JI Hum. Genomics PD AUG 31 PY 2012 VL 6 AR 13 DI 10.1186/1479-7364-6-13 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 121DK UT WOS:000317222800001 PM 23244519 ER PT J AU Kelly, D Burt, K Missaghi, B Barrett, L Keynan, Y Fowke, K Grant, M AF Kelly, Deborah Burt, Kimberley Missaghi, Bayan Barrett, Lisa Keynan, Yoav Fowke, Keith Grant, Michael TI Responses to pandemic ASO3-adjuvanted A/California/07/09 H1N1 influenza vaccine in human immunodeficiency virus-infected individuals SO BMC IMMUNOLOGY LA English DT Article DE HIV; influenza; pandemic; A/California/07/2009 H1N1 HA antigen; AS03 oil in water adjuvant; inflammation; CD4(+) T cells; age ID IMMUNE-RESPONSE; HIV; IMMUNOGENICITY; ADULTS; TRIAL; INFLAMMATION; ACTIVATION; SAFETY AB Background: Influenza infection may be more serious in human immunodeficiency virus (HIV)-infected individuals, therefore, vaccination against seasonal and pandemic strains is highly advised. Seasonal influenza vaccines have had no significant negative effects in well controlled HIV infection, but the impact of adjuvanted pandemic A/California/07/2009 H1N1 influenza hemaglutinin (HA) vaccine, which was used for the first time in the Canadian population as an authorized vaccine in autumn 2009, has not been extensively studied. Objective: Assess vaccine-related effects on CD4(+) T cell counts and humoral responses to the vaccine in individuals attending the Newfoundland and Labrador Provincial HIV clinic. Methods: A single dose of Arepanrix (TM) split vaccine including 3.75 mu g A/California/07/2009 H1N1 HA antigen and ASO3 adjuvant was administered to 81 HIV-infected individuals by intramuscular injection. Plasma samples from shortly before, and 1-5 months after vaccination were collected from 80/81 individuals to assess humoral anti-H1N1 HA responses using a sensitive microbead-based array assay. Data on CD4(+) T cell counts, plasma viral load, antiretroviral therapy and patient age were collected from clinical records of 81 individuals. Results: Overall, 36/80 responded to vaccination either by seroconversion to H1N1 HA or with a clear increase in anti-H1N1 HA antibody levels. Approximately 1/3 (28/80) had pre-existing anti-H1N1 HA antibodies and were more likely to respond to vaccination (22/28). Responders had higher baseline CD4(+) T cell counts and responders without pre-existing antibodies against H1N1 HA were younger than either non-responders or responders with pre-existing antibodies. Compared to changes in their CD4(+) T cell counts observed over a similar time period one year later, vaccine recipients displayed a minor, transient fall in CD4(+) T cell numbers, which was greater amongst responders. Conclusions: We observed low response rates to the 2009 pandemic influenza vaccine among HIV-infected individuals without pre-existing antibodies against H1N1 HA and a minor transient fall in CD4(+) T cell numbers, which was accentuated in responders. A single injection of the Arepanrix (TM) pandemic A/California/07/2009 H1N1 HA split vaccine may be insufficient to induce protective immunity in HIV-infected individuals without pre-existing anti-H1N1 HA responses. C1 [Grant, Michael] Mem Univ Newfoundland & Labrador, Div BioMed Sci, St John, NF, Canada. [Grant, Michael] Mem Univ Newfoundland, Fac Med, St John, NF, Canada. [Kelly, Deborah] Mem Univ Newfoundland & Labrador, Sch Pharm, St John, NF, Canada. [Kelly, Deborah; Burt, Kimberley; Missaghi, Bayan] Eastern Hlth Corp Newfoundland & Labrador, St John, NF, Canada. [Missaghi, Bayan] Mem Univ Newfoundland & Labrador, Div Infect Dis, St John, NF, Canada. [Barrett, Lisa] NIH, Inst Allergy & Infect Dis, Bethesda, MD 20892 USA. [Keynan, Yoav; Fowke, Keith] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. [Keynan, Yoav; Fowke, Keith] Univ Manitoba, Dept Community Hlth Sci, Winnipeg, MB R3T 2N2, Canada. [Keynan, Yoav; Fowke, Keith] Univ Nairobi, Dept Med Microbiol, Nairobi, Kenya. RP Grant, M (reprint author), Mem Univ Newfoundland & Labrador, Div BioMed Sci, St John, NF, Canada. EM mgrant@mun.ca OI Fowke, Keith/0000-0001-8227-6649 FU Canadian Institutes of Health Research grant [HC1-112568] FX We would like to thank all the subjects participating in this study. Maureen Gallant and Katrin Zipperlen sorted, coded and dispensed the plasma samples shipped to Winnipeg for anti-H1N1 HA measurement. This study was supported in part by Canadian Institutes of Health Research grant #HC1-112568 awarded to MG. NR 22 TC 6 Z9 6 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD AUG 31 PY 2012 VL 13 AR 49 DI 10.1186/1471-2172-13-49 PG 9 WC Immunology SC Immunology GA 027JR UT WOS:000310348900001 PM 22937824 ER PT J AU Hernandez-Rocamora, VM Reija, B Garcia, C Natale, P Alfonso, C Minton, AP Zorrilla, S Rivas, G Vicente, M AF Hernandez-Rocamora, Victor M. Reija, Belen Garcia, Concepcion Natale, Paolo Alfonso, Carlos Minton, Allen P. Zorrilla, Silvia Rivas, German Vicente, Miguel TI Dynamic Interaction of the Escherichia coli Cell Division ZipA and FtsZ Proteins Evidenced in Nanodiscs SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOLIPID-BILAYER NANODISCS; MEMBRANE-PROTEINS; IN-VITRO; RING; RECONSTITUTION; ASSOCIATION; MONOMER; BIOLOGY AB The full-length ZipA protein from Escherichia coli, one of the essential components of the division proto-ring that provides membrane tethering to the septation FtsZ protein, has been incorporated in single copy into nanodiscs formed by a membrane scaffold protein encircling an E. coli phospholipid mixture. This is an acellular system that reproduces the assembly of part of the cell division components. ZipA contained in nanodiscs (Nd-ZipA) retains the ability to interact with FtsZ oligomers and with FtsZ polymers. Interactions with FtsZ occur at similar strengths as those involved in the binding of the soluble form of ZipA, lacking the transmembrane region, suggesting that the transmembrane region of ZipA has little influence on the formation of the ZipA.FtsZ complex. Peptides containing partial sequences of the C terminus of FtsZ compete with FtsZ polymers for binding to Nd-ZipA. The affinity of Nd-ZipA for the FtsZ polymer formed with GTP or GMPCPP (a slowly hydrolyzable analog of GTP) is moderate (micromolar range) and of similar magnitude as for FtsZ-GDP oligomers. Polymerization does not stabilize the binding of FtsZ to ZipA. This supports the role of ZipA as a passive anchoring device for the proto-ring with little implication, if any, in the regulation of its assembly. Furthermore, it indicates that the tethering of FtsZ to the membrane shows sufficient plasticity to allow for its release from noncentral regions of the cytoplasmic membrane and its subsequent relocation to midcell when demanded by the assembly of a division ring. C1 [Hernandez-Rocamora, Victor M.; Garcia, Concepcion; Alfonso, Carlos; Rivas, German] CSIC, Ctr Invest Biol, E-28006 Madrid, Spain. [Reija, Belen; Zorrilla, Silvia] CSIC, Inst Quim Fis Rocasolano, E-28006 Madrid, Spain. [Natale, Paolo; Vicente, Miguel] CSIC, Ctr Nacl Biotecnol, E-28006 Madrid, Spain. [Minton, Allen P.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Rivas, G (reprint author), CSIC, Ctr Invest Biol, Velazquez 144, E-28006 Madrid, Spain. EM grivas@cib.csic.es; mvicente@cnb.csic.es RI Zorrilla, Silvia/J-9771-2014; Alfonso, Carlos/K-1316-2014; OI Zorrilla, Silvia/0000-0002-6309-9058; Alfonso, Carlos/0000-0001-7165-4800; Minton, Allen/0000-0001-8459-1247; Rivas, German/0000-0003-3450-7478 FU Human Frontier Science Program [RGP0050/2010]; European Commission [HEALTH-F3-2009-223431]; Spanish Government [BIO2008-04478-C03, CSIC-PIE-201020I001, BFU2010-14910, BIO2011-28941-C03]; NIDDK, National Institutes of Health FX This work was supported in part by the Human Frontier Science Program through Grant RGP0050/2010, the European Commission through Contract HEALTH-F3-2009-223431 (both to M. V. and G. R.), and the Spanish Government through Grants BIO2008-04478-C03 (to M. V. and G. R.), CSIC-PIE-201020I001 (to C. A.), BFU2010-14910 (to S. Z.), and BIO2011-28941-C03 (to M. V., G. R., and S. Z.).; Supported by the Intramural Research Program of the NIDDK, National Institutes of Health. NR 24 TC 21 Z9 21 U1 1 U2 19 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 31 PY 2012 VL 287 IS 36 BP 30097 EP 30104 DI 10.1074/jbc.M112.388959 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 003AF UT WOS:000308579800005 PM 22787144 ER PT J AU Wang, L Jia, Y Rogers, H Wu, YP Huang, SM Noguchi, CT AF Wang, Li Jia, Yi Rogers, Heather Wu, Yun-Ping Huang, Suming Noguchi, Constance Tom TI GATA-binding Protein 4 (GATA-4) and T-cell Acute Leukemia 1 (TAL1) Regulate Myogenic Differentiation and Erythropoietin Response via Cross-talk with Sirtuin1 (Sirt1) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEART TUBE FORMATION; SKELETAL-MUSCLE; TRANSCRIPTION FACTOR; VENTRAL MORPHOGENESIS; HISTONE DEACETYLASES; GENE DISRUPTION; SATELLITE CELLS; MYOD; EXPRESSION; RECEPTOR AB Erythropoietin (EPO), the cytokine required for erythrocyte production, contributes to muscle progenitor cell proliferation and delay myogenic differentiation. However, the underlying mechanism is not yet fully understood. Here, we report that EPO changes the skeletal myogenic regulatory factor expression program and delays differentiation via induction of GATA-4 and the basic helix-loop-helix TAL1 and that knockdown of both factors promotes differentiation. EPO increases the Sirt1 level, a NAD(+)-dependent deacetylase, and also induces the NAD(+)/NADH ratio that further increases Sirt1 activity. Sirt1 knockdown reduced GATA-4 and TAL1 expression, impaired EPO effect on delayed myogenic differentiation, and the Sirt1 knockdown effect was abrogated when combined with overexpression of GATA-4 or TAL1. GATA-4 interacts with Sirt1 and targets Sirt1 to the myogenin promoter and represses myogenin expression, whereas TAL1 inhibits myogenin expression by decreasing MyoD binding to and activation of the myogenin promoter. Sirt1 was found to bind to the GATA-4 promoter to directly regulate GATA-4 expression and GATA-4 binds to the TAL1 promoter to regulate TAL1 expression positively. These data suggest that GATA-4, TAL1, and Sirt1 cross-talk each other to regulate myogenic differentiation and mediate EPO activity during myogenic differentiation with Sirt1 playing a role upstream of GATA-4 and TAL1. Taken together, our findings reveal a novel role for GATA-4 and TAL1 to affect skeletal myogenic differentiation and EPO response via cross-talk with Sirt1. C1 [Wang, Li; Jia, Yi; Rogers, Heather; Noguchi, Constance Tom] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Wu, Yun-Ping] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Huang, Suming] Univ Florida, Coll Med, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. [Huang, Suming] Univ Florida, Coll Med, Shands Canc Ctr, Gainesville, FL 32610 USA. RP Noguchi, CT (reprint author), Bldg 10,Rm 9N319,10 Ctr Dr,MSC 1822, Bethesda, MD 20892 USA. EM connien@niddk.nih.gov FU National Institutes of Health Intramural Research Program of the NIDDK FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the NIDDK. NR 55 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 31 PY 2012 VL 287 IS 36 BP 30157 EP 30169 DI 10.1074/jbc.M112.376640 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 003AF UT WOS:000308579800011 PM 22773876 ER PT J AU Bandyopadhyay, BC Swaim, WD Sarkar, A Liu, XB Ambudkar, IS AF Bandyopadhyay, Bidhan C. Swaim, William D. Sarkar, Ankana Liu, Xibao Ambudkar, Indu S. TI Extracellular Ca2+ Sensing in Salivary Ductal Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CALCIUM-TRANSPORT; EPITHELIAL-CELLS; TRPC3 CHANNELS; PLASMA-MEMBRANE; FLUID SECRETION; CATION CHANNEL; AMINO-ACIDS; RECEPTOR; GLAND; LOCALIZATION AB Ca2+ is secreted from the salivary acinar cells as an ionic constituent of primary saliva. Ions such as Na+ and Cl- get reabsorbed whereas primary saliva flows through the salivary ductal system. Although earlier studies have shown that salivary [Ca2+] decreases as it flows down the ductal tree into the oral cavity, ductal reabsorption of Ca2+ remains enigmatic. Here we report a potential role for the G protein-coupled receptor, calcium-sensing receptor (CSR), in the regulation of Ca2+ reabsorption by salivary gland ducts. Our data show that CSR is present in the apical region of ductal cells where it is co-localized with transient receptor potential canonical 3 (TRPC3). CSRis activated in isolated salivary gland ducts as well as a ductal cell line (SMIE) by altering extracellular [Ca2+] or by aromatic amino acid, L-phenylalanine (L-Phe, endogenous component of saliva), as well as neomycin. CSR activation leads to Ca2+ influx that, in polarized cells grown on a filter support, is initiated in the luminal region. Weshow that TRPC3 contributes to Ca2+ entry triggered by CSR activation. Further, stimulation of CSR in SMIE cells enhances the CSR-TRPC3 association as well as surface expression of TRPC3. Together our findings suggest that CSR could serve as a Ca2+ sensor in the luminal membrane of salivary gland ducts and regulate reabsorption of [Ca2+] from the saliva via TRPC3, thus contributing to maintenance of salivary [Ca2+]. CSR could therefore be a potentially important protective mechanism against formation of salivary gland stones (sialolithiasis) and infection (sialoadenitis). C1 [Bandyopadhyay, Bidhan C.] Vet Affairs Med Ctr, Res Serv, Calcium Signaling Lab, Washington, DC 20422 USA. [Bandyopadhyay, Bidhan C.; Sarkar, Ankana] Georgetown Univ, Dept Physiol & Pharmacol, Washington, DC 20007 USA. [Swaim, William D.; Liu, Xibao; Ambudkar, Indu S.] NIDCR, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Bandyopadhyay, BC (reprint author), DVA Med Ctr, Calcium Signaling Lab, Res Serv 151, 50 Irving St NW, Washington, DC 20422 USA. EM bidhan.bandyopadhyay@va.gov FU National Institutes of Health through NIDCR [DE 019524]; NIDCR Intramural Research FX This study was supported, in whole or in part, by National Institutes of Health Grant DE 019524 through the NIDCR ( to B. C. B) and by NIDCR Intramural Research ( to I. S. A.). NR 50 TC 7 Z9 7 U1 3 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 31 PY 2012 VL 287 IS 36 BP 30305 EP 30316 DI 10.1074/jbc.M112.394122 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 003AF UT WOS:000308579800023 PM 22778254 ER PT J AU Oh, HM Yu, CR Dambuza, I Marrero, B Egwuagu, CE AF Oh, Hyun-Mee Yu, Cheng-Rong Dambuza, Ivy Marrero, Bernadette Egwuagu, Charles E. TI STAT3 Protein Interacts with Class O Forkhead Transcription Factors in the Cytoplasm and Regulates Nuclear/Cytoplasmic Localization of FoxO1 and FoxO3a Proteins in CD4(+) T Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; INTERLEUKIN-10; P27(KIP1); SURVIVAL; BINDING; SYSTEM; IL-2 AB An important feature of the adaptive immune response is its remarkable capacity to regulate the duration of inflammatory responses, and effector T cells have been shown to limit excessive immune responses by producing anti-inflammatory cytokines such as IL-10 and IL-27. However, how anti-inflammatory cytokines mediate their suppressive activities is not well understood. In this study, we show that STAT3 contributes to mechanisms that control the duration of T cell proliferation by regulating the subcellular location of FoxO1 and FoxO3a, two Class O Forkhead transcription factors that mediate lymphocyte quiescence and inhibit T cell activation. We show that active FoxO1 and FoxO3a reside exclusively in the nucleus of naive T cells whereas inactive pFoxO1 and pFoxO3a were most abundant in activated T cells and sequestered in their cytoplasm in association with unphosphorylated STAT3 (U-STAT3) and 14-3-3. We further show that FoxO1/FoxO3a rapidly relocalized into the nucleus in response to pSTAT3 activation by IL-6 or IL-10, and the accumulation of FoxO1/FoxO3a in their nuclei coincided with increased expression of p27(Kip1) and p21(WAF1). STAT3 inhibitors completely abrogated cytokine-induced translocation of FoxO1/FoxO3a into the nucleus. In naive or resting STAT3-deficient T cells, expression of pFoxO1/pFoxO3a was predominantly in the cytoplasm and correlated with defects in p27(Kip1) and p21(WAF1) expression, suggesting requirement of STAT3 for importation or retention of FoxO in the nucleus and attenuation of lymphocyte proliferation. Taken together, these results suggest that U-STAT3 collaborates with 14-3-3 to sequester pFoxO1/pFoxO3a in cytoplasm and thus prolong T cell activation, whereas pSTAT3 activation by anti-inflammatory cytokines would curtail the duration of TCR activation and re-establish lymphocyte quiescence by inducing nuclear localization of FoxO1/FoxO3a and FoxO-mediated expression of growth-inhibitory proteins. C1 [Egwuagu, Charles E.] NEI, Mol Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Oh, Hyun-Mee] Korea Res Inst Biosci & BioTechnol, Bioind Proc Res Ctr, Jeongeup Si 580185, Jeonbuk, South Korea. RP Egwuagu, CE (reprint author), NEI, Mol Immunol Sect, Immunol Lab, NIH, Bldg 10,Rm 10N109A,10 Ctr Dr, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov FU National Institutes of Health NEI Research Program; National Institutes of Health Intramural Research Program FX This work was supported by the National Institutes of Health NEI and Intramural Research Programs. NR 29 TC 11 Z9 11 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 31 PY 2012 VL 287 IS 36 BP 30436 EP 30443 DI 10.1074/jbc.M112.359661 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 003AF UT WOS:000308579800036 PM 22761423 ER PT J AU Chander, P Gentleman, S Poliakov, E Redmond, TM AF Chander, Preethi Gentleman, Susan Poliakov, Eugenia Redmond, T. Michael TI Aromatic Residues in the Substrate Cleft of RPE65 Protein Govern Retinol Isomerization and Modulate Its Progression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VISUAL CYCLE; ISOMEROHYDROLASE ACTIVITY; CAROTENOID OXYGENASE; PIGMENT EPITHELIUM; ISOMERASE; MODEL; COMPLEXES; EFFICIENT; ENZYME; SERVER AB Previously, we showed that mutating RPE65 residue Phe-103 preferentially produces 13-cis-retinol instead of 11-cis-retinol, supporting a carbocation/radical cation mechanism of retinol isomerization. We asked whether this modulation of specificity can occur with residues other than Phe-103 and what role it plays in substrate binding and isomerization. We modeled the substrate-binding cleft of RPE65 to identify residues lining its surface. Many are phenylalanines and tyrosines, including three Phe residues (Phe-61, Phe-312, and Phe-526) forming an arch-like arrangement astride the cleft and Tyr-338. Also, Phe-418 sits at the neck of the cleft, lending a bend to the volume enclosed by the cleft. All mutations of Phe-61, Phe-312, and Phe-418 result in severely impaired or inactive enzyme. However, mutation of Phe-526 and Tyr-338, like Phe-103, decreases 11-cis-retinol formation, whereas increasing the 13-cis isomer. Significantly, 2 of these 3 residues, Phe-103 and Tyr-338, are located on putatively mobile interstrand loops. We propose that residual densities located in the binding cleft of the RPE65 structure represents a post-cleavage snapshot consistent not only with a fatty acid product, as originally modeled, but also an 11-cis-retinol product. Substrate docking simulations permit 11-cis- or 13-cis-retinyl ester binding in this relatively closed cleft, with the latter favored in F103L, F526A, and Y338A mutant structures, but prohibit binding of all-trans-retinyl ester, suggesting that isomerization occurs early in the temporal sequence, with O-alkyl ester cleavage occurring later. These findings provide insight into the mechanism of isomerization central to the visual cycle. C1 [Chander, Preethi; Gentleman, Susan; Poliakov, Eugenia; Redmond, T. Michael] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Redmond, TM (reprint author), NEI, Lab Retinal Cell & Mol Biol, NIH, Bldg 6,Rm 117A, Bethesda, MD 20892 USA. EM redmond@helix.nih.gov OI Redmond, T. Michael/0000-0002-1813-5291 FU National Institutes of Health Intramural Research Program of the NEI FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the NEI. NR 31 TC 12 Z9 12 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 31 PY 2012 VL 287 IS 36 BP 30552 EP 30559 DI 10.1074/jbc.M112.364596 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 003AF UT WOS:000308579800047 PM 22745121 ER PT J AU Gao, R Huang, SYN Marchand, C Pommier, Y AF Gao, Rui Huang, Shar-yin N. Marchand, Christophe Pommier, Yves TI Biochemical Characterization of Human Tyrosyl-DNA Phosphodiesterase 2 (TDP2/TTRAP) A Mg2+/Mn2+-DEPENDENT PHOSPHODIESTERASE SPECIFIC FOR THE REPAIR OF TOPOISOMERASE CLEAVAGE COMPLEXES SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; RECEPTOR-ASSOCIATED FACTORS; BODIES-ASSOCIATED PROTEIN; DIVALENT METAL-IONS; VERTEBRATE CELLS; ACTIVE-SITE; I-TASSER; TTRAP; DAMAGE; TDP1 AB TDP2 is a multifunctional enzyme previously known for its role in signal transduction as TRAF and TNF receptor-associated protein (TTRAP) and ETS1-associated protein 2 (EAPII). The gene has recently been renamed TDP2 because it plays a critical role for the repair of topoisomerase II cleavage complexes (Top2cc) and encodes an enzyme that hydrolyzes 5'-tyrosine-DNA adducts that mimic abortive Top2cc. Here we further elucidate the DNA-processing activities of human recombinant TDP2 and its biochemical characteristics. The preferred substrate for TDP2 is single-stranded DNA or duplex DNA with a four-base pair overhang, which is consistent with the known structure of Top2cc or Top3cc. The k(cat)/K-m of TDP1 and TDP2 was determined. It was found to be 4 x 10(5) s(-1)M(-1) for TDP2 using single-stranded 5'-tyrosyl-DNA. The processing of substrates as short as five nucleotides long suggests that TDP2 can directly bind DNA ends. 5'-Phosphodiesterase activity requires a phosphotyrosyl linkage and tolerates an extended group attached to the tyrosine. TDP2 requires Mg2+ or Mn2+ for efficient catalysis but is weakly active with Ca2+ or Zn2+. Titration with Ca2+ demonstrates a two-metal binding site in TDP2. Sequence alignment suggests that TDP2 contains four conserved catalytic motifs shared by Mg2+-dependent endonucleases, such as APE1. Substitutions at each of the four catalytic motifs identified key residues Asn-120, Glu-152, Asp-262, and His-351, whose mutation to alanine significantly reduced or completely abolished enzymatic activity. Our study characterizes the substrate specificity and kinetic parameters of TDP2. In addition, a two-metal catalytic mechanism is proposed. C1 [Gao, Rui; Huang, Shar-yin N.; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Center for Cancer Research, Intramural Program of the NCI, National Institutes of Health FX This work was supported, in whole or in part, by the Center for Cancer Research, Intramural Program of the NCI, National Institutes of Health. NR 44 TC 25 Z9 28 U1 1 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 31 PY 2012 VL 287 IS 36 BP 30842 EP 30852 DI 10.1074/jbc.M112.393983 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 003AF UT WOS:000308579800072 PM 22822062 ER PT J AU Zheng, QX Ren, YP Tzekov, R Zhang, YP Chen, B Hou, JP Zhao, CH Zhu, JL Zhang, Y Dai, XF Ma, S Li, J Pang, JJ Qu, J Li, WS AF Zheng, Qinxiang Ren, Yueping Tzekov, Radouil Zhang, Yuanping Chen, Bo Hou, Jiangping Zhao, Chunhui Zhu, Jiali Zhang, Ying Dai, Xufeng Ma, Shan Li, Jia Pang, Jijing Qu, Jia Li, Wensheng TI Differential Proteomics and Functional Research following Gene Therapy in a Mouse Model of Leber Congenital Amaurosis SO PLOS ONE LA English DT Article ID CANINE MODEL; RETINAL DEGENERATION; CHILDHOOD BLINDNESS; RPE65 MUTATIONS; RESTORES VISION; PEROXIREDOXIN 6; LIGHT DAMAGE; MURINE MODEL; RAT RETINA; CELL-DEATH AB Leber congenital amaurosis (LCA) is one of the most severe forms of inherited retinal degeneration and can be caused by mutations in at least 15 different genes. To clarify the proteomic differences in LCA eyes, a cohort of retinal degeneration 12 (rd12) mice, an LCA2 model caused by a mutation in the RPE65 gene, were injected subretinally with an AAV vector (scAAV5-smCBA-hRPE65) in one eye, while the contralateral eye served as a control. Proteomics were compared between untreated rd12 and normal control retinas on P14 and P21, and among treated and untreated rd12 retinas and control retinas on P42. Gene therapy in rd12 mice restored retinal function in treated eyes, which was demonstrated by electroretinography (ERG). Proteomic analysis successfully identified 39 proteins expressed differently among the 3 groups. The expression of 3 proteins involved in regulation of apoptosis and neuroptotection (alpha A crystallin, heat shock protein 70 and peroxiredoxin 6) were investigated further. Immunofluorescence, Western blot and real-time PCR confirmed the quantitative changes in their expression. Furthermore, cell culture studies suggested that peroxiredoxin 6 could act in an antioxidant role in rd12 mice. Our findings support the feasibility of gene therapy in LCA2 patients and support a role for alpha A crystallin, heat shock protein 70 and peroxiredoxin 6 in the pathogenetic mechanisms involved in LCA2 disease process. C1 [Zheng, Qinxiang; Ren, Yueping; Hou, Jiangping; Zhao, Chunhui; Zhu, Jiali; Zhang, Ying; Dai, Xufeng; Pang, Jijing; Qu, Jia; Li, Wensheng] Wenzhou Med Coll, Hosp Eye, Wenzhou, Peoples R China. [Tzekov, Radouil] Roskamp Inst, Sarasota, FL USA. [Zhang, Yuanping] Kunming Med Coll, Affiliated Hosp 2, Dept Ophthalmol, Kunming, Peoples R China. [Chen, Bo] Yale Univ, Sch Med, Dept Ophthalmol & Visual Sci, New Haven, CT 06510 USA. [Ma, Shan; Li, Jia] Univ Massachusetts, Sch Med, Dept Ophthalmol, Worcester, MA USA. [Pang, Jijing] Univ Florida, Coll Med, Dept Ophthalmol, Gainesville, FL 32610 USA. [Li, Wensheng] NEI, Neurobiol Neurodegenerat & Repair Lab, Retinal Cell Biol & Degenerat Sect, NIH, Bethesda, MD 20892 USA. RP Zheng, QX (reprint author), Wenzhou Med Coll, Hosp Eye, Wenzhou, Peoples R China. EM jqu@wzmc.net; drlws@163.net OI Tzekov, Radouil/0000-0002-3662-9818 FU Major Projects of the National Science and Technology of China [2009ZX09503]; Specilized Research Fund for the Doctoral Program of Higher Education [20103321110002]; Key Projects of National High-Tech R&D Program (863 Program) of China [2007AA021004]; Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical College, Wenzhou, China FX This research was supported by grants of Major Projects of the National Science and Technology of China (No: 2009ZX09503), Specilized Research Fund for the Doctoral Program of Higher Education (No: 20103321110002), Key Projects of National High-Tech R&D Program (863 Program) of China (No: 2007AA021004), retinal gene therapy study grants from Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical College, Wenzhou, China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 7 Z9 7 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 AUG 31 PY 2012 VL 7 IS 8 AR e44855 DI 10.1371/journal.pone.0044855 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998EY UT WOS:000308221300106 PM 22953002 ER PT J AU Sung, MH Hager, GL AF Sung, Myong-Hee Hager, Gordon L. TI Nonlinear Dependencies of Biochemical Reactions for Context-specific Signaling Dynamics SO SCIENTIFIC REPORTS LA English DT Article ID NF-KAPPA-B; GENE-EXPRESSION; NETWORKS; OSCILLATIONS; MODULE AB Mathematical modeling can provide unique insights and predictions about a signaling pathway. Parameter variations allow identification of key reactions that govern signaling features such as the response time that may have a direct impact on the functional outcome. The effect of varying one parameter, however, may depend on values of another. To address the issue, we performed multi-parameter variations of an experimentally validated mathematical model of NF-kappa B regulatory network, and analyzed the inter-relationships of the parameters in shaping key dynamic features. We find that nonlinear dependencies are ubiquitous among parameters. Such phenomena may underlie the emergence of cell type-specific behaviors from essentially the same molecular network. Our results from a multivariate ensemble of models highlight the hypothesis that cell type specificity in signaling phenotype can arise from quantitatively altered strength of reactions in the pathway, in the absence of tissue-specific factors that re-wire the network for a new topology. C1 [Sung, Myong-Hee; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Sung, MH (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM sungm@mail.nih.gov FU National Institutes of Health FX We thank Alessandra Agresti for helpful discussions. This work was supported in part by the Intramural Research Program of the National Institutes of Health. NR 21 TC 2 Z9 2 U1 0 U2 0 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 AUG 31 PY 2012 VL 2 AR 616 DI 10.1038/srep00616 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 000YU UT WOS:000308427800001 PM 22943002 ER PT J AU Marks, MA Eby, Y Howard, R Gravitt, PE AF Marks, Morgan A. Eby, Yolanda Howard, Roslyn Gravitt, Patti E. TI Comparison of normalization methods for measuring immune markers in cervical secretion specimens SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Cytokines; Cervical secretions; Ophthalmic sponges; Weight adjustment; Protein adjustment ID FEMALE GENITAL-TRACT; VAGINAL SECRETIONS; WOMEN; COLLECTION; IMMUNOGLOBULINS; CYTOKINE; ISSUES; HIV AB Ophthalmic sponges are used to collect undiluted cervical secretions for assessment of markers of genital tract immunity. Heterogeneity in absorbed and extracted sample volumes requires normalization in order to make valid inter-individual comparisons. We evaluated the performance of adjustment by weight and total protein on normalizing inter-individual variability of immune marker measurement due to differences in volume collection. Normalization to total protein resulted in a minimal loss of usable specimens and a significant reduction in the correlation of immune marker concentration to specimen weight compared to weight adjustment. Total protein normalization appeared to be more effective than weight adjustment in reducing the dependence of cervical immune marker concentrations on differences in specimen volume. (C) 2012 Elsevier B.V. All rights reserved. C1 [Eby, Yolanda; Howard, Roslyn; Gravitt, Patti E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Marks, Morgan A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Gravitt, Patti E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. RP Gravitt, PE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,Rm E6148, Baltimore, MD 21205 USA. EM pgravitt@jhsph.edu FU US National Cancer Institute [R01 CA123467]; Institutional Research Cancer Epidemiology Fellowship; National Cancer Institute [T32 CA0009314] FX This work was supported by the US National Cancer Institute R01 CA123467 and the Institutional Research Cancer Epidemiology Fellowship funded by the National Cancer Institute T32 CA0009314. NR 14 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD AUG 31 PY 2012 VL 382 IS 1-2 BP 211 EP 215 DI 10.1016/j.jim.2012.05.012 PG 5 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 983AN UT WOS:000307088700022 PM 22677266 ER PT J AU Youle, RJ van der Bliek, AM AF Youle, Richard J. van der Bliek, Alexander M. TI Mitochondrial Fission, Fusion, and Stress SO SCIENCE LA English DT Review ID PARKIN-MUTANTS; AUTOPHAGY; DEGRADATION; SEGREGATION; DYSFUNCTION; MUTATIONS; CELLS; DROSOPHILA-PINK1; COMPLEMENTATION; PHOSPHORYLATION AB Mitochondrial fission and fusion play critical roles in maintaining functional mitochondria when cells experience metabolic or environmental stresses. Fusion helps mitigate stress by mixing the contents of partially damaged mitochondria as a form of complementation. Fission is needed to create new mitochondria, but it also contributes to quality control by enabling the removal of damaged mitochondria and can facilitate apoptosis during high levels of cellular stress. Disruptions in these processes affect normal development, and they have been implicated in neurodegenerative diseases, such as Parkinson's. C1 [Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [van der Bliek, Alexander M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA. RP Youle, RJ (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov; avan@mednet.ucla.edu FU Intramural Program of the National Institute of Neurological Disorders and Stroke; NIH [GM051866]; NSF [0552271] FX We thank members of the Youle lab for thoughtful comments. This work was supported by Intramural Program of the National Institute of Neurological Disorders and Stroke and grants from the NIH (GM051866) and the NSF (0552271) to A.M.v.d.B. NR 45 TC 552 Z9 567 U1 40 U2 195 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 31 PY 2012 VL 337 IS 6098 BP 1062 EP 1065 DI 10.1126/science.1219855 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 996WP UT WOS:000308125800037 PM 22936770 ER PT J AU Naik, S Bouladoux, N Wilhelm, C Molloy, MJ Salcedo, R Kastenmuller, W Deming, C Quinones, M Koo, L Conlan, S Spencer, S Hall, JA Dzutsev, A Kong, H Campbell, DJ Trinchieri, G Segre, JA Belkaid, Y AF Naik, Shruti Bouladoux, Nicolas Wilhelm, Christoph Molloy, Michael J. Salcedo, Rosalba Kastenmuller, Wolfgang Deming, Clayton Quinones, Mariam Koo, Lily Conlan, Sean Spencer, Sean Hall, Jason A. Dzutsev, Amiran Kong, Heidi Campbell, Daniel J. Trinchieri, Giorgio Segre, Julia A. Belkaid, Yasmine TI Compartmentalized Control of Skin Immunity by Resident Commensals SO SCIENCE LA English DT Article ID REGULATORY T-CELLS; HUMAN MICROBIOME; DENDRITIC CELLS; INNATE IMMUNITY; SYSTEM; RECOGNITION; DIVERSITY; INTESTINE; INFECTION; RESPONSES AB Intestinal commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota have an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident commensal niches in health and disease. C1 [Naik, Shruti; Bouladoux, Nicolas; Wilhelm, Christoph; Molloy, Michael J.; Spencer, Sean; Belkaid, Yasmine] NIAID, Mucosal Immun Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. [Naik, Shruti; Spencer, Sean] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. [Salcedo, Rosalba; Dzutsev, Amiran; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Salcedo, Rosalba; Dzutsev, Amiran] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Kastenmuller, Wolfgang] NIAID, Lymphocyte Biol Sect, Immunol Lab, Bethesda, MD 20892 USA. [Deming, Clayton; Conlan, Sean; Segre, Julia A.] NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Quinones, Mariam] NIAID, Bioinformat & Computat Biosci Branch, Bethesda, MD 20892 USA. [Koo, Lily] NIAID, Res Technol Branch, Bethesda, MD 20892 USA. [Hall, Jason A.] NYU, Sch Med, Skirball Inst Biomol Med, Kimmel Ctr Biol & Med,Mol Pathogenesis Program, New York, NY 10016 USA. [Kong, Heidi] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Campbell, Daniel J.] Benaroya Res Inst, Seattle, WA 98101 USA. [Campbell, Daniel J.] Univ Washington, Sch Med, Dept Immunol, Seattle, WA 98195 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immun Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov OI Kong, Heidi/0000-0003-4424-064X FU Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID); National Human Genome Research Institute, the National Cancer Institute, NIH [F30 DK094708]; Human Frontier Science Program FX Supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID) and by the National Human Genome Research Institute, the National Cancer Institute, NIH grant F30 DK094708 (S. S.), and the Human Frontier Science Program (C. W.). We thank the NIAID gnotobiotic facility staff, in particular C. Acevedo and D. Trageser-Cesler; K. Holmes and the NIAID sorting facility; K. Beacht, B. Kelsall, T. Tamachi, C. Brown, J. Benchley, A. MacDonald, L. Mijares, K. Shenderov, and A. Sher; and Yakult Central Institute for Microbiological Research for sharing SFB via a material transfer agreement. DNA sequence data are available via GenBank (accession no. SRS345653). The data reported in this paper are tabulated in the main paper and in the supplementary materials. NR 33 TC 258 Z9 264 U1 16 U2 100 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 AUG 31 PY 2012 VL 337 IS 6098 BP 1115 EP 1119 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 996WP UT WOS:000308125800053 PM 22837383 ER PT J AU Barone-Adesi, F Chapman, RS Silverman, DT He, XZ Hu, W Vermeulen, R Ning, BF Fraumeni, JF Rothman, N Lan, Q AF Barone-Adesi, Francesco Chapman, Robert S. Silverman, Debra T. He, Xinghzhou Hu, Wei Vermeulen, Roel Ning, Bofu Fraumeni, Joseph F., Jr. Rothman, Nathaniel Lan, Qing TI Risk of lung cancer associated with domestic use of coal in Xuanwei, China: retrospective cohort study SO BRITISH MEDICAL JOURNAL LA English DT Article ID HOUSEHOLD STOVE IMPROVEMENT; INDOOR AIR-POLLUTION; TIN MINERS; MORTALITY; MUTATIONS; SMOKING AB Objective To estimate the risk of lung cancer associated with the use of different types of coal for household cooking and heating. Setting Xuanwei County, Yunnan Province, China. Design Retrospective cohort study (follow-up 1976-96) comparing mortality from lung cancer between lifelong users of "smoky coal" (bituminous) and "smokeless coal" (anthracite). Participants 27 310 individuals using smoky coal and 9962 individuals using smokeless coal during their entire life. Main outcome measures Primary outcomes were absolute and relative risk of death from lung cancer among users of different types of coal. Unadjusted survival analysis was used to estimate the absolute risk of lung cancer, while Cox regression models compared mortality hazards for lung cancer between smoky and smokeless coal users. Results Lung cancer mortality was substantially higher among users of smoky coal than users of smokeless coal. The absolute risks of lung cancer death before 70 years of age for men and women using smoky coal were 18% and 20%, respectively, compared with less than 0.5% among smokeless coal users of both sexes. Lung cancer alone accounted for about 40% of all deaths before age 60 among individuals using smoky coal. Compared with smokeless coal, use of smoky coal was associated with an increased risk of lung cancer death (for men, hazard ratio 36 (95% confidence interval 20 to 65); for women, 99 (37 to 266)). Conclusions In Xuanwei, the domestic use of smoky coal is associated with a substantial increase in the absolute lifetime risk of developing lung cancer and is likely to represent one of the strongest effects of environmental pollution reported for cancer risk. Use of less carcinogenic types of coal could translate to a substantial reduction of lung cancer risk. C1 [Barone-Adesi, Francesco; Silverman, Debra T.; Hu, Wei; Fraumeni, Joseph F., Jr.; Rothman, Nathaniel; Lan, Qing] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Chapman, Robert S.] Chulalongkorn Univ, Coll Publ Hlth Sci, Bangkok 10330, Thailand. [He, Xinghzhou] Chinese Acad Prevent Med, Inst Environm Hlth & Engn, Beijing 100050, Peoples R China. [Vermeulen, Roel] Univ Utrecht, Div Environm Epidemiol, Inst Risk Assessment Sci, NL-3584 CK Utrecht, Netherlands. [Ning, Bofu] Xuanwei Ctr Dis Control, Qujing 655400, Yunnan, Peoples R China. RP Barone-Adesi, F (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Executive Blv,EPS 8015, Bethesda, MD 20892 USA. EM baroneadesif@mail.nih.gov RI Hu, Wei/M-3524-2013; Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU Chinese Academy of Preventive Medicine, Beijing, China; Yunnan Province Antiepidemic Station, Kunming, China; US Environmental Protection Agency [5D2290NFFX]; Intramural Research Program of the National Cancer Institute, National Institutes of Health FX The study was supported by the Chinese Academy of Preventive Medicine, Beijing, China, by the Yunnan Province Antiepidemic Station, Kunming, China, and by contract 5D2290NFFX from the US Environmental Protection Agency. This study was also supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The Xuanwei cohort study has been reviewed by the US Environmental Protection Agency and the National Cancer Institute. The contents do not necessarily reflect the views or policies of these institutions, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The funding source had no role in design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript. NR 24 TC 35 Z9 36 U1 2 U2 24 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BRIT MED J JI Br. Med. J. PD AUG 30 PY 2012 VL 345 AR e5414 DI 10.1136/bmj.e5414 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 036SM UT WOS:000311050800002 PM 22936785 ER PT J AU Simone, CB Morris, JC Stewart, DM Urquhart, NE Janik, JE Kreitman, RJ Lita, E Conlon, K Wharfe, G Waldmann, TA Kaushal, A AF Simone, Charles B., II Morris, John C. Stewart, Donn M. Urquhart, Nicole E. Janik, John E. Kreitman, Robert J. Lita, Elena Conlon, Kevin Wharfe, Gilian Waldmann, Thomas A. Kaushal, Aradhana TI Radiation therapy for the management of patients with HTLV-1-associated adult T-cell leukemia/lymphoma SO BLOOD LA English DT Article ID LEUKEMIA-LYMPHOMA AB Human T-cell leukemia virus type 1-associated adult T-cell leukemia/lymphoma (ATL) typically has survivals measured in months with chemotherapy. One prior published series (1983-1991) assessed local radiotherapy for ATL. Ten consecutive patients with pathologically confirmed ATL treated with radiotherapy were reviewed. Subtypes included acute (n = 7), smoldering (n = 2), and lymphomatous (n = 1). Patients received an average of 2.5 systemic therapy regimens before radiotherapy. Twenty lesions (cutaneous = 10, nodal = 8, extranodal = 2) were treated to a mean of 35.4 Gy/2-3 Gy (range, 12-60 Gy). At 9.0-month mean follow-up (range, 0.1-42.0 months), all lesions symptomatically and radiographically responded, with in-field complete responses in 40.0% (nodal 37.5% vs cutaneous 50.0%; P = .62). No patient experienced in-field progression. Nine patients developed new/progressive out-of-field disease. Median survival was 17.0 months (3-year survival, 30.0%). No Radiation Therapy Oncology Group acute grade >= 3 or any late toxicity was noted. This report is the first to use modern radiotherapy techniques and finds effective local control across ATL subtypes. Radiotherapy should be considered for symptomatic local progression of ATL. (Blood. 2012;120(9):1816-1819) C1 [Simone, Charles B., II; Kaushal, Aradhana] NCI, NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Simone, Charles B., II] Hosp Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Morris, John C.] Univ Cincinnati, Div Hematol Oncol, Cincinnati, OH USA. [Morris, John C.; Stewart, Donn M.; Janik, John E.; Waldmann, Thomas A.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Urquhart, Nicole E.; Wharfe, Gilian] Univ W Indies, Dept Pathol, Jamaica, NY USA. [Kreitman, Robert J.] NCI, Clin Immunotherapy Sect, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Conlon, Kevin] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Kaushal, A (reprint author), NCI, NIH, Radiat Oncol Branch, Bldg 10,CRC Rm B2-3561,10 Ctr Dr,MSC 1682, Bethesda, MD 20892 USA. EM kaushala@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This study is supported, in part, by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 17 TC 4 Z9 4 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 30 PY 2012 VL 120 IS 9 BP 1816 EP 1819 DI 10.1182/blood-2012-01-401349 PG 4 WC Hematology SC Hematology GA 009FM UT WOS:000309011200015 PM 22730536 ER PT J AU Zhao, M Ross, JT Itkin, T Perry, JM Venkatraman, A Haug, JS Hembree, MJ Deng, CX Lapidot, T He, XC Li, LH AF Zhao, Meng Ross, Jason T. Itkin, Tomer Perry, John M. Venkatraman, Aparna Haug, Jeffrey S. Hembree, Mark J. Deng, Chu-Xia Lapidot, Tsvee He, Xi C. Li, Linheng TI FGF signaling facilitates postinjury recovery of mouse hematopoietic system SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; BONE-MARROW NICHE; STEM-CELL NICHE; GROWTH-FACTOR-I; NF-KAPPA-B; PROGENITOR CELLS; RAPID MOBILIZATION; STROMAL CELLS; SELF-RENEWAL; MICE AB Previous studies have shown that fibroblast growth factor (FGF) signaling promotes hematopoietic stem and progenitor cell (HSPC) expansion in vitro. However, it is unknown whether FGF promotes HSPC expansion in vivo. Here we examined FGF receptor 1 (FGFR1) expression and investigated its in vivo function in HSPCs. Conditional knockout (CKO) of Fgfr1 did not affect phenotypical number of HSPCs and homeostatic hematopoiesis, but led to a reduced engraftment only in the secondary transplantation. When treated with 5-fluorouracil (5FU), the Fgfr1 CKO mice showed defects in both proliferation and subsequent mobilization of HSPCs. We identified mega-karyocytes (Mks) as a major resource for FGF production, and further discovered a novel mechanism by which Mks underwent FGF-FGFR signaling dependent expansion to accelerate rapid FGF production under stress. Within HSPCs, we observed an up-regulation of nuclear factor kappa B and CXCR4, a receptor for the chemoattractant SDF-1, in response to bone marrow damage only in control but not in Fgfr1 CKO model, accounting for the corresponding defects in proliferation and migration of HSPCs. This study provides the first in vivo evidence that FGF signaling facilitates postinjury recovery of the mouse hematopoietic system by promoting proliferation and facilitating mobilization of HSPCs. (Blood. 2012; 120(9):1831-1842) C1 [Zhao, Meng; Ross, Jason T.; Perry, John M.; Venkatraman, Aparna; Haug, Jeffrey S.; Hembree, Mark J.; He, Xi C.; Li, Linheng] Stowers Inst Med Res, Kansas City, MO 64110 USA. [Ross, Jason T.; Li, Linheng] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Itkin, Tomer; Lapidot, Tsvee] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. [Venkatraman, Aparna] Christian Med Coll & Hosp, Ctr Stem Cell Res, Vellore, Tamil Nadu, India. [Deng, Chu-Xia] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Li, LH (reprint author), Stowers Inst Med Res, 1000 E 50th St, Kansas City, MO 64110 USA. EM lil@stowers.org RI Lapidot, Tsvee/A-1812-2010; deng, chuxia/N-6713-2016 FU Stowers Institute for Medical Research; Department of Biotechnology, Ministry of S&T, Government of India FX This work was funded by the Stowers Institute for Medical Research. J.M.P. is a Fellow of the Leukemia & Lymphoma Society. A.V. is a recipient of an overseas associateship from Department of Biotechnology, Ministry of S&T, Government of India. NR 49 TC 27 Z9 27 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 30 PY 2012 VL 120 IS 9 BP 1831 EP 1842 DI 10.1182/blood-2011-11-393991 PG 12 WC Hematology SC Hematology GA 009FM UT WOS:000309011200017 PM 22802336 ER PT J AU Bedognetti, D Ansaldi, F Zanardi, E Durando, P Sertoli, MR Massucco, C Balleari, E Racchi, O Zoppoli, G Orsi, A Alicino, C Icardi, G Marincola, FM Zupo, S Ferrarini, M De Maria, A AF Bedognetti, Davide Ansaldi, Filippo Zanardi, Elisa Durando, Paolo Sertoli, Mario Roberto Massucco, Carlotta Balleari, Enrico Racchi, Omar Zoppoli, Gabriele Orsi, Andrea Alicino, Cristiano Icardi, Giancarlo Marincola, Francesco M. Zupo, Simonetta Ferrarini, Manlio De Maria, Andrea TI Seasonal and pandemic (A/H1N1 2009) MF-59-adjuvanted influenza vaccines in complete remission non- Hodgkin lymphoma patients previously treated with rituximab containing regimens SO BLOOD LA English DT Letter ID MEMORY B-CELLS C1 [Bedognetti, Davide; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin,FOCIS Ctr Excellence, Bethesda, MD 20892 USA. [Bedognetti, Davide] NIH, Trans NIH Ctr Human Immunol CHI, Bethesda, MD 20892 USA. [Bedognetti, Davide; Sertoli, Mario Roberto; Balleari, Enrico; Zoppoli, Gabriele; Ferrarini, Manlio] Univ Genoa, Dipartimento Med Interna, Genoa, Italy. [Bedognetti, Davide] IST Ist Nazl Ric Cancro, IRCCS Azienda Osped Univ San Martino, Azienda Osped Univ, SC Oncol Med B,IRCCS, Genoa, Italy. [Ansaldi, Filippo; Durando, Paolo; Orsi, Andrea; Alicino, Cristiano; Icardi, Giancarlo; De Maria, Andrea] Univ Genoa, Dipartimento Sci Salute, Genoa, Italy. [Ansaldi, Filippo; Durando, Paolo; Orsi, Andrea; Alicino, Cristiano; Icardi, Giancarlo] IST Ist Nazl Ric Cancro, IRCCS Azienda Osped Univ San Martino, UO Igiene, Genoa, Italy. [Massucco, Carlotta; Zupo, Simonetta] IST Ist Nazl Ric Cancro, IRCCS Azienda Osped Univ San Martino, SS Diagnost Mol, Genoa, Italy. [Racchi, Omar] Osped Villa Scassi, SS Oncol & Ematol, Genoa, Italy. [Marincola, Francesco M.] NIH, Trans NIH CHI, Bethesda, MD 20892 USA. [Ferrarini, Manlio] IST Ist Nazl Ric Cancro, IRCCS Azienda Osped Univ San Martino, SC Oncol Med C, Genoa, Italy. [De Maria, Andrea] IST Ist Nazl Ric Cancro, IRCCS Azienda Osped Univ San Martino, SS Infettivol, Genoa, Italy. RP Bedognetti, D (reprint author), NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin,FOCIS Ctr Excellence, 10 Ctr Dr,Rm 1N224, Bethesda, MD 20892 USA. EM davide.bedognetti@nih.gov; de-maria@unige.it RI Zoppoli, Gabriele/B-6935-2016; Alicino, Cristiano/J-5325-2016; Balleari, Enrico/R-3119-2016; OI Zoppoli, Gabriele/0000-0003-3890-5588; Alicino, Cristiano/0000-0002-6473-9870; Balleari, Enrico/0000-0003-2186-8012; Bedognetti, Davide/0000-0002-5857-773X; Ferrarini, Manlio/0000-0002-6154-2570 NR 6 TC 2 Z9 2 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 30 PY 2012 VL 120 IS 9 BP 1954 EP 1957 DI 10.1182/blood-2012-06-438689 PG 6 WC Hematology SC Hematology GA 009FM UT WOS:000309011200030 PM 22936740 ER PT J AU Bae, HT Baldwin, CT Sebastiani, P Telen, MJ Ashley-Koch, A Garrett, M Hooper, WC Bean, CJ DeBaun, MR Arking, DE Bhatnagar, P Casella, JF Keefer, JR Barron-Casella, E Gordeuk, V Kato, GJ Minniti, C Taylor, J Campbell, A Luchtman-Jones, L Hoppe, C Gladwin, MT Zhang, YZ Steinberg, MH AF Bae, Harold T. Baldwin, Clinton T. Sebastiani, Paola Telen, Marilyn J. Ashley-Koch, Allison Garrett, Melanie Hooper, W. Craig Bean, Christopher J. DeBaun, Michael R. Arking, Dan E. Bhatnagar, Pallav Casella, James F. Keefer, Jeffrey Renn Barron-Casella, Emily Gordeuk, Victor Kato, Gregory J. Minniti, Caterina Taylor, James Campbell, Andrew Luchtman-Jones, Lori Hoppe, Carolyn Gladwin, Mark T. Zhang, Yingze Steinberg, Martin H. TI Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the major modifiers of HbF in African Americans SO BLOOD LA English DT Letter ID GENOME-WIDE ASSOCIATION; REGULATORY REGION; FETAL-HEMOGLOBIN; DISEASE C1 [Steinberg, Martin H.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Bae, Harold T.; Sebastiani, Paola] Boston Univ, Sch Publ Hlth, Boston, MA 02118 USA. [Telen, Marilyn J.; Ashley-Koch, Allison; Garrett, Melanie] Duke Univ, Sch Med, Durham, NC USA. [Hooper, W. Craig; Bean, Christopher J.] Ctr Dis Control & Prevent, Atlanta, GA USA. [DeBaun, Michael R.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Arking, Dan E.; Bhatnagar, Pallav; Casella, James F.; Keefer, Jeffrey Renn; Barron-Casella, Emily] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Gordeuk, Victor] Univ Illinois, Chicago, IL USA. [Kato, Gregory J.; Minniti, Caterina; Taylor, James] NHLBI, NIH, Bethesda, MD 20892 USA. [Campbell, Andrew] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Luchtman-Jones, Lori] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Hoppe, Carolyn] Childrens Hosp, Res Ctr Oakland, Oakland, CA 94609 USA. [Gladwin, Mark T.; Zhang, Yingze] Univ Pittsburgh, Pittsburgh, PA USA. RP Steinberg, MH (reprint author), Boston Univ, Sch Med, Dept Med, 72 E Concord St, Boston, MA 02118 USA. EM mhsteinb@bu.edu RI Bhatnagar, Pallav/A-1280-2013; Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Steinberg, Martin/0000-0001-8800-8020; sebastiani, paola/0000-0001-6419-1545; Ashley-Koch, Allison/0000-0001-5409-9155; Taylor, James/0000-0002-4421-1809 FU Intramural NIH HHS [ZIA HL005116-06]; NCRR NIH HHS [2M01 RR10284-10]; NHLBI NIH HHS [HL68959, 2R25 HL003679-8, HL079915, R01 HL079912, R01 HL87681, RC2 HL101212, U54HL090515]; NINDS NIH HHS [5-U01-NS042804-07]; PHS HHS [HHSN268200782096C] NR 7 TC 28 Z9 29 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 30 PY 2012 VL 120 IS 9 BP 1961 EP 1962 DI 10.1182/blood-2012-06-432849 PG 2 WC Hematology SC Hematology GA 009FM UT WOS:000309011200033 PM 22936743 ER PT J AU Raafat, A Strizzi, L Lashin, K Ginsburg, E McCurdy, D Salomon, D Smith, GH Medina, D Callahan, R AF Raafat, Ahmed Strizzi, Luigi Lashin, Karim Ginsburg, Erika McCurdy, David Salomon, David Smith, Gilbert H. Medina, Daniel Callahan, Robert TI Effects of Age and Parity on Mammary Gland Lesions and Progenitor Cells in the FVB/N-RC Mice SO PLOS ONE LA English DT Article ID RECEPTOR-ALPHA EXPRESSION; BREAST-CANCER RISK; EPITHELIAL-CELLS; STEM-CELLS; MOUSE; GROWTH; HYPERPLASIA; PREGNANCY; HORMONE AB The FVB/N mouse strain is extensively used in the development of animal models for breast cancer research. Recently it has been reported that the aging FVB/N mice develop spontaneous mammary lesions and tumors accompanied with abnormalities in the pituitary glands. These observations have a great impact on the mouse models of human breast cancer. We have developed a population of inbred FVB/N mice (designated FVB/N-RC) that have been genetically isolated for 20 years. To study the effects of age and parity on abnormalities of the mammary glands of FVB/N-RC mice, twenty-five nulliparous and multiparous (3-4 pregnancies) females were euthanized at 16-22 months of age. Examination of the mammary glands did not reveal macroscopic evidence of mammary gland tumors in either aged-nulliparous or multiparous FVB/N-RC mice (0/25). However, histological analysis of the mammary glands showed rare focal nodules of squamous changes in 2 of the aged multiparous mice. Mammary gland hyperplasia was detected in 8% and 71% of the aged-nulliparous and aged-multiparous mice, respectively. Epithelial contents and serum levels of triiodothyronine were significantly higher in the experimental groups than the 14-wk-old control mice. Immuno-histochemical staining of the pituitary gland pars distalis showed no difference in prolactin staining between the control and the aged mice. Tissue transplant and dilution studies showed no effect of age and/or parity on the ability of putative progenitor cells present among the injected mammary cells to repopulate a cleared fat pad and develop a full mammary gland outgrowth. This FVB/N-RC mouse substrain is suitable to develop mouse models for breast cancer. C1 [Raafat, Ahmed; Lashin, Karim; McCurdy, David; Smith, Gilbert H.; Callahan, Robert] NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. [Strizzi, Luigi] Northwestern Univ, Feinberg Sch Med, Childrens Mem Res Ctr, Robert H Lurie Comprehens Canc Ctr, Chicago, IL USA. [Ginsburg, Erika] NCI, Off Director, NIH, Bethesda, MD 20892 USA. [Salomon, David] NCI, Lab Canc Prevent, NIH, Bethesda, MD 20892 USA. [Medina, Daniel] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. RP Raafat, A (reprint author), NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. EM rc54d@nih.gov FU NCI's Center for Cancer Research Intramural Research Program FX The NCI's Center for Cancer Research Intramural Research Program funded this work. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 12 Z9 12 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 AUG 30 PY 2012 VL 7 IS 8 AR e43624 DI 10.1371/journal.pone.0043624 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 997ZH UT WOS:000308206500018 PM 22952723 ER PT J AU Smith, DB Okur, A Brooks, BR AF Smith, Daniel B. Okur, Asim Brooks, Bernard R. TI MDMS: Molecular dynamics meta-simulator for evaluating exchange type sampling methods SO CHEMICAL PHYSICS LETTERS LA English DT Article ID REPLICA-EXCHANGE; ENERGY LANDSCAPE; STRUCTURE RESERVOIR; EXPLICIT WATER; BETA-HAIRPIN; SYSTEMS; CONVERGENCE; ALGORITHM; MODEL AB Replica exchange methods have become popular tools to explore conformational space for small proteins. For larger biological systems, even with enhanced sampling methods, exploring the free energy landscape remains computationally challenging. This problem has led to the development of many improved replica exchange methods. Unfortunately, testing these methods remains expensive. We propose a molecular dynamics meta-simulator (MDMS) based on transition state theory to simulate a replica exchange simulation, eliminating the need to run explicit dynamics between exchange attempts. MDMS simulations allow for rapid testing of new replica exchange based methods, greatly reducing the amount of time needed for new method development. Published by Elsevier B.V. C1 [Smith, Daniel B.] Univ Pittsburgh, Dept Math, Pittsburgh, PA 15260 USA. [Smith, Daniel B.; Okur, Asim; Brooks, Bernard R.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Smith, DB (reprint author), Univ Pittsburgh, Dept Math, Pittsburgh, PA 15260 USA. EM smithdb3@mail.nih.gov FU Intramural NIH HHS [Z01 HL001051-11, Z99 HL999999] NR 30 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-2614 J9 CHEM PHYS LETT JI Chem. Phys. Lett. PD AUG 30 PY 2012 VL 545 BP 118 EP 124 DI 10.1016/j.cplett.2012.07.015 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 997WW UT WOS:000308199600022 PM 23087450 ER PT J AU Diesner, SC Olivera, A Dillahunt, S Schultz, C Watzlawek, T Forster-Waldl, E Pollak, A Jensen-Jarolim, E Untersmayr, E Rivera, J AF Diesner, Susanne C. Olivera, Ana Dillahunt, Sandra Schultz, Cornelia Watzlawek, Thomas Foerster-Waldl, Elisabeth Pollak, Arnold Jensen-Jarolim, Erika Untersmayr, Eva Rivera, Juan TI Sphingosine-kinase 1 and 2 contribute to oral sensitization and effector phase in a mouse model of food allergy (vol 141, pg 210, 2012) SO IMMUNOLOGY LETTERS LA English DT Correction C1 [Diesner, Susanne C.; Schultz, Cornelia; Watzlawek, Thomas; Jensen-Jarolim, Erika; Untersmayr, Eva] Med Univ Vienna, Dept Pathophysiol & Allergy Res, Ctr Pathophysiol Infectiol & Immunol, A-1090 Vienna, Austria. [Diesner, Susanne C.; Foerster-Waldl, Elisabeth; Pollak, Arnold] Med Univ Vienna, Dept Pediat & Adolescent Med, A-1090 Vienna, Austria. [Diesner, Susanne C.; Olivera, Ana; Dillahunt, Sandra; Rivera, Juan] NIAMS, Immunogenet Mol Lab, NIH, Bethesda, MD 20892 USA. [Jensen-Jarolim, Erika] Univ Vienna, Messerli Inst, Med Univ Vienna, A-1090 Vienna, Austria. [Jensen-Jarolim, Erika] Vet Univ Vienna, A-1090 Vienna, Austria. RP Untersmayr, E (reprint author), Med Univ Vienna, Dept Pathophysiol & Allergy Res, Ctr Pathophysiol Infectiol & Immunol, Waehringer Guertel 18-20,E3Q, A-1090 Vienna, Austria. EM eva.untersmayr@meduniwien.ac.at; juanrivera@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD AUG 30 PY 2012 VL 146 IS 1-2 BP 79 EP 79 DI 10.1016/j.imlet.2012.04.016 PG 1 WC Immunology SC Immunology GA 988ZO UT WOS:000307530200012 ER PT J AU Tsai, PT Hull, C Chu, YX Greene-Colozzi, E Sadowski, AR Leech, JM Steinberg, J Crawley, JN Regehr, WG Sahin, M AF Tsai, Peter T. Hull, Court Chu, YunXiang Greene-Colozzi, Emily Sadowski, Abbey R. Leech, Jarrett M. Steinberg, Jason Crawley, Jacqueline N. Regehr, Wade G. Sahin, Mustafa TI Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice SO NATURE LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; MOUSE MODEL; ULTRASONIC VOCALIZATIONS; BRAIN; DISORDERS; CHILDREN; SURVIVAL; MTORC1 AB Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders(1), but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss(2,3), and isolated cerebellar injury has been associated with a higher incidence of ASDs(4). However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs(5) that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology(6) and correlate cerebellar pathology with increased ASD symptomatology(7,8). Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs(9). However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism. C1 [Tsai, Peter T.; Greene-Colozzi, Emily; Sadowski, Abbey R.; Leech, Jarrett M.; Steinberg, Jason; Sahin, Mustafa] Harvard Univ, Sch Med, Boston Childrens Hosp, FM Kirby Neurobiol Ctr,Dept Neurol, Boston, MA 02115 USA. [Hull, Court; Chu, YunXiang; Regehr, Wade G.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Crawley, Jacqueline N.] NIMH, Lab Behav Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. RP Sahin, M (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, FM Kirby Neurobiol Ctr,Dept Neurol, Boston, MA 02115 USA. EM peter.tsai@childrens.harvard.edu; mustafa.sahin@childrens.harvard.edu OI Hull, Court/0000-0002-0360-8367 FU Developmental Neurology Training grant [T32 NS007473]; American Academy of Neurology; Nancy Lurie Marks Family Foundation; National Institutes of Health (NIH) [R01 NS58956]; John Merck Scholars Fund; Autism Speaks; Boston Children's Hospital Translational Research Program; Manton Center for Orphan Disease Research; Boston Children's Hospital Intellectual and Developmental Disabilities Research Center [P30 HD18655]; Intramural Research Program, National Institute of Mental Health; NIH [R01NS032405]; Simons Foundation [SFARI 232304]; Howard Hughes Medical Institute Medical Research Fellowship FX We thank G. Corfas, M. Fagiolini, P. Rosenberg, S. Goldman and the Neurodevelopmental Behavioral Core of Boston Children's Hospital for assistance with behavioural experiments. We are grateful to C. Walsh, L. Benowitz and members of the Sahin laboratory for critical reading of the manuscript, and to M. Gregas for advice regarding statistical analysis. P. T. T. received support from the Developmental Neurology Training grant (T32 NS007473), American Academy of Neurology, and the Nancy Lurie Marks Family Foundation. This work and M. S. are supported in part by the National Institutes of Health (NIH; grant R01 NS58956), the John Merck Scholars Fund, Autism Speaks, the Nancy Lurie Marks Family Foundation, Boston Children's Hospital Translational Research Program, Manton Center for Orphan Disease Research and Boston Children's Hospital Intellectual and Developmental Disabilities Research Center (grant P30 HD18655). J.N.C. is supported by the Intramural Research Program, National Institute of Mental Health. W. G. R. is supported by the NIH (grant R01NS032405) and the Simons Foundation (grant SFARI 232304). Y.X.C. is supported by the Howard Hughes Medical Institute Medical Research Fellowship. NR 38 TC 215 Z9 219 U1 5 U2 51 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 30 PY 2012 VL 488 IS 7413 BP 647 EP + DI 10.1038/nature11310 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 996NC UT WOS:000308095100054 PM 22763451 ER PT J AU Westreich, D Cole, SR Schisterman, EF Platt, RW AF Westreich, Daniel Cole, Stephen R. Schisterman, Enrique F. Platt, Robert W. TI A simulation study of finite-sample properties of marginal structural Cox proportional hazards models SO STATISTICS IN MEDICINE LA English DT Article DE bias; causal inference; marginal structural models; Monte Carlo study ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; INVERSE PROBABILITY WEIGHTS; ADJUSTED SURVIVAL CURVES; CARDIOVASCULAR MORTALITY; CAUSAL INFERENCE; CONTROLLED-TRIAL; HIV-INFECTION; TUBERCULOSIS; DISEASE AB Motivated by a previously published study of HIV treatment, we simulated data subject to time-varying confounding affected by prior treatment to examine some finite-sample properties of marginal structural Cox proportional hazards models. We compared (a)?unadjusted, (b)?regression-adjusted, (c)?unstabilized, and (d)?stabilized marginal structural (inverse probability-of-treatment [IPT] weighted) model estimators of effect in terms of bias, standard error, root mean squared error (MSE), and 95% confidence limit coverage over a range of research scenarios, including relatively small sample sizes and 10 study assessments. In the base-case scenario resembling the motivating example, where the true hazard ratio was 0.5, both IPT-weighted analyses were unbiased, whereas crude and adjusted analyses showed substantial bias towards and across the null. Stabilized IPT-weighted analyses remained unbiased across a range of scenarios, including relatively small sample size; however, the standard error was generally smaller in crude and adjusted models. In many cases, unstabilized weighted analysis showed a substantial increase in standard error compared with other approaches. Root MSE was smallest in the IPT-weighted analyses for the base-case scenario. In situations where time-varying confounding affected by prior treatment was absent, IPT-weighted analyses were less precise and therefore had greater root MSE compared with adjusted analyses. The 95% confidence limit coverage was close to nominal for all stabilized IPT-weighted but poor in crude, adjusted, and unstabilized IPT-weighted analysis. Under realistic scenarios, marginal structural Cox proportional hazards models performed according to expectations based on?large-sample theory and provided accurate estimates of the hazard ratio. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Westreich, Daniel] Duke Univ, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Westreich, Daniel] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Cole, Stephen R.] UNC Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Bethesda, MD USA. [Platt, Robert W.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. RP Westreich, D (reprint author), Duke Univ, Dept Obstet & Gynecol, Durham, NC 27710 USA. EM daniel.westreich@duke.edu RI Platt, Robert/G-5847-2012; OI Platt, Robert/0000-0002-5981-8443; Schisterman, Enrique/0000-0003-3757-641X FU National Institutes of Health, National Institute of Allergy and Infectious Disease [T32-AI-07001, R01-AA-01759]; National Institutes of Health the Eunice Kennedy Shriver National Institute of Child Health and Human Development [K99-HD-06-3961, 4R00-HD-06-3961-02]; Chercheur-Boursier award; Fonds de la Recherche en Sante' du Quebec; National Institute of Allergy and Infectious Diseases [UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; National Institute of Child Health and Human Development [UO1-HD32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources (UCSF-CTSI) [UL1 RR024131]; National Institute of Allergy and Infectious Diseases; National Cancer Institute [UO1-AI-35042, UL1-RR025005, UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041] FX This work was supported by the National Institutes of Health, National Institute of Allergy and Infectious Disease [grant number T32-AI-07001 to D. W.; grant number R01-AA-01759 to S. R. C.]; the National Institutes of Health the Eunice Kennedy Shriver National Institute of Child Health and Human Development [Intramural Research Program to E. F. S.; grant numbers K99-HD-06-3961 and 4R00-HD-06-3961-02 to D. W.]; and the Chercheur-Boursier award and by core support to the Montreal Children's Hospital Research Institute, from the Fonds de la Recherche en Sante' du Quebec to [R. W. P.].; Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (Principal Investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington, DC, Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the National Institute of Child Health and Human Development (UO1-HD32632). The study is co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.; Data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS) with centers (Principal Investigators) at The Johns Hopkins Bloomberg School of Public Health (Joseph B. Margolick, Lisa P. Jacobson), Howard Brown Health Center, Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services (John P. Phair, Steven M. Wolinsky), University of California, Los Angeles (Roger Detels), and University of Pittsburgh (Charles R. Rinaldo). The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (UO1-AI-35042, UL1-RR025005 (GCRC), UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, and UO1-AI-35041). Website is located at http://www.statepi.jhsph.edu/macs/macs.html. NR 42 TC 10 Z9 10 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD AUG 30 PY 2012 VL 31 IS 19 BP 2098 EP 2109 DI 10.1002/sim.5317 PG 12 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 974XW UT WOS:000306471900006 PM 22492660 ER PT J AU Wang, AR Chandran, S Shah, SA Chiu, Y Paria, BC Aghamolla, T Alvarez-Downing, MM Lee, CCR Singh, S Li, T Dudley, ME Restifo, NP Rosenberg, SA Kammula, US AF Wang, Anran Chandran, Smita Shah, Syed A. Chiu, Yu Paria, Biman C. Aghamolla, Tamara Alvarez-Downing, Melissa M. Lee, Chyi-Chia Richard Singh, Sanmeet Li, Thomas Dudley, Mark E. Restifo, Nicholas P. Rosenberg, Steven A. Kammula, Udai S. TI The Stoichiometric Production of IL-2 and IFN-gamma mRNA Defines Memory T Cells That Can Self-Renew After Adoptive Transfer in Humans SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID METASTATIC MELANOMA; TRANSFER THERAPY; PROTECTIVE IMMUNITY; ANTITUMOR IMMUNITY; CANCER REGRESSION; PERIPHERAL-BLOOD; SUPPRESSOR-CELLS; TUMOR-REGRESSION; LYMPHOCYTES; IMMUNOTHERAPY AB Adoptive immunotherapy using ex vivo-expanded tumor-reactive lymphocytes can mediate durable cancer regression in selected melanoma patients. Analyses of these trials have associated the in vivo engraftment ability of the transferred cells with their antitumor efficacy. Thus, there is intensive clinical interest in the prospective isolation of tumor-specific T cells that can reliably persist after transfer. Animal studies have suggested that central memory CD8(+) T cells (T-CM) have divergent capabilities including effector differentiation to target antigen and stem cell-like self-renewal that enable long-term survival after adoptive transfer. We sought to isolate human melanoma-specific T-CM to define their in vivo fate and function after autologous therapeutic transfer to metastatic patients. To facilitate the high-throughput identification of these rare cells from patients, we report that T-CM have a defined stoichiometric production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) mRNA after antigen stimulation. Melanoma-specific T cells screened for high relative IL-2 production had a TCM phenotype and superior in vitro proliferative capacity compared to cells with low IL-2 production. To investigate in vivo effector function and self-renewal capability, we allowed melanoma-specific T-CM to undergo in vitro expansion and differentiation into lytic effector clones and then adoptively transferred them back into their hosts. These clones targeted skin melanocytes in all five patients and persisted long term and reacquired parental T-CM attributes in four patients after transfer. These findings demonstrate the favorable engraftment fitness for human T-CM-derived clones, but further efforts to improve their antitumor efficacy are still necessary. C1 [Wang, Anran; Chandran, Smita; Shah, Syed A.; Chiu, Yu; Paria, Biman C.; Aghamolla, Tamara; Alvarez-Downing, Melissa M.; Lee, Chyi-Chia Richard; Singh, Sanmeet; Li, Thomas; Dudley, Mark E.; Restifo, Nicholas P.; Rosenberg, Steven A.; Kammula, Udai S.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20817 USA. RP Kammula, US (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20817 USA. EM udai_kammula@nih.gov RI Restifo, Nicholas/A-5713-2008; Lee, Chyi-Chia/I-1938-2013; OI Lee, Chyi-Chia/0000-0002-5306-7781; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural Research Program of the NIH, NCI, Center for Cancer Research FX We thank the Surgery Branch cell production facility and the immunotherapy clinical and support staff for their contributions. Funding: This research was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. NR 40 TC 23 Z9 23 U1 0 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD AUG 29 PY 2012 VL 4 IS 149 AR 149ra120 DI 10.1126/scitranslmed.3004306 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 001WT UT WOS:000308491600011 PM 22932225 ER PT J AU Marincola, FM Sheikh, JI AF Marincola, Francesco M. Sheikh, Javaid I. TI A road map to Translational Medicine in Qatar and a model for the world SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID CLINICAL-RESEARCH ENTERPRISE; VITAMIN-D INSUFFICIENCY; CANCER-IMMUNOTHERAPY; BIOMEDICAL-RESEARCH; BASIC SCIENCE; OBSTACLES; OPPORTUNITIES; SCIENTISTS; CHALLENGES; THERAPIES AB Translational Medicine (TM) in Qatar is part of a concerted effort of the Qatari medical and scientific leadership supported by a strong political will by Qatari authorities to deliver world-class health care to Qatari residents while participating in the worldwide quest to bridge the gap between bench-to-bedside-to-community. TM programs should embrace the Qatar National vision for research to become an international hub of excellence in research and development, based on intellectual merit, contributing to global knowledge and adhering to international standards, to innovate by translating new and original ideas into useful applications, to be inclusive at the national and international level, to build and maintain a competitive and diversified economy and ultimately improve the health and well-being of the Qatar's population. Although this writing focuses on Qatar, we hope that the thoughts expressed here may be of broader use for the development of any TM program particularly in regions where an established academic community surrounded by a rich research infrastructure and/or a vibrant biotechnology enterprise is not already present. C1 [Marincola, Francesco M.; Sheikh, Javaid I.] Qatar Fdn, Off Dean, Weill Cornell Med Coll Qatar, Doha, Qatar. [Marincola, Francesco M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), Qatar Fdn, Off Dean, Weill Cornell Med Coll Qatar, POB 24144, Doha, Qatar. EM fmarincola@mail.cc.nih.gov NR 70 TC 4 Z9 4 U1 1 U2 9 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 AUG 29 PY 2012 VL 10 AR 177 DI 10.1186/1479-5876-10-177 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 002OX UT WOS:000308542600001 PM 22929646 ER PT J AU Civiero, L Vancraenenbroeck, R Belluzzi, E Beilina, A Lobbestael, E Reyniers, L Gao, FY Micetic, I De Maeyer, M Bubacco, L Baekelandt, V Cookson, MR Greggio, E Taymans, JM AF Civiero, Laura Vancraenenbroeck, Renee Belluzzi, Elisa Beilina, Alexandra Lobbestael, Evy Reyniers, Lauran Gao, Fangye Micetic, Ivan De Maeyer, Marc Bubacco, Luigi Baekelandt, Veerle Cookson, Mark R. Greggio, Elisa Taymans, Jean-Marc TI Biochemical Characterization of Highly Purified Leucine-Rich Repeat Kinases 1 and 2 Demonstrates Formation of Homodimers SO PLOS ONE LA English DT Article ID DISEASE-ASSOCIATED MUTATIONS; FAMILIAL PARKINSONS-DISEASE; ROC DOMAIN; GTP-BINDING; CYTOPLASMIC LOCALIZATION; DOMINANT PARKINSONISM; PROTEIN-KINASES; LRRK2 MUTATION; GENE LRRK2; LEUCINE-RICH-REPEAT-KINASE-2 AB Leucine-rich repeat kinase 1 and 2 (LRRK1 and LRRK2) are large multidomain proteins containing kinase, GTPase and multiple protein-protein interaction domains, but only mutations in LRRK2 are linked to familial Parkinson's disease (PD). Independent studies suggest that LRRK2 exists in the cell as a complex compatible with the size of a dimer. However, whether this complex is truly a homodimer or a heterologous complex formed by monomeric LRRK2 with other proteins has not been definitively proven due to the limitations in obtaining highly pure proteins suitable for structural characterization. Here, we used stable expression of LRRK1 and LRRK2 in HEK293T cell lines to produce recombinant LRRK1 and LRRK2 proteins of greater than 90% purity. Both purified LRRKs are folded, with a predominantly alpha-helical secondary structure and are capable of binding GTP with similar affinity. Furthermore, recombinant LRRK2 exhibits robust autophosphorylation activity, phosphorylation of model peptides in vitro and ATP binding. In contrast, LRRK1 does not display significant autophosphorylation activity and fails to phosphorylate LRRK2 model substrates, although it does bind ATP. Using these biochemically validated proteins, we show that LRRK1 and LRRK2 are capable of forming homodimers as shown by single-particle transmission electron microscopy and immunogold labeling. These LRRK dimers display an elongated conformation with a mean particle size of 145 angstrom and 175 angstrom respectively, which is disrupted by addition of 6M guanidinium chloride. Immunogold staining revealed double-labeled particles also in the pathological LRRK2 mutant G2019S and artificial mutants disrupting GTPase and kinase activities, suggesting that point mutations do not hinder the dimeric conformation. Overall, our findings indicate for the first time that purified and active LRRK1 and LRRK2 can form dimers in their full-length conformation. C1 [Civiero, Laura; Belluzzi, Elisa; Micetic, Ivan; Bubacco, Luigi; Greggio, Elisa] Univ Padua, Dept Biol, Padua, Italy. [Vancraenenbroeck, Renee; Lobbestael, Evy; Reyniers, Lauran; Gao, Fangye; Baekelandt, Veerle; Taymans, Jean-Marc] Katholieke Univ Leuven, Lab Neurobiol & Gene Therapy, Louvain, Belgium. [Vancraenenbroeck, Renee; De Maeyer, Marc] Katholieke Univ Leuven, Lab Biomol Modelling, B-3001 Heverlee, Belgium. [Beilina, Alexandra; Cookson, Mark R.] NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, Bethesda, MD 20892 USA. RP Civiero, L (reprint author), Univ Padua, Dept Biol, Padua, Italy. EM elisa.greggio@unipd.it; jean-marc.taymans@med.kuleuven.be RI Greggio, Elisa/H-6119-2013; Micetic, Ivan/A-7146-2015; OI Greggio, Elisa/0000-0002-8172-3598; Micetic, Ivan/0000-0003-1691-8425; Taymans, Jean-Marc/0000-0001-5503-5524; Belluzzi, Elisa/0000-0003-1129-2574; Bubacco, Luigi/0000-0001-7927-9208 FU Michael J Fox Foundation; Rientro dei Cervelli Program (lncentivazione alla mobilita di studiosi stranieri e italiani residenti all'estero) from the Italian Ministry of Education, University and Research; PRIN2008 [55YP79]; Intramural Research Program of the National Institutes of Health, National Institute on Aging; Research Foundation - Flanders Fonds Wetenschappelijk Onderzoek (FWO) [G.0666.09]; project Neuro-TARGET [IWT SBO/80020]; KULeuven [OT/08/052A, IOF-KP/07/001] FX Funding provided by the Michael J Fox Foundation; the Rientro dei Cervelli Program (lncentivazione alla mobilita di studiosi stranieri e italiani residenti all'estero) from the Italian Ministry of Education, University and Research (EG); PRIN2008 (55YP79) (LB); the Intramural Research Program of the National Institutes of Health, National Institute on Aging; the Research Foundation - Flanders Fonds Wetenschappelijk Onderzoek (FWO project G.0666.09, PhD fellowships to RVC, EL and senior researcher fellowship to J-MT); the IWT SBO/80020 project Neuro-TARGET; the KULeuven (OT/08/052A and IOF-KP/07/001); and the Fund Druwe-Eerdekens managed by the King Baudouin Foundation (J-MT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 31 Z9 33 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 AUG 29 PY 2012 VL 7 IS 8 AR e43472 DI 10.1371/journal.pone.0043472 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 997ZC UT WOS:000308206000037 PM 22952686 ER PT J AU Wang, TG Lee, MH Choi, E Pardo-Villamizar, CA Bin Lee, S Yang, IH Calabresi, PA Nath, A AF Wang, Tongguang Lee, Myoung-Hwa Choi, Elliot Pardo-Villamizar, Carlos A. Bin Lee, Sung Yang, In Hong Calabresi, Peter A. Nath, Avindra TI Granzyme B-Induced Neurotoxicity Is Mediated via Activation of PAR-1 Receptor and Kv1.3 Channel SO PLOS ONE LA English DT Article ID PROTEIN-COUPLED RECEPTOR; LONG-TERM-MEMORY; POTASSIUM CHANNELS; T-CELLS; HIPPOCAMPAL-NEURONS; NOTCH-1 ACTIVATION; MULTIPLE-SCLEROSIS; THERAPEUTIC TARGET; SIGNALING PATHWAYS; CASPASE ACTIVATION AB Increasing evidence supports a critical role of T cells in neurodegeneration associated with acute and subacute brain inflammatory disorders. Granzyme B (GrB), released by activated T cells, is a cytotoxic proteinase which may induce perforin-independent neurotoxicity. Here, we studied the mechanism of perforin-independent GrB toxicity by treating primary cultured human neuronal cells with recombinant GrB. GrBactivated the protease-activated receptor (PAR)-1 receptor on the neuronal cell surface leading to decreased intracellular cyclic AMP levels. This was followed by increased expression and translocation of the voltage gated potassium channel, Kv1.3 to the neuronal cell membrane. Similar expression of Kv1.3 was also seen in neurons of the cerebral cortex adjacent to active inflammatory lesions in patients with multiple sclerosis. Kv1.3 expression was followed by activation of Notch-1 resulting in neurotoxicity. Blocking PAR-1, Kv1.3 or Notch-1 activation using specific pharmacological inhibitors or siRNAs prevented GrB-induced neurotoxicity. Furthermore, clofazimine protected against GrB-induced neurotoxicity in rat hippocampus, in vivo. These observations indicate that GrB released from T cells induced neurotoxicity by interacting with the membrane bound Gi-coupled PAR-1 receptor and subsequently activated Kv1.3 and Notch-1. These pathways provide novel targets to treat T cell-mediated neuroinflammatory disorders. Kv1.3 is of particular interest since it is expressed on the cell surface, only under pathological circumstances, and early in the cascade of events making it an attractive therapeutic target. C1 [Wang, Tongguang; Lee, Myoung-Hwa; Choi, Elliot; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Pardo-Villamizar, Carlos A.; Calabresi, Peter A.; Nath, Avindra] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Bin Lee, Sung; Yang, In Hong] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. [Yang, In Hong] Natl Univ Singapore, Singapore Inst Nanotechnol, Singapore 117548, Singapore. RP Wang, TG (reprint author), NINDS, Sect Infect Nervous Syst, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM natha@ninds.nih.gov RI Yang, In Hong/F-9125-2015 FU National Multiple Sclerosis Society; National Institutes of Health (NIH) [NS41435]; NIH intramural funds; Project Restore-Bart Mclean Fund for Neuroimmunology Research; Maryland Stem Cell Research Fund FX The work was supported by grants from the National Multiple Sclerosis Society, the National Institutes of Health (NIH) (NS41435, PAC), NIH intramural funds, Project Restore-Bart Mclean Fund for Neuroimmunology Research, and the Maryland Stem Cell Research Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 9 Z9 9 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 29 PY 2012 VL 7 IS 8 AR e43950 DI 10.1371/journal.pone.0043950 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 997ZC UT WOS:000308206000062 PM 22952817 ER PT J AU Cavanaugh, J Joiner, WM Wurtz, RH AF Cavanaugh, James Joiner, Wilsaan M. Wurtz, Robert H. TI Suppressive Surrounds of Receptive Fields In Monkey Frontal Eye Field SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LATERAL INTRAPARIETAL AREA; MACAQUE V1 NEURONS; VISUAL-CORTEX; ORGANIZATION; MODULATION; RESPONSES; SIGNALS; SELECTIVITY; ATTENTION; SACCADES AB A critical step in determining how a neuron contributes to visual processing is determining its visual receptive field (RF). While recording from neurons in frontal eye field (FEF) of awake monkeys (Macaca mulatta), we probed the visual field with small spots of light and found excitatory RFs that decreased in strength from RF center to periphery. However, presenting stimuli with different diameters centered on the RF revealed suppressive surrounds that overlapped the previously determined excitatory RF and reduced responses by 84%, on average. Consequently, in that overlap area, stimulation produced excitation or suppression, depending on the stimulus. Strong stimulation of the RF periphery with annular stimuli allowed us to quantify this effect. A modified difference of Gaussians model that independently varied center and surround activation accounted for the nonlinear activity in the overlap area. Our results suggest that (1) the suppressive surrounds found in FEF are fundamentally the same as those in V1 except for the size and strength of excitatory and suppressive mechanisms, (2) methodically assaying suppressive surrounds in FEF is essential for correctly interpreting responses to large and/or peripheral stimuli and therefore understanding the effects of stimulus context, and (3) regulating the relative strength of the surround clearly changes neuronal responses and may therefore play a significant part in the neuronal changes resulting from visual attention and stimulus salience. C1 [Cavanaugh, James; Joiner, Wilsaan M.; Wurtz, Robert H.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20982 USA. RP Cavanaugh, J (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20982 USA. EM jrc@lsr.nei.nih.gov FU National Eye Institute Intramural Research Program at the National Institutes of Health FX This work was supported by the National Eye Institute Intramural Research Program at the National Institutes of Health. We are grateful to Altah Nichols and Tom Ruffner for machine shop support. NR 26 TC 15 Z9 15 U1 1 U2 7 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 AUG 29 PY 2012 VL 32 IS 35 BP 12284 EP 12293 DI 10.1523/JNEUROSCI.0864-12.2012 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 998CD UT WOS:000308213900034 PM 22933810 ER PT J AU Rotimi, CN AF Rotimi, Charles N. TI Health disparities in the genomic era: the case for diversifying ethnic representation SO GENOME MEDICINE LA English DT Editorial Material DE Genomics; genomic medicine; health disparity; minority health; genetic awareness; pharmacogenomics complex diseases; community outreach; international collaboration AB A report on the meeting 'Why we can't wait: conference to eliminate health disparities in genomic medicine', Miami, Florida, USA, 31 May to 1 June 2012. C1 NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Rotimi, CN (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. EM rotimic@mail.nih.gov NR 0 TC 4 Z9 4 U1 0 U2 1 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 AUG 28 PY 2012 VL 4 AR 65 DI 10.1186/gm366 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 084XZ UT WOS:000314575300001 PM 22929582 ER PT J AU Yoon, J Park, HS Damiano, DL AF Yoon, Jungwon Park, Hyung-Soon Damiano, Diane Louise TI A novel walking speed estimation scheme and its application to treadmill control for gait rehabilitation SO JOURNAL OF NEUROENGINEERING AND REHABILITATION LA English DT Article DE Body-weight supported treadmill training; Walking velocity estimation; Self-selected treadmill speed control; Gait analysis; Temporal-spatial gait parameters ID STROKE PATIENTS; LOCOMOTION INTERFACE; LOKOMAT; SYSTEM; POSTSTROKE; KINEMATICS; FEEDBACK; INJURY; ADULTS; TRIAL AB Background: Virtual reality (VR) technology along with treadmill training (TT) can effectively provide goal-oriented practice and promote improved motor learning in patients with neurological disorders. Moreover, the VR + TT scheme may enhance cognitive engagement for more effective gait rehabilitation and greater transfer to over ground walking. For this purpose, we developed an individualized treadmill controller with a novel speed estimation scheme using swing foot velocity, which can enable user-driven treadmill walking (UDW) to more closely simulate over ground walking (OGW) during treadmill training. OGW involves a cyclic acceleration-deceleration profile of pelvic velocity that contrasts with typical treadmill-driven walking (TDW), which constrains a person to walk at a preset constant speed. In this study, we investigated the effects of the proposed speed adaptation controller by analyzing the gait kinematics of UDW and TDW, which were compared to those of OGW at three pre-determined velocities. Methods: Ten healthy subjects were asked to walk in each mode (TDW, UDW, and OGW) at three pre-determined speeds (0.5 m/s, 1.0 m/s, and 1.5 m/s) with real time feedback provided through visual displays. Temporal-spatial gait data and 3D pelvic kinematics were analyzed and comparisons were made between UDW on a treadmill, TDW, and OGW. Results: The observed step length, cadence, and walk ratio defined as the ratio of stride length to cadence were not significantly different between UDW and TDW. Additionally, the average magnitude of pelvic acceleration peak values along the anterior-posterior direction for each step and the associated standard deviations (variability) were not significantly different between the two modalities. The differences between OGW and UDW and TDW were mainly in swing time and cadence, as have been reported previously. Also, step lengths between OGW and TDW were different for 0.5 m/s and 1.5 m/s gait velocities, and walk ratio between OGS and UDW was different for 1.0 m/s gait velocities. Conclusions: Our treadmill control scheme implements similar gait biomechanics of TDW, which has been used for repetitive gait training in a small and constrained space as well as controlled and safe environments. These results reveal that users can walk as stably during UDW as TDW and employ similar strategies to maintain walking speed in both UDW and TDW. Furthermore, since UDW can allow a user to actively participate in the virtual reality (VR) applications with variable walking velocity, it can induce more cognitive activities during the training with VR, which may enhance motor learning effects. C1 [Yoon, Jungwon; Park, Hyung-Soon; Damiano, Diane Louise] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Yoon, Jungwon] Gyeongsang Natl Univ, Sch Mech Engn, Jinju, South Korea. [Yoon, Jungwon] Gyeongsang Natl Univ, ReCAPT, Jinju, South Korea. RP Park, HS (reprint author), NIH, Dept Rehabil Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM parkhs@cc.nih.gov RI Park, Hyung-Soon/B-3334-2010; Damiano, Diane/B-3338-2010; OI Park, Hyung-Soon/0000-0003-4274-7420; Damiano, Diane/0000-0002-2770-5356; Yoon, Jungwon/0000-0003-1350-5334 FU NIH [90-CC-0168]; LG Yeonam foundation [NRF 2011-0031383] FX This research was supported by NIH protocol number 90-CC-0168 and LG Yeonam foundation Foreigner Research Professor Program & the Priority Research Centers Program under Grant NRF 2011-0031383. NR 44 TC 10 Z9 10 U1 1 U2 27 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-0003 J9 J NEUROENG REHABIL JI J. NeuroEng. Rehabil. PD AUG 28 PY 2012 VL 9 AR 62 DI 10.1186/1743-0003-9-62 PG 13 WC Engineering, Biomedical; Neurosciences; Rehabilitation SC Engineering; Neurosciences & Neurology; Rehabilitation GA 072CU UT WOS:000313646900001 PM 22929169 ER PT J AU Arora, R del Alcazar, CM Morrisey, EE Naiche, LA Papaioannou, VE AF Arora, Ripla del Alcazar, Chelsea M. Morrisey, Edward E. Naiche, L. A. Papaioannou, Virginia E. TI Candidate Gene Approach Identifies Multiple Genes and Signaling Pathways Downstream of Tbx4 in the Developing Allantois SO PLOS ONE LA English DT Article ID EARLY EMBRYONIC LETHALITY; BETA-CATENIN GENE; MURINE ALLANTOIS; VASCULAR DEVELOPMENT; MOUSE EMBRYOS; DEFECTS; VASCULOGENESIS; MICE; HYALURONAN; MESODERM AB Loss of Tbx4 results in absence of chorio-allantoic fusion and failure of formation of the primary vascular plexus of the allantois leading to embryonic death at E10.5. We reviewed the literature for genes implicated in chorio-allantoic fusion, cavitation and vascular plexus formation, processes affected in Tbx4 mutant allantoises. Using this candidate gene approach, we identified a number of genes downstream of Tbx4 in the allantois including extracellular matrix molecules Vcan, Has2, and Itga5, transcription factors Snai1 and Twist, and signaling molecules Bmp2, Bmp7, Notch2, Jag1 and Wnt2. In addition, we show that the canonical Wnt signaling pathway contributes to the vessel-forming potential of the allantois. Ex vivo, the Tbx4 mutant phenotype can be rescued using agonists of the Wnt signaling pathway and, in wildtype allantoises, an inhibitor of the canonical Wnt signaling pathway disrupts vascular plexus formation. In vivo, Tbx4 and Wnt2 double heterozygous placentas show decreased vasculature suggesting interactions between Tbx4 and the canonical Wnt signaling pathway in the process of allantois-derived blood vessel formation. C1 [Arora, Ripla; del Alcazar, Chelsea M.; Papaioannou, Virginia E.] Columbia Univ, Dept Genet & Dev, Med Ctr, New York, NY 10027 USA. [Morrisey, Edward E.] Univ Penn, Dept Med & Cell & Dev Biol, Philadelphia, PA 19104 USA. [Naiche, L. A.] NCI, Canc & Dev Biol Lab, Frederick, MD 21701 USA. RP Arora, R (reprint author), Columbia Univ, Dept Genet & Dev, Med Ctr, New York, NY 10027 USA. EM vep1@columbia.edu OI Papaioannou, Virginia/0000-0001-7558-8601 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [R37HD033082] FX The project was supported by grant number R37HD033082 (V. E. P.) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NICHD or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 5 Z9 5 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 AUG 28 PY 2012 VL 7 IS 8 AR e43581 DI 10.1371/journal.pone.0043581 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998CA UT WOS:000308213600033 PM 22952711 ER PT J AU Reperant, LA Kuiken, T Grenfell, BT Osterhaus, ADME Dobson, AP AF Reperant, Leslie A. Kuiken, Thijs Grenfell, Bryan T. Osterhaus, Albert D. M. E. Dobson, Andrew P. TI Linking Influenza Virus Tissue Tropism to Population-Level Reproductive Fitness SO PLOS ONE LA English DT Article ID ADAPTIVE IMMUNE-RESPONSE; LOWER RESPIRATORY-TRACT; A VIRUS; PANDEMIC INFLUENZA; WITHIN-HOST; H5N1 VIRUS; RECEPTOR SPECIFICITY; METABOLIC PROPERTIES; INFECTIOUS-DISEASES; HUMAN-LUNG AB Influenza virus tissue tropism defines the host cells and tissues that support viral replication and contributes to determining which regions of the respiratory tract are infected in humans. The location of influenza virus infection along the respiratory tract is a key determinant of virus pathogenicity and transmissibility, which are at the basis of influenza burdens in the human population. As the pathogenicity and transmissibility of influenza virus ultimately determine its reproductive fitness at the population level, strong selective pressures will shape influenza virus tissue tropisms that maximize fitness. At present, the relationships between influenza virus tissue tropism within hosts and reproductive fitness at the population level are poorly understood. The selective pressures and constraints that shape tissue tropism and thereby influence the location of influenza virus infection along the respiratory tract are not well characterized. We use mathematical models that link within-host infection dynamics in a spatially-structured human respiratory tract to between-host transmission dynamics, with the aim of characterizing the possible selective pressures on influenza virus tissue tropism. The results indicate that spatial heterogeneities in virus clearance, virus pathogenicity or both, resulting from the unique structure of the respiratory tract, may drive optimal receptor binding affinity-that maximizes influenza virus reproductive fitness at the population level-towards sialic acids with alpha 2,6 linkage to galactose. The expanding cell pool deeper down the respiratory tract, in association with lower clearance rates, may result in optimal infectivity rates-that likewise maximize influenza virus reproductive fitness at the population level-to exhibit a decreasing trend towards deeper regions of the respiratory tract. Lastly, pre-existing immunity may drive influenza virus tissue tropism towards upper regions of the respiratory tract. The proposed framework provides a new template for the cross-scale study of influenza virus evolutionary and epidemiological dynamics in humans. C1 [Reperant, Leslie A.; Kuiken, Thijs; Osterhaus, Albert D. M. E.] Erasmus MC, Dept Virol, Rotterdam, Netherlands. [Reperant, Leslie A.; Grenfell, Bryan T.; Dobson, Andrew P.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Reperant, LA (reprint author), Erasmus MC, Dept Virol, Rotterdam, Netherlands. EM l.reperant@erasmusmc.nl RI Barley, Kamal/F-9579-2011; OI Barley, Kamal/0000-0003-1874-9813; Osterhaus, Albert/0000-0002-6074-1172; Reperant, Leslie/0000-0002-7212-1595 FU Dutch Ministry of Economic Affairs; VIRGO Consortium; Dutch government [BSIK03012]; European Commission [044490, 258084]; Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NSF [0742373]; NIH [R01 GM083983-01]; ERC [250136]; EU [223498] FX LAR, ADMEO and TK were supported by the Dutch Ministry of Economic Affairs grant "Impuls Veterinair Influenza Onderzoek Nederland". ADMEO and TK were supported by the VIRGO Consortium, an innovative cluster approved by the Netherlands Genomics Initiative, and partially funded by the Dutch government (grant number BSIK03012); European Commission grant no. 044490 "New-FluBird", and European Commission grant no. 258084 "Flupig". BTG was supported by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health, and by grants NSF 0742373, and NIH R01 GM083983-01. ADMEO was supported by the ERC advanced grant no. 250136 "FluPlan", and EU FP7 grant no. 223498 "Emperie". The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 86 TC 16 Z9 16 U1 3 U2 21 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 AUG 28 PY 2012 VL 7 IS 8 AR e43115 DI 10.1371/journal.pone.0043115 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998CA UT WOS:000308213600016 PM 22952637 ER PT J AU Thurber, KR Tycko, R AF Thurber, Kent R. Tycko, Robert TI Theory for cross effect dynamic nuclear polarization under magic-angle spinning in solid state nuclear magnetic resonance: The importance of level crossings SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID NMR-SPECTROSCOPY; 14.1 T; SPECTROMETER; RELAXATION; TRANSITION; DIFFUSION; PROTEINS; SYSTEM AB We present theoretical calculations of dynamic nuclear polarization (DNP) due to the cross effect in nuclear magnetic resonance under magic-angle spinning (MAS). Using a three-spin model (two electrons and one nucleus), cross effect DNP with MAS for electron spins with a large g-anisotropy can be seen as a series of spin transitions at avoided crossings of the energy levels, with varying degrees of adiabaticity. If the electron spin-lattice relaxation time T-1e is large relative to the MAS rotation period, the cross effect can happen as two separate events: (i) partial saturation of one electron spin by the applied microwaves as one electron spin resonance (ESR) frequency crosses the microwave frequency and (ii) flip of all three spins, when the difference of the two ESR frequencies crosses the nuclear frequency, which transfers polarization to the nuclear spin if the two electron spins have different polarizations. In addition, adiabatic level crossings at which the two ESR frequencies become equal serve to maintain non-uniform saturation across the ESR line. We present analytical results based on the Landau-Zener theory of adiabatic transitions, as well as numerical quantum mechanical calculations for the evolution of the time-dependent three-spin system. These calculations provide insight into the dependence of cross effect DNP on various experimental parameters, including MAS frequency, microwave field strength, spin relaxation rates, hyperfine and electron-electron dipole coupling strengths, and the nature of the biradical dopants. [http://dx.doi.org/10.1063/1.4747449] C1 [Thurber, Kent R.; Tycko, Robert] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Thurber, KR (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM thurberk@niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX 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. We thank Dr. Kan-Nian Hu and Dr. Alexey Potapov for helpful discussions about DNP mechanisms, and Dr. Akiva Feintuch for discussions regarding the solid effect. Numerical calculations used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health. NR 47 TC 63 Z9 63 U1 12 U2 90 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD AUG 28 PY 2012 VL 137 IS 8 AR 084508 DI 10.1063/1.4747449 PG 14 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 000VB UT WOS:000308416800042 PM 22938251 ER PT J AU Battisti, AJ Meng, G Winkler, DC McGinnes, LW Plevka, P Steven, AC Morrison, TG Rossmann, MG AF Battisti, Anthony J. Meng, Geng Winkler, Dennis C. McGinnes, Lori W. Plevka, Pavel Steven, Alasdair C. Morrison, Trudy G. Rossmann, Michael G. TI Structure and assembly of a paramyxovirus matrix protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NEWCASTLE-DISEASE VIRUS; RESPIRATORY SYNCYTIAL VIRUS; CRYSTAL-STRUCTURE; SENDAI-VIRUS; PARTICLES; REVEALS; NUCLEOCAPSIDS; GLYCOPROTEINS; ECTODOMAIN; EVOLUTION AB Many pleomorphic, lipid-enveloped viruses encode matrix proteins that direct their assembly and budding, but the mechanism of this process is unclear. We have combined X-ray crystallography and cryoelectron tomography to show that the matrix protein of Newcastle disease virus, a paramyxovirus and relative of measles virus, forms dimers that assemble into pseudotetrameric arrays that generate the membrane curvature necessary for virus budding. We show that the glycoproteins are anchored in the gaps between the matrix proteins and that the helical nucleocapsids are associated in register with the matrix arrays. About 90% of virions lack matrix arrays, suggesting that, in agreement with previous biological observations, the matrix protein needs to dissociate from the viral membrane during maturation, as is required for fusion and release of the nucleocapsid into the host's cytoplasm. Structure and sequence conservation imply that other paramyxovirus matrix proteins function similarly. C1 [Battisti, Anthony J.; Meng, Geng; Plevka, Pavel; Rossmann, Michael G.] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Winkler, Dennis C.; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [McGinnes, Lori W.; Morrison, Trudy G.] Univ Massachusetts, Sch Med, Program Immunol & Virol, Dept Microbiol & Physiol Syst, Worcester, MA 01655 USA. RP Rossmann, MG (reprint author), Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. EM mr@purdue.edu RI Plevka, Pavel/H-8661-2014 OI Plevka, Pavel/0000-0003-4215-3315 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; National Institutes of Health [AI11219]; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institutes of Health/General Medicine [T32 GM008296-20]; Purdue University Graduate School FX We thank Anastasia Aksyuk and Giovanni Cardone for helpful comments and suggestions regarding image processing; Ken Hibler and Zhiheng Yu for assistance with the FEI Titan Krios Microscope; Paul Chipman, Siyang Sun, and Ye Xiang for helpful comments and suggestions throughout the course of this project; Xinzheng Zhang for assistance with electron microscopy; and Sheryl Kelly for help in the preparation of this manuscript. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract DE-AC02-06CH11357. We thank National Institutes of Health for both an individual research award (AI11219 to M.G.R.) and support via the intramural research program of National Institute of Arthritis and Musculoskeletal and Skin Diseases (to A.C.S.). Support for A.J.B. was provided by a Biophysics Training Grant (T32 GM008296-20) from the National Institutes of Health/General Medicine (C.V. Stauffacher, principal investigator) and a Bilsland Dissertation Fellowship from Purdue University Graduate School. NR 33 TC 29 Z9 32 U1 0 U2 20 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 AUG 28 PY 2012 VL 109 IS 35 BP 13996 EP 14000 DI 10.1073/pnas.1210275109 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002VP UT WOS:000308565300031 PM 22891297 ER PT J AU Shaked, H Hofseth, LJ Chumanevich, A Chumanevich, AA Wang, J Wang, YS Taniguchi, K Guma, M Shenouda, S Clevers, H Harris, CC Karin, M AF Shaked, Helena Hofseth, Lorne J. Chumanevich, Alena Chumanevich, Alexander A. Wang, Jin Wang, Yinsheng Taniguchi, Koji Guma, Monica Shenouda, Steve Clevers, Hans Harris, Curtis C. Karin, Michael TI Chronic epithelial NF-kappa B activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NITRIC-OXIDE; COLORECTAL-CANCER; DNA-DAMAGE; TRANSCRIPTION FACTOR; ULCERATIVE-COLITIS; COLON-CANCER; MOUSE MODEL; RAG2-DEFICIENT MICE; MAMMALIAN-CELLS; APC(MIN/+) MICE AB The role of NF-kappa B activation in tumor initiation has not been thoroughly investigated. We generated Ikk beta(EE)(IEC) transgenic mice expressing constitutively active I kappa B kinase beta (IKK beta) in intestinal epithelial cells (IECs). Despite absence of destructive colonic inflammation, Ikk beta(EE)(IEC) mice developed intestinal tumors after a long latency. However, when crossed to mice with IEC-specific allelic deletion of the adenomatous polyposis coli (Apc) tumor suppressor locus, Ikk beta(EE)(IEC) mice exhibited more beta-catenin(+) early lesions and visible small intestinal and colonic tumors relative to Apc(+/Delta IEC) mice, and their survival was severely compromised. IEC of Ikk beta(EE)(IEC) mice expressed high amounts of inducible nitric oxide synthase (iNOS) and elevated DNA damage markers and contained more oxidative DNA lesions. Treatment of Ikk beta(EE)(IEC)/Apc(+/Delta IEC) mice with an iNOS inhibitor decreased DNA damage markers and reduced early beta-catenin(+) lesions and tumor load. The results suggest that persistent NF-kappa B activation in IEC may accelerate loss of heterozygocity by enhancing nitrosative DNA damage. C1 [Shaked, Helena; Taniguchi, Koji; Guma, Monica; Karin, Michael] Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA. [Shenouda, Steve] Univ Calif San Diego, Lab Mucosal Immun, Sch Med, La Jolla, CA 92093 USA. [Shenouda, Steve] Univ Calif San Diego, William K Warren Med Res Ctr Celiac Dis, Sch Med, La Jolla, CA 92093 USA. [Hofseth, Lorne J.; Chumanevich, Alena; Chumanevich, Alexander A.] Univ S Carolina, S Carolina Coll Pharm, Dept Pharmaceut & Biomed Sci, Columbia, SC 29208 USA. [Wang, Jin; Wang, Yinsheng] Univ Calif Riverside, Dept Chem, Riverside, CA 92521 USA. [Taniguchi, Koji] Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan. [Clevers, Hans] Hubrecht Inst Dev Biol & Stem Cell Res, NL-3584 CT Utrecht, Netherlands. [Harris, Curtis C.] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Karin, M (reprint author), Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA. EM karinoffice@ucsd.edu RI Shaked, Helena/M-9682-2014 FU National Institutes of Health [AI043477, CA101864]; William K. Warren Foundation [DK035108]; Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation FX This work was supported by National Institutes of Health Grants AI043477 (to M.K.) and CA101864 (to Y.W.), William K. Warren Foundation Grant DK035108 (to M.K.), and the Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation (K.T.). NR 55 TC 51 Z9 54 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 AUG 28 PY 2012 VL 109 IS 35 BP 14007 EP 14012 DI 10.1073/pnas.1211509109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002VP UT WOS:000308565300033 PM 22893683 ER PT J AU Lin, PL Dartois, V Johnston, PJ Janssen, C Via, L Goodwin, MB Klein, E Barry, CE Flynn, JL AF Lin, Philana Ling Dartois, Veronique Johnston, Paul J. Janssen, Christopher Via, Laura Goodwin, Michael B. Klein, Edwin Barry, Clifton E., III Flynn, JoAnne L. TI Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CYNOMOLGUS MACAQUES; GUINEA-PIGS; MODEL; GRANULOMA; RESEMBLES; THERAPY; DISEASE AB Targeting Mycobacterium tuberculosis bacilli in low-oxygen microenvironments, such as caseous granulomas, has been hypothesized to have the potential to shorten therapy for active tuberculosis (TB) and prevent reactivation of latent infection. We previously reported that upon low-dose M. tuberculosis infection, equal proportions of cynomolgus macaques develop active disease or latent infection and that latently infected animals reactivated upon neutralization of TNF. Using this model we now show that chemoprophylaxis of latently infected cynomolgus macaques with 6 mo of isoniazid (INH) effectively prevented anti-TNF antibody-induced reactivation. Similarly, 2-mo treatment of latent animals with a combination of INH and rifampicin (RIF) was highly effective at preventing reactivation disease in this model. Metronidazole (MTZ), which has activity only against anaerobic, nonreplicating bacteria, was as effective as either of these treatments in preventing reactivation of latent infection. Because hypoxic lesions also occur during active TB, we further showed that addition of MTZ to INH/RIF effectively treated animals with active TB within 2 mo. Healing lesions were associated with distinct changes in cellular pathology, with a shift toward increasingly fibrotic and calcified lesions. Our data in the nonhuman primate model of active and latent TB supports targeting bacteria in hypoxic environments for preventing reactivation of latent infection and possibly shortening the duration of therapy in active TB. C1 [Johnston, Paul J.; Flynn, JoAnne L.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15261 USA. [Lin, Philana Ling] Univ Pittsburgh, Sch Med, Div Infect Dis, Dept Pediat,Childrens Hosp Pittsburgh UPMC, Pittsburgh, PA 15224 USA. [Dartois, Veronique] Novartis Inst Trop Dis, Dept Pharmacol, Singapore, Singapore. [Janssen, Christopher; Klein, Edwin] Univ Pittsburgh, Div Lab Anim Res, Pittsburgh, PA 15261 USA. [Via, Laura; Goodwin, Michael B.; Barry, Clifton E., III] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. RP Flynn, JL (reprint author), Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15261 USA. EM joanne@pitt.edu RI Barry, III, Clifton/H-3839-2012; OI Via, Laura/0000-0001-6074-9521 FU National Institute of Allergy and Infectious Diseases [HHSN266200400091C]; Bill and Melinda Gates Foundation; Otis Foundation; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Mark Rodgers, Lekneitah Smith, Catherine Cochran, Kang Min Low, and Carolyn Bigbee for technical assistance; Melanie O'Malley, Jennifer Kerr, Daniel Fillmore, and Jaime Tomko for veterinary technician expertise; Matthew Bigbee for assistance with figures; Charles Scanga; and the Grand Challenge 11 consortium members, particularly Douglas Young, for invaluable advice and discussion on research design and interpretation and for comments on the manuscript. BEI Resources, National Institute of Allergy and Infectious Diseases Contract HHSN266200400091C, provided Culture Filtrate Protein. This study was funded by the Bill and Melinda Gates Foundation Grand Challenge 11 "Drugs for Latent TB"; the Otis Foundation (P.L.L.); and, in part, by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 26 TC 45 Z9 45 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 AUG 28 PY 2012 VL 109 IS 35 BP 14188 EP 14193 DI 10.1073/pnas.1121497109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002VP UT WOS:000308565300064 PM 22826237 ER PT J AU Singh, A Hodgson, N Yan, M Joo, J Gu, L Sang, H Gregory-Bryson, E Wood, WG Ni, YS Smith, K Jackson, SH Coleman, WG AF Singh, Aparna Hodgson, Nathaniel Yan, Ming Joo, Jungsoo Gu, Lei Sang, Hong Gregory-Bryson, Emmalena Wood, William G. Ni, Yisheng Smith, Kimberly Jackson, Sharon H. Coleman, William G. TI Screening Helicobacter pylori genes induced during infection of mouse stomachs SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Helicobacter pylori; In vivo expression technology; Virulence genes; Mice; Infection ID VIVO EXPRESSION TECHNOLOGY; DNA ADENINE METHYLATION; BACTERIAL GENES; ESCHERICHIA-COLI; VIRULENCE GENES; HOST TISSUES; CAGA PROTEIN; SELECTION; REPLICATION; SHIGELLA AB AIM: To investigate the effect of in vivo environment on gene expression in Helkobacter pylori (H. pylon) as it relates to its survival in the host. METHODS: In vivo expression technology (IVET) systems are used to identify microbial virulence genes. We modified the DIET-transcriptional fusion vector, pIVET8, which uses antibiotic resistance as the basis for selection of candidate genes in host tissues to develop two unique IVET-promoter-screening vectors, pIVET11 and pIVET12. Our novel IVET systems were developed by the fusion of random Sau3A DNA fragments of H. pylori and a tandem-reporter system of chloramphenicol acetyltransferase and beta-galactosidase. Additionally, each vector contains a kanamycin resistance gene. We used a mouse macrophage cell line, RAW 264.7 and mice, as selective media to identify specific genes that H. pylori expresses in vivo. Gene expression studies were conducted by infecting RAW 264.7 cells with H. pylori. This was followed by real time polymerase chain reaction (PCR) analysis to determine the relative expression levels of in vivo induced genes. RESULTS: In this study, we have identified 31 in vivo induced (ivi) genes in the initial screens. These 31 genes belong to several functional gene families, including several well-known virulence factors that are expressed by the bacterium in infected mouse stomachs. Virulence factors, vacA and cagA, were found in this screen and are known to play important roles in H. pylori infection, colonization and pathogenesis. Their detection validates the efficacy of these screening systems. Some of the identified ivi genes have already been implicated to play an important role in the pathogenesis of H. pylon and other bacterial pathogens such as Escherichia coli and Vibrio cholerae. Transcription profiles of all ivi genes were confirmed by real time PCR analysis of H. pylori RNA isolated from H. pylori infected RAW 264.7 macrophages. We compared the expression profile of H. pylori and RAW 264.7 coculture with that of H. pylori only. Some genes such as cagA, vacA, IpxC, murI, tlpC, trxB, sodB, tnpB, pgi, rbfA and infB showed a 2-20 fold upregulation. Statistically significant upregulation was obtained for all the above mentioned genes (P < 0.05). tlpC, cagA, vacA, sodB, rbfA, tnpB, IpxC and murl were also significantly upregulated (P < 0.01). These data suggest a strong correlation between results obtained in vitro in the macrophage cell line and in the intact animal. CONCLUSION: The positive identification of these genes demonstrates that our IVET systems are powerful tools for studying H. pylori gene expression in the host environment. (C) 2012 Baishideng. All rights reserved. C1 [Singh, Aparna; Hodgson, Nathaniel; Yan, Ming; Joo, Jungsoo; Gu, Lei; Sang, Hong; Gregory-Bryson, Emmalena; Ni, Yisheng; Smith, Kimberly; Coleman, William G.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Wood, William G.; Jackson, Sharon H.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Coleman, WG (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Room 2A02,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wc3z@nih.gov FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease; Division of Intramural Research of the National Institute of Allergy and Infectious Diseases; National Institute on Minority Health and Health Disparities [Y3-DK-3521-07] FX Supported by Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease; The Division of Intramural Research of the National Institute of Allergy and Infectious Diseases; An Inter-Agency Agreement (Y3-DK-3521-07) with the National Institute on Minority Health and Health Disparities NR 52 TC 7 Z9 7 U1 0 U2 12 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD AUG 28 PY 2012 VL 18 IS 32 BP 4323 EP 4334 DI 10.3748/wjg.v18.i32.4323 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 005VZ UT WOS:000308779500009 PM 22969195 ER PT J AU Chirenje, ZM Masse, BR Maslankowski, LA Ramjee, G Coletti, AS Tembo, TN Magure, TM Soto-Torres, L Kelly, C Hillier, S Karim, A AF Chirenje, Zvavahera M. Masse, Benoit R. Maslankowski, Lisa A. Ramjee, Gita Coletti, Anne S. Tembo, Tchangani N. Magure, Tsitsi M. Soto-Torres, Lydia Kelly, Cliff Hillier, Sharon Karim, Abdool TI Utility of colposcopy in a phase 2 portion of a microbicide clinical trial of BufferGel and 0.5% PRO 2000 Gel SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Article DE colposcopic evaluations; topical microbicides; genital epithelium; phase 2; HIV; investigational product ID HIV-1 INFECTION; VAGINAL GEL; PREVENTION; TRANSMISSION; SAFETY; WOMEN; NONOXYNOL-9; HEALTHY AB Background: The majority of new HIV infections are acquired through heterosexual transmission. There is urgent need for prevention methods to compliment behavior change and condom use. Topical microbicide represent a potential strategy for reduction of HIV transmission in women. Methods: Monthly Colposcopy evaluations were performed during pelvic examinations among 299 women enrolled in the Phase 2 portion of HPTN 035 study at four sites (1 in USA, 3 in Southern Africa). This was a phase 2/2b, multisite, randomized, and controlled clinical trial with four arms: BufferGel, 0.5% PRO2000 Gel, placebo gel and no gel. At two of the sites, pelvic examinations were conducted by the use of naked eye without colposcopy. Results: A colposcopy finding of any kind was detected in 48% of participants at baseline compared to 40% at 3 months (p = 0.04). The lower rates were also observed in vaginal discharge (22% at baseline, 16% at 3 months, p = 0.06), erythema (15% at baseline, 8% at 3 months, p = 0.004). The trend towards significance at p = 0.05 disappear when utilizing stringent statistical significance levels. A pelvic finding of any kind was detected in 71% of colposcopy participants compared to 41% of participants who had naked eye examination only conducted at two sites that performed both colposcopy and naked eye without colposcopy. Use of colposcopy yielded significantly higher rates of participants with deep epithelial disruption, erythema and ecchymosis. We observed no cases of incident Chlamydia, Gonorrhea, or Syphilis during the three month follow up. There were 2 cases of incident HIV during 3-month study period neither of which was associated with any abnormal colposcopy evaluation findings. Conclusion: No safety signals were observed in the 4 study arms, allowing seamless transition from phase 2 to 2b. Colposcopy utility in microbicide clinical trials has minimal value given high rates of background noise findings of no relevant clinical significance. C1 [Masse, Benoit R.; Kelly, Cliff] Fred Hutchinson Canc Res Ctr, SCHARP, Seattle, WA 98104 USA. [Maslankowski, Lisa A.] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Ramjee, Gita] Med Res Council S Africa, Durban, South Africa. [Coletti, Anne S.] Fhi360, Durham, NC USA. [Tembo, Tchangani N.] Univ N Carolina Project, Lilongwe, Malawi. [Soto-Torres, Lydia] NIAID, Bethesda, MD 20892 USA. [Hillier, Sharon] Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Karim, Abdool] Doris Duke Med Res Inst, Ctr AIDS Program Res S Africa, Congella, South Africa. [Chirenje, Zvavahera M.; Magure, Tsitsi M.] Univ Zimbabwe, Coll Hlth Sci, Dept Obstet & Gynaecol, Harare, Zimbabwe. RP Chirenje, ZM (reprint author), Univ Zimbabwe, Coll Hlth Sci, Dept Obstet & Gynaecol, POB A178, Harare, Zimbabwe. EM chirenje@uz-ucsf.co.zw OI Masse, Benoit/0000-0002-4944-8098 FU US National Institutes of Health (NIH); National Institute of Allergy and infectious Diseases (NIAID); National Institute of Child Health and Development (NICHD); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); NIAID of the U.S. National Institutes of Health [5UM1AI068633]; NICHD of the U.S. National Institutes of Health [5UM1AI068633]; NIMH U.S. National Institutes of Health [5UM1AI068633] FX We would like to thank all the women who participated in this study. The study was sponsored by the US National Institutes of Health (NIH). The study was designed and implemented by HIV Prevention trials Network (HPTN) and the Microbicide Trials Network (MTN). The HPTN (UM1AI46749) has been funded by the National Institute of Allergy and infectious Diseases (NIAID), National Institute of Child Health and Development (NICHD), National Institute of Drug Abuse (NIDA), and National Institute of Mental Health (NIMH). MTN is funded by NIAID, NICHD and NIMH, all of the U.S. National Institutes of Health (5UM1AI068633). NR 21 TC 1 Z9 1 U1 1 U2 1 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD AUG 27 PY 2012 VL 15 AR 17376 DI 10.7448/IAS.15.2.17376 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 025PM UT WOS:000310203900001 PM 22944480 ER PT J AU Meredith, MM Liu, K Kamphorst, AO Idoyaga, J Yamane, A Guermonprez, P Rihn, S Yao, KH Silva, IT Oliveira, TY Skokos, D Casellas, R Nussenzweig, MC AF Meredith, Matthew M. Liu, Kang Kamphorst, Alice O. Idoyaga, Juliana Yamane, Arito Guermonprez, Pierre Rihn, Suzannah Yao, Kai-Hui Silva, Israel T. Oliveira, Thiago Y. Skokos, Dimitris Casellas, Rafael Nussenzweig, Michel C. TI Zinc finger transcription factor zDC is a negative regulator required to prevent activation of classical dendritic cells in the steady state SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID GERMINAL-CENTER FORMATION; IN-VIVO; LYMPH-NODE; COMMITTED PROGENITORS; LINEAGE COMMITMENT; IMMUNE-SYSTEM; EXPRESSION; INFLAMMATION; BCL-6; HOMEOSTASIS AB Classical dendritic cells (cDCs) process and present antigens to T cells. Under steady-state conditions, antigen presentation by cDCs induces tolerance. In contrast, during infection or inflammation, cDCs become activated, express higher levels of cell surface MHC molecules, and induce strong adaptive immune responses. We recently identified a cDC-restricted zinc finger transcription factor, zDC (also known as Zbtb46 or Btbd4), that is not expressed by other immune cell populations, including plasmacytoid DCs, monocytes, or macrophages. We define the zDC consensus DNA binding motif and the genes regulated by zDC using chromatin immunoprecipitation and deep sequencing. By deleting zDC from the mouse genome, we show that zDC is primarily a negative regulator of cDC gene expression. zDC deficiency alters the cDC subset composition in the spleen in favor of CD8(+) DCs, up-regulates activation pathways in steady-state cDCs, including elevated MHC II expression, and enhances cDC production of vascular endothelial growth factor leading to increased vascularization of skin-draining lymph nodes. Consistent with these observations, zDC protein expression is rapidly down-regulated after TLR stimulation. Thus, zDC is a TLR-responsive, cDC-specific transcriptional repressor that is in part responsible for preventing cDC maturation in the steady state. C1 [Meredith, Matthew M.; Kamphorst, Alice O.; Guermonprez, Pierre; Yao, Kai-Hui; Silva, Israel T.; Oliveira, Thiago Y.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Idoyaga, Juliana] Rockefeller Univ, Cellular Physiol & Immunol Lab, New York, NY 10065 USA. [Rihn, Suzannah] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10065 USA. [Liu, Kang] Columbia Univ, Dept Microbiol & Immunol, New York, NY 10032 USA. [Kamphorst, Alice O.] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Yamane, Arito; Casellas, Rafael] NIAMSD, NIH, Bethesda, MD 20892 USA. [Skokos, Dimitris] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. [Nussenzweig, Michel C.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussen@rockefeller.edu RI Yamane, Arito/A-2959-2013; Silva, Israel/N-3858-2014; OI Silva, Israel/0000-0002-4687-1499; Oliveira, Thiago/0000-0002-2654-0879 FU NIH [AI051573]; NIH Immunity and Infectious Disease Training Grant; Dana Neuroimmunology grant; Columbia University Medical Center Skin Disease Research Center (CUMCSDRC) [P30 AR044535/AR/NIAMS/NIH] FX This work was supported in part by NIH grant number AI051573. M.M. Meredith was supported by an NIH Immunity and Infectious Disease Training Grant. K. Liu was supported by Dana Neuroimmunology grant and a Pilot Grant funded by P30 AR044535/AR/NIAMS/NIH Columbia University Medical Center Skin Disease Research Center (CUMCSDRC). M.C. Nussenzweig is an HHMI investigator. NR 47 TC 47 Z9 47 U1 0 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 27 PY 2012 VL 209 IS 9 BP 1583 EP 1593 DI 10.1084/jem.20121003 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 000XK UT WOS:000308423900006 PM 22851594 ER PT J AU Cataisson, C Salcedo, R Hakim, S Moffitt, BA Wright, L Yi, M Stephens, R Dai, RM Lyakh, L Schenten, D Yuspa, HS Trinchieri, G AF Cataisson, Christophe Salcedo, Rosalba Hakim, Shakeeb Moffitt, B. Andrea Wright, Lisa Yi, Ming Stephens, Robert Dai, Ren-Ming Lyakh, Lyudmila Schenten, Dominik Yuspa, H. Stuart Trinchieri, Giorgio TI IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID PROTEIN-KINASE-C; NF-KAPPA-B; SQUAMOUS-CELL CARCINOMA; DIFFERENTIATION-ASSOCIATED KERATINS; PROMOTES TUMOR-GROWTH; SKIN CARCINOGENESIS; ONCOGENIC RAS; IN-VIVO; INTRAEPIDERMAL INFLAMMATION; TARGETED DISRUPTION AB Constitutively active RAS plays a central role in the development of human cancer and is sufficient to induce tumors in two-stage skin carcinogenesis. RAS-mediated tumor formation is commonly associated with up-regulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. In this study, we report that mice lacking IL-1R or MyD88 are less sensitive to topical skin carcinogenesis than their respective wild-type (WT) controls. MyD88(-/-) or IL-1R(-/-) keratinocytes expressing oncogenic RAS are hyperproliferative and fail to up-regulate proinflammatory genes or down-regulate differentiation markers characteristic of RAS-expressing WT keratinocytes. Although RAS-expressing MyD88(-/-) keratinocytes form only a few small tumors in orthotopic grafts, IL-1R-deficient RAS-expressing keratinocytes retain the ability to form tumors in orthotopic grafts. Using both genetic and pharmacological approaches, we find that the differentiation and proinflammatory effects of oncogenic RAS in keratinocytes require the establishment of an autocrine loop through IL-1 alpha, IL-1R, and MyD88 leading to phosphorylation of I kappa B alpha and NF-kappa B activation. Blocking IL-1 alpha-mediated NF-kappa B activation in RAS-expressing WT keratinocytes reverses the differentiation defect and inhibits proinflammatory gene expression. Collectively, these results demonstrate that MyD88 exerts a cell-intrinsic function in RAS-mediated transformation of keratinocytes. C1 [Cataisson, Christophe; Hakim, Shakeeb; Moffitt, B. Andrea; Wright, Lisa; Yuspa, H. Stuart] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Dai, Ren-Ming; Lyakh, Lyudmila; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Bethesda, MD 20892 USA. [Yi, Ming; Stephens, Robert] Adv Biomed Comp Ctr, Informat Syst Program, Frederick, MD 21701 USA. [Salcedo, Rosalba; Dai, Ren-Ming] SAIC Frederick Inc, Frederick, MD 21701 USA. [Schenten, Dominik] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06510 USA. [Schenten, Dominik] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. RP Yuspa, HS (reprint author), NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. EM yuspas@mail.nih.gov; trinchig@mail.nih.gov OI Moffitt, Andrea/0000-0001-5964-7851 FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 79 TC 40 Z9 42 U1 0 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 27 PY 2012 VL 209 IS 9 BP 1689 EP 1702 DI 10.1084/jem.20101355 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 000XK UT WOS:000308423900013 PM 22908325 ER PT J AU Wray, S Self, M Lewis, PA Taanman, JW Ryan, NS Mahoney, CJ Liang, YY Devine, MJ Sheerin, UM Houlden, H Morris, HR Healy, D Marti-Masso, JF Preza, E Barker, S Sutherland, M Corriveau, RA D'Andrea, M Schapira, AHV Uitti, RJ Guttman, M Opala, G Jasinska-Myga, B Puschmann, A Nilsson, C Espay, AJ Slawek, J Gutmann, L Boeve, BF Boylan, K Stoessl, AJ Ross, OA Maragakis, NJ Van Gerpen, J Gerstenhaber, M Gwinn, K Dawson, TM Isacson, O Marder, KS Clark, LN Przedborski, SE Finkbeiner, S Rothstein, JD Wszolek, ZK Rossor, MN Hardy, J AF Wray, Selina Self, Matthew Lewis, Patrick A. Taanman, Jan-Willem Ryan, Natalie S. Mahoney, Colin J. Liang, Yuying Devine, Michael J. Sheerin, Una-Marie Houlden, Henry Morris, Huw R. Healy, Daniel Marti-Masso, Jose-Felix Preza, Elisavet Barker, Suzanne Sutherland, Margaret Corriveau, Roderick A. D'Andrea, Michael Schapira, Anthony H. V. Uitti, Ryan J. Guttman, Mark Opala, Grzegorz Jasinska-Myga, Barbara Puschmann, Andreas Nilsson, Christer Espay, Alberto J. Slawek, Jaroslaw Gutmann, Ludwig Boeve, Bradley F. Boylan, Kevin Stoessl, A. Jon Ross, Owen A. Maragakis, Nicholas J. Van Gerpen, Jay Gerstenhaber, Melissa Gwinn, Katrina Dawson, Ted M. Isacson, Ole Marder, Karen S. Clark, Lorraine N. Przedborski, Serge E. Finkbeiner, Steven Rothstein, Jeffrey D. Wszolek, Zbigniew K. Rossor, Martin N. Hardy, John CA NINDS Parkinson's Dis IPSC NINDS Huntington's Dis IPSC NINDS ALS IPSC Consortium TI Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research SO PLOS ONE LA English DT Article ID FAMILIAL ALZHEIMERS-DISEASE; PLURIPOTENT STEM-CELLS; ONSET-PARKINSON-DISEASE; AUTOSOMAL-DOMINANT PARKINSONISM; AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; ALPHA-SYNUCLEIN LOCUS; HUMAN SOMATIC-CELLS; CLINICAL-FEATURES; MISSENSE MUTATIONS AB Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community. C1 [Wray, Selina; Lewis, Patrick A.; Devine, Michael J.; Sheerin, Una-Marie; Houlden, Henry; Preza, Elisavet; Hardy, John] UCL, Dept Mol Neurosci, Inst Neurol, London, England. [Self, Matthew; D'Andrea, Michael] Coriell Inst Med Res, Camden, NJ USA. [Ryan, Natalie S.; Mahoney, Colin J.; Liang, Yuying; Barker, Suzanne; Rossor, Martin N.] UCL, Dementia Res Ctr, Dept Neurodegenerat Dis, Inst Neurol, London, England. [Taanman, Jan-Willem; Healy, Daniel; Schapira, Anthony H. V.] UCL, Dept Clin Neurosci, Inst Neurol, London, England. [Morris, Huw R.] Univ Cardiff, Sch Med, Cardiff, S Glam, Wales. [Marti-Masso, Jose-Felix] Hosp Donastia, San Sebastian, Spain. [Sutherland, Margaret; Corriveau, Roderick A.] NINDS, NIH, Bethesda, MD 20892 USA. [Uitti, Ryan J.; Boylan, Kevin; Ross, Owen A.; Van Gerpen, Jay; Wszolek, Zbigniew K.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Uitti, Ryan J.; Boylan, Kevin; Ross, Owen A.; Van Gerpen, Jay; Wszolek, Zbigniew K.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Guttman, Mark] Ctr Movement Disorders, Dept Neurol, Toronto, ON, Canada. [Opala, Grzegorz; Jasinska-Myga, Barbara] Med Univ Silesia, Dept Neurol, Katowice, Poland. [Puschmann, Andreas; Nilsson, Christer] Lund Univ, Dept Geriatr Psychiat, Lund, Sweden. [Espay, Alberto J.] Univ Cincinnati, Dept Neurol, Cincinnati, OH USA. [Slawek, Jaroslaw] Med Univ Gdansk, Dept Neurol & Psychiat Nursing, Gdansk, Poland. [Gutmann, Ludwig] W Virginia Univ, Dept Neurol, Morgantown, WV 26506 USA. [Boeve, Bradley F.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Stoessl, A. Jon] Univ British Columbia, Div Neurol, Pacific Parkinsons Res Ctr, Vancouver, BC V5Z 1M9, Canada. [Maragakis, Nicholas J.] Johns Hopkins Univ, Dept Neurol & Neurosci, Sch Med, Baltimore, MD USA. [Gerstenhaber, Melissa; Rothstein, Jeffrey D.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Sch Med, Baltimore, MD USA. [Dawson, Ted M.] Johns Hopkins Univ, Neuroregenerat Program, Inst Cell Engn, Dept Neurol, Baltimore, MD USA. [Dawson, Ted M.] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD USA. [Isacson, Ole] Harvard Univ, Sch Med, Ctr Neuroregenerat Res, Belmont, MA 02178 USA. [Marder, Karen S.; Clark, Lorraine N.] Columbia Univ, Gertrude H Sergievsky Ctr, Dept Neurol, New York, NY 10027 USA. [Marder, Karen S.; Clark, Lorraine N.] Columbia Univ, Taub Inst, Coll Phys & Surg, New York, NY USA. [Przedborski, Serge E.] Columbia Univ, Ctr Motor Neuron Biol & Dis, Dept Neurol, Coll Phys & Surg, New York, NY USA. [Przedborski, Serge E.] Columbia Univ, Ctr Motor Neuron Biol & Dis, Dept Pathol, Coll Phys & Surg, New York, NY USA. [Przedborski, Serge E.] Columbia Univ, Ctr Motor Neuron Biol & Dis, Dept Cell Biol, Coll Phys & Surg, New York, NY USA. [Gwinn, Katrina] Baylor Coll Med, Dept Genet, Houston, TX 77030 USA. [Finkbeiner, Steven] Univ Calif San Francisco, Dept Neurol, Gladstone Inst Neurol Dis, Taube Koret Ctr Huntingtons Dis Res, San Francisco, CA USA. [Finkbeiner, Steven] Univ Calif San Francisco, Dept Physiol, Gladstone Inst Neurol Dis, Taube Koret Ctr Huntingtons Dis Res, San Francisco, CA USA. RP Wray, S (reprint author), UCL, Dept Mol Neurosci, Inst Neurol, London, England. EM j.hardy@ucl.ac.uk RI Morris, Huw/B-8527-2008; Wray, Selina/C-3682-2009; Hardy, John/C-2451-2009; Taanman, Jan/A-5379-2011; Kemp, Paul/A-4634-2010; Lewis , Patrick/C-3674-2009; Preza, Elisavet/C-1829-2013; rothstein, jeffrey/C-9470-2013; Ross, Owen/D-7573-2013; Schapira, Anthony/A-1245-2010; Houlden, Henry/C-1532-2008; Marti Masso, Jose Felix/D-8619-2013 OI CATTANEO, ELENA/0000-0002-0755-4917; Espay, Alberto/0000-0002-3389-136X; Puschmann, Andreas/0000-0002-3201-8198; Lewis, Patrick/0000-0003-4537-0489; Devine, Mike/0000-0001-6076-3382; Gwinn, Katrina/0000-0002-8277-651X; Morris, Huw/0000-0002-5473-3774; Wray, Selina/0000-0003-3062-7050; Taanman, Jan/0000-0002-5476-9785; Kemp, Paul/0000-0003-2773-973X; Schapira, Anthony/0000-0002-3018-3966; Houlden, Henry/0000-0002-2866-7777; Marti Masso, Jose Felix/0000-0001-8428-4386 FU Alzheimer's Research UK; Alzheimer's Society; Parkinson's UK; Medical Research Council; National Institute of Neurological Disorders and Stroke (National Institute of Neurological Disorders and Stroke/National Institutes of Health) [NS38377, NS060113, NS036630, NS050487]; GO grants [RC2NS069395, RC2NS069422, RC2 NS070276]; Mayo Clinic Morris K. Udall Center [P50NS072187, P50 NS072187-01S2]; Columbia Udall grant [P50NS38370]; MDSCF grant [2007-MSCRFI-0420-00]; Parkinson's Disease Foundation; Swedish Parkinson Academy; Michael J. Fox Foundation; Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme; Wellcome Trust/Medical Research Council (MRC) [WT089698]; P2ALS FX This work was supported by the following grants and funding agencies: Alzheimer's Research UK (SW and JH), The Alzheimer's Society (MNR), Parkinson's UK (PAL and JH), the Medical Research Council, the National Institute of Neurological Disorders and Stroke (National Institute of Neurological Disorders and Stroke/National Institutes of Health grants NS38377 [TD], NS060113 [LNC], NS036630 [KSM], NS050487 [LNC]), GO grants RC2NS069395, RC2NS069422, RC2 NS070276, Mayo Clinic Morris K. Udall Center grants P50NS072187 and P50 NS072187-01S2 (ZKW, RJU, OAR), Columbia Udall grant P50NS38370 (SP), MDSCF grant 2007-MSCRFI-0420-00 (TD), P2ALS (JDR), The Parkinson's Disease Foundation (LNC, SP, KSM), The Swedish Parkinson Academy (AP and CN) and the Michael J. Fox Foundation (JH, KSM, LNC). This work was partly undertaken at University College London Hospitals/University College London (UCL), which receives a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. This work was also supported in part by the Wellcome Trust/Medical Research Council (MRC) Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium, whose members are from the UCL Institute of Neurology, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 17 Z9 17 U1 0 U2 20 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 AUG 27 PY 2012 VL 7 IS 8 AR e43099 DI 10.1371/journal.pone.0043099 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 995WH UT WOS:000308044800019 PM 22952635 ER PT J AU Laurence, A Amarnath, S Mariotti, J Kim, YC Foley, J Eckhaus, M O'Shea, JJ Fowler, DH AF Laurence, Arian Amarnath, Shoba Mariotti, Jacopo Kim, Yong Chan Foley, Jason Eckhaus, Michael O'Shea, John J. Fowler, Daniel H. TI STAT3 Transcription Factor Promotes Instability of nTreg Cells and Limits Generation of iTreg Cells during Acute Murine Graft-versus-Host Disease SO IMMUNITY LA English DT Article ID REGULATORY T-CELLS; BONE-MARROW-TRANSPLANTATION; TGF-BETA; IN-VIVO; FOXP3 EXPRESSION; TH17 CELLS; HELPER-CELLS; DIFFERENTIATION; PROGRAM; T(H)17 AB Acute graft-versus-host disease (GvHD) is a major cause of mortality in allogeneic bone marrow transplantation (BMT), for which administration of FoxP3(+) regulatory T (Treg) cells has been proposed as a therapy. However, the phenotypic stability of Treg cells is controversial, and STAT3-dependent cytokines can inhibit FoxP3 expression. We assessed whether the elimination of STAT3 in T cells could limit the severity of GvHD. We found STAT3 limited FoxP3(+) Treg cell numbers following allogeneic BMT by two pathways: instability of natural Treg (nTreg) cells and inhibition of induced Treg (iTreg) cell polarization from naive CD4(+) T cells. Deletion of STAT3 within only the nTreg cell population was not sufficient to protect against lethal GvHD. In contrast, transfer of STAT3-deficient naive CD4(+) T cells increased FoxP3(+) Treg cells post-BMT and prevented lethality, suggesting that the consequence of STAT3 signaling may be greater for iTreg rather than nTreg cells during GvHD. C1 [Laurence, Arian; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Amarnath, Shoba; Mariotti, Jacopo; Foley, Jason; Fowler, Daniel H.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Kim, Yong Chan] NIAID, Immunol Lab, Bethesda, MD 20892 USA. [Eckhaus, Michael] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. RP Laurence, A (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. EM laurencea@mail.nih.gov RI Laurence, Arian/A-8770-2009 OI Laurence, Arian/0000-0003-0942-8292 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases; Center for Cancer Research, NCI FX We thank J. Simone, J. Lay, and W.G. Telford for flow cytometry support; P. Muranski and N.P. Restifo for providing mice. This work was supported by the Intramural Research programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Center for Cancer Research, NCI. NR 48 TC 79 Z9 82 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 24 PY 2012 VL 37 IS 2 BP 209 EP 222 DI 10.1016/j.immuni.2012.05.027 PG 14 WC Immunology SC Immunology GA 998SX UT WOS:000308261800007 PM 22921119 ER PT J AU Tsuji, Y Watanabe, T Kudo, M Arai, H Strober, W Chiba, T AF Tsuji, Yoshihisa Watanabe, Tomohiro Kudo, Masatoshi Arai, Hidenori Strober, Warren Chiba, Tsutomu TI Sensing of Commensal Organisms by the Intracellular Sensor NOD1 Mediates Experimental Pancreatitis SO IMMUNITY LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; ACINAR-CELLS; BACTERIAL PEPTIDOGLYCAN; INTESTINAL HOMEOSTASIS; SIGNAL TRANSDUCER; T-CELLS; ACTIVATION; MICE; INFLAMMATION; RECOGNITION AB The intracellular sensor NOD1 has important host-defense functions relating to a variety of pathogens. Here, we showed that this molecule also participates in the induction of a noninfectious pancreatitis via its response to commensal organisms. Pancreatitis induced by high-dose cerulein (a cholecystokinin receptor agonist) administration depends on NOD1 stimulation by gut microflora. To analyze this NOD1 activity, we induced pancreatitis by simultaneous administration of a low dose of cerulein (that does not itself induce pancreatitis) and FK156, an activator of NOD1 that mimics the effect of gut bacteria that have breached the mucosal barrier. The pancreatitis was dependent on acinar cell production of the chemokine MCP-1 and the intrapancreatic influx of CCR2(+) inflammatory cells. Moreover, MCP-1 production involved activation of the transcription factors NF-kappa B and STAT3, each requiring complementary NOD1 and cerulein signaling. These studies indicate that gut commensals enable noninfectious pancreatic inflammation via NOD1 signaling in pancreatic acinar cells. C1 [Tsuji, Yoshihisa; Watanabe, Tomohiro; Chiba, Tsutomu] Kyoto Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Kyoto 6068507, Japan. [Watanabe, Tomohiro] Kyoto Univ, Grad Sch Med, Ctr Innovat Immunoregulat Technol & Therapeut, Kyoto 6068507, Japan. [Arai, Hidenori] Kyoto Univ, Grad Sch Med, Dept Human Hlth Sci, Kyoto 6068507, Japan. [Watanabe, Tomohiro; Strober, Warren] NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20852 USA. [Kudo, Masatoshi] Kinki Univ, Sch Med, Dept Gastroenterol & Hepatol, Osaka 5898511, Japan. RP Watanabe, T (reprint author), Kyoto Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Kyoto 6068507, Japan. EM tmhrwtnb@kuhp.kyoto-u.ac.jp OI Kudo, Masatoshi/0000-0002-4102-3474 FU Japan Society for the Promotion of Science [21590532, 21229009, 24229005, 24659363]; Takeda Science Foundation; Astellas Foundation for Research on Metabolic Disorders; Yakult Bioscience Foundation; Cell Science Research Foundation; Kato Memorial Trust for Nambyo Research; Uehara Memorial Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research; National Institutes of Health FX This work was supported by Grant-in-Aid for Scientific Research (21590532, 21229009, 24229005, and 24659363) from Japan Society for the Promotion of Science, Takeda Science Foundation, Astellas Foundation for Research on Metabolic Disorders, Yakult Bioscience Foundation, Cell Science Research Foundation, Kato Memorial Trust for Nambyo Research, Uehara Memorial Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Intramural Research Program of the National Institutes of Health. We would like to thank N. Asano for critical reading of this manuscript and S. Ueno for thoughtful support of our experiments. NR 35 TC 19 Z9 20 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 24 PY 2012 VL 37 IS 2 BP 326 EP 338 DI 10.1016/j.immuni.2012.05.024 PG 13 WC Immunology SC Immunology GA 998SX UT WOS:000308261800016 PM 22902233 ER PT J AU Gerner, MY Kastenmuller, W Ifrim, I Kabat, J Germain, RN AF Gerner, Michael Y. Kastenmuller, Wolfgang Ifrim, Ina Kabat, Juraj Germain, Ronald N. TI Histo-Cytometry: A Method for Highly Multiplex Quantitative Tissue Imaging Analysis Applied to Dendritic Cell Subset Microanatomy in Lymph Nodes SO IMMUNITY LA English DT Article ID IN-VIVO; IMMUNE-SYSTEM; T-CELLS; LANGERHANS CELLS; TRANSGENIC MICE; AFFERENT LYMPH; MARGINAL ZONE; MICROSCOPY; RECEPTOR; EXPRESSION AB Flow cytometry allows highly quantitative analysis of complex dissociated populations at the cost of neglecting their tissue localization. In contrast, conventional microscopy methods provide spatial information, but visualization and quantification of cellular subsets defined by complex phenotypic marker combinations is challenging. Here, we describe an analytical microscopy method, "histo-cytometry," for visualizing and quantifying phenotypically complex cell populations directly in tissue sections. This technology is based on multiplexed antibody staining, tiled high-resolution confocal microscopy, voxel gating, volumetric cell rendering, and quantitative analysis. We have tested this technology on various innate and adaptive immune populations in murine lymph nodes (LNs) and were able to identify complex cellular subsets and phenotypes, achieving quantitatively similar results to flow cytometry, while also gathering cellular positional information. Here, we employ histo-cytometry to describe the spatial segregation of resident and migratory dendritic cell subsets into specialized microanatomical domains, suggesting an unexpected LN demarcation into discrete functional compartments. C1 [Gerner, Michael Y.; Kastenmuller, Wolfgang; Ifrim, Ina; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Kabat, Juraj] NIAID, Biol Imaging Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Gerner, MY (reprint author), NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. EM gernermy@niaid.nih.gov; rgermain@nih.gov FU NIAID, NIH FX Several individuals contributed to the development of this work. O.M. Schwartz and S. Becker provided training and expertise for confocal imaging. M. Roederer provided essential expertise in spillover correction and data transformation for FlowJo-based analysis. D.H. Kaplan and B.Z. Igyarto provided the (human-promoter)Langerin-Cre x eYFP-flox mice and advice in migratory DC visualization. J. Schenkel provided advice with antibody clone selection. T. Laemmerman and K.A. Casey provided critical manuscript reviews and general project advice. This work was supported by the Intramural Research Program of NIAID, NIH. NR 51 TC 71 Z9 71 U1 0 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 24 PY 2012 VL 37 IS 2 BP 364 EP 376 DI 10.1016/j.immuni.2012.07.011 PG 13 WC Immunology SC Immunology GA 998SX UT WOS:000308261800019 PM 22863836 ER PT J AU Thorne, N Shen, M Lea, WA Simeonov, A Lovell, S Auld, DS Inglese, J AF Thorne, Natasha Shen, Min Lea, Wendy A. Simeonov, Anton Lovell, Scott Auld, Douglas S. Inglese, James TI Firefly Luciferase in Chemical Biology: A Compendium of Inhibitors, Mechanistic Evaluation of Chemotypes, and Suggested Use As a Reporter SO CHEMISTRY & BIOLOGY LA English DT Article ID GENE ASSAYS; IDENTIFICATION; BIOLUMINESCENCE; CHEMISTRY; LIBRARIES; PTC124; KINASE; CELLS AB Firefly luciferase (FLuc) is frequently used as a reporter in high-throughput screening assays, owing to the exceptional sensitivity, dynamic range, and rapid measurement that bioluminescence affords. However, interaction of small molecules with FLuc has, to some extent, confounded its use in chemical biology and drug discovery. To identify and characterize chemotypes interacting with FLuc, we determined potency values for 360,864 compounds found in the NIH Molecular Libraries Small Molecule Repository, available in PubChem. FLuc inhibitory activity was observed for 12% of this library with discernible SAR. Characterization of 151 inhibitors demonstrated a variety of inhibition modes, including FLuc-catalyzed formation of multisubstrate adduct enzyme inhibitor complexes. As in some cell-based FLuc reporter assays, compounds acting as FLuc inhibitors yield paradoxical luminescence increases, thus data on compounds acquired from FLuc-dependent assays require careful analysis as described here. C1 [Thorne, Natasha; Shen, Min; Lea, Wendy A.; Simeonov, Anton; Auld, Douglas S.; Inglese, James] Natl Ctr Advancing Translat Sci, Bethesda, MD 20892 USA. [Inglese, James] Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. [Lovell, Scott] Univ Kansas, Struct Biol Ctr, Lawrence, KS 66047 USA. RP Auld, DS (reprint author), Novartis Inst Biomed Res, Cambridge, MA 02139 USA. EM douglas.auld@novartis.com; jinglese@mail.nih.gov FU Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research [1 U54 MH084681-01]; National Human Genome Research Institute, National Institutes of Health; Hauptman-Woodward Medical Research Institute; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; National Center for Research Resources [5P20RR017708-10]; National Institute of General Medical Sciences from the National Institutes of Health [8 P20 GM103420-10] FX We thank W. Leister and J. Bougie for their expert assistance with LC/MS analysis, D.-T. Nguyen for maximum common structure analysis, R. MacArthur for help in data mining, P. Shinn and D. van Leer for compound management support, K. P. Battaile for X-ray data collection, and S. Michael for his HTS expertise. This work was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research (1 U54 MH084681-01) and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. Use of the KU COBRE Protein Structure Laboratory was supported by grants from the National Center for Research Resources (5P20RR017708-10) and the National Institute of General Medical Sciences (8 P20 GM103420-10) from the National Institutes of Health. NR 33 TC 45 Z9 45 U1 1 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD AUG 24 PY 2012 VL 19 IS 8 BP 1060 EP 1072 DI 10.1016/j.chembiol.2012.07.015 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 011GH UT WOS:000309152500018 PM 22921073 ER PT J AU Leboucher, GP Tsai, YC Yang, M Shaw, KC Zhou, M Veenstra, TD Glickman, MH Weissman, AM AF Leboucher, Guillaume P. Tsai, Yien Che Yang, Mei Shaw, Kristin C. Zhou, Ming Veenstra, Timothy D. Glickman, Michael H. Weissman, Allan M. TI Stress-Induced Phosphorylation and Proteasomal Degradation of Mitofusin 2 Facilitates Mitochondrial Fragmentation and Apoptosis SO MOLECULAR CELL LA English DT Article ID RETICULUM-ASSOCIATED DEGRADATION; DYNAMIN-RELATED PROTEIN-1; E3 UBIQUITIN LIGASE; ENDOPLASMIC-RETICULUM; STRUCTURAL BASIS; FUSION; MFN2; BAX; ACTIVATION; FISSION AB Mitochondria play central roles in integrating pro- and antiapoptotic stimuli, and JNK is well known to have roles in activating apoptotic pathways. We establish a critical link between stress-induced JNK activation, mitofusin 2, which is an essential component of the mitochondrial outer membrane fusion apparatus, and the ubiquitin-proteasome system (UPS). JNK phosphorylation of mitofusin 2 in response to cellular stress leads to recruitment of the ubiquitin ligase (E3) Huwe1/Mule/ARF-BP1/HectH9/E3Histone/Lasu1 to mitofusin 2, with the BH3 domain of Huwe1 implicated in this interaction. This results in ubiquitin-mediated proteasomal degradation of mitofusin 2, leading to mitochondrial fragmentation and enhanced apoptotic cell death. The stability of a non-phosphorylatable mitofusin 2 mutant is unaffected by stress and protective against apoptosis. Conversely, a mitofusin 2 phosphomimic is more rapidly degraded without cellular stress. These findings demonstrate how proximal signaling events can influence both mitochondrial dynamics and apoptosis through phosphorylation-stimulated degradation of the mitochondrial fusion machinery. C1 [Leboucher, Guillaume P.; Tsai, Yien Che; Yang, Mei; Shaw, Kristin C.; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. [Leboucher, Guillaume P.; Glickman, Michael H.] Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. [Zhou, Ming; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. RP Tsai, YC (reprint author), NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. EM tsaiyien@mail.nih.gov; weissmaa@mail.nih.gov OI Tsai, Yien Che/0000-0001-9624-1092 FU National Cancer Institute (NCI); National Institutes of Health (NIH) Intramural Research Program [NO1-CO-12400]; NCI Director's Innovation Award; Michael J. Fox Foundation; USA-Israel Bi-National Science Foundation FX We thank Mickael Cohen, Gustavo Gutierrez, Antonio Iavorone, Anna Lasorella, Stephen Lockett, Deborah Morrison, Daniel Flitt, Ze'ev Ronai, and Thomas Turbyville for helpful discussions; Wei Gu, Gustavo Gutierrez, J. Silvio Gutkind, Wu Ou, Ze'ev Ronai, and Xiaodong Wang for invaluable reagents; and Stanley Lipkowitz and Daniel Stringer for critical review of this manuscript. This work was supported by the National Cancer Institute (NCI), National Institutes of Health (NIH) Intramural Research Program and Contract NO1-CO-12400 (M.Z. and T.D.V.), a NCI Director's Innovation Award (Y.C.T.), a grant from the Michael J. Fox Foundation (A.M.W.), and a grant from the USA-Israel Bi-National Science Foundation (A.M.W. and M.H.G.). NR 62 TC 83 Z9 87 U1 1 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 24 PY 2012 VL 47 IS 4 BP 547 EP 557 DI 10.1016/j.molcel.2012.05.041 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 996CH UT WOS:000308061100007 PM 22748923 ER PT J AU Yoon, JH Abdelmohsen, K Srikantan, S Yang, XL Martindale, JL De, S Huarte, M Zhan, M Becker, KG Gorospe, M AF Yoon, Je-Hyun Abdelmohsen, Kotb Srikantan, Subramanya Yang, Xiaoling Martindale, Jennifer L. De, Supriyo Huarte, Maite Zhan, Ming Becker, Kevin G. Gorospe, Myriam TI LincRNA-p21 Suppresses Target mRNA Translation SO MOLECULAR CELL LA English DT Article ID BINDING PROTEIN HUR; LONG NONCODING RNAS; EXPRESSION; REPRESSION; DISEASE AB Mammalian long intergenic noncoding RNAs (lincRNAs) are best known for modulating transcription. Here we report a posttranscriptional function for lincRNA-p21 as a modulator of translation. Association of the RNA-binding protein HuR with lincRNA-p21 favored the recruitment of let-7/Ago2 to lincRNA-p21, leading to lower lincRNA-p21 stability. Under reduced HuR levels, lincRNA-p21 accumulated in human cervical carcinoma He La cells, increasing its association with JUNB and CTNNB1 mRNAs and selectively lowering their translation. With elevated HuR, lincRNA-p21 levels declined, which in turn derepressed JunB and beta-catenin translation and increased the levels of these proteins. We propose that HuR controls translation of a subset of target mRNAs by influencing lincRNA-p21 levels. Our findings uncover a role for lincRNA as a posttranscriptional inhibitor of translation. C1 [Yoon, Je-Hyun; Abdelmohsen, Kotb; Srikantan, Subramanya; Yang, Xiaoling; Martindale, Jennifer L.; Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [De, Supriyo; Becker, Kevin G.] NIA, Res Resources Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Huarte, Maite] Univ Navarra, CIMA, Dept Oncol, Pamplona 31008, Spain. [Zhan, Ming] Methodist Hosp, Dept Syst Med & Bioengn, Res Inst, Houston, TX 77030 USA. RP Gorospe, M (reprint author), NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov RI Huarte, Maite/J-6903-2014; OI Huarte, Maite/0000-0003-3753-6493; srikantan, subramanya/0000-0003-1810-6519; abdelmohsen, Kotb/0000-0001-6240-5810; De, Supriyo/0000-0002-2075-7655; Becker, Kevin/0000-0002-6794-6656 FU NIA-IRP, NIH; NIH [U54CA149169] FX We thank D.L. Kontoyiannis, G.J. Hannon, N. Mukherjee, and J.D. Keene for providing reagents and information. J.-H.Y., K.A., S.S., X.Y., J.L.M., S.D., K.G.B., and M.G. were supported by the NIA-IRP, NIH. M.Z. was supported by NIH U54CA149169. NR 29 TC 258 Z9 284 U1 3 U2 54 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 24 PY 2012 VL 47 IS 4 BP 648 EP 655 DI 10.1016/j.molcel.2012.06.027 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 996CH UT WOS:000308061100015 PM 22841487 ER PT J AU De Pisapia, N Sandrini, M Braver, TS Cattaneo, L AF De Pisapia, Nicola Sandrini, Marco Braver, Todd S. Cattaneo, Luigi TI Integration in Working Memory: A Magnetic Stimulation Study on the Role of Left Anterior Prefrontal Cortex SO PLOS ONE LA English DT Article ID BASAL GANGLIA; BRAIN; INVOLVEMENT; RETRIEVAL; FACILITATION; NEUROSCIENCE; INFORMATION; RETENTION; COGNITION; CAPACITY AB Integration is a fundamental working memory operation, requiring the insertion of information from one task into the execution of another concurrent task. Previous neuroimaging studies have suggested the involvement of left anterior prefrontal cortex (L-aPFC) in relation to working memory integration demands, increasing during presentation of information to be integrated (loading), throughout its maintenance during a secondary task, up to the integration step, and then decreasing afterward (unloading). Here we used short bursts of 5 Hz repetitive Transcranic Magnetic Stimulation (rTMS) to modulate L-aPFC activity and to assess its causal role in integration. During experimental blocks, rTMS was applied (N = 10) over L-aPFC or vertex (control site) at different time-points of a task involving integration of a preloaded digit into a sequence of arithmetical steps, and contrasted with a closely matched task without integration demand (segregation). When rTMS was applied during the loading phase, reaction times during secondary task were faster, without significant changes in error rates. RTMS instead worsened performance when applied during information unloading. In contrast, no effects were observed when rTMS was applied during the other phases of integration, or during the segregation condition. These results confirm the hypothesis that L-aPFC is causally and selectively involved in the integration of information in working memory. They additionally suggest that pre-integration loading and post-integration unloading of information involving this area may be active and resource-consuming processes. C1 [De Pisapia, Nicola; Sandrini, Marco; Cattaneo, Luigi] Univ Trent, CIMeC Ctr Mind Brain Sci, Rovereto, TN, Italy. [De Pisapia, Nicola] Univ Trent, DiSCoF Dept Cognit Sci & Educ, Rovereto, TN, Italy. [Sandrini, Marco] Uniformed Serv Univ Hlth Sci, Henry M Jackson Fdn, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Sandrini, Marco] NINDS, Human Cort Physiol & Stroke Neuro Rehabil Sect, NIH, Bethesda, MD USA. [Braver, Todd S.] Washington Univ, Dept Psychol, Cognit Control & Psychopathol CCP Lab, St Louis, MO 63130 USA. RP De Pisapia, N (reprint author), Univ Trent, CIMeC Ctr Mind Brain Sci, Rovereto, TN, Italy. EM nicola.depisapia@unitn.it RI Sandrini, Marco/J-2276-2014; OI Sandrini, Marco/0000-0002-1664-5722; Braver, Todd/0000-0002-2631-3393; Cattaneo, Luigi/0000-0001-8905-7529; De Pisapia, Nicola/0000-0002-1089-8841 FU Societa Scienze Mente Cervello (SMC)/Fondazione Cassa di Risparmio di Trento e Rovereto; Provincia Autonoma di Trento FX Study supported by the Societa Scienze Mente Cervello (SMC)/Fondazione Cassa di Risparmio di Trento e Rovereto and by the Provincia Autonoma di Trento. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 5 Z9 5 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 AUG 24 PY 2012 VL 7 IS 8 AR e43731 DI 10.1371/journal.pone.0043731 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998GM UT WOS:000308225500087 PM 22937085 ER PT J AU Ledberg, A Montagnini, A Coppola, R Bressler, SL AF Ledberg, Anders Montagnini, Anna Coppola, Richard Bressler, Steven L. TI Reduced Variability of Ongoing and Evoked Cortical Activity Leads to Improved Behavioral Performance SO PLOS ONE LA English DT Article ID VISUAL-CORTEX V1; CEREBRAL-CORTEX; PSYCHOPHYSICS TOOLBOX; RESPONSE VARIABILITY; NEURAL ACTIVITY; STRIATE CORTEX; EYE-MOVEMENTS; REACTION-TIME; AREA V4; ATTENTION AB Sensory responses of the brain are known to be highly variable, but the origin and functional relevance of this variability have long remained enigmatic. Using the variable foreperiod of a visual discrimination task to assess variability in the primate cerebral cortex, we report that visual evoked response variability is not only tied to variability in ongoing cortical activity, but also predicts mean response time. We used cortical local field potentials, simultaneously recorded from widespread cortical areas, to gauge both ongoing and visually evoked activity. Trial-to-trial variability of sensory evoked responses was strongly modulated by foreperiod duration and correlated both with the cortical variability before stimulus onset as well as with response times. In a separate set of experiments we probed the relation between small saccadic eye movements, foreperiod duration and manual response times. The rate of eye movements was modulated by foreperiod duration and eye position variability was positively correlated with response times. Our results indicate that when the time of a sensory stimulus is predictable, reduction in cortical variability before the stimulus can improve normal behavioral function that depends on the stimulus. C1 [Ledberg, Anders] Univ Pompeu Fabra, Ctr Brain & Cognit, Dept Informat & Commun Technol, Barcelona, Spain. [Montagnini, Anna] Ctr Natl Rech Sci, Inst Neurosci Timone, Marseille, France. [Montagnini, Anna] Aix Marseille Univ, Marseille, France. [Coppola, Richard] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. [Bressler, Steven L.] Florida Atlantic Univ, Ctr Complex Syst & Brain Sci, Dept Psychol, Boca Raton, FL 33431 USA. RP Ledberg, A (reprint author), Univ Pompeu Fabra, Ctr Brain & Cognit, Dept Informat & Commun Technol, Barcelona, Spain. EM anders.ledberg@gmail.com OI Ledberg, Anders/0000-0003-3827-8721 FU European Union [269921]; Ramon y Cajal program from the Spanish government FX The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 269921 (BrainScaleS). AL is supported by the Ramon y Cajal program from the Spanish government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 6 Z9 6 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 AUG 24 PY 2012 VL 7 IS 8 AR e43166 DI 10.1371/journal.pone.0043166 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998GM UT WOS:000308225500033 PM 22937021 ER PT J AU Purdue, MP Hofmann, JN Colt, JS Hoxha, M Ruterbusch, JJ Davis, FG Rothman, N Wacholder, S Schwartz, KL Baccarelli, A Chow, WH AF Purdue, Mark P. Hofmann, Jonathan N. Colt, Joanne S. Hoxha, Mirjam Ruterbusch, Julie J. Davis, Faith G. Rothman, Nathaniel Wacholder, Sholom Schwartz, Kendra L. Baccarelli, Andrea Chow, Wong-Ho TI A Case-Control Study of Peripheral Blood Mitochondrial DNA Copy Number and Risk of Renal Cell Carcinoma SO PLOS ONE LA English DT Article ID ACTIVATION; CANCER AB Background: Low mitochondrial DNA (mtDNA) copy number is a common feature of renal cell carcinoma (RCC), and may influence tumor development. Results from a recent case-control study suggest that low mtDNA copy number in peripheral blood may be a marker for increased RCC risk. In an attempt to replicate that finding, we measured mtDNA copy number in peripheral blood DNA from a U. S. population-based case-control study of RCC. Methodology/Principal Findings: Relative mtDNA copy number was measured in triplicate by a quantitative real-time PCR assay using DNA extracted from peripheral whole blood. Cases (n = 603) had significantly lower mtDNA copy number than controls (n = 603; medians 0.85, 0.91 respectively; P = 0.0001). In multiple logistic regression analyses, the lowest quartile of mtDNA copy number was associated with a 60% increase in RCC risk relative to the highest quartile (OR = 1.6, 95% CI = 1.1-2.2; P-trend = 0.009). This association remained in analyses restricted to cases treated by surgery alone (OR (Q1) = 1.4, 95% CI = 1.0-2.1) and to localized tumors (2.0, 1.3-2.8). Conclusions/Significance: Our findings from this investigation, to our knowledge the largest of its kind, offer important confirmatory evidence that low mtDNA copy number is associated with increased RCC risk. Additional research is needed to assess whether the association is replicable in prospective studies. C1 [Purdue, Mark P.; Hofmann, Jonathan N.; Colt, Joanne S.; Rothman, Nathaniel; Wacholder, Sholom; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hoxha, Mirjam; Baccarelli, Andrea] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Ctr Mol & Genet Epidemiol, Dept Prevent Med, Milan, Italy. [Hoxha, Mirjam; Baccarelli, Andrea] Univ Milan, Dept Environm & Occupat Hlth, Milan, Italy. [Ruterbusch, Julie J.] Wayne State Univ, Sch Med, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Ruterbusch, Julie J.] Wayne State Univ, Sch Med, Barbara Ann Karmanos Inst, Detroit, MI USA. [Davis, Faith G.; Schwartz, Kendra L.] Univ Illinois, Sch Publ Hlth, Dept Epidemiol, Chicago, IL USA. [Baccarelli, Andrea] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. RP Purdue, MP (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM purduem@mail.nih.gov RI Purdue, Mark/C-9228-2016; OI Purdue, Mark/0000-0003-1177-3108; Baccarelli, Andrea/0000-0002-3436-0640 FU Intramural Research Program of the National Institutes of Health; National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 14 TC 23 Z9 23 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 24 PY 2012 VL 7 IS 8 AR e43149 DI 10.1371/journal.pone.0043149 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998GM UT WOS:000308225500032 PM 22937019 ER PT J AU Zhan, M Riordon, DR Yan, B Tarasova, YS Bruweleit, S Tarasov, KV Li, RA Wersto, RP Boheler, KR AF Zhan, Ming Riordon, Daniel R. Yan, Bin Tarasova, Yelena S. Bruweleit, Sarah Tarasov, Kirill V. Li, Ronald A. Wersto, Robert P. Boheler, Kenneth R. TI The B-MYB Transcriptional Network Guides Cell Cycle Progression and Fate Decisions to Sustain Self-Renewal and the Identity of Pluripotent Stem Cells SO PLOS ONE LA English DT Article ID DEVELOPMENTAL REGULATORS; CHROMATIN STATE; MOUSE EMBRYOS; ES CELLS; DIFFERENTIATION; POLYCOMB; GENES; PHOSPHORYLATION; METHYLATION; DNA AB Embryonic stem cells (ESCs) are pluripotent and have unlimited self-renewal capacity. Although pluripotency and differentiation have been examined extensively, the mechanisms responsible for self-renewal are poorly understood and are believed to involve an unusual cell cycle, epigenetic regulators and pluripotency-promoting transcription factors. Here we show that B-MYB, a cell cycle regulated phosphoprotein and transcription factor critical to the formation of inner cell mass, is central to the transcriptional and co-regulatory networks that sustain normal cell cycle progression and self-renewal properties of ESCs. Phenotypically, B-MYB is robustly expressed in ESCs and induced pluripotent stem cells (iPSCs), and it is present predominantly in a hypo-phosphorylated state. Knockdown of B-MYB results in functional cell cycle abnormalities that involve S, G2 and M phases, and reduced expression of critical cell cycle regulators like ccnb1 and plk1. By conducting gene expression profiling on control and B-MYB deficient cells, ChIP-chip experiments, and integrative computational analyses, we unraveled a highly complex B-MYB-mediated transcriptional network that guides ESC self-renewal. The network encompasses critical regulators of all cell cycle phases and epigenetic regulators, pluripotency transcription factors, and differentiation determinants. B-MYB along with E2F1 and c-MYC preferentially co-regulate cell cycle target genes. B-MYB also co-targets genes regulated by OCT4, SOX2 and NANOG that are significantly associated with stem cell differentiation, embryonic development, and epigenetic control. Moreover, loss of B-MYB leads to a breakdown of the transcriptional hierarchy present in ESCs. These results coupled with functional studies demonstrate that B-MYB not only controls and accelerates cell cycle progression in ESCs it contributes to fate decisions and maintenance of pluripotent stem cell identity. C1 [Zhan, Ming; Yan, Bin] NIA, Bioinformat Unit, NIH, Baltimore, MD 21224 USA. [Riordon, Daniel R.; Tarasova, Yelena S.; Bruweleit, Sarah; Tarasov, Kirill V.; Boheler, Kenneth R.] NIA, Mol Cardiol & Stem Cell Unit, NIH, Baltimore, MD 21224 USA. [Wersto, Robert P.] NIA, Flow Cytometry Unit, NIH, Baltimore, MD 21224 USA. [Zhan, Ming] Cornell Univ, Weill Cornell Med Coll, Methodist Hosp, Res Inst, Houston, TX USA. [Yan, Bin] Hong Kong Baptist Univ, Dept Biol, Hong Kong, Hong Kong, Peoples R China. [Li, Ronald A.; Boheler, Kenneth R.] Univ Hong Kong, Stem Cell & Regenerat Med Consortium, LKS Fac Med, Hong Kong, Hong Kong, Peoples R China. RP Zhan, M (reprint author), Cornell Univ, Weill Cornell Med Coll, Methodist Hosp, Res Inst, Houston, TX USA. EM bohelerk@grc.nia.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging; Boehringer Ingelheim Fonds, Foundation for Basic Research in Medicine (Heidesheim, Germany) FX This research was supported in by the Intramural Research Program of the NIH, National Institute on Aging, and by a scholarship (SB) from Boehringer Ingelheim Fonds, Foundation for Basic Research in Medicine (Heidesheim, Germany). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 11 Z9 11 U1 1 U2 22 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 AUG 24 PY 2012 VL 7 IS 8 AR e42350 DI 10.1371/journal.pone.0042350 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998GM UT WOS:000308225500012 PM 22936984 ER PT J AU Mizuno, N Varkey, J Kegulian, NC Hegde, BG Cheng, NQ Langen, R Steven, AC AF Mizuno, Naoko Varkey, Jobin Kegulian, Natalie C. Hegde, Balachandra G. Cheng, Naiqian Langen, Ralf Steven, Alasdair C. TI Remodeling of Lipid Vesicles into Cylindrical Micelles by alpha-Synuclein in an Extended alpha-Helical Conformation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSMISSION ELECTRON-MICROSCOPY; FAMILIAL PARKINSONS-DISEASE; NEURONAL DYSFUNCTION; INTERMEDIATE STRUCTURES; ALZHEIMERS-DISEASE; BROKEN HELIX; IN-VITRO; BINDING; PROTEIN; CELLS AB alpha-Synuclein (alpha S) is a protein with multiple conformations and interactions. Natively unfolded in solution, alpha S accumulates as amyloid in neurological tissue in Parkinson disease and interacts with membranes under both physiological and pathological conditions. Here, we used cryoelectron microscopy in conjunction with electron paramagnetic resonance (EPR) and other techniques to characterize the ability of alpha S to remodel vesicles. At molar ratios of 1: 5 to 1: 40 for protein/lipid (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol), large spherical vesicles are converted into cylindrical micelles similar to 50 angstrom in diameter. Other lipids of the same charge (negative) exhibit generally similar behavior, although bilayer tubes of 150-500 angstrom in width are also produced, depending on the lipid acyl chains. At higher protein/lipid ratios, discoid particles, 70-100 angstrom across, are formed. EPR data show that, on cylindrical micelles, alpha S adopts an extended amphipathic alpha-helical conformation, with its long axis aligned with the tube axis. The observed geometrical relationship between alpha S and the micelle suggests that the wedging of its long alpha-helix into the outer leaflet of a membrane may cause curvature and an anisotropic partition of lipids, leading to tube formation. C1 [Mizuno, Naoko; Cheng, Naiqian; Steven, Alasdair C.] NIAMS, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Varkey, Jobin; Kegulian, Natalie C.; Hegde, Balachandra G.; Langen, Ralf] Univ So Calif, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. RP Mizuno, N (reprint author), Max Planck Inst Biochem, Klopferspitz 18, D-82152 Martinsried, Germany. EM mizuno@biochem.mpg.de; langen@med.usc.edu; stevena@mail.nih.gov FU National Institutes of Health [2 R01 GM063915]; Intramural Research Program of NIAMS FX This work was supported, in whole or in part, by National Institutes of Health Grant 2 R01 GM063915 (to R. L.) and the Intramural Research Program of NIAMS. NR 71 TC 33 Z9 33 U1 4 U2 38 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 24 PY 2012 VL 287 IS 35 BP 29301 EP 29311 DI 10.1074/jbc.M112.365817 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 999CO UT WOS:000308286900010 PM 22767608 ER PT J AU Rostovtseva, TK Gurnev, PA Chen, MY Bezrukov, SM AF Rostovtseva, Tatiana K. Gurnev, Philip A. Chen, Meng-Yang Bezrukov, Sergey M. TI Membrane Lipid Composition Regulates Tubulin Interaction with Mitochondrial Voltage-dependent Anion Channel SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOLIPID-VESICLES; BIOLOGICAL-MEMBRANES; PROTEIN-INTERACTIONS; PACKING STRESS; VDAC; APOPTOSIS; MICROTUBULES; CONDUCTANCE; CARDIOLIPIN; PERSPECTIVE AB Elucidating molecular mechanisms by which lipids regulate protein function within biological membranes is critical for understanding the many cellular processes. Recently, we have found that dimeric alpha beta-tubulin, a subunit of microtubules, regulates mitochondrial respiration by blocking the voltage-dependent anion channel (VDAC) of mitochondrial outer membrane. Here, we show that the mechanism of VDAC blockage by tubulin involves tubulin interaction with the membrane as a critical step. The on-rate of the blockage varies up to 100-fold depending on the particular lipid composition used for bilayer formation in reconstitution experiments and increases with the increasing content of dioleoylphosphatidylethanolamine (DOPE) in dioleoylphosphatidylcholine (DOPC) bilayers. At physiologically low salt concentrations, the on-rate is decreased by the charged lipid. The off-rate of VDAC blockage by tubulin does not depend on the lipid composition. Using confocal fluorescence microscopy, we compared tubulin binding to the membranes of giant unilamellar vesicles (GUVs) made from DOPC and DOPC/DOPE mixtures. We found that detectable binding of the fluorescently labeled dimeric tubulin to GUV membranes requires the presence of DOPE. We propose that prior to the characteristic blockage of VDAC, tubulin first binds to the membrane in a lipid-dependent manner. We thus reveal a new potent regulatory role of the mitochondrial lipids in control of the mitochondrial outer membrane permeability and hence mitochondrial respiration through tuning VDAC sensitivity to blockage by tubulin. More generally, our findings give an example of the lipid-controlled protein-protein interaction where the choice of lipid species is able to change the equilibrium binding constant by orders of magnitude. C1 [Rostovtseva, Tatiana K.; Gurnev, Philip A.; Chen, Meng-Yang; Bezrukov, Sergey M.] Eunice Kennedy Shriver NICHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Rostovtseva, TK (reprint author), NICHD, NIH, 9000 Rockville Pike,Bldg 9,Rm 1E-106, Bethesda, MD 20892 USA. EM rostovtt@mail.nih.gov FU National Institutes of Health Intramural Research Program, Eunice Kennedy Shriver NICHD FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program, Eunice Kennedy Shriver NICHD. NR 56 TC 20 Z9 20 U1 3 U2 16 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 24 PY 2012 VL 287 IS 35 BP 29589 EP 29598 DI 10.1074/jbc.M112.378778 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 999CO UT WOS:000308286900034 PM 22763701 ER PT J AU Laughton, B Cornell, M Grove, D Kidd, M Springer, PE Dobbels, E van Rensburg, AJ Violari, A Babiker, AG Madhi, SA Jean-Philippe, P Gibb, DM Cotton, MF AF Laughton, Barbara Cornell, Morna Grove, Debbie Kidd, Martin Springer, Priscilla E. Dobbels, Els van Rensburg, Anita J. Violari, Avy Babiker, Abdel G. Madhi, Shabir A. Jean-Philippe, Patrick Gibb, Diana M. Cotton, Mark F. TI Early antiretroviral therapy improves neurodevelopmental outcomes in infants SO AIDS LA English DT Article DE early antiretroviral therapy; HIV; infants; neurodevelopment ID PERINATAL HIV-INFECTION; CHILDREN; MANIFESTATIONS AB Objectives: To evaluate the effect of early versus deferred antiretroviral therapy (ART) on the neurodevelopment of infants from Cape Town participating in the Children with HIV Early Antiretroviral Therapy (CHER) trial. Design: HIV-infected infants were randomized to early (<3 months) or deferred ART. HIV-uninfected infants (HIV-exposed and HIV-unexposed) provide background data. Methods: Neurological examination and Griffiths Mental Development Scales (GMDS) were administered between 10-16 months of age by testers blind to HIV status and randomized allocation. Mean quotients were compared using paired Student's t-tests. Results: Sixty-four infants on early ART and 26 on deferred ART (of potential 77 and 38 respectively on CHER trial) were assessed at median age 11 months (range 10-16). On the GMDS, all scores were lower in the deferred arm and the General Griffiths and Locomotor Scores were significantly lower: mean (SD) = 100.1 (13.8) vs. 106.3 (10.6) P= 0.02; and 88.9 (16.3) vs. 97.7 (12.5), P < 0.01, respectively. Children with HIV who received early ART performed as well as children without HIV except on the Locomotor subscale. Both infected and uninfected mean GMDS scores were within the average range. Conclusion: Infants initiated on early ART have significantly better Locomotor and general scores on the GMDS at median age 11 months compared to infants on deferred ART, despite careful monitoring and ready access to ART in the latter. (c) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Laughton, Barbara; Dobbels, Els; van Rensburg, Anita J.; Cotton, Mark F.] Univ Stellenbosch, Childrens Infect Dis Clin Res Unit, Dept Paediat & Child Hlth, Cape Town, South Africa. [Laughton, Barbara; Springer, Priscilla E.; Dobbels, Els; van Rensburg, Anita J.; Cotton, Mark F.] Tygerberg Childrens Hosp, Cape Town, South Africa. [Cornell, Morna] Univ Cape Town, Sch Publ Hlth & Family Med, Ctr Infect Dis Epidemiol & Res, ZA-7700 Rondebosch, South Africa. [Grove, Debbie] Univ Stellenbosch, Dept Obstet & Gynaecol, Cape Town, South Africa. [Kidd, Martin] Univ Stellenbosch, Ctr Stat Consultat, ZA-7600 Stellenbosch, South Africa. [Violari, Avy] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Babiker, Abdel G.; Gibb, Diana M.] MRC, Clin Trials Unit, London, England. [Madhi, Shabir A.] Univ Witwatersrand, Natl Res Fdn Vaccine Preventable Dis, Dept Sci & Technol, Johannesburg, South Africa. [Jean-Philippe, Patrick] NIAID, Henry Jackson Fdn Div DAIDS HJF DAIDS, NIH, Bethesda, MD 20892 USA. RP Laughton, B (reprint author), Univ Stellenbosch, Childrens Infect Dis Clin Res Unit, Dept Paediat & Child Hlth, Cape Town, South Africa. EM BL2@sun.ac.za RI Laughton, Barbara/Q-3496-2016; OI Laughton, Barbara/0000-0001-7260-7723; Cornell, Morna/0000-0001-7149-8799 FU MRC; US National Institute of Allergy and Infectious Diseases (NIAID) through the CIPRA network [U19 AI53217]; Department of Health of the Western Cape; Department of Health of the Gauteng; Departments of Health of the South Africa; GlaxoSmithKline; Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States Department of Health and Human Services [HHSN272200800014C]; Harry Crossley Foundation; South African Medical Research Council (MRC) FX Although the work was supported by the MRC, the d views and opinions expressed are not those of the MRC but of the authors of the material produced.; Support for this study was provided by the US National Institute of Allergy and Infectious Diseases (NIAID) through the CIPRA network, Grant U19 AI53217; the Departments of Health of the Western Cape and Gauteng, South Africa; and GlaxoSmithKline. Additional support was provided with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States Department of Health and Human Services, under Contract No. HHSN272200800014C.; This study was funded through grants from the Harry Crossley Foundation and the South African Medical Research Council (MRC). NR 19 TC 51 Z9 52 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD AUG 24 PY 2012 VL 26 IS 13 BP 1685 EP 1690 DI 10.1097/QAD.0b013e328355d0ce PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 989AH UT WOS:000307532100012 PM 22614886 ER PT J AU Achhra, AC Amin, J Sabin, C Chu, HT Dunn, D Kuller, LH Kovacs, JA Cooper, DA Emery, S Law, MG AF Achhra, Amit C. Amin, Janaki Sabin, Caroline Chu, Haitao Dunn, David Kuller, Lewis H. Kovacs, Joseph A. Cooper, David A. Emery, Sean Law, Matthew G. CA INSIGHT ESPRIT Study Grp SMART Study Grp TI Reclassification of risk of death with the knowledge of D-dimer in a cohort of treated HIV-infected individuals SO AIDS LA English DT Article DE biomarker; cohort analysis; D-dimer; HAART; HIV; net reclassification improvement; prognosis; risk assessment ID ROC CURVE; ANTIRETROVIRAL TREATMENT; CARDIOVASCULAR-DISEASE; MORTALITY; PREDICTION; INFLAMMATION; BIOMARKERS; THERAPY; ADULTS; INTERLEUKIN-2 AB Objective: To evaluate the change in categories of risk of death by adding D-dimer to conventional mortality risk factors. Design: Cohort study. Methods: Data on HIV-infected participants receiving standard combination antiretroviral therapy in two clinical trials (Evaluation of Subcutaneous Proleukin in a Randomized International Trial and Strategic Management of antiretroviral therapy), who had baseline D-dimer measured, were randomly split into two equal training and a validation clatasets. A multivariable survival model was built using the training dataset and included only conventional mortality risk factors measured at baseline. D-dimer was added to create the comparison model. The level of reclassification of mortality risk, for those with at least 5-years of follow-up, was then assessed by tabulating mortality risk defined as low (<= 2% predicted rate), moderate (2-5%) or high (>5%). Reclassification analyses were then repeated on the validation dataset. Results: The analysis population at baseline had a mean age of 43 years, median CD4(+) cell count of 535 cells/mu l (IQR: 420-712), and 83% had HIV RNA of at least 500 copies/ml. In the training dataset (n = 1946, 8939 person-years), there were 83 deaths at a rate of 0.93 per 100 person-years. Addition of D-dimer to the reference model resulted in 6% or fewer (P > 0.05) being correctly reassigned, either up or down, to a new risk category, in both, training and validation clatasets. The integrated discrimination improvement in training and validation datasets was 0.60% (P = 0.084) and 0.45% (P = 0.168), respectively. Conclusion: In this relatively well population, at the given risk cutoffs, D-dimer appeared to only modestly improve the discernment of risk. Risk reclassification provides a method for assessing the clinical utility of biomarkers in HIV cohort studies. (c) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Achhra, Amit C.; Amin, Janaki; Cooper, David A.; Emery, Sean; Law, Matthew G.] Univ New S Wales, Kirby Inst Infect & Immun Soc, Sydney, NSW 2052, Australia. [Sabin, Caroline] UCL, Res Dept Infect & Populat Hlth, London, England. [Chu, Haitao] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Dunn, David] MRC, Clin Trials Unit, London, England. [Kuller, Lewis H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Kovacs, Joseph A.] NIH, Dept Crit Care Med, NIH Clin Ctr, Bethesda, MD 20892 USA. RP Achhra, AC (reprint author), Univ New S Wales, Kirby Inst, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW 2052, Australia. EM aachhra@kirby.unsw.edu.au RI Chu, Haitao /J-7576-2012; Emery, Sean/H-4920-2013; OI Emery, Sean/0000-0001-6072-8309; Chu, Haitao/0000-0003-0932-598X FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [U01AI46957, U01AI068641, U01AI042170, U01AI46362] FX The study was funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health [grant numbers: U01AI46957 and U01AI068641 (ESPRIT); U01AI042170 and U01AI46362 (SMART)]. NR 42 TC 8 Z9 8 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD AUG 24 PY 2012 VL 26 IS 13 BP 1707 EP 1717 DI 10.1097/QAD.0b013e328355c1659 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 989AH UT WOS:000307532100014 PM 22614887 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Does the central dogma still stand? SO BIOLOGY DIRECT LA English DT Article ID DNA-SEQUENCE DIFFERENCES; MESSENGER-RNA DECAY; HUMAN TRANSCRIPTOME; WIDESPREAD RNA; GENETIC-VARIATION; SACCHAROMYCES-CEREVISIAE; ENVIRONMENTAL-STRESS; PRENATAL EXPOSURE; MOLECULAR-BIOLOGY; SCRAPIE PRIONS AB Prions are agents of analog, protein conformation-based inheritance that can confer beneficial phenotypes to cells, especially under stress. Combined with genetic variation, prion-mediated inheritance can be channeled into prion-independent genomic inheritance. Latest screening shows that prions are common, at least in fungi. Thus, there is non-negligible flow of information from proteins to the genome in modern cells, in a direct violation of the Central Dogma of molecular biology. The prion-mediated heredity that violates the Central Dogma appears to be a specific, most radical manifestation of the widespread assimilation of protein (epigenetic) variation into genetic variation. The epigenetic variation precedes and facilitates genetic adaptation through a general 'look-ahead effect' of phenotypic mutations. This direction of the information flow is likely to be one of the important routes of environment-genome interaction and could substantially contribute to the evolution of complex adaptive traits. C1 Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Koonin, EV (reprint author), Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services (National Library of Medicine) FX The author's research is supported by intramural funds of the US Department of Health and Human Services (National Library of Medicine). NR 93 TC 13 Z9 13 U1 7 U2 52 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 AUG 23 PY 2012 VL 7 AR 27 DI 10.1186/1745-6150-7-27 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 020NH UT WOS:000309817600001 PM 22913395 ER PT J AU Kim, DS Zhang, W Millman, SE Hwang, BJ Kwon, SJ Clayberger, C Pagano, M Krensky, AM AF Kim, Dong Seok Zhang, Wei Millman, Scott E. Hwang, Byung Joon Kwon, Seok Joo Clayberger, Carol Pagano, Michele Krensky, Alan M. TI Fbw7 gamma-mediated degradation of KLF13 prevents RANTES expression in resting human but not murine T lymphocytes SO BLOOD LA English DT Article ID E3 UBIQUITIN LIGASE; KRUPPEL-LIKE FACTOR; CYCLIN-E; IN-VIVO; TRANSCRIPTION FACTOR; CHEMOKINE RANTES; CYTOKINE RANTES; ACTIVATION; PROTEIN; CELLS AB RANTES (CCL5) is a chemokine implicated in many human diseases. We previously showed that the transcription factor Kruppel-like factor 13 (KLF13) controls the late (3-5 days after activation) expression of RANTES in T lymphocytes and that KLF13 itself is translationally regulated through the 5'-untranslated region of its mRNA. Here, we show that KLF13 levels are further regulated by ubiquitination and degradation. KLF13 protein is undetectable in resting human T lymphocytes, but treatment with either proteosomal or lysosomal inhibitors increases KLF13 protein levels. Glycogen synthase kinase 3 beta (GSK3 beta)-mediated phosphorylation of KLF13 triggers the ubiquitination of KLF13 by the E3 ligase Fbw7 gamma, resulting in KLF13 protein degradation. Knock-down of either Fbw7 gamma or GSK3 beta by small interfering RNA increases KLF13 expression in resting human T lymphocytes. In contrast, in murine T lymphocytes, KLF13 protein is abundant because of the absence of Fbw7 gamma. Treatment of unactivated human lymphocytes with lysosomal inhibitors stabilizes KLF13 protein, resulting in an increase of RANTES mRNA and protein. Taken together, these studies found that tightly regulated control of both synthesis and degradation allows rapid changes in the level of KLF13 in human T lymphocytes. (Blood. 2012;120(8):1658-1667) C1 [Kim, Dong Seok; Zhang, Wei; Hwang, Byung Joon; Kwon, Seok Joo; Clayberger, Carol; Krensky, Alan M.] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. [Millman, Scott E.; Pagano, Michele] NYU, Sch Med, Inst Canc, New York, NY USA. [Hwang, Byung Joon] Kangwon Natl Univ, Coll Biomed Sci, Dept Mol Biosci, Chunchon, South Korea. [Pagano, Michele] NYU, Sch Med, Howard Hughes Med Inst, New York, NY USA. RP Krensky, AM (reprint author), NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. EM krenskya@mail.nih.gov RI zhang, wei/A-7015-2011; OI pagano, michele/0000-0003-3210-2442 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, and the Center for Cancer Research. NR 42 TC 5 Z9 5 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 23 PY 2012 VL 120 IS 8 BP 1658 EP 1667 DI 10.1182/blood-2012-03-415968 PG 10 WC Hematology SC Hematology GA 009DK UT WOS:000309005600021 PM 22797700 ER PT J AU Chen, X Sassano, MF Zheng, LY Setola, V Chen, M Bai, X Frye, SV Wetsel, WC Roth, BL Jin, J AF Chen, Xin Sassano, Maria F. Zheng, Lianyou Setola, Vincent Chen, Meng Bai, Xu Frye, Stephen V. Wetsel, William C. Roth, Bryan L. Jin, Jian TI Structure-Functional Selectivity Relationship Studies of beta-Arrestin-Biased Dopamine D-2 Receptor Agonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IN-VITRO; ANTIPSYCHOTIC EFFICACY; SIGNAL-TRANSDUCTION; SEROTONIN; ARIPIPRAZOLE; LIGANDS; DERIVATIVES; ANTAGONISTS; ACTIVATION; BINDING AB Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and noncanonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side effects of drugs. However, few such ligands have been created, and very little purposeful attention has been devoted to studying what we term: "structure-functional selectivity relationships" (SFSR). We recently disclosed the first beta-arrestin-biased dopamine D-2 receptor (D2R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these beta-arrestin-biased D2R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered. C1 [Chen, Xin; Zheng, Lianyou; Frye, Stephen V.; Jin, Jian] Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery, Div Chem Biol & Med Chem, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Sassano, Maria F.; Setola, Vincent; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Sassano, Maria F.; Setola, Vincent; Roth, Bryan L.] Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. [Zheng, Lianyou; Bai, Xu] Jilin Univ, Ctr Combinatorial Chem & Drug Discovery, Changchun 130012, Jilin, Peoples R China. [Chen, Meng; Wetsel, William C.] Duke Univ, Dept Psychiat & Behav Sci, Med Ctr, Durham, NC 27710 USA. [Chen, Meng; Wetsel, William C.] Duke Univ, Dept Cell Biol, Med Ctr, Durham, NC 27710 USA. [Chen, Meng; Wetsel, William C.] Duke Univ, Dept Neurobiol, Med Ctr, Durham, NC 27710 USA. RP Jin, J (reprint author), Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery, Div Chem Biol & Med Chem, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. EM bryan_roth@med.unc.edu; jianjin@unc.edu RI sassano, maria/G-4941-2013; Roth, Bryan/F-3928-2010 FU NIH [U19MH082441S1, U19MH082441] FX We thank the NIH (U19MH082441S1 and U19MH082441) for financial support and Dr. Weihe Zhang for critical reading of synthetic procedures and characterization data. NR 46 TC 45 Z9 46 U1 2 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 23 PY 2012 VL 55 IS 16 BP 7141 EP 7153 DI 10.1021/jm300603y PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 992BB UT WOS:000307748800012 PM 22845053 ER PT J AU Browne, SK Burbelo, PD Chetchotisakd, P Suputtamongkol, Y Kiertiburanakul, S Shaw, PA Kirk, JL Jutivorakool, K Zaman, R Ding, L Hsu, AP Patel, SY Olivier, KN Lulitanond, V Mootsikapun, P Anunnatsiri, S Angkasekwinai, N Sathapatayavongs, B Hsueh, PR Shieh, CC Brown, MR Thongnoppakhun, W Claypool, R Sampaio, EP Thepthai, C Waywa, D Dacombe, C Reizes, Y Zelazny, AM Saleeb, P Rosen, LB Mo, A Iadarola, M Holland, SM AF Browne, Sarah K. Burbelo, Peter D. Chetchotisakd, Ploenchan Suputtamongkol, Yupin Kiertiburanakul, Sasisopin Shaw, Pamela A. Kirk, Jennifer L. Jutivorakool, Kamonwan Zaman, Rifat Ding, Li Hsu, Amy P. Patel, Smita Y. Olivier, Kenneth N. Lulitanond, Viraphong Mootsikapun, Piroon Anunnatsiri, Siriluck Angkasekwinai, Nasikarn Sathapatayavongs, Boonmee Hsueh, Po-Ren Shieh, Chi-Chang Brown, Margaret R. Thongnoppakhun, Wanna Claypool, Reginald Sampaio, Elizabeth P. Thepthai, Charin Waywa, Duangdao Dacombe, Camilla Reizes, Yona Zelazny, Adrian M. Saleeb, Paul Rosen, Lindsey B. Mo, Allen Iadarola, Michael Holland, Steven M. TI Adult-Onset Immunodeficiency in Thailand and Taiwan SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NONTUBERCULOUS MYCOBACTERIAL INFECTION; INTERFERON-GAMMA AUTOANTIBODY; IFN-GAMMA; AVIUM COMPLEX; PATIENT; DISEASES; SUSCEPTIBILITY; RECURRENT; HIV AB BACKGROUND Autoantibodies against interferon-gamma are associated with severe disseminated opportunistic infection, but their importance and prevalence are unknown. METHODS We enrolled 203 persons from sites in Thailand and Taiwan in five groups: 52 patients with disseminated, rapidly or slowly growing, nontuberculous mycobacterial infection (group 1); 45 patients with another opportunistic infection, with or without nontuberculous mycobacterial infection (group 2); 9 patients with disseminated tuberculosis (group 3); 49 patients with pulmonary tuberculosis (group 4); and 48 healthy controls (group 5). Clinical histories were recorded, and blood specimens were obtained. RESULTS Patients in groups 1 and 2 had CD4+ T-lymphocyte counts that were similar to those in patients in groups 4 and 5, and they were not infected with the human immunodeficiency virus (HIV). Washed cells obtained from patients in groups 1 and 2 had intact cytokine production and a response to cytokine stimulation. In contrast, plasma obtained from these patients inhibited the activity of interferon-gamma in normal cells. High-titer anti-interferon-gamma autoantibodies were detected in 81% of patients in group 1, 96% of patients in group 2, 11% of patients in group 3, 2% of patients in group 4, and 2% of controls (group 5). Forty other anticytokine autoantibodies were assayed. One patient with cryptococcal meningitis had autoantibodies only against granulocyte-macrophage colony-stimulating factor. No other anticytokine autoantibodies or genetic defects correlated with infections. There was no familial clustering. CONCLUSIONS Neutralizing anti-interferon-gamma autoantibodies were detected in 88% of Asian adults with multiple opportunistic infections and were associated with an adult-onset immunodeficiency akin to that of advanced HIV infection. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research; ClinicalTrials.gov number, NCT00814827.) C1 [Browne, Sarah K.; Jutivorakool, Kamonwan; Zaman, Rifat; Ding, Li; Hsu, Amy P.; Olivier, Kenneth N.; Brown, Margaret R.; Claypool, Reginald; Sampaio, Elizabeth P.; Saleeb, Paul; Rosen, Lindsey B.; Mo, Allen; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Shaw, Pamela A.; Kirk, Jennifer L.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Burbelo, Peter D.; Iadarola, Michael] Natl Inst Dent & Craniofacial Res, Lab Sensory Biol, NIH, Bethesda, MD USA. [Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Dacombe, Camilla; Reizes, Yona] Systex, Rockville, MD USA. [Chetchotisakd, Ploenchan; Lulitanond, Viraphong; Mootsikapun, Piroon; Anunnatsiri, Siriluck] Khon Kaen Univ, Srinagarind Hosp, Khon Kaen, Thailand. [Suputtamongkol, Yupin; Angkasekwinai, Nasikarn; Thongnoppakhun, Wanna; Thepthai, Charin; Waywa, Duangdao] Mahidol Univ, Siriraj Hosp, Bangkok 10700, Thailand. [Browne, Sarah K.; Sathapatayavongs, Boonmee] Mahidol Univ, Ramathibodi Hosp, Fac Med, Bangkok 10400, Thailand. [Jutivorakool, Kamonwan] Chulalongkorn Univ, Fac Med, Dept Med, Bangkok 10330, Thailand. [Jutivorakool, Kamonwan] Thai Red Cross Soc, King Chulalongkorn Mem Hosp, Bangkok, Thailand. [Patel, Smita Y.] Univ Oxford, John Radcliffe Hosp, Oxford OX3 9DU, England. [Hsueh, Po-Ren] Natl Taiwan Univ, Taipei 10764, Taiwan. [Shieh, Chi-Chang] Natl Cheng Kung Univ, Tainan 70101, Taiwan. [Sampaio, Elizabeth P.] Inst Oswaldo Cruz, Leprosy Lab, BR-20001 Rio De Janeiro, Brazil. [Mo, Allen] Colgate Univ, Hamilton, NY 13346 USA. RP Browne, SK (reprint author), CRC B3-4141,MSC 1684,9000 Rockville Pike, Bethesda, MD 20892 USA. EM brownesa@niaid.nih.gov OI HSUEH, PO-REN/0000-0002-7502-9225 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health; National Institute of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research FX Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and the Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health.; Funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research NR 30 TC 115 Z9 119 U1 2 U2 12 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 23 PY 2012 VL 367 IS 8 BP 725 EP 734 DI 10.1056/NEJMoa1111160 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 992CX UT WOS:000307754200007 PM 22913682 ER PT J AU Gregory, AP Dendrou, CA Attfield, KE Haghikia, A Xifara, DK Butter, F Poschmann, G Kaur, G Lambert, L Leach, OA Promel, S Punwani, D Felce, JH Davis, SJ Gold, R Nielsen, FC Siegel, RM Mann, M Bell, JI McVean, G Fugger, L AF Gregory, Adam P. Dendrou, Calliope A. Attfield, Kathrine E. Haghikia, Aiden Xifara, Dionysia K. Butter, Falk Poschmann, Gereon Kaur, Gurman Lambert, Lydia Leach, Oliver A. Proemel, Simone Punwani, Divya Felce, James H. Davis, Simon J. Gold, Ralf Nielsen, Finn C. Siegel, Richard M. Mann, Matthias Bell, John I. McVean, Gil Fugger, Lars TI TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis SO NATURE LA English DT Article ID TUMOR-NECROSIS-FACTOR; GENOME-WIDE ASSOCIATION; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; RESONANCE ENERGY-TRANSFER; SUSCEPTIBILITY LOCI; DISEASE SUSCEPTIBILITY; METAANALYSIS; DEMYELINATION; INHIBITION; MECHANISMS AB Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS)(1), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance(2). Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS)(3,4), but not with other autoimmune conditions such as rheumatoid arthritis(5), psoriasis(6) and Crohn's disease(7). By analysing MS GWAS(3,4) data in conjunction with the 1000 Genomes Project data(8) we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS9-11, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation. C1 [Gregory, Adam P.; Kaur, Gurman; Punwani, Divya; Felce, James H.; Davis, Simon J.; Fugger, Lars] Univ Oxford, Weatherall Inst Mol Med, John Radcliffe Hosp, MRC Human Immunol Unit, Oxford OX3 9DS, England. [Dendrou, Calliope A.; Attfield, Kathrine E.; Haghikia, Aiden; Lambert, Lydia; Leach, Oliver A.; Proemel, Simone; Fugger, Lars] Univ Oxford, John Radcliffe Hosp, Div Clin Neurol, Nuffield Dept Clin Neurosci, Oxford OX3 9DS, England. [Haghikia, Aiden; Gold, Ralf] Ruhr Univ Bochum, St Josef Hosp Bochum, Dept Neurol, D-44791 Bochum, Germany. [Xifara, Dionysia K.; McVean, Gil] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Butter, Falk; Mann, Matthias] Max Planck Inst Biochem, Dept Prote & Signal Transduct, D-82152 Martinsried, Germany. [Poschmann, Gereon] Univ Dusseldorf, Biol Med Forschungszentrum, Mol Prote Lab, D-40225 Dusseldorf, Germany. [Nielsen, Finn C.] Univ Copenhagen, Rigshosp, Ctr Genom Med, DK-2100 Copenhagen O, Denmark. [Siegel, Richard M.] NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Bell, John I.] Univ Oxford, Oxford OX3 7DG, England. [Fugger, Lars] Skejby Sygehus, Aarhus Univ Hosp, Inst Clin, DK-8200 Aarhus N, Denmark. RP Fugger, L (reprint author), Univ Oxford, Weatherall Inst Mol Med, John Radcliffe Hosp, MRC Human Immunol Unit, Oxford OX3 9DS, England. EM lars.fugger@imm.ox.ac.uk RI Mann, Matthias/A-3454-2013; OI Mann, Matthias/0000-0003-1292-4799; McVean, Gil/0000-0002-5012-4162; Felce, James/0000-0001-5531-9244; Dendrou, Calliope/0000-0003-1179-4021; Butter, Falk/0000-0002-7197-7279 FU UK Medical Research Council (MRC); European Union [FP7/2007-2013]; Naomi Bramson Trust; Wellcome Trust [090532/Z/09/Z, 086084/Z/08/Z]; MRC; Deutsche Forschungsgemeinschaft; Christopher Welch Scholarship; MS Society; Dorothy Hodgkin Postgraduate Award FX We thank the volunteers who donated blood samples, the IMSGC and WTCCC2 for data access, A. Auton for help with association analysis data preparation, G. R. Screaton for providing TNFR1 constructs, and A. Vincent and N. Willcox for critical reading of the manuscript. Work in the authors' laboratories is supported by the UK Medical Research Council (MRC), the European Union through grant FP7/2007-2013 (SYBILLA), the Naomi Bramson Trust (L.F.), and the Wellcome Trust (090532/Z/09/Z and 086084/Z/08/Z; G.M.). A.P.G., A.H., L.L., O.A.L. and D.P. are supported by an MRC studentship, the Deutsche Forschungsgemeinschaft, a Christopher Welch Scholarship, funding from the MRC and the MS Society, and a Dorothy Hodgkin Postgraduate Award, respectively. NR 30 TC 131 Z9 133 U1 2 U2 58 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 23 PY 2012 VL 488 IS 7412 BP 508 EP + DI 10.1038/nature11307 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992FS UT WOS:000307761600036 PM 22801493 ER PT J AU Bousema, T Dinglasan, RR Morlais, I Gouagna, LC van Warmerdam, T Awono-Ambene, PH Bonnet, S Diallo, M Coulibaly, M Tchuinkam, T Mulder, B Targett, G Drakeley, C Sutherland, C Robert, V Doumbo, O Toure, Y Graves, PM Roeffen, W Sauerwein, R Birkett, A Locke, E Morin, M Wu, YM Churcher, TS AF Bousema, Teun Dinglasan, Rhoel R. Morlais, Isabelle Gouagna, Louis C. van Warmerdam, Travis Awono-Ambene, Parfait H. Bonnet, Sarah Diallo, Mouctar Coulibaly, Mamadou Tchuinkam, Timoleon Mulder, Bert Targett, Geoff Drakeley, Chris Sutherland, Colin Robert, Vincent Doumbo, Ogobara Toure, Yeya Graves, Patricia M. Roeffen, Will Sauerwein, Robert Birkett, Ashley Locke, Emily Morin, Merribeth Wu, Yimin Churcher, Thomas S. TI Mosquito Feeding Assays to Determine the Infectiousness of Naturally Infected Plasmodium falciparum Gametocyte Carriers SO PLOS ONE LA English DT Article ID TRANSMISSION-BLOCKING IMMUNITY; ANOPHELES-GAMBIAE; MALARIA TRANSMISSION; WESTERN KENYA; SEX-RATIO; INFECTIVITY; REDUCTION; CAMEROON; HOST; PYRIMETHAMINE AB Introduction: In the era of malaria elimination and eradication, drug-based and vaccine-based approaches to reduce malaria transmission are receiving greater attention. Such interventions require assays that reliably measure the transmission of Plasmodium from humans to Anopheles mosquitoes. Methods: We compared two commonly used mosquito feeding assay procedures: direct skin feeding assays and membrane feeding assays. Three conditions under which membrane feeding assays are performed were examined: assays with i) whole blood, ii) blood pellets resuspended with autologous plasma of the gametocyte carrier, and iii) blood pellets resuspended with heterologous control serum. Results: 930 transmission experiments from Cameroon, The Gambia, Mali and Senegal were included in the analyses. Direct skin feeding assays resulted in higher mosquito infection rates compared to membrane feeding assays (odds ratio 2.39, 95% confidence interval 1.94-2.95) with evident heterogeneity between studies. Mosquito infection rates in membrane feeding assays and direct skin feeding assays were strongly correlated (p < 0.0001). Replacing the plasma of the gametocyte donor with malaria naive control serum resulted in higher mosquito infection rates compared to own plasma (OR 1.92, 95% CI 1.68-2.19) while the infectiousness of gametocytes may be reduced during the replacement procedure (OR 0.60, 95% CI 0.52-0.70). Conclusions: Despite a higher efficiency of direct skin feeding assays, membrane feeding assays appear suitable tools to compare the infectiousness between individuals and to evaluate transmission-reducing interventions. Several aspects of membrane feeding procedures currently lack standardization; this variability makes comparisons between laboratories challenging and should be addressed to facilitate future testing of transmission-reducing interventions. C1 [Bousema, Teun; Targett, Geoff; Drakeley, Chris; Sutherland, Colin] London Sch Hyg & Trop Med, Dept Immun & Infect, London WC1, England. [Bousema, Teun; Roeffen, Will; Sauerwein, Robert] Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, NL-6525 ED Nijmegen, Netherlands. [Dinglasan, Rhoel R.; van Warmerdam, Travis] Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Dinglasan, Rhoel R.; van Warmerdam, Travis] Malaria Res Inst, Baltimore, MD USA. [Morlais, Isabelle; Awono-Ambene, Parfait H.; Tchuinkam, Timoleon] Inst Rech Dev, Org Coordinat Lutte Endemies Afrique Cent OCEAC, Lab Rech Paludisme, Yaounde, Cameroon. [Morlais, Isabelle; Gouagna, Louis C.; Robert, Vincent] Inst Rech Dev, MIVEGEC, Montpellier, France. [Bonnet, Sarah] Agence Natl Secur Sanit, USC INRA Bartonella Tiques, Maisons Alfort, France. [Diallo, Mouctar; Coulibaly, Mamadou; Doumbo, Ogobara; Toure, Yeya] Univ Sci Tech & Technol, Malaria Res & Training Ctr, Bamako, Mali. [Tchuinkam, Timoleon] Univ Dschang, Lab Appl Biol & Ecol, Malaria Res Unit, Dschang, Cameroon. [Mulder, Bert] Microbiol Lab Twente, Dept Med Microbiol, Enschede, Netherlands. [Graves, Patricia M.] James Cook Univ, Sch Publ Hlth Trop Med & Rehabil Sci, Cairns, Qld, Australia. [Birkett, Ashley; Locke, Emily; Morin, Merribeth] PATH Malaria Vaccine Initiat, Washington, DC USA. [Wu, Yimin] NIAID, Lab Malaria Immunol & Vaccinol, Rockville, MD USA. [Churcher, Thomas S.] Univ London Imperial Coll Sci Technol & Med, Infect Dis Epidemiol MRC Ctr Outbreak Anal & Mode, London, England. RP Bousema, T (reprint author), London Sch Hyg & Trop Med, Dept Immun & Infect, London WC1, England. EM teun.bousema@lshtm.ac.uk RI Sauerwein, Robert/C-8519-2013; Morlais, Isabelle/F-5078-2014; Graves, Patricia/J-8691-2014; Roeffen, W.F.G./L-4607-2015; Bousema, Teun/N-3574-2014; OI Morlais, Isabelle/0000-0002-2962-7670; Sutherland, Colin/0000-0003-1592-6407; Graves, Patricia/0000-0002-5215-3901; Dinglasan, Rhoel/0000-0001-5433-8179; Dinglasan, Rhoel/0000-0001-6563-1506; Churcher, Thomas/0000-0002-8442-0525 FU Bill & Melinda Gates Foundation; European FP7 framework (REDMAL) [242079]; PATH Malaria Vaccine Initiative (MVI); MVI; Bloomberg Family Foundation; Johns Hopkins Malaria Research Institute; Institut de Recherche pour le Developpement; TMRC; NIAID/NIH; Division of Intramural Research, National Institute of Allergy and Infectious Diseases; Imperial College London; EC FP7 Collaborative project TransMalariaBloc [HEALTH-F3-2008-223736] FX The work of TB is supported by grants from the Bill & Melinda Gates Foundation and the European FP7 framework (REDMAL project, # 242079) and the PATH Malaria Vaccine Initiative (MVI). RRD and TW were supported by MVI, the Bloomberg Family Foundation and the Johns Hopkins Malaria Research Institute. IM, LCG, PHAA, SB and VR were partly supported by the Institut de Recherche pour le Developpement. The MRTC group in Mali is supported by extramural (TMRC) and intramural grants from NIAID/NIH. YW is supported by Division of Intramural Research, National Institute of Allergy and Infectious Diseases. TSC is supported by a Junior Research Fellowship from Imperial College London and an EC FP7 Collaborative project TransMalariaBloc (HEALTH-F3-2008-223736). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 58 Z9 58 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 AUG 22 PY 2012 VL 7 IS 8 AR e42821 DI 10.1371/journal.pone.0042821 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 999CI UT WOS:000308286300026 PM 22936993 ER PT J AU Mancini, M Salarian, A Carlson-Kuhta, P Zampieri, C King, L Chiari, L Horak, FB AF Mancini, Martina Salarian, Arash Carlson-Kuhta, Patricia Zampieri, Cris King, Laurie Chiari, Lorenzo Horak, Fay B. TI ISway: a sensitive, valid and reliable measure of postural control SO JOURNAL OF NEUROENGINEERING AND REHABILITATION LA English DT Article DE Postural control; Accelerometers; Inertial sensors; Parkinson's disease ID DEEP BRAIN-STIMULATION; PARKINSONS-DISEASE; TRUNK ACCELEROMETRY; SPONTANEOUS-SWAY; BALANCE; INSTABILITY; GAIT; RELIABILITY; WALKING; STANCE AB Background: Clinicians need a practical, objective test of postural control that is sensitive to mild neurological disease, shows experimental and clinical validity, and has good test-retest reliability. We developed an instrumented test of postural sway (ISway) using a body-worn accelerometer to offer an objective and practical measure of postural control. Methods: We conducted two separate studies with two groups of subjects. Study I: sensitivity and experimental concurrent validity. Thirteen subjects with early, untreated Parkinson's disease (PD) and 12 age-matched control subjects (CTR) were tested in the laboratory, to compare sway from force-plate COP and inertial sensors. Study II: test-retest reliability and clinical concurrent validity. A different set of 17 early-to-moderate, treated PD (tested ON medication), and 17 age-matched CTR subjects were tested in the clinic to compare clinical balance tests with sway from inertial sensors. For reliability, the sensor was removed, subjects rested for 30 min, and the protocol was repeated. Thirteen sway measures (7 time-domain, 5 frequency-domain measures, and JERK) were computed from the 2D time series acceleration (ACC) data to determine the best metrics for a clinical balance test. Results: Both center of pressure (COP) and ACC measures differentiated sway between CTR and untreated PD. JERK and time-domain measures showed the best test-retest reliability (JERK ICC was 0.86 in PD and 0.87 in CTR; time-domain measures ICC ranged from 0.55 to 0.84 in PD and from 0.60 to 0.89 in CTR). JERK, all but one time-domain measure, and one frequency measure were significantly correlated with the clinical postural stability score (r ranged from 0.50 to 0.63, 0.01 < p < 0.05). Conclusions: Based on these results, we recommend a subset of the most sensitive, reliable, and valid ISway measures to characterize posture control in PD: 1) JERK, 2) RMS amplitude and mean velocity from the time-domain measures, and 3) centroidal frequency as the best frequency measure, as valid and reliable measures of balance control from ISway. C1 [Mancini, Martina; Salarian, Arash; Carlson-Kuhta, Patricia; King, Laurie; Horak, Fay B.] Oregon Hlth & Sci Univ, Dept Neurol, Sch Med, Beaverton, OR 97006 USA. [Mancini, Martina; Chiari, Lorenzo] Alma Mater Studiorum Univ Bologna, Biomed Engn Unit, Dept Elect Comp Sci & Syst, I-40136 Bologna, Italy. [Zampieri, Cris] NIH, Funct & Appl Biomech Lab, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Mancini, M (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, Sch Med, 505 NW 185th Ave, Beaverton, OR 97006 USA. EM mancinim@ohsu.edu RI Salarian, Arash/E-8311-2016; OI Salarian, Arash/0000-0001-7332-0062; Chiari, Lorenzo/0000-0002-2318-4370 FU Kinetics Foundation; NIH [RC1 NS068678, R37 AG006457]; Intramural Research Program of the NIH, Clinical Center, Rehabilitation Medicine Department FX We thank Kelsey Priest and Triana Nagel for scheduling and testing subjects. This publication was made possible with support from Kinetics Foundation, NIH grants RC1 NS068678 and R37 AG006457, and in part by the Intramural Research Program of the NIH, Clinical Center, Rehabilitation Medicine Department. NR 44 TC 68 Z9 71 U1 3 U2 34 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-0003 J9 J NEUROENG REHABIL JI J. NeuroEng. Rehabil. PD AUG 22 PY 2012 VL 9 AR 59 DI 10.1186/1743-0003-9-59 PG 8 WC Engineering, Biomedical; Neurosciences; Rehabilitation SC Engineering; Neurosciences & Neurology; Rehabilitation GA 026IW UT WOS:000310270000001 PM 22913719 ER PT J AU Suzuki, N Fukushi, M Kosaki, K Doyle, AD de Vega, S Yoshizaki, K Akazawa, C Arikawa-Hirasawa, E Yamada, Y AF Suzuki, Nobuharu Fukushi, Masaya Kosaki, Keisuke Doyle, Andrew D. de Vega, Susana Yoshizaki, Keigo Akazawa, Chihiro Arikawa-Hirasawa, Eri Yamada, Yoshihiko TI Teneurin-4 Is a Novel Regulator of Oligodendrocyte Differentiation and Myelination of Small-Diameter Axons in the CNS SO JOURNAL OF NEUROSCIENCE LA English DT Article ID FOCAL ADHESION KINASE; CENTRAL-NERVOUS-SYSTEM; BRAIN; MOUSE; GENES; ASTROCYTES; OUTGROWTH AB Myelination is essential for proper functioning of the CNS. In this study, we have identified a mouse mutation, designated furue, which causes tremors and hypomyelination in the CNS, particularly in the spinal cord, but not in the sciatic nerve of the PNS. In the spinal cord of the furue mice, myelination of small-diameter axons was dramatically reduced, and differentiation of oligodendrocytes, the myelin-forming cells in the CNS, was inhibited. We subsequently found that the furue mutation was associated with a transgene insertion into the teneurin-4 (Ten-4, Ten-m4/Odz4) gene, encoding a transmembrane protein of unknown function. Ten-4 was strongly expressed in the spinal cord of wild-type mice and was induced during normal oligodendrocyte differentiation. In contrast, in the furue mice, the expression of Ten-4 was absent. Differentiation and cellular process formation of oligodendrocytes were inhibited in primary cell culture from the furue mice. Cell differentiation and process formation were also inhibited in the oligodendrocyte progenitor cell line CG-4 after suppression of Ten-4 expression by shRNA. Furthermore, Ten-4 positively regulated focal adhesion kinase, an essential signaling molecule for oligodendrocyte process formation and myelination of small-diameter axons. These findings suggest that Ten-4 is a novel regulator of oligodendrocyte differentiation and that it plays a critical role in the myelination of small-diameter axons in the CNS. C1 [Suzuki, Nobuharu; Fukushi, Masaya; Kosaki, Keisuke; Doyle, Andrew D.; de Vega, Susana; Yoshizaki, Keigo; Yamada, Yoshihiko] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20814 USA. [Suzuki, Nobuharu; Akazawa, Chihiro] Tokyo Med & Dent Univ, Dept Biochem & Biophys, Grad Sch Hlth Care Sci, Tokyo 1138510, Japan. [de Vega, Susana; Arikawa-Hirasawa, Eri] Juntendo Univ, Res Inst Dis Old Age, Fac Med, Tokyo 1138421, Japan. [de Vega, Susana; Arikawa-Hirasawa, Eri] Juntendo Univ, Dept Neurol, Fac Med, Tokyo 1138421, Japan. RP Yamada, Y (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, 30 Convent Dr, Bethesda, MD 20814 USA. EM yyamada@dir.nidcr.nih.gov FU National Institute of Dental and Craniofacial Research; National Institutes of Health; Japan Society for the Promotion of Science for Young Scientists; [23790979] FX This work was supported by grants from the Intramural Program of the National Institute of Dental and Craniofacial Research and the National Institutes of Health (Y.Y.). N.S. was supported in part by the Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists and the Grant-in-Aid for Young Scientists 23790979. We thank Andrew Cho and Ashok B. Kulkarni for creating the transgenic mouse lines, Franca Cambi and Tadashi Yamamoto for providing the CG-4 cell line, and Kenneth M. Yamada for providing the FAK constructs. We also thank Tadahiro Numakawa, Naoki Adachi, and Makoto Horiuchi for their help for the primary culture, Kang Feng and Reinhard Fassler for their help during the initial stage of the work, and Hynda K. Kleinman and Matthew P. Hoffman for their suggestions. NR 28 TC 17 Z9 18 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 22 PY 2012 VL 32 IS 34 BP 11586 EP 11599 DI 10.1523/JNEUROSCI.2045-11.2012 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 997BZ UT WOS:000308140500007 PM 22915103 ER PT J AU Fanous, S Goldart, EM Theberge, FRM Bossert, JM Shaham, Y Hope, BT AF Fanous, Sanya Goldart, Evan M. Theberge, Florence R. M. Bossert, Jennifer M. Shaham, Yavin Hope, Bruce T. TI Role of Orbitofrontal Cortex Neuronal Ensembles in the Expression of Incubation of Heroin Craving SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CONTEXT-INDUCED REINSTATEMENT; MEDIAL PREFRONTAL CORTEX; GAMMA-AMINOBUTYRIC-ACID; DOPAMINE D-1-FAMILY RECEPTORS; COCAINE-SEEKING BEHAVIOR; FOS PROTEIN EXPRESSION; NUCLEUS-ACCUMBENS CORE; TIME-DEPENDENT CHANGES; DRUG-SEEKING; INDUCED RELAPSE AB In humans, exposure to cues previously associated with heroin use often provokes relapse after prolonged withdrawal periods. In rats, cue-induced heroin seeking progressively increases after withdrawal (incubation of heroin craving). Here, we examined the role of orbitofrontal cortex (OFC) neuronal ensembles in the enhanced response to heroin cues after prolonged withdrawal or the expression of incubation of heroin craving. We trained rats to self-administer heroin (6 h/d for 10 d) and assessed cue-induced heroin seeking in extinction tests after 1 or 14 withdrawal days. Cue-induced heroin seeking increased from 1 to 14 d and was accompanied by increased Fos expression in similar to 12% of OFC neurons. Nonselective inactivation of OFC neurons with the GABA agonists baclofen + muscimol decreased cue-induced heroin seeking on withdrawal day 14 but not day 1. We then used the Daun02 inactivation procedure to assess a causal role of the minority of selectively activated Fos-expressing OFC neurons (that presumably form cue-encoding neuronal ensembles) in cue-induced heroin seeking after 14 withdrawal days. We trained c-fos-lacZ transgenic rats to self-administer heroin and 11 d later reexposed them to heroin-associated cues or novel cues for 15 min (induction day), followed by OFC Daun02 or vehicle injections 90 min later; we then tested the rats in extinction tests 3 d later. Daun02 selectively decreased cue-induced heroin seeking in rats previously reexposed to the heroin-associated cues on induction day but not in rats exposed previously to novel cues. Results suggest that heroin-cue-activated OFC neuronal ensembles contribute to the expression of incubation of heroin craving. C1 [Fanous, Sanya; Goldart, Evan M.; Theberge, Florence R. M.; Bossert, Jennifer M.; Shaham, Yavin; Hope, Bruce T.] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,US Dept HHS, Baltimore, MD 21224 USA. RP Hope, BT (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,US Dept HHS, 251 Bayview Dr, Baltimore, MD 21224 USA. EM bhope@intra.nida.nih.gov RI Hope, Bruce/A-9223-2010; shaham, yavin/G-1306-2014 OI Hope, Bruce/0000-0001-5804-7061; FU National Institutes of Health/National Institute on Drug Abuse Intramural Research Program FX This research was supported by the National Institutes of Health/National Institute on Drug Abuse Intramural Research Program. We thank Dr. Kenner Rice (National Institute on Drug Abuse/Intramural Research Program) for synthesizing Daun02 and Dr. Geoff Schoenbaum for helpful comments on this manuscript. NR 72 TC 31 Z9 33 U1 1 U2 12 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 22 PY 2012 VL 32 IS 34 BP 11600 EP 11609 DI 10.1523/JNEUROSCI.1914-12.2012 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 997BZ UT WOS:000308140500008 PM 22915104 ER PT J AU Ohm, DT Bloss, EB Janssen, WG Dietz, KC Wadsworth, S Lou, WD Gee, NA Lasley, BL Rapp, PR Morrison, JH AF Ohm, Daniel T. Bloss, Erik B. Janssen, William G. Dietz, Karen C. Wadsworth, Shannon Lou, Wendy Gee, Nancy A. Lasley, Bill L. Rapp, Peter R. Morrison, John H. TI Clinically Relevant Hormone Treatments Fail to Induce Spinogenesis in Prefrontal Cortex of Aged Female Rhesus Monkeys SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SURGICALLY MENOPAUSAL WOMEN; DENDRITIC SPINE DENSITY; ESTROGEN REPLACEMENT; COGNITIVE FUNCTION; POSTMENOPAUSAL WOMEN; PYRAMIDAL NEURONS; WORKING-MEMORY; PROGESTERONE; THERAPY; ESTRADIOL AB Preclinical animal models have provided strong evidence that estrogen (E) therapy (ET) enhances cognition and induces spinogenesis in neuronal circuits. However, clinical studies have been inconsistent, with some studies revealing adverse effects of ET, including an increased risk of dementia. In an effort to bridge this disconnect between the preclinical and clinical data, we have developed a nonhuman primate (NHP) model of ET combined with high-resolution dendritic spine analysis of dorsolateral prefrontal cortical (dlPFC) neurons. Previously, we reported cyclic ET in aged, ovariectomized NHPs increased spine density on dlPFC neurons. Here, we report that monkeys treated with cyclic E treatment paired with cyclic progesterone (P), continuous E combined with P (either cyclic or continuous), or unopposed continuous E failed to increase spines on dlPFC neurons. Given that the most prevalent form of ET prescribed to women is a combined and continuous E and P, these data bring into convergence the human neuropsychological findings and preclinical neurobiological evidence that standard hormone therapy in women is unlikely to yield the synaptic benefit presumed to underlie the cognitive enhancement reported in animal models. C1 [Ohm, Daniel T.; Bloss, Erik B.; Janssen, William G.; Dietz, Karen C.; Wadsworth, Shannon; Morrison, John H.] Mt Sinai Sch Med, Fishberg Dept Neurosci, Friedman Brain Inst, Kastor Neurobiol Aging Lab, New York, NY 10029 USA. [Morrison, John H.] Mt Sinai Sch Med, Dept Geriatr & Palliat Care, New York, NY 10029 USA. [Morrison, John H.] Mt Sinai Sch Med, Grad Sch Biol Sci, New York, NY 10029 USA. [Lou, Wendy] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5T 3M7, Canada. [Gee, Nancy A.; Lasley, Bill L.] Univ Calif Davis, Ctr Hlth & Environm, Davis, CA 95616 USA. [Gee, Nancy A.; Lasley, Bill L.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Rapp, Peter R.] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. RP Morrison, JH (reprint author), Mt Sinai Sch Med, Fishberg Dept Neurosci, Friedman Brain Inst, Kastor Neurobiol Aging Lab, Box 1065,1 Gustave L Levy Pl, New York, NY 10029 USA. EM john.morrison@mssm.edu FU NIA [AG034794, AG016765, AG006647, AG010606]; NIA Intramural Research Program FX This work was supported by NIA Grant AG034794 (to E. B. B.); NIA Grants AG016765, AG006647, and AG010606 (to J.H.M.); and the NIA Intramural Research Program (to P. R. R.). We thank Drs. Mark Baxter, Patrick Hof, Dani Dumitriu, Yuko Hara, Jiandong Hao, and Rishi Puri for expert advice and assistance. NR 34 TC 16 Z9 16 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 22 PY 2012 VL 32 IS 34 BP 11700 EP 11705 DI 10.1523/JNEUROSCI.1881-12.2012 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 997BZ UT WOS:000308140500016 PM 22915112 ER PT J AU Wu, T Wang, J Wang, CD Hallett, M Zang, YF Wu, XL Chan, P AF Wu, Tao Wang, Jue Wang, Chaodong Hallett, Mark Zang, Yufeng Wu, Xiaoli Chan, Piu TI Basal ganglia circuits changes in Parkinson's disease patients SO NEUROSCIENCE LETTERS LA English DT Article DE Parkinson's disease; Basal ganglia circuits; Dopaminergic deficits; Granger causality analysis; Substantia nigra ID SUBSTANTIA-NIGRA; DEFAULT MODE; CONNECTIVITY; CEREBELLUM AB Functional changes in basal ganglia circuitry are responsible for the major clinical features of Parkinson's disease (PD). Current models of basal ganglia circuitry can only partially explain the cardinal symptoms in PD. We used functional MRI to investigate the causal connectivity of basal ganglia networks from the substantia nigra pars compacta (SNc) in PD in the movement and resting state. In controls, SNc activity predicted increased activity in the supplementary motor area, the default mode network, and dorsolateral prefrontal cortex, but, in patients, activity predicted decreases in the same structures. The SNc had decreased connectivity with the striatum, globus pallidus, subthalamic nucleus, thalamus, supplementary motor area, dorsolateral prefrontal cortex, insula, default mode network, temporal lobe, cerebellum, and pons in patients compared to controls. Levodopa administration partially normalized the pattern of connectivity. Our findings show how the dopaminergic system exerts influences on widespread brain networks, including motor and cognitive networks. The pattern of basal ganglia network connectivity is abnormal in PD secondary to dopamine depletion, and is more deviant in more severe disease. Use of functional MRI with network analysis appears to be a useful method to demonstrate basal ganglia pathways in vivo in human subjects. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Wu, Tao; Wang, Chaodong; Wu, Xiaoli; Chan, Piu] Capital Med Univ, Xuanwu Hosp, Beijing Inst Geriatr, Minist Educ,Dept Neurobiol,Key Lab Neurodegenerat, Beijing 100053, Peoples R China. [Wang, Jue; Zang, Yufeng] Hangzhou Normal Univ, Affiliated Hosp, Ctr Cognit & Brain Disorders, Hangzhou, Zhejiang, Peoples R China. [Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Wu, T (reprint author), Capital Med Univ, Xuanwu Hosp, Beijing Inst Geriatr, Minist Educ,Dept Neurobiol,Key Lab Neurodegenerat, Beijing 100053, Peoples R China. EM wutao69@gmail.com RI ZANG, Yu-Feng/J-1558-2012 OI ZANG, Yu-Feng/0000-0003-1833-8010 FU National Science Foundation of China [30870693, 81071012] FX This work was supported by grants from the National Science Foundation of China (grant numbers 30870693 and 81071012). NR 26 TC 36 Z9 36 U1 4 U2 39 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD AUG 22 PY 2012 VL 524 IS 1 BP 55 EP 59 DI 10.1016/j.neulet.2012.07.012 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 000LA UT WOS:000308386600012 PM 22813979 ER PT J AU Snitkin, ES Zelazny, AM Thomas, PJ Stock, F Henderson, DK Palmore, TN Segre, JA AF Snitkin, Evan S. Zelazny, Adrian M. Thomas, Pamela J. Stock, Frida Henderson, David K. Palmore, Tara N. Segre, Julia A. CA NISC Comparative Sequencing TI Tracking a Hospital Outbreak of Carbapenem-Resistant Klebsiella pneumoniae with Whole-Genome Sequencing SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID INTENSIVE-CARE-UNIT; ACINETOBACTER-BAUMANNII; EPIDEMIOLOGY; INFECTIONS; STRAIN; ENTEROBACTERIACEAE; TRANSMISSION; SPREAD; COLONIZATION; EVOLUTION AB The Gram-negative bacteria Klebsiella pneumoniae is a major cause of nosocomial infections, primarily among immunocompromised patients. The emergence of strains resistant to carbapenems has left few treatment options, making infection containment critical. In 2011, the U. S. National Institutes of Health Clinical Center experienced an outbreak of carbapenem-resistant K. pneumoniae that affected 18 patients, 11 of whom died. Whole-genome sequencing was performed on K. pneumoniae isolates to gain insight into why the outbreak progressed despite early implementation of infection control procedures. Integrated genomic and epidemiological analysis traced the outbreak to three independent transmissions from a single patient who was discharged 3 weeks before the next case became clinically apparent. Additional genomic comparisons provided evidence for unexpected transmission routes, with subsequent mining of epidemiological data pointing to possible explanations for these transmissions. Our analysis demonstrates that integration of genomic and epidemiological data can yield actionable insights and facilitate the control of nosocomial transmission. C1 [Zelazny, Adrian M.; Stock, Frida; Henderson, David K.; Palmore, Tara N.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Snitkin, Evan S.; Thomas, Pamela J.; Segre, Julia A.] NHGRI, Bethesda, MD 20892 USA. [NISC Comparative Sequencing] NIH, Intramural Sequencing Ctr NISC, Bethesda, MD 20892 USA. RP Palmore, TN (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM tpalmore@mail.nih.gov; jsegre@nhgri.nih.gov FU National Human Genome Research Institute; NIH; Pharmacology Research Associate Training Fellowship, National Institute of General Medical Sciences FX Funding: Supported by the National Human Genome Research Institute and NIH Clinical Center Intramural Research Programs and by an NIH Director's Challenge Award for genome sequencing. E. S. S. is supported by a Pharmacology Research Associate Training Fellowship, National Institute of General Medical Sciences. NR 46 TC 250 Z9 253 U1 9 U2 51 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD AUG 22 PY 2012 VL 4 IS 148 AR 148ra116 DI 10.1126/scitranslmed.3004129 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 997GB UT WOS:000308151500006 PM 22914622 ER PT J AU Yeboah, J McClelland, RL Polonsky, TS Burke, GL Sibley, CT O'Leary, D Carr, JJ Goff, DC Greenland, P Herrington, DM AF Yeboah, Joseph McClelland, Robyn L. Polonsky, Tamar S. Burke, Gregory L. Sibley, Christopher T. O'Leary, Daniel Carr, Jeffery J. Goff, David C., Jr. Greenland, Philip Herrington, David M. TI Comparison of Novel Risk Markers for Improvement in Cardiovascular Risk Assessment in Intermediate-Risk Individuals SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY-HEART-DISEASE; INTIMA-MEDIA THICKNESS; ANKLE-BRACHIAL INDEX; C-REACTIVE PROTEIN; ATHEROSCLEROSIS; PREDICTION; ADULTS; SCORE; EVENTS; CLASSIFICATION AB Context Risk markers including coronary artery calcium, carotid intima-media thickness, ankle-brachial index, brachial flow-mediated dilation, high-sensitivity C-reactive protein (CRP), and family history of coronary heart disease (CHD) have been reported to improve on the Framingham Risk Score (FRS) for prediction of CHD, but there are no direct comparisons of these markers for risk prediction in a single cohort. Objective We compared improvement in prediction of incident CHD/cardiovascular disease (CVD) of these 6 risk markers within intermediate-risk participants (FRS >5%-<20%) in the Multi-Ethnic Study of Atherosclerosis (MESA). Design, Setting, and Participants Of 6814 MESA participants from 6 US field centers, 1330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002, with follow-up through May 2011. Probability-weighted Cox proportional hazard models were used to estimate hazard ratios (HRs). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement were used to compare incremental contributions of each marker when added to the FRS, plus race/ethnicity. Main Outcome Measures Incident CHD defined as myocardial infarction, angina followed by revascularization, resuscitated cardiac arrest, or CHD death. Incident CVD additionally included stroke or CVD death. Results After 7.6-year median follow-up (IQR, 7.3-7.8), 94 CHD and 123 CVD events occurred. Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independently associated with incident CHD in multivariable analyses (HR, 2.60 [95% CI, 1.94-3.50]; HR, 0.79 [95% CI, 0.66-0.95]; HR, 1.28 [95% CI, 1.00-1.64]; and HR, 2.18 [95% CI, 1.38-3.42], respectively). Carotid intima-media thickness and brachial flow-mediated dilation were not associated with incident CHD in multivariable analyses (HR, 1.17 [95% CI, 0.95-1.45] and HR, 0.95 [95% CI, 0.78-1.14]). Although addition of the markers individually to the FRS plus race/ethnicity improved AUC, coronary artery calcium afforded the highest increment (0.623 vs 0.784), while brachial flow-mediated dilation had the least (0.623 vs 0.639). For incident CHD, the net reclassification improvement with coronary artery calcium was 0.659, brachial flow-mediated dilation was 0.024, ankle-brachial index was 0.036, carotid intima-media thickness was 0.102, family history was 0.160 and high-sensitivity CRP was 0.079. Similar results were obtained for incident CVD. Conclusions Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independent predictors of incident CHD/CVD in intermediate-risk individuals. Coronary artery calcium provided superior discrimination and risk reclassification compared with other risk markers. JAMA. 2012;308(8):788-795 www.jama.com C1 [Yeboah, Joseph] Wake Forest Univ, Wake Forest Baptist Hlth, Dept Internal Med Cardiol, Sch Med, Winston Salem, NC 27157 USA. [Carr, Jeffery J.] Wake Forest Univ, Sch Med, Dept Radiol, Winston Salem, NC 27157 USA. [Burke, Gregory L.; Carr, Jeffery J.] Wake Forest Univ, Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [McClelland, Robyn L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Polonsky, Tamar S.] Univ Chicago, Cardiol Sect, Dept Internal Med, Chicago, IL 60637 USA. [Sibley, Christopher T.] NIH, Bethesda, MD 20892 USA. [O'Leary, Daniel] Tufts Med Ctr, Brookline, MA USA. [Goff, David C., Jr.] Univ Colorado, Sch Publ Hlth, Aurora, CO USA. [Greenland, Philip] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. RP Yeboah, J (reprint author), Wake Forest Univ, Wake Forest Baptist Hlth, Dept Internal Med Cardiol, Sch Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jyeboah@wakehealth.edu RI Sibley, Christopher/C-9900-2013; Carr, John/A-1938-2012 OI Carr, John/0000-0002-4398-8237 FU National Institutes of Health (NIH); National Heart, Lung, and Blood Institute (NHLBI); NIH/NHLBI; Merck Co; NIH; [N01-HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [R01HL098445] FX Dr McClelland reports receipt of an institutional grant or pending grant from the National Institutes of Health (NIH) for contracts that fund the Multi-Ethnic Study of Atherosclerosis (MESA) study. Dr Burke reports receipt of an institutional grant from the National Heart, Lung, and Blood Institute (NHLBI). Dr O'Leary reports receipt of an institutional grant and support (to the institution) for travel to meetings for the study or other purposes from NIH. Dr Carr reports receiptof an institutional grant from NIH/NHLBI and receipt of consultancy fees from Merck & Co. Dr Goff reports receipt of an institutional grant and support (to the institution) for travel to meetings for the study or other purposes from NHLBI, board membership on the data and safety monitoring committee for a clinical trial from Takeda, and receipt of consultancy (operations committee member for a clinical trial) fees from Merck & Co. Dr Greenland reports receipt of an institutional grant and support (to the institution) for travel to meetings for the study or other purposes) from NHLBI, receipt of a grant or pending grant from NIH, and payment for lectures including service on speakers bureaus from univeristies and NIH, Dr Herrington reports receipt of an institutional grant from NIH. Drs Yeboah, Polonsky, and Sibley report no disclosures. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.; This research was supported by contracts N01-HC-95159. 60, 61, 62, 63, 64, 65, 66, and N01-HC-95167 and Diversity Supplement R01HL098445 (primary investigator, Dr Carr). A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. NR 27 TC 331 Z9 340 U1 4 U2 34 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 22 PY 2012 VL 308 IS 8 BP 788 EP 795 DI 10.1001/jama.2012.9624 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 991ML UT WOS:000307705300022 PM 22910756 ER PT J AU Dent, AE Moormann, AM Yohn, CT Kimmel, RJ Sumba, PO Vulule, J Long, CA Narum, DL Crabb, BS Kazura, JW Tisch, DJ AF Dent, Arlene E. Moormann, Ann M. Yohn, Christopher T. Kimmel, Rhonda J. Sumba, Peter O. Vulule, John Long, Carole A. Narum, David L. Crabb, Brendan S. Kazura, James W. Tisch, Daniel J. TI Broadly reactive antibodies specific for Plasmodium falciparum MSP-1(19) are associated with the protection of naturally exposed children against infection SO MALARIA JOURNAL LA English DT Article DE Plasmodium falciparum; Antibodies; Merozoite surface protein; Malaria infection; Children ID MEROZOITE SURFACE PROTEIN-1; INVASION-INHIBITORY ANTIBODIES; MALARIA VACCINE ANTIGEN; PAPUA-NEW-GUINEA; ARTEMETHER-LUMEFANTRINE; TERMINAL FRAGMENT; GHANAIAN CHILDREN; SERUM ANTIBODIES; HOLOENDEMIC AREA; CLINICAL MALARIA AB Background: The 19 kDa C-terminal region of Plasmodium falciparum Merozoite Surface Protein-1 is a known target of naturally acquired humoral immunity and a malaria vaccine candidate. MSP-1(19) has four predominant haplotypes resulting in amino acid changes labelled EKNG, QKNG, QTSR and ETSR. IgG antibodies directed against all four variants have been detected, but it is not known if these variant specific antibodies are associated with haplotype-specific protection from infection. Methods: Blood samples from 201 healthy Kenyan adults and children who participated in a 12-week treatment time-to-infection study were evaluated. Venous blood drawn at baseline (week 0) was examined for functional and serologic antibodies to MSP-1(19) and MSP-1(42) variants. MSP-1(19) haplotypes were detected by a multiplex PCR assay at baseline and weekly throughout the study. Generalized linear models controlling for age, baseline MSP-1(19) haplotype and parasite density were used to determine the relationship between infecting P. falciparum MSP-1(19) haplotype and variant-specific antibodies. Results: A total of 964 infections resulting in 1,533 MSP-1(19) haplotypes detected were examined. The most common haplotypes were EKNG and QKNG, followed by ETSR and QTSR. Children had higher parasite densities, greater complexity of infection (>1 haplotype), and more frequent changes in haplotypes over time compared to adults. Infecting MSP-1(19) haplotype at baseline (week 0) had no influence on haplotypes detected over the subsequent 11 weeks among children or adults. Children but not adults with MSP-1(19) and some MSP-1(42) variant antibodies detected by serology at baseline had delayed time-to-infection. There was no significant association of variant-specific serology or functional antibodies at baseline with infecting haplotype at baseline or during 11 weeks of follow up among children or adults. Conclusions: Variant transcending IgG antibodies to MSP-1(19) are associated with protection from infection in children, but not adults. These data suggest that inclusion of more than one MSP-1(19) variant may not be required in a malaria blood stage vaccine. C1 [Dent, Arlene E.; Yohn, Christopher T.; Kimmel, Rhonda J.; Kazura, James W.; Tisch, Daniel J.] Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. [Dent, Arlene E.] Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Moormann, Ann M.] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA USA. [Sumba, Peter O.; Vulule, John] Kenya Govt Med Res Ctr, Kisumu, Kenya. [Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Narum, David L.] NIAID, Malaria Vaccine Dev Branch, NIH, Bethesda, MD 20892 USA. [Crabb, Brendan S.] Burnet Inst Med Res, Melbourne, Vic, Australia. [Tisch, Daniel J.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. RP Dent, AE (reprint author), Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. EM arlene.dent@case.edu RI Crabb, Brendan/F-5287-2013 FU NIH [A143906]; Intramural Program of the National Institute of Allergy and Infectious Diseases/NIH; BWF CAMS [1006818]; Fogarty [TW006576] FX We are grateful to the study participants for their contribution. This work was supported by NIH A143906 (JWK). CAL and DLN are supported by the Intramural Program of the National Institute of Allergy and Infectious Diseases/NIH. AED is supported by BWF CAMS 1006818. POS is supported by Fogarty grant TW006576. This work was performed with the permission of the Director of the Kenya Medical Research Institute. NR 45 TC 4 Z9 5 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD AUG 21 PY 2012 VL 11 AR 287 DI 10.1186/1475-2875-11-287 PG 15 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 046GE UT WOS:000311752700001 PM 22909378 ER PT J AU Uccellini, L De Giorgi, V Zhao, YD Tumaini, B Erdenebileg, N Dudley, ME Tomei, S Bedognetti, D Ascierto, ML Liu, QZ Simon, R Kottyan, L Kaufman, KM Harley, JB Wang, E Rosenberg, SA Marincola, FM AF Uccellini, Lorenzo De Giorgi, Valeria Zhao, Yingdong Tumaini, Barbara Erdenebileg, Narnygerel Dudley, Mark E. Tomei, Sara Bedognetti, Davide Ascierto, Maria Libera Liu, Qiuzhen Simon, Richard Kottyan, Leah Kaufman, Kenneth M. Harley, John B. Wang, Ena Rosenberg, Steven A. Marincola, Francesco M. TI IRF5 gene polymorphisms in melanoma SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; INTERFERON REGULATORY FACTOR; METASTATIC MELANOMA; IMMUNOLOGICAL CONSTANT; MULTIPLE-SCLEROSIS; CELL-LINES; RISK; INTERFERON-REGULATORY-FACTOR-5; VARIANTS; THERAPY AB Background: Interferon regulatory factor (IRF)-5 is a transcription factor involved in type I interferon signaling whose germ line variants have been associated with autoimmune pathogenesis. Since relationships have been observed between development of autoimmunity and responsiveness of melanoma to several types of immunotherapy, we tested whether polymorphisms of IRF5 are associated with responsiveness of melanoma to adoptive therapy with tumor infiltrating lymphocytes (TILs). Methods: 140 TILs were genotyped for four single nucleotide polymorphisms (rs10954213, rs11770589, rs6953165, rs2004640) and one insertion-deletion in the IRF5 gene by sequencing. Gene-expression profile of the TILs, 112 parental melanoma metastases (MM) and 9 cell lines derived from some metastases were assessed by Affymetrix Human Gene ST 1.0 array. Results: Lack of A allele in rs10954213 (G > A) was associated with non-response (p < 0.005). Other polymorphisms in strong linkage disequilibrium with rs10954213 demonstrated similar trends. Genes differentially expressed in vitro between cell lines carrying or not the A allele could be applied to the transcriptional profile of 112 melanoma metastases to predict their responsiveness to therapy, suggesting that IRF5 genotype may influence immune responsiveness by affecting the intrinsic biology of melanoma. Conclusions: This study is the first to analyze associations between melanoma immune responsiveness and IRF5 polymorphism. The results support a common genetic basis which may underline the development of autoimmunity and melanoma immune responsiveness. C1 [Uccellini, Lorenzo; De Giorgi, Valeria; Erdenebileg, Narnygerel; Tomei, Sara; Bedognetti, Davide; Ascierto, Maria Libera; Liu, Qiuzhen; Wang, Ena; Rosenberg, Steven A.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Uccellini, Lorenzo; De Giorgi, Valeria; Erdenebileg, Narnygerel; Tomei, Sara; Bedognetti, Davide; Ascierto, Maria Libera; Liu, Qiuzhen; Wang, Ena; Rosenberg, Steven A.] NIH, Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. [Uccellini, Lorenzo] Univ Milan, Inst Infect Dis, L Sacco Hosp, Milan, Italy. [Uccellini, Lorenzo] Univ Milan, Inst Trop Dis, L Sacco Hosp, Milan, Italy. [Zhao, Yingdong] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Tumaini, Barbara] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Bedognetti, Davide; Ascierto, Maria Libera] Univ Genoa, Dept Internal Med DiMI, I-16132 Genoa, Italy. [Dudley, Mark E.; Kottyan, Leah; Kaufman, Kenneth M.; Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol CAGE, Cincinnati, OH 45229 USA. [Kaufman, Kenneth M.; Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH 45229 USA. [Marincola, Francesco M.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Uccellini, L (reprint author), NIH, IDIS, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM uccellinilorenzo@gmail.com; fmarincola@mail.cc.nih.gov RI De Giorgi, Valeria/D-4582-2017; OI Bedognetti, Davide/0000-0002-5857-773X; Kottyan, Leah/0000-0003-3979-2220 FU Conquer Cancer Foundation of the American Society of Clinical Oncology FX DB's fellowship was supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology. NR 33 TC 17 Z9 17 U1 0 U2 4 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 AUG 21 PY 2012 VL 10 AR 170 DI 10.1186/1479-5876-10-170 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 033LJ UT WOS:000310797500001 PM 22909381 ER PT J AU Raji, OY Duffy, SW Agbaje, OF Baker, SG Christiani, DC Cassidy, A Field, JK AF Raji, Olaide Y. Duffy, Stephen W. Agbaje, Olorunshola F. Baker, Stuart G. Christiani, David C. Cassidy, Adrian Field, John K. TI Predictive Accuracy of the Liverpool Lung Project Risk Model for Stratifying Patients for Computed Tomography Screening for Lung Cancer A Case-Control and Cohort Validation Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID DECISION CURVE ANALYSIS; BREAST-CANCER; PROGNOSTIC MODELS; CLINICAL-PRACTICE; INDIVIDUAL RISK; IMPACT; MULTICENTER; PREVENTION; WORKSHOP; DISEASE AB Background: External validation of existing lung cancer risk prediction models is limited. Using such models in clinical practice to guide the referral of patients for computed tomography (CT) screening for lung cancer depends on external validation and evidence of predicted clinical benefit. Objective: To evaluate the discrimination of the Liverpool Lung Project (LLP) risk model and demonstrate its predicted benefit for stratifying patients for CT screening by using data from 3 independent studies from Europe and North America. Design: Case-control and prospective cohort study. Setting: Europe and North America. Patients: Participants in the European Early Lung Cancer (EUELC) and Harvard case-control studies and the LLP population-based prospective cohort (LLPC) study. Measurements: 5-year absolute risks for lung cancer predicted by the LLP model. Results: The LLP risk model had good discrimination in both the Harvard (area under the receiver-operating characteristic curve [AUC], 0.76 [95% CI, 0.75 to 0.78]) and the LLPC (AUC, 0.82 [CI, 0.80 to 0.85]) studies and modest discrimination in the EUELC (AUC, 0.67 [CI, 0.64 to 0.69]) study. The decision utility analysis, which incorporates the harms and benefit of using a risk model to make clinical decisions, indicates that the LLP risk model performed better than smoking duration or family history alone in stratifying high-risk patients for lung cancer CT screening. Limitations: The model cannot assess whether including other risk factors, such as lung function or genetic markers, would improve accuracy. Lack of information on asbestos exposure in the LLPC limited the ability to validate the complete LLP risk model. Conclusion: Validation of the LLP risk model in 3 independent external data sets demonstrated good discrimination and evidence of predicted benefits for stratifying patients for lung cancer CT screening. Further studies are needed to prospectively evaluate model performance and evaluate the optimal population risk thresholds for initiating lung cancer screening. C1 [Field, John K.] Univ Liverpool, Inst Translat Med, Roy Castle Lung Canc Res Programme, Canc Res Ctr, Liverpool L3 9TA, Merseyside, England. Queen Mary Univ London, Wolfson Inst Prevent Med, Barts & London Sch Med & Dent, Kings Coll London, London, England. Guys Hosp, London SE1 9RT, England. NCI, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Field, JK (reprint author), Univ Liverpool, Inst Translat Med, Roy Castle Lung Canc Res Programme, Canc Res Ctr, Liverpool L3 9TA, Merseyside, England. EM J.K.Field@liv.ac.uk OI Field, John/0000-0003-3951-6365 FU Roy Castle Lung Cancer Foundation; National Institute for Health; American Cancer Society; National Cancer Institute, National Institutes of Health [CA74386, CA092824, CA090578] FX By the Roy Castle Lung Cancer Foundation, the National Institute for Health Research Health Technology Assessment program, and the American Cancer Society, as well as grants CA74386, CA092824, and CA090578 from the National Cancer Institute, National Institutes of Health (Dr. Christiani). NR 43 TC 63 Z9 65 U1 1 U2 11 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 AUG 21 PY 2012 VL 157 IS 4 BP 242 EP + DI 10.7326/0003-4819-157-4-201208210-00004 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 992XG UT WOS:000307813200015 PM 22910935 ER PT J AU Smyth, JT Beg, AM Wu, SL Putney, JW Rusan, NM AF Smyth, Jeremy T. Beg, Amber M. Wu, Shilan Putney, James W., Jr. Rusan, Nasser M. TI Phosphoregulation of STIM1 Leads to Exclusion of the Endoplasmic Reticulum from the Mitotic Spindle SO CURRENT BIOLOGY LA English DT Article ID OPERATED CALCIUM-ENTRY; END-TRACKING PROTEINS; MAMMALIAN-CELLS; PHOSPHORYLATION; GOLGI; DYNAMICS; BINDING; ER; APPARATUS; MEMBRANE AB The endoplasmic reticulum (ER) undergoes significant reorganization between interphase and mitosis, but the underlying mechanisms are unknown [1]. Stromal interaction molecule 1 (STIM1) is an ER Ca2+ sensor that activates store-operated Ca2+ entry (SOCE) [2, 3] and also functions in ER morphogenesis through its interaction with the microtubule +TIP protein end binding 1 (EB1) [4]. We previously demonstrated that phosphorylation of STIM1 during mitosis suppresses SOCE [5]. We now show that STIM1 phosphorylation is a major regulatory mechanism that excludes ER from the mitotic spindle. In mitotic He La cells, the ER forms concentric sheets largely excluded from the mitotic spindle. We show that STIM1 dissociates from EB1 in mitosis and localizes to the concentric ER sheets. However, a nonphosphorylatable STIM1 mutant (STIM1(10A)) colocalized extensively with EB1 and drove ER mislocalization by pulling ER tubules into the spindle. This effect was rescued by mutating the EB1 interaction site of STIM1(10A), demonstrating that aberrant association of STIM1(10A) with EB1 is responsible for the ER mislocalization. A STIM1 phosphomimetic exhibited significantly impaired +TIP tracking in interphase but was ineffective at inhibiting SOCE, suggesting different mechanisms of regulation of these two STIM1 functions by phosphorylation. Thus, ER spindle exclusion and ER-dependent Ca2+ signaling during mitosis require multi-modal STIM1 regulation by phosphorylation. C1 [Wu, Shilan; Putney, James W., Jr.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Smyth, Jeremy T.; Beg, Amber M.; Rusan, Nasser M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov; nasser@nih.gov RI Rusan, Nasser/P-3511-2016 FU NIH, National Heart, Lung and Blood Institute; National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Heart, Lung and Blood Institute, and National Institute of Environmental Health Sciences. We acknowledge Christian Combs in the NHLBI Light Microscopy Core Facility, Jeff Tucker and Agnes Janoshazi in the NIEHS Confocal Core Facility, and Leigh Samsel and Pradeep Dagur in the NHLBI Flow Cytometry Core Facility for assistance with experiments. We also thank Brian Galletta, Dorothy Lent, Stephen Shears, and Carmen Williams for helpful comments on the manuscript. NR 25 TC 36 Z9 37 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 21 PY 2012 VL 22 IS 16 BP 1487 EP 1493 DI 10.1016/j.cub.2012.05.057 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 992QO UT WOS:000307795000021 PM 22748319 ER PT J AU Haspel, G Schwartz, A Streets, A Camacho, DE Soares, D AF Haspel, Gal Schwartz, Adina Streets, Amy Escobar Camacho, Daniel Soares, Daphne TI By the teeth of their skin, cavefish find their way SO CURRENT BIOLOGY LA English DT Letter ID LATERAL-LINE; ASTYANAX-FASCIATUS; FISH C1 [Haspel, Gal] NINDS, Neural Control Lab, Sect Dev Neurobiol, NIH, Bethesda, MD 20892 USA. [Schwartz, Adina; Streets, Amy; Soares, Daphne] Univ Maryland, Coll Comp Math & Nat Sci, Dept Biol, College Pk, MD 20742 USA. [Escobar Camacho, Daniel] Pontificia Univ Catolica Ecuador, Fac Ciencias Exactas & Nat, EC-170109 Quito, Pichincha, Ecuador. RP Haspel, G (reprint author), NINDS, Neural Control Lab, Sect Dev Neurobiol, NIH, Bethesda, MD 20892 USA. EM daph@umd.edu OI Haspel, Gal/0000-0001-6701-697X FU Intramural NIH HHS [Z99 NS999999] NR 10 TC 4 Z9 4 U1 0 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 21 PY 2012 VL 22 IS 16 BP R629 EP R630 DI 10.1016/j.cub.2012.06.035 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 992QO UT WOS:000307795000006 PM 22917507 ER PT J AU Hassan, SA AF Hassan, Sergio A. TI Self-consistent treatment of the local dielectric permittivity and electrostatic potential in solution for polarizable macromolecular force fields SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID POISSON-BOLTZMANN EQUATION; FINITE-ELEMENT SOLUTION; LIQUID-STRUCTURE FORCES; PROTEIN HYDRATION; POLAR LIQUIDS; AMINO-ACID; WATER; SOLVATION; MODEL; DENSITY AB A self-consistent method is presented for the calculation of the local dielectric permittivity and electrostatic potential generated by a solute of arbitrary shape and charge distribution in a polar and polarizable liquid. The structure and dynamics behavior of the liquid at the solute/liquid interface determine the spatial variations of the density and the dielectric response. Emphasis here is on the treatment of the interface. The method is an extension of conventional methods used in continuum protein electrostatics, and can be used to estimate changes in the static dielectric response of the liquid as it adapts to charge redistribution within the solute. This is most relevant in the context of polarizable force fields, during electron structure optimization in quantum chemical calculations, or upon charge transfer. The method is computationally efficient and well suited for code parallelization, and can be used for on-the-fly calculations of the local permittivity in dynamics simulations of systems with large and heterogeneous charge distributions, such as proteins, nucleic acids, and polyelectrolytes. Numerical calculation of the system free energy is discussed for the general case of a liquid with field-dependent dielectric response. [http://dx.doi.org/10.1063/1.4742910] C1 NIH, Ctr Mol Modeling, DCB CIT, US DHHS, Bethesda, MD 20892 USA. RP Hassan, SA (reprint author), NIH, Ctr Mol Modeling, DCB CIT, US DHHS, Bethesda, MD 20892 USA. EM hassan@mail.nih.gov FU National of Institutes of Health (NIH), Center for Information Technology FX This study was supported by the Intramural Research Program of the National of Institutes of Health (NIH), Center for Information Technology, and utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD, USA. NR 66 TC 4 Z9 4 U1 1 U2 16 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD AUG 21 PY 2012 VL 137 IS 7 AR 074102 DI 10.1063/1.4742910 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 999AE UT WOS:000308280700002 PM 22920098 ER PT J AU Wishart, GC Bajdik, CD Dicks, E Provenzano, E Schmidt, MK Sherman, M Greenberg, DC Green, AR Gelmon, KA Kosma, VM Olson, JE Beckmann, MW Winqvist, R Cross, SS Severi, G Huntsman, D Pylkas, K Ellis, I Nielsen, TO Giles, G Blomqvist, C Fasching, PA Couch, FJ Rakha, E Foulkes, WD Blows, FM Begin, LR van't Veer, LJ Southey, M Nevanlinna, H Mannermaa, A Cox, A Cheang, M Baglietto, L Caldas, C Garcia-Closas, M Pharoah, PDP AF Wishart, G. C. Bajdik, C. D. Dicks, E. Provenzano, E. Schmidt, M. K. Sherman, M. Greenberg, D. C. Green, A. R. Gelmon, K. A. Kosma, V-M Olson, J. E. Beckmann, M. W. Winqvist, R. Cross, S. S. Severi, G. Huntsman, D. Pylkas, K. Ellis, I. Nielsen, T. O. Giles, G. Blomqvist, C. Fasching, P. A. Couch, F. J. Rakha, E. Foulkes, W. D. Blows, F. M. Begin, L. R. van't Veer, L. J. Southey, M. Nevanlinna, H. Mannermaa, A. Cox, A. Cheang, M. Baglietto, L. Caldas, C. Garcia-Closas, M. Pharoah, P. D. P. TI PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2 SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; HER2; prognostic model; HER2 ID POPULATION-BASED VALIDATION; ADJUVANT CHEMOTHERAPY; TUMOR CHARACTERISTICS; PREMENOPAUSAL WOMEN; RANDOMIZED-TRIALS; FOLLOW-UP; SURVIVAL; INDEX; RISK; TRASTUZUMAB AB BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict +), and to compare its performance with the original Predict and Adjuvantl. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict I, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvantl. In the subset of patients with HER2-positive tumours, Predict + performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict + is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients. British Journal of Cancer (2012) 107, 800-807. doi:10.1038/bjc.2012.338 www.bjcancer.com Published online 31 July 2012 (C) 2012 Cancer Research UK C1 [Dicks, E.; Provenzano, E.; Blows, F. M.; Caldas, C.; Pharoah, P. D. P.] Univ Cambridge, Dept Oncol, Strangeways Res Lab, Cambridge CB1 8RN, England. [Wishart, G. C.] Addenbrookes Hosp, Cambridge Breast Unit, Cambridge, England. [Bajdik, C. D.] British Columbia Canc Agcy, Canc Control Res Program, Vancouver, BC V5Z 4E6, Canada. [Schmidt, M. K.; van't Veer, L. J.] Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands. [Schmidt, M. K.; van't Veer, L. J.] Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands. [Sherman, M.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Greenberg, D. C.] Eastern Canc Registrat & Informat Ctr, Cambridge, England. [Green, A. R.] Univ Nottingham, Sch Mol Med Sci, Dept Pathol, Nottingham NG7 2RD, England. [Gelmon, K. A.] Univ British Columbia, British Columbia Canc Agcy, Dept Med Oncol, Vancouver, BC V5Z 1M9, Canada. [Kosma, V-M; Mannermaa, A.] Univ Eastern Finland, Sch Med, Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Kosma, V-M; Mannermaa, A.] Kuopio Univ Hosp, Dept Pathol, SF-70210 Kuopio, Finland. [Olson, J. E.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Beckmann, M. W.; Fasching, P. A.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Univ Breast Ctr Franconia, Dept Gynecol & Obstet, Erlangen, Germany. [Winqvist, R.] Univ Oulu, Dept Clin Genet, Canc Genet Lab, Oulu, Finland. [Winqvist, R.] Univ Oulu, Bioctr, Oulu, Finland. [Winqvist, R.] Oulu Univ Hosp, Oulu, Finland. [Cross, S. S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Severi, G.; Giles, G.; Southey, M.; Baglietto, L.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Huntsman, D.; Nielsen, T. O.; Cheang, M.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Pylkas, K.; Blomqvist, C.] Univ Helsinki, Dept Oncol, Helsinki, Finland. [Pylkas, K.; Blomqvist, C.; Nevanlinna, H.] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Ellis, I.; Rakha, E.] Nottingham Univ Hosp NHS Trust, Sch Mol Med Sci, Dept Histopathol, Nottingham, England. [Ellis, I.; Rakha, E.] Univ Nottingham, Nottingham NG7 2RD, England. [Couch, F. J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Foulkes, W. D.] McGill Univ, Dept Oncol, Program Canc Genet, Montreal, PQ, Canada. [Foulkes, W. D.] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada. [Begin, L. R.] McGill Univ, Dept Pathol, Montreal, PQ, Canada. [Begin, L. R.] Hop Sacre, Montreal, PQ, Canada. [Nevanlinna, H.] Univ Helsinki, Dept Obstet & Gynaecol, Helsinki, Finland. [Cox, A.] Univ Sheffield, Inst Canc Studies, Dept Oncol, Sheffield, S Yorkshire, England. [Garcia-Closas, M.] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Garcia-Closas, M.] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Sutton, Surrey, England. RP Pharoah, PDP (reprint author), Univ Cambridge, Dept Oncol, Strangeways Res Lab, Worts Causeway, Cambridge CB1 8RN, England. EM paul.pharoah@srl.cam.ac.uk RI Caldas, Carlos/A-7543-2008; Garcia-Closas, Montserrat /F-3871-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Cross, Simon/0000-0003-2044-1754; Nevanlinna, Heli/0000-0002-0916-2976; foulkes, william/0000-0001-7427-4651; Cox, Angela/0000-0002-5138-1099; Giles, Graham/0000-0003-4946-9099 FU Breast Cancer Campaign, Cancer Research UK [C490/A10119, C490/A10124]; US National Institutes of Health [CA122340, CA122340Z, CA116201]; special Government Funding (EVO) of Kuopio University Hospital; Cancer Fund of North Savo; Finnish Cancer Organisation; Academy of Finland [132473]; University of Eastern Finland; Helsinki University Central Hospital Research Fund; Finnish Cancer Society; Sigrid Juselius Foundation; Susan G Komen for the Cure, Yorkshire Cancer Research; Cambridge NIHR Biomedical Research Centre; Cambridge Experimental Cancer Medicine Centre; Michael Smith Foundation For Health Research; Dutch Cancer Society [NKI DCS 2009-4363] FX We thank all the patients who took part in the component BCAC studies and the many other individuals who have made these studies possible. In particular, we thank Hans Peterse, Rob Tollenaar, Vincent Smit, Renate de Groot, Renate Udo, Flora van Leeuwen (ABCS); Claudia Rauh, Julia Wessel (BBCC); the BC Cancer Registry and Breast Cancer Outcomes Unit (BCCA); Paivi Heikkila, Kirsimari Aaltonen, Kristiina Aittomaki,Ari Ristimaki, Laura Hautala, Mira Heinonen, RN Hanna Jantti, Irja Erkkila, and the Finnish Cancer Registry (HEBCS); Lars A Akslen (JGH); Vicky Cafourek, Matthew Kosel and Zachary Fredericksen (MCBCS); John Hopper, Dallas English and Helen Kelsall (MCCS), (NOBCS); Arja Jukkola-Vuorinen, Taina Turpeenniemi-Hujanen, Mervi Grip, Saila Kauppila, Kari Mononen and Meeri Otsukka (OBCS); Louise Brinton, Jonine Figueroa, Kelly Bolton, Neonila, Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, and Michael Stagner (PBCS); Sabapathy, Balasubramanian, Malcolm WR Reed, Helen Cramp, and Dan Connley (SBCS); Sarah-Jane Dawson and the SEARCH team (SEARCH). The contributing studies are funded by grants from Breast Cancer Campaign (2004Nov49), Cancer Research UK (C490/A10119, C490/A10124); US National Institutes of Health (CA122340, CA122340Z, CA116201); special Government Funding (EVO) of Kuopio University Hospital; the Cancer Fund of North Savo; the Finnish Cancer Organisation; the Academy of Finland (132473); strategic funding of the University of Eastern Finland; the Helsinki University Central Hospital Research Fund; the Finnish Cancer Society; the Sigrid Juselius Foundation; Susan G Komen for the Cure, Yorkshire Cancer Research. GCW and CC received research funding from the Cambridge NIHR Biomedical Research Centre and the Cambridge Experimental Cancer Medicine Centre. CDB, TN and DH are partly supported through Career Awards from the Michael Smith Foundation For Health Research. MKS is funded by the Dutch Cancer Society (NKI DCS 2009-4363). NR 42 TC 32 Z9 32 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG 21 PY 2012 VL 107 IS 5 BP 800 EP 807 DI 10.1038/bjc.2012.338 PG 8 WC Oncology SC Oncology GA 992JG UT WOS:000307771100007 PM 22850554 ER PT J AU Nasrollahzadeh, D Malekzadeh, R Aghcheli, K Sotoudeh, M Merat, S Islami, F Kamangar, F Abnet, CC Shakeri, R Pourshams, A Semnani, S Boffetta, P Dawsey, SM Ye, W AF Nasrollahzadeh, D. Malekzadeh, R. Aghcheli, K. Sotoudeh, M. Merat, S. Islami, F. Kamangar, F. Abnet, C. C. Shakeri, R. Pourshams, A. Semnani, S. Boffetta, P. Dawsey, S. M. Ye, W. TI Gastric atrophy and oesophageal squamous cell carcinoma: possible interaction with dental health and oral hygiene habit SO BRITISH JOURNAL OF CANCER LA English DT Article DE atrophic gastritis; oesophageal neoplasm; relative risk; dental health; oral hygiene; pepsinogen ID HELICOBACTER-PYLORI INFECTION; HIGH-RISK AREA; SERUM PEPSINOGENS; GOLESTAN COHORT; TOOTH LOSS; CANCER; IRAN; STOMACH; TOBACCO AB BACKGROUND: Gastric fundal atrophy has been hypothesised to increase the risk of oesophageal squamous cell carcinoma (OSCC), but studies have shown inconsistent results. METHODS: We measured serum pepsinogen I (PGI) and pepsinogen II (PGII) among 293 incident cases and 524 matched neighbourhood controls in a high-risk area of Northern Iran. Conditional logistic regression model was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: After controlling for age, sex, residence area and other potential confounders, gastric atrophy (defined by a validated criterion, PGI <55 mu g dl(-1)) was associated with a two-fold increased risk (OR = 2.01, 95% CI: 1.18, 3.45) of OSCC in the absence of nonatrophic pangastritis (defined as PGII < 11.8 mu g dl(-1)). Stratification by PGII decreased the misclassification errors due to cancer-induced gastritis. Presence of both poor dental health, indicated by higher than median sum of decayed, missing, and filled teeth (DMFT score), and gastric atrophy further increased the risk of OSCC (OR = 4.15, 95% CI: 2.04, 8.42) with relative excess risk due to interaction (RERI) of 1.47 (95% CI: - 1.15, 4.1). Coexistence of poor oral hygiene habit with gastric atrophy elevated OSCC risk eight times (OR = 8.65, 95% CI: 3.65, 20.46) and the additive interaction index was marginally statistically significant (RERI = 4.34, 95% CI: - 1.07, 9.76). CONCLUSION: Gastric atrophy is a risk factor for OSCC, and poor dental health and oral hygiene habit may act synergistically in increasing the risk. British Journal of Cancer (2012) 107, 888-894. doi: 10.1038/bjc.2012.332 www.bjcancer.com Published online 19 July 2012 (C) 2012 Cancer Research UK C1 [Nasrollahzadeh, D.; Malekzadeh, R.; Aghcheli, K.; Sotoudeh, M.; Merat, S.; Islami, F.; Kamangar, F.; Shakeri, R.; Pourshams, A.] Univ Tehran Med Sci, Digest Dis Res Ctr, Tehran 14117, Iran. [Nasrollahzadeh, D.; Ye, W.] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Islami, F.; Boffetta, P.] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY 10029 USA. [Islami, F.; Boffetta, P.] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Kamangar, F.] Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Baltimore, MD 21251 USA. [Abnet, C. C.; Dawsey, S. M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Semnani, S.] Gorgan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan 491751141, Iran. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Digest Dis Res Ctr, N Karegar Ave, Tehran 14117, Iran. EM malek@ams.ac.ir; weimin.ye@ki.se RI Abnet, Christian/C-4111-2015; Semnani, Shahryar/N-2270-2016; OI Abnet, Christian/0000-0002-3008-7843; Semnani, Shahryar/0000-0002-8768-6142; , Ramin/0000-0003-0487-3629; Malekzadeh, Reza/0000-0003-1043-3814 FU Digestive Disease Research Centre of Tehran University of Medical Sciences [82-603]; Swedish Research Council [VR-60535801]; National Cancer Institute at the National Institutes of Health; Martin Rinds Foundation (Sweden); KID grant, Karolinska Institutet faculty funds for postgraduate students FX We thank the local health network workers (Behvarz) for their contribution to this study. This work was supported by Digestive Disease Research Centre of Tehran University of Medical Sciences (Grant 82-603), Swedish Research Council (VR-60535801), intramural funds of the National Cancer Institute at the National Institutes of Health, Martin Rinds Foundation (Sweden), and KID grant, Karolinska Institutet faculty funds for postgraduate students (December 2008). NR 31 TC 8 Z9 9 U1 1 U2 6 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 AUG 21 PY 2012 VL 107 IS 5 BP 888 EP 894 DI 10.1038/bjc.2012.332 PG 7 WC Oncology SC Oncology GA 992JG UT WOS:000307771100018 PM 22814581 ER PT J AU Koulaouzidis, A Karargyris, A AF Koulaouzidis, Anastasios Karargyris, Alexandros TI Three-dimensional image reconstruction in capsule endoscopy SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Capsule endoscopy; Three-dimensional; Reconstruction; Angioectasias; Software ID SHAPE AB To date, limited research has been carried out in developing methods and materials that offer three-dimensional (3-D) representation of the digestive tract. In the field of capsule endoscopy (CE), hardware approaches have been developed that provide real time both 3-D information and texture using an infrared projector and a complementary metal oxide semiconductor camera. The major drawbacks of this system are its size, power consumption and packaging issues. A software approach to approximate a 3-D representation of digestive tract surface utilising current CE technology has been proposed. The algorithm utilizes the Shape from Shading technique and seem to provide promising results for polypoid structures and angioectasias. Further clinical evaluation is currently under way. (C) 2012 Baishideng. All rights reserved. C1 [Koulaouzidis, Anastasios] Royal Infirm Edinburgh NHS Trust, Ctr Liver & Digest Disorders, Edinburgh EH16 4SA, Midlothian, Scotland. [Karargyris, Alexandros] NIH, Natl Lib Med, Bethesda, MD 20814 USA. RP Koulaouzidis, A (reprint author), Royal Infirm Edinburgh NHS Trust, Ctr Liver & Digest Disorders, 51 Little France Crescent, Edinburgh EH16 4SA, Midlothian, Scotland. EM akoulaouzidis@hotmail.com NR 17 TC 9 Z9 10 U1 1 U2 11 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD AUG 21 PY 2012 VL 18 IS 31 BP 4086 EP 4090 DI 10.3748/wjg.v18.i31.4086 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 995CZ UT WOS:000307986800003 PM 22919239 ER PT J AU Spehalski, E Kovalchuk, AL Collins, JT Liang, GQ Dubois, W Morse, HC Ferguson, DO Casellas, R Dunnick, WA AF Spehalski, Elizabeth Kovalchuk, Alexander L. Collins, John T. Liang, Genqing Dubois, Wendy Morse, Herbert. C., III Ferguson, David O. Casellas, Rafael Dunnick, Wesley A. TI Oncogenic Myc translocations are independent of chromosomal location and orientation of the immunoglobulin heavy chain locus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID INDUCED CYTIDINE DEAMINASE; CLASS-SWITCH RECOMBINATION; PLASMA-CELL TUMORS; C-MYC; B-CELL; GENOMIC INSTABILITY; SEQUENCING REVEALS; TRANSGENIC MICE; LYMPHOMA-CELLS; CONTROL REGION AB Many tumors are characterized by recurrent translocations between a tissue-specific gene and a proto-oncogene. The juxtaposition of the Ig heavy chain gene and Myc in Burkitt's lymphoma and in murine plasmacytoma is a classic example. Regulatory elements within the heavy chain constant region locus are required for Myc translocation and/or deregulation. However, many genes are regulated by cis-acting elements at distances up to 1,000 kb outside the locus. Such putative distal elements have not been examined for the heavy chain locus, particularly in the context of Myc translocations. We demonstrate that a transgene containing the Ig heavy chain constant region locus, inserted into five different chromosomal locations, can undergo translocations involving Myc. Furthermore, these translocations are able to generate plasmacytomas in each transgenic line. We conclude that the heavy chain constant region locus itself includes all of the elements necessary for both the translocation and the deregulation of the proto-oncogene. C1 [Collins, John T.; Dunnick, Wesley A.] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Spehalski, Elizabeth; Ferguson, David O.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. [Kovalchuk, Alexander L.; Dubois, Wendy; Morse, Herbert. C., III] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Liang, Genqing; Casellas, Rafael] NIAMSD, Immunogenet Mol Lab, Bethesda, MD 20892 USA. [Liang, Genqing; Casellas, Rafael] NIH, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dunnick, WA (reprint author), Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. EM wesadunn@umich.edu OI Morse, Herbert/0000-0002-9331-3705 FU National Institutes of Health (NIH) [AI068749, AI076057, HL079118, T32-AI007413]; Intramural Research Program of the NIH; National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases FX We thank Drs. Michael Potter, Seigfried Janz, and Konrad Huppi for advice; Jian Shi for technical assistance; and Dr. Gary Huffnagel for the use of his labotatory's cytospin centrifuge and reagents. This work was supported by National Institutes of Health (NIH) Grants AI068749 and AI076057 (to W.D.), HL079118 (to D.O.F.), and T32-AI007413 (to E.S.) and, in part, by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases, National Cancer Institute, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. NR 41 TC 5 Z9 5 U1 0 U2 0 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 AUG 21 PY 2012 VL 109 IS 34 BP 13728 EP 13732 DI 10.1073/pnas.1202882109 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 996KJ UT WOS:000308085200058 PM 22869734 ER PT J AU Liu, SH Bachran, C Gupta, P Miller-Randolph, S Wang, HL Crown, D Zhang, Y Wein, AN Singh, R Fattah, R Leppla, SH AF Liu, Shihui Bachran, Christopher Gupta, Pradeep Miller-Randolph, Sharmina Wang, Hailun Crown, Devorah Zhang, Yi Wein, Alexander N. Singh, Rajat Fattah, Rasem Leppla, Stephen H. TI Diphthamide modification on eukaryotic elongation factor 2 is needed to assure fidelity of mRNA translation and mouse development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CAPILLARY MORPHOGENESIS PROTEIN-2; ADP-RIBOSYLATING TOXINS; PSEUDOMONAS EXOTOXIN-A; DIPHTHERIA-TOXIN; SACCHAROMYCES-CEREVISIAE; ANTHRAX TOXIN; FACTOR-II; RESISTANT MUTANTS; BIOSYNTHESIS; CELLS AB To study the role of the diphthamide modification on eukaryotic elongation factor 2 (eEF2), we generated an eEF2 Gly(717)Arg mutant mouse, in which the first step of diphthamide biosynthesis is prevented. Interestingly, the Gly(717)-to-Arg mutation partially compensates the eEF2 functional loss resulting from diphthamide deficiency, possibly because the added + 1 charge compensates for the loss of the + 1 charge on diphthamide. Therefore, in contrast to mouse embryonic fibroblasts (MEFs) from OVCA1(-/-) mice, eEF2(G717R/G717R) MEFs retain full activity in polypeptide elongation and have normal growth rates. Furthermore, eEF2(G717R/G717R) mice showed milder phenotypes than OVCA1(-/-) mice (which are 100% embryonic lethal) and a small fraction survived to adulthood without obvious abnormalities. Moreover, eEF2(G717R/G717R/OVCA1-/-) double mutant mice displayed the milder phenotypes of the eEF2(G717R/G717R) mice, suggesting that the embryonic lethality of OVCA1(-/-) mice is due to diphthamide deficiency. We confirmed that the diphthamide modification is essential for eEF2 to prevent -1 frameshifting during translation and show that the Gly(717)-to-Arg mutation cannot rescue this defect. C1 [Liu, Shihui; Bachran, Christopher; Gupta, Pradeep; Miller-Randolph, Sharmina; Wang, Hailun; Crown, Devorah; Zhang, Yi; Wein, Alexander N.; Singh, Rajat; Fattah, Rasem; Leppla, Stephen H.] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Liu, SH (reprint author), NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM shliu@niaid.nih.gov; sleppla@niaid.nih.gov OI Singh, Rajat/0000-0002-9542-1929 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Dr. Richard R. Behringer for providing OVCA1-targeted mice, Drs. Dominic Dulude and Lea Brakier-Gingras for providing pDual-HIV(-1) plasmid, and Dr. Mahtab Moayeri for helpful discussion. This research was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 30 TC 22 Z9 22 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 21 PY 2012 VL 109 IS 34 BP 13817 EP 13822 DI 10.1073/pnas.1206933109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 996KJ UT WOS:000308085200073 PM 22869748 ER PT J AU Giedd, JN Raznahan, A Mills, KL Lenroot, RK AF Giedd, Jay N. Raznahan, Armin Mills, Kathryn L. Lenroot, Rhoshel K. TI Review: magnetic resonance imaging of male/female differences in human adolescent brain anatomy SO BIOLOGY OF SEX DIFFERENCES LA English DT Article ID HUMAN CORPUS-CALLOSUM; ADULT HUMAN BRAIN; WHITE-MATTER ARCHITECTURE; NORMAL SEXUAL-DIMORPHISM; CORTICAL THICKNESS; CEREBRAL-CORTEX; GRAY-MATTER; GENDER DIFFERENCES; MOUSE-BRAIN; AGE AB Improvements in neuroimaging technologies, and greater access to their use, have generated a plethora of data regarding male/female differences in the developing brain. Examination of these differences may shed light on the pathophysiology of the many illnesses that differ between the sexes and ultimately lead to more effective interventions. In this review, we attempt to synthesize the anatomic magnetic resonance imaging (MRI) literature of male/female brain differences with emphasis on studies encompassing adolescence - a time of divergence in physical and behavioral characteristics. Across all ages total brain size is consistently reported to be about 10% larger in males. Structures commonly reported to be different between sexes include the caudate nucleus, amygdala, hippocampus, and cerebellum - all noted to have a relatively high density of sex steroid receptors. The direction and magnitude of reported brain differences depends on the methodology of data acquisition and analysis, whether and how the subcomponents are adjusted for the total brain volume difference, and the age of the participants in the studies. Longitudinal studies indicate regional cortical gray matter volumes follow inverted U shaped developmental trajectories with peak size occurring one to three years earlier in females. Cortical gray matter differences are modulated by androgen receptor genotyope and by circulating levels of hormones. White matter volumes increase throughout childhood and adolescence in both sexes but more rapidly in adolescent males resulting in an expanding magnitude of sex differences from childhood to adulthood. C1 [Giedd, Jay N.; Raznahan, Armin; Mills, Kathryn L.] NIMH, Child Psychiat Branch, Brain Imaging Unit, NIH, Bethesda, MD 20892 USA. RP Giedd, JN (reprint author), NIMH, Child Psychiat Branch, Brain Imaging Unit, NIH, 10 Ctr Dr,MSC 1367,Bldg 10,Room 4 C110, Bethesda, MD 20892 USA. EM jg@nih.gov RI Raznahan, Armin/F-4534-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-2002-8978 NR 104 TC 69 Z9 72 U1 4 U2 28 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2042-6410 J9 BIOL SEX DIFFER JI Biol. Sex Differ. PD AUG 21 PY 2012 VL 3 AR 19 DI 10.1186/2042-6410-3-19 PG 9 WC Endocrinology & Metabolism; Genetics & Heredity SC Endocrinology & Metabolism; Genetics & Heredity GA 110CV UT WOS:000316420600001 PM 22908911 ER PT J AU Tsourkas, PK Das, SC Yu-Yang, P Liu, WL Pierce, SK Raychaudhuri, S AF Tsourkas, Philippos K. Das, Somkanya C. Yu-Yang, Paul Liu, Wanli Pierce, Susan K. Raychaudhuri, Subhadip TI Formation of BCR oligomers provides a mechanism for B cell affinity discrimination SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Antigen; B cell receptor; Lymphocyte signaling; Lyn; Monte Carlo ID RESPONSES IN-VIVO; SYNAPSE FORMATION; ANTIGEN RECEPTOR; LYMPH-NODE; SUBCAPSULAR SINUS; DENDRITIC CELLS; T-CELLS; ACTIVATION; INITIATION; THRESHOLD AB B cells encounter antigen over a wide affinity range, from K-A=10(5) M-1 to K-A=10(10) M-1. The strength of B cell antigen receptor (BCR) signaling in response to antigen increases with affinity, a process known as "affinity discrimination". In this work, we use a computational simulation of B cell surface dynamics and membrane-proximal signaling to show that affinity discrimination can arise from the formation of BCR oligomers. It is known that BCRs form oligomers upon encountering antigen, and that the size and rate of formation of these oligomers both increase with affinity. In our simulation, we have introduced a requirement that only BCR-antigen complexes that are part of an oligomer can engage cytoplasmic signaling molecules such as Src-family kinases. Our simulation shows that as affinity increases, BCR signaling activity increases in addition to the number of collected antigen. Our results are also consistent with the existence of an experimentally-observed threshold affinity of activation at K-A=10(5)-10(6) M-1 (no signaling activity below this affinity value) and affinity discrimination ceiling of K-A=10(10) M-1 (no affinity discrimination above this affinity value). Comparison with experiments shows that the time scale of BCR oligomer formation predicted by our model (less than 10 s) is well within the time scale of experimentally observed association of BCR with Src-family kinases (10-20 s). (C) 2012 Elsevier Ltd. All rights reserved. C1 [Tsourkas, Philippos K.; Das, Somkanya C.; Yu-Yang, Paul; Raychaudhuri, Subhadip] Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA. [Liu, Wanli; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Raychaudhuri, S (reprint author), Univ Calif Davis, Dept Biomed Engn, 1 Shields Ave, Davis, CA 95616 USA. EM raychaudhuri@ucdavis.edu RI liu, wanli/H-5690-2011; Tsourkas, Philippos/G-4026-2014; OI liu, wanli/0000-0003-2624-6802; Raychaudhuri, Subhadip/0000-0002-9873-6475 FU NIAID NIH HHS [R01 AI074022] NR 39 TC 3 Z9 3 U1 1 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD AUG 21 PY 2012 VL 307 BP 174 EP 182 DI 10.1016/j.jtbi.2012.05.008 PG 9 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 974PD UT WOS:000306447700018 PM 22613800 ER PT J AU Chen, Y Wang, Y Zhang, JZ Deng, YQ Jiang, L Song, E Wu, XFS Hammer, JA Xu, T Lippincott-Schwartz, J AF Chen, Yu Wang, Yan Zhang, Jinzhong Deng, Yongqiang Jiang, Li Song, Eli Wu, Xufeng S. Hammer, John A. Xu, Tao Lippincott-Schwartz, Jennifer TI Rab10 and myosin-Va mediate insulin-stimulated GLUT4 storage vesicle translocation in adipocytes SO JOURNAL OF CELL BIOLOGY LA English DT Article ID GTPASE-ACTIVATING-PROTEIN; GLUCOSE-TRANSPORTER GLUT4; REGULATED TRANSPORT; 3T3-L1 ADIPOCYTES; MEMBRANE; TRAFFICKING; AS160; GLUCOSE-TRANSPORTER-4; EXOCYTOSIS; REQUIRES AB Rab proteins are important regulators of insulin-stimulated GLUT4 translocation to the plasma membrane (PM), but the precise steps in GLUT4 trafficking modulated by particular Rab proteins remain unclear. Here, we systematically investigate the involvement of Rab proteins in GLUT4 trafficking, focusing on Rab proteins directly mediating GLUT4 storage vesicle (GSV) delivery to the PM. Using dual-color total internal reflection fluorescence (TIRF) microscopy and an insulin-responsive aminopeptidase (IRAP)-pHluorin fusion assay, we demonstrated that Rab10 directly facilitated GSV translocation to and docking at the PM. Rab14 mediated GLUT4 delivery to the PM via endosomal compartments containing transferrin receptor (TfR), whereas Rab4A, Rab4B, and Rab8A recycled GLUT4 through the endosomal system. Myosin-Va associated with GSVs by interacting with Rab10, positioning peripherally recruited GSVs for ultimate fusion. Thus, multiple Rab proteins regulate the trafficking of GLUT4, with Rab10 coordinating with myosin-Va to mediate the final steps of insulin-stimulated GSV translocation to the PM. C1 [Chen, Yu; Lippincott-Schwartz, Jennifer] Eugene Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Wu, Xufeng S.; Hammer, John A.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Wang, Yan; Zhang, Jinzhong; Deng, Yongqiang; Jiang, Li; Song, Eli; Xu, Tao] Chinese Acad Sci, Inst Biophys, Beijing 100101, Peoples R China. RP Lippincott-Schwartz, J (reprint author), Eugene Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM xutao@ibp.ac.cn; lippincj@mail.nih.gov RI Chen, Yu/G-8724-2013; Zhang, Jinzhong/E-5670-2012 OI Zhang, Jinzhong/0000-0002-2540-2749 FU Major State Basic Research Program of the People's Republic of China [2010CB833701]; National Science Foundation of China [30900268]; Beijing Natural Science Foundation [5092017] FX This work was supported by grants from the Major State Basic Research Program of the People's Republic of China (2010CB833701), the National Science Foundation of China (30900268), and the Beijing Natural Science Foundation (5092017). NR 42 TC 60 Z9 69 U1 0 U2 18 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD AUG 20 PY 2012 VL 198 IS 4 BP 545 EP 560 DI 10.1083/jcb.201111091 PG 16 WC Cell Biology SC Cell Biology GA 994LL UT WOS:000307932200009 PM 22908308 ER PT J AU Hultcrantz, M Kristinsson, SY Andersson, TML Landgren, O Eloranta, S Derolf, AR Dickman, PW Bjorkholm, M AF Hultcrantz, Malin Kristinsson, Sigurdur Yngvi Andersson, Therese M. -L. Landgren, Ola Eloranta, Sandra Derolf, Asa Rangert Dickman, Paul W. Bjorkholm, Magnus TI Patterns of Survival Among Patients With Myeloproliferative Neoplasms Diagnosed in Sweden From 1973 to 2008: A Population-Based Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INTERNATIONAL WORKING GROUP; TYROSINE KINASE JAK2; ESSENTIAL THROMBOCYTHEMIA; POLYCYTHEMIA-VERA; PRIMARY MYELOFIBROSIS; LIFE EXPECTANCY; MYELOID METAPLASIA; PROGNOSTIC-FACTORS; CONSECUTIVE PATIENTS; OLMSTED COUNTY AB Purpose Reported survival in patients with myeloproliferative neoplasms (MPNs) shows great variation. Patients with primary myelofibrosis (PMF) have substantially reduced life expectancy, whereas patients with polycythemia vera (PV) and essential thrombocythemia (ET) have moderately reduced survival in most, but not all, studies. We conducted a large population-based study to establish patterns of survival in more than 9,000 patients with MPNs. Patients and Methods We identified 9,384 patients with MPNs (from the Swedish Cancer Register) diagnosed from 1973 to 2008 (divided into four calendar periods) with follow-up to 2009. Relative survival ratios (RSRs) and excess mortality rate ratios were computed as measures of survival. Results Patient survival was considerably lower in all MPN subtypes compared with expected survival in the general population, reflected in 10-year RSRs of 0.64 (95% CI, 0.62 to 0.67) in patients with PV, 0.68 (95% CI, 0.64 to 0.71) in those with ET, and 0.21 (95% CI, 0.18 to 0.25) in those with PMF. Excess mortality was observed in patients with any MPN subtype during all four calendar periods (P < .001). Survival improved significantly over time (P < .001); however, the improvement was less pronounced after the year 2000 and was confined to patients with PV and ET. Conclusion We found patients with any MPN subtype to have significantly reduced life expectancy compared with the general population. The improvement over time is most likely explained by better overall clinical management of patients with MPN. The decreased life expectancy even in the most recent calendar period emphasizes the need for new treatment options for these patients. C1 [Hultcrantz, Malin; Kristinsson, Sigurdur Yngvi; Landgren, Ola; Derolf, Asa Rangert; Bjorkholm, Magnus] Karolinska Univ Hosp, Stockholm, Sweden. [Andersson, Therese M. -L.; Eloranta, Sandra; Dickman, Paul W.] Karolinska Inst, Stockholm, Sweden. [Landgren, Ola] NCI, NIH, Bethesda, MD 20892 USA. RP Hultcrantz, M (reprint author), Karolinska Univ Hosp Solna, Div Hematol, Dept Med, SE-17176 Stockholm, Sweden. EM malin.hultcrantz@karolinska.se RI Dickman, Paul/B-4572-2013; Kristinsson, Sigurdur /M-2910-2015; Andersson, Therese/E-7107-2016 OI Dickman, Paul/0000-0002-5788-3380; Kristinsson, Sigurdur /0000-0002-4964-7476; Andersson, Therese/0000-0001-8644-9041 FU Swedish Cancer Society [CAN 2009/1203]; Stockholm County Council [SLL 20090201]; Karolinska Institutet [SLL 20090201]; Karolinska Institutet Foundations [2009Fobi0072]; Shire Pharmaceuticals; Adolf H. Lundin Charitable Foundation FX Supported by Grant No. CAN 2009/1203 from the Swedish Cancer Society; by Grant No. SLL 20090201 from the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet; by Grant No. 2009Fobi0072 from the Karolinska Institutet Foundations; by an unrestricted grant from Shire Pharmaceuticals; and by the Adolf H. Lundin Charitable Foundation. NR 52 TC 52 Z9 53 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2012 VL 30 IS 24 BP 2995 EP 3001 DI 10.1200/JCO.2012.42.1925 PG 7 WC Oncology SC Oncology GA 996JR UT WOS:000308082300015 PM 22802311 ER PT J AU Basch, E Oliver, TK Vickers, A Thompson, I Kantoff, P Parnes, H Loblaw, DA Roth, B Williams, J Nam, RK AF Basch, Ethan Oliver, Thomas K. Vickers, Andrew Thompson, Ian Kantoff, Philip Parnes, Howard Loblaw, D. Andrew Roth, Bruce Williams, James Nam, Robert K. TI Screening for Prostate Cancer With Prostate-Specific Antigen Testing: American Society of Clinical Oncology Provisional Clinical Opinion SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; SERVICES-TASK-FORCE; FOLLOW-UP; CONSERVATIVE MANAGEMENT; MORTALITY; COMPLICATIONS; STATISTICS; OUTCOMES; BIOPSY; RISK AB Purpose An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to the ASCO membership after publication or presentation of potentially practice-changing data from major studies. This PCO addresses the role of prostate-specific antigen (PSA) testing in the screening of men for prostate cancer. Clinical Context Prostate cancer is the second leading cause of cancer deaths among men in the United States. The rationale for screening men for prostate cancer is the potential to reduce the risk of death through early detection. Recent Data Evidence from a 2011 Agency for Healthcare Research and Quality systematic review primarily informs this PCO on the benefits and harms of PSA-based screening. An update search was conducted to March 16, 2012, for additional evidence related to the topic. Results In one randomized trial, PSA testing in men who would not otherwise have been screened resulted in reduced death rates from prostate cancer, but it is uncertain whether the size of the effect was worth the harms associated with screening and subsequent unnecessary treatment. Although there are limitations to the existing data, there is evidence to suggest that men with longer life expectancy may benefit from PSA testing. Adverse events associated with prostate biopsy are low for the majority of men; however, several population-based studies have shown increasing rates of infectious complications after prostate biopsy, which is a concern. C1 [Oliver, Thomas K.; Nam, Robert K.] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. [Basch, Ethan; Vickers, Andrew] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Thompson, Ian] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Kantoff, Philip] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Parnes, Howard] NCI, Rockville, MD USA. [Loblaw, D. Andrew; Nam, Robert K.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Odette Canc Ctr, Toronto, ON, Canada. [Roth, Bruce] Washington Univ, St Louis, MO USA. [Williams, James] Penn Prostate Canc Coalit, Camp Hill, PA USA. RP Nam, RK (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org OI Vickers, Andrew/0000-0003-1525-6503 NR 46 TC 65 Z9 69 U1 0 U2 15 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2012 VL 30 IS 24 BP 3020 EP 3025 DI 10.1200/JCO.2012.43.3441 PG 6 WC Oncology SC Oncology GA 996JR UT WOS:000308082300018 PM 22802323 ER PT J AU Kleinerman, RA Yu, CL Little, MP Li, Y Abramson, DH Seddon, JM Tucker, MA AF Kleinerman, Ruth A. Yu, Chu-Ling Little, Mark P. Li, Yi Abramson, David H. Seddon, Johanna M. Tucker, Margaret A. TI Risk Factors for the Incidence of Second Cancers in Survivors of Retinoblastoma With a Family History Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Kleinerman, Ruth A.; Little, Mark P.; Tucker, Margaret A.] NCI, NIH, Rockville, MD USA. [Yu, Chu-Ling] Kaiser Permanente, Midatlantic Permanente Res Inst, Rockville, MD USA. [Li, Yi] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Abramson, David H.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Seddon, Johanna M.] Tufts Univ New England Med Ctr, Boston, MA USA. RP Kleinerman, RA (reprint author), NCI, NIH, Rockville, MD USA. RI Tucker, Margaret/B-4297-2015; OI Kleinerman, Ruth/0000-0001-7415-2478 NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2012 VL 30 IS 24 BP 3028 EP 3029 DI 10.1200/JCO.2012.44.2657 PG 3 WC Oncology SC Oncology GA 996JR UT WOS:000308082300021 ER PT J AU Wang, S Shin, IS Hancock, H Jang, BS Kim, HS Lee, SM Zderic, V Frenkel, V Pastan, I Paik, CH Dreher, MR AF Wang, Shutao Shin, In Soo Hancock, Hilary Jang, Beom-su Kim, Hyung-sub Lee, Sang Myung Zderic, Vesna Frenkel, Victor Pastan, Ira Paik, Chang H. Dreher, Matthew R. TI Pulsed high intensity focused ultrasound increases penetration and therapeutic efficacy of monoclonal antibodies in murine xenograft tumors SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Monoclonal antibodies; Pulsed-HIFU; Radioimmunotherapy; Penetration; Binding site barrier ID SOLID TUMORS; INTERSTITIAL PRESSURE; BREAST-CANCER; NANOPARTICLE PENETRATION; CARCINOMA XENOGRAFTS; DELIVERY; RADIOIMMUNOTHERAPY; MACROMOLECULES; ENHANCEMENT; MECHANISMS AB The success of radioimmunotherapy for solid tumors remains elusive due to poor biodistribution and insufficient tumor accumulation, in part, due to the unique tumor microenvironment resulting in heterogeneous tumor antibody distribution. Pulsed high intensity focused ultrasound (pulsed-HIFU) has previously been shown to increase the accumulation of In-111 labeled B3 antibody (recognizes Lewis(y) antigen). The objective of this study was to investigate the tumor penetration and therapeutic efficacy of pulsed-HIFU exposures combined with Y-90 labeled B3 mAb in an A431 solid tumor model. The ability of pulsed-HIFU (1MHz, spatial averaged temporal peak intensity = 2685Wcm(-2); pulse repetition frequency=1Hz; duty cycle=5%) to improve the tumor penetration and therapeutic efficacy of Y-90 labeled B3 mAb (Y-90-B3) was evaluated in Le(y)-positive A431 tumors. Antibody penetration from the tumor surface and blood vessel surface was evaluated with fluorescently labeled B3, epi-fluorescent microscopy, and custom image analysis. Tumor size was monitored to determine treatment efficacy, indicated by survival, following various treatments with pulsed-HIFU and/or Y-90-B3. The pulsed-HIFU exposures did not affect the vascular parameters including microvascular density, vascular size, and vascular architecture; although 1.6-fold more antibody was delivered to the solid tumors when combined with pulsed-HIFU. The distribution and penetration of the antibodies were significantly improved (p-valueb0.05) when combined with pulsed-HIFU, only in the tumor periphery. Pretreatment with pulsed-HIFU significantly improved (p-valueb0.05) survival over control treatments. Published by Elsevier B. V. C1 [Shin, In Soo; Jang, Beom-su; Kim, Hyung-sub; Lee, Sang Myung; Paik, Chang H.] NIH, Div Nucl Med, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Shutao; Zderic, Vesna] George Washington Univ, Dept Elect & Comp Engn, Washington, DC USA. [Frenkel, Victor] Catholic Univ Amer, Dept Biomed Engn, Washington, DC 20064 USA. [Pastan, Ira] NCI, NIH, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dreher, MR (reprint author), NIH, Div Nucl Med, Dept Radiol & Imaging Sci, Ctr Clin, Bldg 10,Room 2N212 MSC1182, Bethesda, MD 20892 USA. EM dreherm@cc.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); Center for Interventional Oncology; National Cancer Institute; Center for Cancer Research FX This research was supported by in part by the Intramural Research Program of the National Institutes of Health (NIH), Center for Interventional Oncology, National Cancer Institute, and Center for Cancer Research. We thank Dr. Bradford J. Wood for his useful discussion and support of this study. NR 48 TC 22 Z9 23 U1 3 U2 34 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 AUG 20 PY 2012 VL 162 IS 1 BP 218 EP 224 DI 10.1016/j.jconrel.2012.06.025 PG 7 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 992IP UT WOS:000307769200026 PM 22732476 ER PT J AU Tyagi, RK Garg, NK Sahu, T AF Tyagi, Rajeev K. Garg, Neeraj K. Sahu, Tejram TI Vaccination Strategies against Malaria: novel carrier(s) more than a tour de force SO JOURNAL OF CONTROLLED RELEASE LA English DT Review DE Hemagglutinin; Immunopotentiating reconstituted influenza virosomes; pH-sensitive liposome; Cationic lipid; TAP (Transcription activator protein); Transfection; Immunogenicity; Subunit vaccines; Adjuvant; Microsphere; Virosomes ID VACCINIA VIRUS ANKARA; RECONSTITUTED INFLUENZA VIROSOMES; TRANSMISSION-BLOCKING IMMUNITY; PLASMODIUM-FALCIPARUM MALARIA; C-TERMINAL FRAGMENT; FOWLPOX STRAIN FP9; T-CELL; GENE-DELIVERY; CIRCUMSPOROZOITE PROTEIN; IN-VITRO AB The introduction of vaccine technology has facilitated an unprecedented multi-antigen approach to develop an effective vaccine against complex systemic inflammatory pathogens such as Plasmodium spp. that cause severe malaria. The capacity of multi subunit DNA vaccine encoding different stage Plasmodium antigens to induce CD8(+) cytotoxic T lymphocytes and interferon-gamma responses in mice, monkeys and humans has been observed. Moreover, genetic vaccination may be capable of eliciting both cell mediated and humoral immune responses. The cytotoxic T cell responses are categorically needed against intracellular hepatic stage and humoral response with antibodies targeted against antigens from all stages of malaria parasite life cycle. Therefore, the key to success for any DNA based vaccine is to design a vector able to serve as a safe and efficient delivery system. This has encouraged the development of non-viral DNA-mediated gene transfer techniques such as liposome, virosomes, microsphere and nanoparticles. Efficient and relatively safe DNA transfection using lipoplexes makes them an appealing alternative to be explored for gene delivery. Also, liposome-entrapped DNA has been shown to enhance the potency of DNA vaccines, possibly by facilitating uptake of the plasmid by antigen-presenting cells (APC). Another recent technology using cationic lipids has been deployed and has generated substantial interest in this approach to gene transfer. In this review we discussed various aspects that could be decisive in the formulation of efficient and stable carrier system(s) for the development of malaria vaccine. Published by Elsevier B. V. C1 [Tyagi, Rajeev K.] Univ S Florida, Coll Publ Hlth, Dept Global Hlth, Global Hlth Infect Dis Res Program, Tampa, FL 33612 USA. [Garg, Neeraj K.] Dr Hari Singh Gour Vishwavidyalaya, Dept Pharmaceut Sci, Sagar 470003, MP, India. [Garg, Neeraj K.] Sanofi Co, Shantha Biotechn Ltd, Res & Dev, Hyderabad 501401, Andhra Pradesh, India. [Sahu, Tejram] NIAID, NIH, Rockville, MD USA. RP Tyagi, RK (reprint author), Univ S Florida, Coll Publ Hlth, Dept Global Hlth, Global Hlth Infect Dis Res Program, 3720 Spectrum Blvd, Tampa, FL 33612 USA. EM rtyagi@health.usf.edu OI Sahu, Tejram/0000-0002-0912-7660 FU Department of Biotechnology; Council of Scientific and Industrial Research; University Grant Commission, New Delhi, India FX The research work is supported by various grants from Department of Biotechnology, Council of Scientific and Industrial Research and University Grant Commission, New Delhi, India. We are thankful to analytical instrument facility of All India Institute of Medical Sciences, New Delhi, India. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. NR 167 TC 12 Z9 12 U1 1 U2 25 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 AUG 20 PY 2012 VL 162 IS 1 BP 242 EP 254 DI 10.1016/j.jconrel.2012.04.037 PG 13 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 992IP UT WOS:000307769200029 PM 22564369 ER PT J AU Rivero, MR Miras, SL Feliziani, C Zamponi, N Quiroga, R Hayes, SF Ropolo, AS Touz, MC AF Rivero, Maria R. Miras, Silvana L. Feliziani, Constanza Zamponi, Nahuel Quiroga, Rodrigo Hayes, Stanley F. Ropolo, Andrea S. Touz, Maria C. TI Vacuolar Protein Sorting Receptor in Giardia lamblia SO PLOS ONE LA English DT Article ID ACID-PHOSPHATASE-ACTIVITY; CRYSTALLOID ENDOPLASMIC-RETICULUM; COMBINED TRANSMEMBRANE TOPOLOGY; SIGNAL PEPTIDE PREDICTION; CYST WALL PROTEINS; PRIMITIVE EUKARYOTE; LEISHMANIA-DONOVANI; MEMBRANE-PROTEIN; SURFACE PROTEIN; QUANTITATIVE-ANALYSIS AB In Giardia, lysosome-like peripheral vacuoles (PVs) need to specifically coordinate their endosomal and lysosomal functions to be able to successfully perform endocytosis, protein degradation and protein delivery, but how cargo, ligands and molecular components generate specific routes to the PVs remains poorly understood. Recently, we found that delivering membrane Cathepsin C and the soluble acid phosphatase (AcPh) to the PVs is adaptin (AP1)-dependent. However, the receptor that links AcPh and AP1 was never described. We have studied protein-binding to AcPh by using H6-tagged AcPh, and found that a membrane protein interacted with AcPh. This protein, named GlVps (for Giardia lamblia Vacuolar protein sorting), mainly localized to the ER-nuclear envelope and in some PVs, probably functioning as the sorting receptor for AcPh. The tyrosine-binding motif found in the C-terminal cytoplasmic tail domain of GlVps was essential for its exit from the endoplasmic reticulum and transport to the vacuoles, with this motif being necessary for the interaction with the medium subunit of AP1. Thus, the mechanism by which soluble proteins, such as AcPh, reach the peripheral vacuoles in Giardia appears to be very similar to the mechanism of lysosomal protein-sorting in more evolved eukaryotic cells. C1 [Rivero, Maria R.; Miras, Silvana L.; Feliziani, Constanza; Zamponi, Nahuel; Ropolo, Andrea S.; Touz, Maria C.] Univ Nacl Cordoba, Inst Invest Med Mercedes & Martin Ferreyra, RA-5000 Cordoba, Argentina. [Quiroga, Rodrigo] Univ Nacl Cordoba, Fac Ciencias Quim, Dept Quim Biol, RA-5000 Cordoba, Argentina. [Hayes, Stanley F.] NIAID, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. RP Rivero, MR (reprint author), Univ Nacl Cordoba, Inst Invest Med Mercedes & Martin Ferreyra, RA-5000 Cordoba, Argentina. EM ctouz@immf.uncor.edu OI Quiroga, Rodrigo/0000-0001-5015-0531 FU Fogarty International Center [R01TW00724]; Argentine National Agency for the Promotion of Science and Technology (FONCyT); National Council for Sciences and Technology (CONICET) FX The project was supported by Grant Number R01TW00724 from the Fogarty International Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Fogarty International Center or the National Institutes of Health. This research was also supported in part by the Argentine National Agency for the Promotion of Science and Technology (FONCyT), and the National Council for Sciences and Technology (CONICET). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 85 TC 4 Z9 4 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 AUG 20 PY 2012 VL 7 IS 8 AR e43712 DI 10.1371/journal.pone.0043712 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 991WJ UT WOS:000307733800097 PM 22916299 ER PT J AU Anfinrud, P Schotte, F Cho, HS Kataoka, M Kamikubo, H Kyndt, J AF Anfinrud, Philip Schotte, Friedrich Cho, Hyun Sun Kataoka, Mikio Kamikubo, Hironari Kyndt, John TI Picosecond time-resolved X-ray studies of photactive yellow protein SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Anfinrud, Philip; Schotte, Friedrich; Cho, Hyun Sun] NIH, Chem Phys Lab, Bethesda, MD 20892 USA. [Kataoka, Mikio; Kamikubo, Hironari] NAIST, Nara, Japan. [Kyndt, John] Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA. EM anfinrud@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 311-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621807463 ER PT J AU Appella, DH AF Appella, Daniel H. TI Multivalent peptide nucleic acid nanoscaffolds that are precise, programmable, and regulate cancer metastasis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 711-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621807007 ER PT J AU Appella, DH Jenkins, LM Kumar, P Wang, DY Ott, DE AF Appella, Daniel H. Jenkins, Lisa M. Kumar, Pankaj Wang, Deyun Ott, David E. TI Inactivation of HIV-1 nucleocapsid NCp7 with a small molecule scaffold: In vitro mechanism and in vivo efficacy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Appella, Daniel H.; Jenkins, Lisa M.; Kumar, Pankaj; Wang, Deyun; Ott, David E.] NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 23-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621805653 ER PT J AU Bhattacharyya, S Wei, L Riffle, L Hill, GC Jacobs, PM Tatum, J Doroshow, J Kalen, J AF Bhattacharyya, Sibaprasad Wei, Ling Riffle, Lisa Hill, Gordon C. Jacobs, Paula M. Tatum, James Doroshow, James Kalen, Joseph TI Immuno-PET with 89Zr labeled Panitumumab for the assessment of HER1-expression level in carcinomas SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Bhattacharyya, Sibaprasad; Wei, Ling] SAIC Frederick Natl Lab Canc Res, ADRD, Frederick, MD 21702 USA. [Riffle, Lisa; Kalen, Joseph] SAIC Frederick Natl Lab Canc Res, SAIP, Frederick, MD 21702 USA. [Hill, Gordon C.] SAIC Frederick Natl Lab Canc Res, CMRP, Frederick, MD 21702 USA. [Jacobs, Paula M.; Tatum, James; Doroshow, James] NCI, DCTD, Bethesda, MD 20892 USA. EM bhattacharyyas2@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 96-NUCL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621806242 ER PT J AU Biswas, D Saavedra, JE Keefer, LK Holland, RJ Cao, Z Deschamps, JR AF Biswas, Debanjan Saavedra, Joseph E. Keefer, Larry K. Holland, Ryan J. Cao, Zhao Deschamps, Jeffrey R. TI O-2-Functionalized methylamine diazeniumdiolates as potential nitroxyl prodrugs SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Biswas, Debanjan; Saavedra, Joseph E.; Keefer, Larry K.; Holland, Ryan J.; Cao, Zhao] NCI, Drug Design Sect, Biol Chem Lab, Frederick, MD 21702 USA. [Deschamps, Jeffrey R.] Naval Res Lab, Washington, DC 20375 USA. EM biswasd@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 391-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621806113 ER PT J AU Bozza, WP Yang, K Wang, JL Dexheimer, TS Ngan, CH Vajda, S Simeonov, A Zhuang, ZH AF Bozza, William P. Yang, Kun Wang, Jialiang Dexheimer, Thomas S. Ngan, Chi Ho Vajda, Sandor Simeonov, Anton Zhuang, Zhihao TI Developing peptide-based multivalent antagonists of human proliferating cell nuclear antigen SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Bozza, William P.; Yang, Kun; Wang, Jialiang; Zhuang, Zhihao] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. [Dexheimer, Thomas S.; Simeonov, Anton] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Ngan, Chi Ho; Vajda, Sandor] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. EM wbozza1@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 167-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621800729 ER PT J AU Brooks, BR AF Brooks, Bernard R. TI Recent techniques in CHARMM for exploring potential energy surfaces in quantum chemistry involving complex QM/MM systems SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Brooks, Bernard R.] NHLBI, Lab Computat Biol, Rockville, MD 20892 USA. EM brb@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 451-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803366 ER PT J AU Chen, YH Tarasova, N AF Chen, Yuhong Tarasova, Nadya TI Fully synthetic self-assembling virus-like nanoparticles targeting prostate cancer cells SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Chen, Yuhong; Tarasova, Nadya] Frederick Natl Lab Canc Res, Ctr Canc Res, Canc & Inflammat Program, Frederick, MD 21702 USA. EM cheny8@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 19-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621806271 ER PT J AU Daniel, MC Ghann, WE Aras, O Fleiter, T AF Daniel, Marie-Christine Ghann, William E. Aras, Omer Fleiter, Thorsten TI Lisinopril-coated gold nanoparticles as targeted CT nanoprobes for monitoring of cardiovascular diseases SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Daniel, Marie-Christine; Ghann, William E.] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. [Aras, Omer] NIH, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Aras, Omer] NIH, Mol Imaging Program, Bethesda, MD 20892 USA. [Fleiter, Thorsten] Univ Maryland Med Syst, Dept Radiol, Baltimore, MD 21201 USA. EM mdaniel@umbc.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 388-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621802574 ER PT J AU Dix, AV AF Dix, Andrew V. TI Probing adenosine A2A receptor multivalency using peptide nucleic acid based nanoscaffolds SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Dix, Andrew V.] NIH, Biol Chem Lab, Bethesda, MD 20892 USA. EM Andrew.Dix@NIH.GOV NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 710-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621807006 ER PT J AU Englund, EA Micklitsch, CM Onyshchenko, MI Neumann, RD Panyutin, IG Appella, DH AF Englund, Ethan A. Micklitsch, Christopher M. Onyshchenko, Mykola I. Neumann, Ronald D. Panyutin, Igor G. Appella, Daniel H. TI Targeting DNA G-quadruplex structures with pyrazolo[3,4-d]pyrimidine guanine PNA oligomers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Englund, Ethan A.; Micklitsch, Christopher M.; Appella, Daniel H.] NIDDK, Lab Bioorgan Chemsitry, NIH, Bethesda, MD 20814 USA. [Onyshchenko, Mykola I.; Neumann, Ronald D.; Panyutin, Igor G.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Onyshchenko, Mykola I.] NIBIB, Imaging Sci Training Program, NIH, Bethesda, MD 20892 USA. EM englunde@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 755-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621807042 ER PT J AU Fawzi, NL Ying, JF Torchia, DA Clore, GM AF Fawzi, Nicolas L. Ying, Jinfa Torchia, Dennis A. Clore, G. Marius TI Dyanamics on the surface of amyloid-beta protofibrils in solution: Dark-state exchange saturation transfer NMR SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Fawzi, Nicolas L.; Ying, Jinfa; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Torchia, Dennis A.] NIDCR, NIH, Bethesda, MD 20892 USA. EM fawzin@helix.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 225-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621807380 ER PT J AU Gangjee, A Pavana, RK Ihnat, MA Hamel, E AF Gangjee, Aleem Pavana, Roheeth Kumar Ihnat, Michael A. Hamel, Ernest TI Design, synthesis, and preclinical evaluation of 7-benzyl -N-substituted phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with antitubulin and antiangiogenic activity as antitumor agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Gangjee, Aleem; Pavana, Roheeth Kumar] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA. [Ihnat, Michael A.] Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73117 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. EM kp.roheeth@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 321-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621806049 ER PT J AU Gangjee, A Devambatla, RKV Choudhary, S Bai, R Hamel, E AF Gangjee, Aleem Devambatla, Ravi Kumar Vyas Choudhary, Shruti Bai, Ruoli Hamel, Ernest TI Design, synthesis, and biological evaluation of substituted furo[2,3-d]pyrimidines as potent antimitotic agents that circumvent Pgp and bIII-tubulin mediated resistance SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Gangjee, Aleem; Devambatla, Ravi Kumar Vyas; Choudhary, Shruti] Duquesne Univ, Div Med Chem, Pittsburgh, PA 15282 USA. [Bai, Ruoli; Hamel, Ernest] Frederick Natl Lab Canc Res, Div Canc Treatment & Diag, Frederick, MD 21702 USA. EM drk_vyas@yahoo.co.in NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 320-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621806048 ER PT J AU Garcia, CL Marquez, VE Comin, MJ AF Garcia, Cynthia L. Marquez, Victor E. Comin, Maria J. TI Synthesis of N-methylsubstituted indololactones as selective activators of Ras guanyl nucleotide-release proteins (RasGRP) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Garcia, Cynthia L.; Comin, Maria J.] Inst Nacl Tecnol Ind, Dept Chem, Buenos Aires, DF, Argentina. [Marquez, Victor E.] NIH, Biol Chem Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. EM cgarcia@inti.gob.ar NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 302-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621806031 ER PT J AU Giano, MC Schneider, JP AF Giano, Michael C. Schneider, Joel P. TI Controlled degradation of self-assembled b-hairpin hydrogels by proteolysis with matrix metalloproteinase-13 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Giano, Michael C.; Schneider, Joel P.] NCI, Dept Biol Chem, Frederick, MD 21701 USA. [Giano, Michael C.] Univ Delaware, Dept Chem & Biochem, Newark, DE 19711 USA. EM gianomc@mail.nih.gov NR 0 TC 0 Z9 0 U1 2 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 222-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621808391 ER PT J AU Gildersleeve, J AF Gildersleeve, Jeffrey TI Antiglycan antibodies as biomarkers for personalized medicine SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Gildersleeve, Jeffrey] NCI, Biol Chem Lab, Frederick, MD 21702 USA. EM gildersj@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 86-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621801239 ER PT J AU Gupta, P Appella, DH AF Gupta, Pankaj Appella, Daniel H. TI Synthesis of pyrrole derivatives for selective inhibition of Wip-1 phosphatase SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Gupta, Pankaj; Appella, Daniel H.] NIDDK, NIH, Bethesda, MD 20892 USA. EM kumarp5@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 41-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621805669 ER PT J AU Hassink, MD Appella, D AF Hassink, Matthew D. Appella, Daniel TI Synthesis of small molecule ligands and their expression in a multivalent sense on a PNA scaffold SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Hassink, Matthew D.; Appella, Daniel] NIDDK, Bethesda, MD 20892 USA. EM matthew.hassink@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 758-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621807045 ER PT J AU Hogan, M Bahta, M Zhao, B Cherry, S Tropea, JE Lountos, GT Burke, TR Waugh, DS Ulrich, RG AF Hogan, Megan Bahta, Medhanit Zhao, Bryan Cherry, Scott Tropea, Joseph E. Lountos, George T. Burke, Terrence R. Waugh, David S. Ulrich, Robert G. TI Investigation of the interaction kinetics between small molecule inhibitors and the protein tyrosine phosphatase YopH from Yersinia pestis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Hogan, Megan; Zhao, Bryan] Oak Ridge Associated Univ, Fac Res Participat Program, Belcamp, MD 21017 USA. [Hogan, Megan; Zhao, Bryan; Ulrich, Robert G.] US Army Med Res Inst Infect Dis, Lab Mol Immunol, Frederick, MD 21702 USA. [Bahta, Medhanit; Burke, Terrence R.] NCI, Biol Chem Lab, Ctr Canc Res, NIH,Frederick Natl Lab, Frederick, MD 21702 USA. [Cherry, Scott; Tropea, Joseph E.; Lountos, George T.; Waugh, David S.] NCI, Macromol Crystallog Lab, Ctr Canc Res, NIH,Frederick Natl Lab, Frederick, MD 21702 USA. RI Lountos, George/B-3983-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 402-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621806124 ER PT J AU Horkay, F Basser, PJ Hecht, AM Geissler, E AF Horkay, Ferenc Basser, Peter J. Hecht, Anne-Marie Geissler, Erik TI Hierarchy and organization of hyaluronic acid in physiological salt solutions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Horkay, Ferenc; Basser, Peter J.] NICHD, NIH, Bethesda, MD 20892 USA. [Hecht, Anne-Marie; Geissler, Erik] Univ J Fourier Grenoble, Spectrometrie Phys Lab, St Martin Dheres, France. EM horkay@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 186-PMSE PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621807850 ER PT J AU Horkay, F Horkayne-Szakaly, I Dimitriadis, EK Silva, C Basser, PJ AF Horkay, Ferenc Horkayne-Szakaly, Iren Dimitriadis, Emilios K. Silva, Candida Basser, Peter J. TI Cartilage: Structure and osmotic properties SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Horkay, Ferenc; Horkayne-Szakaly, Iren; Silva, Candida; Basser, Peter J.] NICHD, NIH, Bethesda, MD 20892 USA. [Dimitriadis, Emilios K.] NIBIB, NIH, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 202-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621800755 ER PT J AU Hu, X Southall, N Barnaeva, E Bryant-Genevier, M Titus, S Xiao, JB Ferrer, M Marugan, J Free, RB Sibley, DR AF Hu, Xin Southall, Noel Barnaeva, Elena Bryant-Genevier, Melanie Titus, Steve Xiao, Jingbo Ferrer, Marc Marugan, Juan Free, R. Benjamin Sibley, David R. TI Modeling and virtual screening of the D-2 dopamine receptor SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Hu, Xin; Southall, Noel; Barnaeva, Elena; Bryant-Genevier, Melanie; Titus, Steve; Xiao, Jingbo; Ferrer, Marc; Marugan, Juan] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Free, R. Benjamin; Sibley, David R.] NINDS, NIH, Rockville, MD 20850 USA. EM hux61@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 310-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803248 ER PT J AU Hummer, G Zhu, FQ AF Hummer, Gerhard Zhu, Fangqiang TI Water fluctuations in the hydrophobic gate of an ion channel SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Zhu, Fangqiang] Indiana Univ Purdue Univ, Dept Phys, Indianapolis, IN 46202 USA. EM gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 57-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621807221 ER PT J AU Hummer, G Rozycki, B Kim, YC AF Hummer, Gerhard Rozycki, Bartosz Kim, Young C. TI Structure and dynamics of multiprotein assemblies from simulation and experiment SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Rozycki, Bartosz] Max Planck Inst Colloids & Interfaces, Dept Theory & Biosyst, Potsdam, Germany. [Kim, Young C.] Naval Res Lab, Ctr Computat Mat Sci, Washington, DC 20375 USA. EM gerhard.hummer@nih.gov RI Rozycki, Bartosz/B-7005-2009; Hummer, Gerhard/A-2546-2013 OI Rozycki, Bartosz/0000-0001-5938-7308; Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 248-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803189 ER PT J AU Jacobson, KA AF Jacobson, Kenneth A. TI Structure-based discovery of novel ligands of GPCRs: Adenosine receptors and P2Y receptors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 241-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621805861 ER PT J AU Jayasekara, MPS Barchi, JJ Phan, K Kumar, TS Zhang, GF Tosh, DK Gao, ZG Jacobson, KA AF Jayasekara, M. P. Suresh Barchi, Joseph J. Phan, Khai Kumar, T. Santhosh Zhang, Guofeng Tosh, Dilip K. Gao, Zhan-Guo Jacobson, Kenneth A. TI Design of adenosine receptor agonist- and antagonist-conjugated gold nanoparticles for therapeutic applications including cancer SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Jayasekara, M. P. Suresh; Phan, Khai; Kumar, T. Santhosh; Tosh, Dilip K.; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Barchi, Joseph J.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Zhang, Guofeng] Biomed Engn & Phys Sci Shared Resource NIBIB, NIH, Bethesda, MD 20892 USA. EM pushpa.mudiyanselage@nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 49-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621805677 ER PT J AU Jin, AJ Sackett, DL Lafer, EM Smith, PD Nossal, R AF Jin, Albert J. Sackett, Dan L. Lafer, Eileen M. Smith, Paul D. Nossal, Ralph TI Assessing clathrin-clathrin interactions and clathrin hair-pin folds by atomic force spectroscopy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Jin, Albert J.; Smith, Paul D.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, Bethesda, MD 20892 USA. [Sackett, Dan L.; Nossal, Ralph] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. [Lafer, Eileen M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. EM ajjin@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 154-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621800718 ER PT J AU Kabir, MS Peng, YF Jacobson, AE Rice, KC AF Kabir, M. Shahjahan Peng, Yuefeng Jacobson, Arthur E. Rice, Kenner C. TI Probes for narcotic receptor mediated phenomena: Examination of the large-scale synthesis of C-8-substituted 5-phenylmorphans SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Kabir, M. Shahjahan; Peng, Yuefeng; Jacobson, Arthur E.; Rice, Kenner C.] NIDA, NIH, Rockville, MD 20852 USA. EM kabirms@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 562-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621806762 ER PT J AU Kaila, VRI Hummer, G AF Kaila, Ville R. I. Hummer, Gerhard TI Energetics of direct and water mediated proton-coupled electron transfer SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Kaila, Ville R. I.; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM ville.kaila@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 239-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803181 ER PT J AU Kim, S Bolton, EE Bryant, SH AF Kim, Sunghwan Bolton, Evan E. Bryant, Stephen H. TI Statistical significance of 3D molecular similarity scores SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Kim, Sunghwan; Bolton, Evan E.; Bryant, Stephen H.] NIH, Natl Lib Med, Bethesda, MD 20894 USA. EM kimsungh@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 137-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621802198 ER PT J AU Konig, G Miller, BT Boresch, S Wu, XW Brooks, BR AF Koenig, Gerhard Miller, Benjamin T. Boresch, Stefan Wu, Xiongwu Brooks, Bernard R. TI Enhanced sampling in free energy calculations SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Koenig, Gerhard; Miller, Benjamin T.; Wu, Xiongwu; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Rockville, MD 20852 USA. [Boresch, Stefan] Univ Vienna, Dept Computat Biol Chem, Vienna, Austria. EM gerhard.koenig@nih.gov RI Boresch, Stefan/F-3467-2014 OI Boresch, Stefan/0000-0002-2793-6656 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 347-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803278 ER PT J AU Kraft, ML Frisz, JF Klitzing, HA Lou, KY Lizunov, V Carpenter, KJ Weber, PK Zimmerberg, J AF Kraft, Mary L. Frisz, Jessica F. Klitzing, Haley A. Lou, Kaiyan Lizunov, Vladimir Carpenter, Kevin J. Weber, Peter K. Zimmerberg, Joshua TI Imaging the sphingolipid and cholesterol distribution in the plasma membrane using secondary ion mass spectrometry SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Kraft, Mary L.; Lou, Kaiyan] Univ Illinois, Dept Chem & Biomol Engn, Urbana, IL 61801 USA. [Kraft, Mary L.; Frisz, Jessica F.; Klitzing, Haley A.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA. [Lizunov, Vladimir; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, Bethesda, MD 20892 USA. [Carpenter, Kevin J.; Weber, Peter K.] Lawrence Livermore Natl Lab, Glenn T Seaborg Inst, Livermore, CA 94511 USA. EM mlkraft@illinois.edu NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 236-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621801100 ER PT J AU Lee, J Bhondwe, RS Kang, DW Kim, MS Kim, HS Park, SG Son, K Choi, S Kuhs, KAL Pavlyukovets, VA Pearce, LV Blumberg, PM AF Lee, Jeewoo Bhondwe, Rahul S. Kang, Dong Wook Kim, Myeong Seop Kim, Ho Shin Park, Seul-gi Son, Karam Choi, Sun Kuhs, Krystle A. Lang Pavlyukovets, Vladimir A. Pearce, Larry V. Blumberg, Peter M. TI Structure activity relationships and molecular modeling of the N-(3-pivaloyloxy-2-benzylpropyl)-N '-[4-(methylsulfonylamino)benzyl] thiourea template for TRPV1 antagonism SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Lee, Jeewoo; Bhondwe, Rahul S.; Kang, Dong Wook; Kim, Myeong Seop; Kim, Ho Shin] Seoul Natl Univ, Coll Pharm, Seoul, South Korea. [Park, Seul-gi; Son, Karam; Choi, Sun] Ewha Womans Univ, Coll Pharm, Seoul, South Korea. [Kuhs, Krystle A. Lang; Pavlyukovets, Vladimir A.; Pearce, Larry V.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. EM jeewoo@snu.ac.kr NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 376-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621806099 ER PT J AU Lucas, HR AF Lucas, Heather R. TI Amyloids and copper biochemistry: Effects of metal dyshomeostasis in Alzheimer's and Parkinson's disease SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Lucas, Heather R.] NIA, NIH, Baltimore, MD 21224 USA. EM lucash@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 39-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621800037 ER PT J AU Mallajosyula, SS Barchi, JJ Adams, KM MacKerell, AD AF Mallajosyula, Sairam S. Barchi, Joseph J. Adams, Kristie M. MacKerell, Alexander D., Jr. TI Structure-activity studies on antiproliferative factor (APF) glycopeptide derivatives SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Mallajosyula, Sairam S.; MacKerell, Alexander D., Jr.] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Barchi, Joseph J.; Adams, Kristie M.] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res, Frederick, MD 21702 USA. EM sairam.umb@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 333-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803266 ER PT J AU Mayer, ML AF Mayer, Mark L. TI Crystallographic studies on glutamate receptor ligand binding domains SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Mayer, Mark L.] NIH, Lab Cellular & Mol Neurophysiol, Bethesda, MD 20892 USA. EM mayerm@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 206-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621805827 ER PT J AU Miller, B Woodcock, HL Brooks, B AF Miller, Benjamin Woodcock, Henry Lee Brooks, Bernard TI Novel uses of CHARMM for highly distributed and cloud resources: MSCALE and CHARMMing SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Miller, Benjamin; Brooks, Bernard] NHLBI, Lab Computat Biol, NIH, Rockville, MD 20892 USA. [Woodcock, Henry Lee] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. EM btmiller@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 146-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803092 ER PT J AU Nadadur, SS AF Nadadur, Srikanth S. TI Nanotechnology environmental health and safety: The need for multidisciplinary consortium apporaches SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Nadadur, Srikanth S.] Natl Inst Environm Hlth Sci, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. EM nadadurs@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 138-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621808758 ER PT J AU Nagy, KJ Schneider, JP AF Nagy, Katelyn J. Schneider, Joel P. TI Enhanced mechanical rigidity of hydrogels formed from enantiomeric peptide assemblies SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Nagy, Katelyn J.] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. [Nagy, Katelyn J.; Schneider, Joel P.] NCI, Biol Chem Lab, Frederick, MD 21701 USA. EM kjnagy@udel.edu NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 226-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621808394 ER PT J AU Naumiec, GR Morse, CL Shetty, U Cai, LS Pike, VW AF Naumiec, Gregory R. Morse, Cheryl L. Shetty, Umesha Cai, Lisheng Pike, Victor W. TI Radiosynthesis of [C-11]CNS 1261, a positron emission tomography radiotracer for imaging the phencyclidine site of the N-methyl-D-aspartate receptor SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Naumiec, Gregory R.; Morse, Cheryl L.; Shetty, Umesha; Cai, Lisheng; Pike, Victor W.] NIH, Bethesda, MD 20892 USA. EM naumiecgr@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 165-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621805789 ER PT J AU Nussinov, R Jang, H AF Nussinov, Ruth Jang, Hyunbum TI Toxic beta-amyloid Alzheimer's ion channels: From structure to function and design SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Nussinov, Ruth; Jang, Hyunbum] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 434-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803350 ER PT J AU Nussinov, R AF Nussinov, Ruth TI Structural proteome scale prediction of protein-protein interactions using interfaces SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Nussinov, Ruth] NCI Frederick, Ctr Canc Res SAIC, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 103-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803050 ER PT J AU Okur, A Smith, D Brooks, BR AF Okur, Asim Smith, Daniel Brooks, Bernard R. TI Using simulation of simulations to evaluate and improve Reservoir Replica Exchange methods through transition state theory SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Okur, Asim; Brooks, Bernard R.] NHLBI, NIH, Bethesda, MD 20892 USA. [Smith, Daniel] Univ Pittsburgh, Pittsburgh, PA 15260 USA. EM okura@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 124-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803070 ER PT J AU Opina, AC Coble, V Vasalatiy, O Kobayashi, H Choyke, PL Griffiths, GL AF Opina, Ana Christina Coble, Vincent Vasalatiy, Olga Kobayashi, Hisataka Choyke, Peter L. Griffiths, Gary L. TI Conjugation of Gd(III) complexes to G5 dendrimer as MRI contrast agents for lymphangiography SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Opina, Ana Christina; Coble, Vincent; Vasalatiy, Olga; Griffiths, Gary L.] NIH, Imaging Probe Dev Ctr, Rockville, MD 20850 USA. [Kobayashi, Hisataka; Choyke, Peter L.] NIH, Mol Imaging Program, Bethesda, MD 20817 USA. EM opinaal@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 219-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621805079 ER PT J AU Patri, AK AF Patri, Anil K. TI Intelligent designs for promising cancer cures: Lessons learned from preclinical assessment of nanomedicines SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Patri, Anil K.] Frederick Natl Lab Canc Res, Nanotechnol Characterizat Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM patria@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 203-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621801073 ER PT J AU Pickard, FC Miller, BT Brooks, BR AF Pickard, Frank C. Miller, Benjamin T. Brooks, Bernard R. TI Thermochemical analysis of two small fast-folding proteins using coarse-grained simulation SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Pickard, Frank C.; Miller, Benjamin T.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM frank.pickard@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 395-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803320 ER PT J AU Sathaye, S Jia, XQ Schneider, JP Pochan, DJ AF Sathaye, Sameer Jia, Xinqiao Schneider, Joel P. Pochan, Darrin J. TI Hybrid networks from hyaluronic acid and hierarchically self-assembled b-sheet peptide networks SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Sathaye, Sameer; Jia, Xinqiao; Pochan, Darrin J.] Univ Delaware, Dept Mat Sci & Engn, Newark, DE 19716 USA. [Schneider, Joel P.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. EM sameers@udel.edu NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 221-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621808390 ER PT J AU Smith, DJ Yap, GPA Kelley, JA Schneider, JP AF Smith, Daniel J. Yap, Glenn P. A. Kelley, James A. Schneider, Joel P. TI Enhanced stereoselectivity of a Cu(II) complex chiral auxiliary in the synthesis of Fmoc-L-g-carboxyglutamic acid SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Smith, Daniel J.; Kelley, James A.; Schneider, Joel P.] Frederick Natl Lab Canc Res, Biol Chem Lab, Frederick, MD 21702 USA. [Smith, Daniel J.; Yap, Glenn P. A.] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. EM smithdj@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 227-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621808395 ER PT J AU Sonmez, C Schneider, JP AF Sonmez, Cem Schneider, Joel P. TI Bacterial expression of a self-assembling peptide hydrogelator SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Sonmez, Cem; Schneider, Joel P.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Sonmez, Cem] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. EM cem.sonmez@nih.gov RI Sonmez, Cem/C-2730-2015 OI Sonmez, Cem/0000-0002-6071-641X NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 223-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621808392 ER PT J AU Sun, HM Sakamuru, S Xia, MH Austin, CP Huang, RL AF Sun, Hongmao Sakamuru, Srilatha Xia, Menghang Austin, Christopher P. Huang, Ruili TI Genetic algorithm guided optimization of pharmacophore models for estrogen receptor agonists SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Sun, Hongmao; Sakamuru, Srilatha; Xia, Menghang; Austin, Christopher P.; Huang, Ruili] NIH, NCATS, Rockville, MD 20850 USA. EM hongmao.sun@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 233-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803175 ER PT J AU Tan, ML Cendagorta, JR Ichiye, T AF Tan, Mingliang Cendagorta, Joseph R. Ichiye, Toshiko TI Solvation of amphiphilic molecules by SSDQO water SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Tan, Mingliang; Cendagorta, Joseph R.; Ichiye, Toshiko] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. [Ichiye, Toshiko] NHBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM ti9@georgetown.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 277-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803217 ER PT J AU Tan, ML Ichiye, T AF Tan, Mingliang Ichiye, Toshiko TI Soft-sticky dipole-quadrupole-octopole model of liquid water SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Tan, Mingliang; Ichiye, Toshiko] Georgetown Univ, Dept Chem, Wa, DC 20057 USA. [Ichiye, Toshiko] NHBI, NIH, Bethesda, MD 20892 USA. EM ti9@georgetown.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 99-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803046 ER PT J AU Tao, P Brooks, BR AF Tao, Peng Brooks, Bernard R. TI Free energy profile along reference reaction path through rigid structure dynamics SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Tao, Peng; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM peng.tao@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 171-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803116 ER PT J AU Tsai, DH Elzey, S DelRio, FW Keene, AM Tyner, KM Clogston, JD MacCuspie, RI Guha, S Zachariah, MR Hackley, VA AF Tsai, De-Hao Elzey, Sherrie DelRio, Frank W. Keene, Athena M. Tyner, Katherine M. Clogston, Jeffrey D. MacCuspie, Robert I. Guha, Suvajyoti Zachariah, Michael R. Hackley, Vincent A. TI Tumor necrosis factor interaction with gold nanoparticles SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Tsai, De-Hao; Elzey, Sherrie; DelRio, Frank W.; MacCuspie, Robert I.; Guha, Suvajyoti; Zachariah, Michael R.; Hackley, Vincent A.] NIST, Mat Measurement Lab, Gaithersburg, MD 20899 USA. [Keene, Athena M.; Tyner, Katherine M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Clogston, Jeffrey D.] NCI Frederick, Nanotechnol Characterizat Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Guha, Suvajyoti; Zachariah, Michael R.] Univ Maryland, Dept Mech Engn, College Pk, MD 20742 USA. [Guha, Suvajyoti; Zachariah, Michael R.] Univ Maryland, Dept Chem, College Pk, MD 20742 USA. EM dhtsai@nist.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 493-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621802673 ER PT J AU Weidlich, IE Filippov, IV Thorpe, I AF Weidlich, Iwona E. Filippov, Igor V. Thorpe, Ian TI Improving drug development by connecting medicinal chemistry with drug repositioning and modern machine learning methods SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Weidlich, Iwona E.; Thorpe, Ian] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. [Filippov, Igor V.] NIH, Biol Chem Lab, Basic Sci Program, SAIC Frederick Inc,Frederick Natl Lab, Frederick, MD 21702 USA. EM iweidlic@umbc.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 22-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621802105 ER PT J AU Yang, W AF Yang, Wei TI Structural basis of human DNA polymerase h-mediated chemoresistance to Cisplatin SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Yang, Wei] NIDDK, LMB, NIH, Bethesda, MD 20892 USA. EM wei.yang@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 36-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621808657 ER PT J AU Zakharov, AV Peach, ML Sitzmann, M Filippov, IV Nicklaus, MC AF Zakharov, Alexey V. Peach, Megan L. Sitzmann, Markus Filippov, Igor V. Nicklaus, Marc C. TI QSAR modeling of human liver microsomal stability SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Zakharov, Alexey V.; Sitzmann, Markus; Nicklaus, Marc C.] NCI, Biol Chem Lab, NIH, DHHS, Frederick, MD 21702 USA. [Peach, Megan L.; Filippov, Igor V.] SAIC Frederick Inc, Biol Chem Lab, Basic Sci Program, Frederick, MD 21702 USA. EM alexey.zakharov@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 81-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621803030 ER PT J AU Zhao, C Micklitsch, CM Oquare, BY Appella, DH AF Zhao, Chao Micklitsch, Christopher M. Oquare, Bereket Y. Appella, Daniel H. TI Rational design of functional peptide nucleic acids for the direct and ultra high sensitive detection of HIV-1 DNA and RNA with a sandwich-hybridization assay SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Zhao, Chao; Micklitsch, Christopher M.; Oquare, Bereket Y.; Appella, Daniel H.] NIDDK, NIH, Bethesda, MD 20892 USA. EM chao.zhao@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 180-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621805802 ER PT J AU Zhao, XZ Maddali, K Smith, SJ Metifiot, M Hare, S Cherepanov, P Hughes, SH Pommier, Y Burke, TR AF Zhao, Xue Zhi Maddali, Kasthuraiah Smith, Steven J. Metifiot, Mathieu Hare, Stephen Cherepanov, Peter Hughes, Stephen H. Pommier, Yves Burke, Terrence R., Jr. TI Hydroxy-pyrrolopyridine-trione based HIV-1 integrase inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Zhao, Xue Zhi; Burke, Terrence R., Jr.] NCI, Frederick Natl Lab Canc Res, NIH, Biol Chem Lab, Frederick, MD 21702 USA. [Maddali, Kasthuraiah; Metifiot, Mathieu; Pommier, Yves] NCI, Ctr Canc Res, NIH, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Smith, Steven J.; Hughes, Stephen H.] NCI, Frederick Natl Lab Canc Res, NIH, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Hare, Stephen; Cherepanov, Peter] Univ London Imperial Coll Sci Technol & Med, Div Infect Dis, London W2 1PG, England. EM zhaoxue@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 141-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621805765 ER PT J AU Zhou, ZL Yu, PP Geller, H Ober, C AF Zhou, Zhaoli Yu, Panpan Geller, Herbert Ober, Christopher TI Biomaterials with tethered acetylcholine functionalities for neuronal cell culture and patterning SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Zhou, Zhaoli] Cornell Univ, Dept Chem & Chem Biol, Ithaca, NY 14853 USA. [Ober, Christopher] Cornell Univ, Dept Mat Sci & Engn, Ithaca, NY 14853 USA. [Yu, Panpan; Geller, Herbert] NHLBI, Dev Neurobiol Sect, Div Intramural Res, NIH, Bethesda, MD 20892 USA. EM zz56@cornell.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 307-PMSE PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621808067 ER PT J AU Carver, FW Elvevag, B Altamura, M Weinberger, DR Coppola, R AF Carver, Frederick W. Elvevag, Brita Altamura, Mario Weinberger, Daniel R. Coppola, Richard TI The Neuromagnetic Dynamics of Time Perception SO PLOS ONE LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; SUPPLEMENTARY MOTOR AREA; PREFRONTAL CORTEX; BRAIN ACTIVATION; BASAL GANGLIA; FMRI; MEMORY; CLOCK; DISCRIMINATION; SCHIZOPHRENIA AB Examining real-time cortical dynamics is crucial for understanding time perception. Using magnetoencephalography we studied auditory duration discrimination of short (<.5 s) versus long tones (>.5 s) versus a pitch control. Time-frequency analysis of event-related fields showed widespread beta-band (13-30 Hz) desynchronization during all tone presentations. Synthetic aperture magnetometry indicated automatic primarily sensorimotor responses in short and pitch conditions, with activation specific to timing in bilateral inferior frontal gyrus. In the long condition, a right lateralized network was active, including lateral prefrontal cortices, inferior frontal gyrus, supramarginal gyrus and secondary auditory areas. Activation in this network peaked just after attention to tone duration was no longer necessary, suggesting a role in sustaining representation of the interval. These data expand our understanding of time perception by revealing its complex cortical spatiotemporal signature. C1 [Carver, Frederick W.; Coppola, Richard] NIMH, MEG Core Facil, Bethesda, MD 20892 USA. [Elvevag, Brita; Altamura, Mario; Weinberger, Daniel R.; Coppola, Richard] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Carver, FW (reprint author), NIMH, MEG Core Facil, Bethesda, MD 20892 USA. EM brita@elvevaag.net FU National Institute of Mental Health, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health: http://intramural.nimh.nih.gov/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 2 Z9 2 U1 1 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 AUG 17 PY 2012 VL 7 IS 8 AR e42618 DI 10.1371/journal.pone.0042618 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 996DG UT WOS:000308063700016 PM 22912714 ER PT J AU Pripuzova, N Wang, R Tsai, S Li, BJ Hung, GC Ptak, RG Lo, SC AF Pripuzova, Natalia Wang, Richard Tsai, Shien Li, Bingjie Hung, Guo-Chiuan Ptak, Roger G. Lo, Shyh-Ching TI Development of Real-Time PCR Array for Simultaneous Detection of Eight Human Blood-Borne Viral Pathogens SO PLOS ONE LA English DT Article ID DISEASES (RAPID)-BIOACTIVE AMPLIFICATION; RELIABLE ASSAY PROTOCOL; B-VIRUS DNA; WEST-NILE-VIRUS; RAPID DETECTION; PROBING BAP; HIV TYPE-1; GROUP-O; IDENTIFICATION; QUANTIFICATION AB Background: Real-time PCR array for rapid detection of multiple viral pathogens should be highly useful in cases where the sample volume and the time of testing are limited, i.e. in the eligibility testing of tissue and organ donors. Findings: We developed a real-time PCR array capable of simultaneously detecting eight human viral pathogens: human immunodeficiency virus types 1 and 2 (HIV-1 and -2), hepatitis B virus (HBV), hepatitis C virus (HCV), human T-cell leukemia virus-1 and -2 (HTLV-1 and -2), vaccinia virus (VACV) and West Nile virus (WNV). One hundred twenty (120) primers were designed using a combination of bioinformatics approaches, and, after experimental testing, 24 primer sets targeting eight viral pathogens were selected to set up the array with SYBR Green chemistry. The specificity and sensitivity of the virus-specific primer sets selected for the array were evaluated using analytical panels with known amounts of viruses spiked into human plasma. The array detected: 10 genome equivalents (geq)/ml of HIV-2 and HCV, 50 geq of HIV-1 (subtype B), HBV (genotype A) and WNV. It detected 100-1,000 geq/ml of plasma of HIV-1 subtypes (A - G), group N and CRF (AE and AG) isolates. Further evaluation with a panel consisting of 28 HIV-1 and HIV-2 clinical isolates revealed no cross-reactivity of HIV-1 or HIV-2 specific primers with another type of HIV. All 28 viral isolates were identified with specific primer sets targeting the most conserved genome areas. The PCR array correctly identified viral infections in a panel of 17 previously quantified clinical plasma samples positive for HIV-1, HCV or HBV at as low as several geq per PCR reaction. Conclusions: The viral array described here demonstrated adequate performance in the testing of donors' clinical samples. Further improvement in its sensitivity for the broad spectrum of HIV-1 subtypes is under development. C1 [Pripuzova, Natalia; Tsai, Shien; Li, Bingjie; Hung, Guo-Chiuan; Lo, Shyh-Ching] US FDA, Tissue Microbiol Lab, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapy,Ctr Biol Evalu, Bethesda, MD 20014 USA. [Wang, Richard] NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Ptak, Roger G.] So Res Inst, Dept Infect Dis Res, Frederick, MD USA. RP Pripuzova, N (reprint author), US FDA, Tissue Microbiol Lab, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapy,Ctr Biol Evalu, Bethesda, MD 20014 USA. EM ShyhChing.Lo@fda.hhs.gov NR 43 TC 5 Z9 5 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 17 PY 2012 VL 7 IS 8 AR e43246 DI 10.1371/journal.pone.0043246 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 996DG UT WOS:000308063700066 PM 22912836 ER PT J AU Vargas, M Karamsetty, R Leppla, SH Chaudry, GJ AF Vargas, Micaela Karamsetty, Raghavendra Leppla, Stephen H. Chaudry, G. Jilani TI Broad Expression Analysis of Human ANTXR1/TEM8 Transcripts Reveals Differential Expression and Novel Splizce Variants SO PLOS ONE LA English DT Article ID ANTHRAX LETHAL FACTOR; PROTEIN-KINASE KINASE; PROTECTIVE ANTIGEN; TOXIN RECEPTOR; CAPILLARY MORPHOGENESIS; TUMOR ENDOTHELIUM; DEPENDENT PROCESS; EUKARYOTIC CELLS; MAMMALIAN-CELLS; FACTOR CLEAVES AB Tumor endothelial marker 8 (TEM8; ANTXR1) is one of two anthrax toxin receptors; the other is capillary morphogenesis gene 2 protein (CMG2; ANTXR2). TEM8 shows enhanced expression in certain tumor endothelia, and is thought to be a player in tumor vasculature formation. However, a comprehensive expression profile of individual TEM8 variants in normal or cancerous tissues is lacking. In this work we carried out an extensive analysis of all splice variants of human TEM8 in 12 digestive tissues, and 8 each fetal and adult tissues, 6 of them cognate pairs. Using variant-specific primers, we first ascertained the status of full-length transcripts by nested PCR. We then carried out quantitative analysis of each transcript by real-time PCR. Three splice variants of TEM8 were reported before, two single-pass integral membrane forms (V1 and V2) and one secreted (V3). Our analysis has revealed two new variants, one encoding a membrane-bound form of the receptor and the other secreted, which we have designated V4 and V5, respectively. All tissues had V1, V2, V3, and V4, but only prostate had V5. Real-time PCR revealed that all variants are present at different levels in various tissues. V3 appeared the most abundant of all. To ascertain its functionality for anthrax toxin, we expressed the newly identified form V4 in a receptor-negative host cell, and included V1 and V2 for comparison. Cytotoxicity, toxin binding, and internalization assays showed V4 to be as efficient a receptor as V1 and V2. C1 [Vargas, Micaela; Karamsetty, Raghavendra; Chaudry, G. Jilani] Univ Texas San Antonio, Dept Biol, Cell & Mol Biol Program, San Antonio, TX USA. [Leppla, Stephen H.] NIAID, Microbial Pathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Vargas, M (reprint author), Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60680 USA. EM jilani.chaudry@utsa.edu FU University of Texas at San Antonio; San Antonio Area Foundation; National Institute of Allergy and Infectious Diseases/National Institute of General Medical Sciences [SC1AI081654]; Minority Biomedical Research Support-Research Initiative for Scientific Enhancement [GM60655] FX Funding for this work was provided to GJC by The University of Texas at San Antonio, San Antonio Area Foundation, and National Institute of Allergy and Infectious Diseases/National Institute of General Medical Sciences grant SC1AI081654 (Minority Biomedical Research Support-Support of Competitive Research). MV was supported for her PhD by the Minority Biomedical Research Support-Research Initiative for Scientific Enhancement grant GM60655 to the University of Texas at San Antonio. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 5 Z9 7 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 AUG 17 PY 2012 VL 7 IS 8 AR e43174 DI 10.1371/journal.pone.0043174 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 996DG UT WOS:000308063700055 PM 22912819 ER PT J AU Cui, HT Thomas, JD Burke, TR Rader, C AF Cui, Huiting Thomas, Joshua D. Burke, Terrence R., Jr. Rader, Christoph TI Chemically Programmed Bispecific Antibodies That Recruit and Activate T Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CANCER-THERAPY; ENGAGING ANTIBODY; TUMOR-CELLS; LYSIS; IMMUNOTHERAPY; THERAPEUTICS; GENERATION; RECEPTORS; INTEGRIN; BINDING AB Bispecific antibodies (biAbs) that mediate cytotoxicity by recruiting and activating endogenous immune cells are an emerging class of next-generation antibody therapeutics. Of particular interest are biAbs of relatively small size (similar to 50 kDa) that can redirect cytotoxic T cells through simultaneous binding of tumor cells. Here we describe a conceptually unique class of biAbs in which the tumor cell specificity of a humanized antibody fragment that recognizes CD3 on T cells is chemically programmed through a C-terminal selenocysteine (Sec) residue. We demonstrate that through chemically programmed specificity for integrin alpha(4)beta(1) or folate receptor 1 (FOLR1), and common specificity for CD3, these hybrid molecules exert potent and specific in vitro and ex vivo cytotoxicity toward tumor cell lines and primary tumor cells in the presence of primary T cells. Importantly, the generic nature of chemical programming allows one to apply our approach to virtually any specificity, promising a broad utility of chemically programmed biAbs in cancer therapy. C1 [Cui, Huiting; Rader, Christoph] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Thomas, Joshua D.; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Frederick Natl Lab Canc Res, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Rader, C (reprint author), Scripps Florida, Scripps Res Inst, Dept Canc Biol, 130 Scripps Way 2C1, Jupiter, FL 33458 USA. EM crader@scripps.edu RI Burke, Terrence/N-2601-2014 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported, in whole or in part, by the intramural research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 33 TC 11 Z9 11 U1 0 U2 23 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2012 VL 287 IS 34 BP 28206 EP 28214 DI 10.1074/jbc.M112.384594 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 996HD UT WOS:000308074600001 PM 22761439 ER PT J AU Doyle, SM Hoskins, JR Wickner, S AF Doyle, Shannon M. Hoskins, Joel R. Wickner, Sue TI DnaK Chaperone-dependent Disaggregation by Caseinolytic Peptidase B (ClpB) Mutants Reveals Functional Overlap in the N-terminal Domain and Nucleotide-binding Domain-1 Pore Tyrosine SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; PROTEIN DISAGGREGATION; SUBSTRATE RECOGNITION; AGGREGATED PROTEINS; ATP HYDROLYSIS; AAA; HSP104; THERMOTOLERANCE; ATPASES; HSP70 AB Protein disaggregation in Escherichia coli is carried out by ClpB, an AAA(+) (ATPases associated with various cellular activities) molecular chaperone, together with the DnaK chaperone system. Conformational changes in ClpB driven by ATP binding and hydrolysis promote substrate binding, unfolding, and translocation. Conserved pore tyrosines in both nucleotide-binding domain-1 (NBD-1) and -2 (NBD-2), which reside in flexible loops extending into the central pore of the ClpB hexamer, bind substrates. When the NBD-1 pore loop tyrosine is substituted with alanine (Y251A), ClpB can collaborate with the DnaK system in disaggregation, although activity is reduced. The N-domain has also been implicated in substrate binding, and like the NBD-1 pore loop tyrosine, it is not essential for disaggregation activity. To further probe the function and interplay of the ClpB N-domain and the NBD-1 pore loop, we made a double mutant with an N-domain deletion and a Y251A substitution. This ClpB double mutant is inactive in substrate disaggregation with the DnaK system, although each single mutant alone can function with DnaK. Our data suggest that this loss in activity is primarily due to a decrease in substrate engagement by ClpB prior to substrate unfolding and translocation and indicate an overlapping function for the N-domain and NBD-1 pore tyrosine. Furthermore, the functional overlap seen in the presence of the DnaK system is not observed in the absence of DnaK. For innate ClpB unfolding activity, the NBD-1 pore tyrosine is required, and the presence of the N-domain is insufficient to overcome the defect of the ClpB Y251A mutant. C1 [Doyle, Shannon M.; Hoskins, Joel R.; Wickner, Sue] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,Bldg 37,Rm 5144, Bethesda, MD 20892 USA. EM wickners@mail.nih.gov FU National Institutes of Health Intramural Research Program, NCI, Center for Cancer Research FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program, NCI, Center for Cancer Research. NR 45 TC 9 Z9 9 U1 2 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2012 VL 287 IS 34 BP 28470 EP 28479 DI 10.1074/jbc.M112.383091 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 996HD UT WOS:000308074600022 PM 22745126 ER PT J AU Ramakrishnan, B Boeggeman, E Qasba, PK AF Ramakrishnan, Boopathy Boeggeman, Elizabeth Qasba, Pradman K. TI Binding of N-Acetylglucosamine (GlcNAc) beta 1-6-branched Oligosaccharide Acceptors to beta 4-Galactosyltransferase I Reveals a New Ligand Binding Mode SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALPHA-LACTALBUMIN; CRYSTAL-STRUCTURE; LACTOSE SYNTHETASE; GALACTOSYLTRANSFERASE; BETA-1,4-GALACTOSYLTRANSFERASE-I; COMPLEX; MUTANT; IDENTIFICATION; SPECIFICITY; METASTASIS AB N-Acetyllactosamine is the most prevalent disaccharide moiety in the glycans on the surface of mammalian cells and often found as repeat units in the linear and branched polylactosamines, known as i- and I-antigen, respectively. The beta 1-4-galactosyltransferase- I (beta 4Gal-T1) enzyme is responsible for the synthesis of the N-acetyllactosamine moiety. To understand its oligosaccharide acceptor specificity, we have previously investigated the binding of tri- and pentasaccharides of N-glycan with a GlcNAc at their nonreducing end and found that the extended sugar moiety in these acceptor substrates binds to the crevice present at the acceptor substrate binding site of the beta 4Gal-T1 molecule. Here we report seven crystal structures of beta 4Gal-T1 in complex with an oligosaccharide acceptor with a nonreducing end GlcNAc that has a beta 1-6-glycosidic link and that are analogous to either N-glycan or i/I-antigen. In the crystal structure of the complex of beta 4Gal-T1 with I-antigen analog pentasaccharide, the beta 1-6-branched GlcNAc moiety is bound to the sugar acceptor binding site of the beta 4Gal-T1 molecule in a way similar to the crystal structures described previously; however, the extended linear tetrasaccharide moiety does not interact with the previously found extended sugar binding site on the beta 4Gal-T1 molecule. Instead, it interacts with the different hydrophobic surface of the protein molecule formed by the residues Tyr-276, Trp-310, and Phe-356. Results from the present and previous studies suggest that beta 4Gal-T1 molecule has two different oligosaccharide binding regions for the binding of the extended oligosaccharide moiety of the acceptor substrate. C1 [Ramakrishnan, Boopathy; Boeggeman, Elizabeth; Qasba, Pradman K.] NIH, Struct Glycobiol Sect, SAIC Frederick Inc,Ctr Canc Res Nanobiol Program, Ctr Canc Res,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Ramakrishnan, Boopathy; Boeggeman, Elizabeth] NIH, Basic Sci Program, SAIC Frederick Inc,Ctr Canc Res Nanobiol Program, Ctr Canc Res,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), Frederick Natl Lab, Struct Glycobiol Sect, CCRNP, CCR, Bldg 469,Rm 221, Frederick, MD 21702 USA. EM qasba@helix.nih.gov FU National Institutes of Health through the NCI [HHSN261200800001E]; National Institutes of Health, Frederick National Laboratory for Cancer Research FX This work was supported, in whole or in part, by National Institutes of Health Contract HHSN261200800001E through the NCI. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, Frederick National Laboratory for Cancer Research. NR 35 TC 3 Z9 3 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 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2012 VL 287 IS 34 BP 28666 EP 28674 DI 10.1074/jbc.M112.373514 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 996HD UT WOS:000308074600040 PM 22740701 ER PT J AU Colaianni, G Sun, L Di Benedetto, A Tamma, R Zhu, LL Cao, J Grano, M Yuen, T Colucci, S Cuscito, C Mancini, L Li, JH Nishimori, K Bab, I Lee, HJ Iqbal, J Young, WS Rosen, C Zallone, A Zaidi, M AF Colaianni, Graziana Sun, Li Di Benedetto, Adriana Tamma, Roberto Zhu, Ling-Ling Cao, Jay Grano, Maria Yuen, Tony Colucci, Sylvia Cuscito, Concetta Mancini, Lucia Li, Jianhua Nishimori, Katsuhiko Bab, Itai Lee, Heon-Jin Iqbal, Jameel Young, W. Scott, III Rosen, Clifford Zallone, Alberta Zaidi, Mone TI Bone Marrow Oxytocin Mediates the Anabolic Action of Estrogen on the Skeleton SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR; EXPRESSION; HORMONE; MICE; LACTATION; GENE; DIFFERENTIATION; PARTURITION; CELLS; ACTH AB Estrogen uses two mechanisms to exert its effect on the skeleton: it inhibits bone resorption by osteoclasts and, at higher doses, can stimulate bone formation. Although the antiresorptive action of estrogen arises from the inhibition of the MAPK JNK, the mechanism of its effect on the osteoblast remains unclear. Here, we report that the anabolic action of estrogen in mice occurs, at least in part, through oxytocin (OT) produced by osteoblasts in bone marrow. We show that the absence of OT receptors (OTRs) in OTR-/- osteoblasts or attenuation of OTR expression in silenced cells inhibits estrogen-induced osteoblast differentiation, transcription factor up-regulation, and/or OT production in vitro. In vivo, OTR-/- mice, known to have a bone formation defect, fail to display increases in trabecular bone volume, cortical thickness, and bone formation in response to estrogen. Furthermore, osteoblast-specific Col2.3-Cre(+)/OTRfl/fl mice, but not TRAP-Cre(+)/OTRfl/fl mice, mimic the OTR-/- phenotype and also fail to respond to estrogen. These data attribute the phenotype of OTR deficiency to an osteoblastic rather than an osteoclastic defect. Physiologically, feed-forward OT release in bone marrow by a rising estrogen concentration may facilitate rapid skeletal recovery during the latter phases of lactation. C1 [Colaianni, Graziana; Di Benedetto, Adriana; Tamma, Roberto; Grano, Maria; Colucci, Sylvia; Cuscito, Concetta; Mancini, Lucia; Zallone, Alberta] Univ Bari, Sch Med, Dept Human Anat & Histol, I-70124 Bari, Italy. [Colaianni, Graziana; Sun, Li; Zhu, Ling-Ling; Yuen, Tony; Li, Jianhua; Iqbal, Jameel; Zaidi, Mone] Mt Sinai Sch Med, Mt Sinai Bone Program, New York, NY 10029 USA. [Cao, Jay] Grand Forks Human Nutr Res Ctr, ARS, USDA, Grand Forks, ND 58201 USA. [Nishimori, Katsuhiko] Tohoku Univ, Grad Sch Agr Sci, Aoba Ku, Sendai, Miyagi 9818555, Japan. [Bab, Itai] Hebrew Univ Jerusalem, Bone Lab, IL-91120 Jerusalem, Israel. [Lee, Heon-Jin] Kyungpook Natl Univ, Dept Oral Microbiol, Sch Dent, Taegu 702701, South Korea. [Young, W. Scott, III] NIMH, Sect Neural Gene Express, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rosen, Clifford] Maine Med Ctr, Res Inst, Scarborough, ME 04074 USA. RP Zallone, A (reprint author), Univ Bari, Sch Med, Dept Human Anat & Histol, I-70124 Bari, Italy. EM alberta.zallone@fastwebnet.it; mone.zaidi@mssm.edu RI Young, W Scott/A-9333-2009; tamma, roberto/C-3679-2016; OI , Heon-Jin/0000-0002-1911-5014; Young, W Scott/0000-0001-6614-5112; Colaianni, Graziana/0000-0001-8501-5399; Grano, Maria/0000-0002-7121-5899 FU National Institutes of Health from NIA [AG023176, AG040132]; NIDDK [DK080459]; National Institute of Mental Health [Z01-MH-002498-23]; Italian Space Agency; European Space Agency; Ministero dell'Istruzione, dell'Universita della Ricerca; United States Department of Agriculture Agricultural Research Service [5450-51000-046-00D]; American Federation for Aging Research FX This work was supported, in whole or in part, by National Institutes of Health Grants AG023176 and AG040132 from NIA (to M. Z.) and DK080459 from NIDDK (to M. Z. and L. S.) and by National Institute of Mental Health Intramural Research Program Grant Z01-MH-002498-23 (to H.-J. L. and W. S. Y.). This work was also supported by grants from the Italian Space Agency (Osteoporosis and Muscular Atrophy Project), the European Space Agency (European Research in Space and Terrestrial Osteoporosis Microgravity Application Promotion Project), and the Ministero dell'Istruzione, dell'Universita della Ricerca (to A. Z.); by United States Department of Agriculture Agricultural Research Service Current Research Information System Program Grant 5450-51000-046-00D (to J. C.); and by the American Federation for Aging Research (to J. I.). NR 33 TC 26 Z9 28 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2012 VL 287 IS 34 BP 29159 EP 29167 DI 10.1074/jbc.M112.365049 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 996HD UT WOS:000308074600081 PM 22761429 ER PT J AU Boonnak, K Paskel, M Matsuoka, Y Vogel, L Subbarao, K AF Boonnak, Kobporn Paskel, Myeisha Matsuoka, Yumiko Vogel, Leatrice Subbarao, Kanta TI Evaluation of replication, immunogenicity and protective efficacy of a live attenuated cold-adapted pandemic H1N1 influenza virus vaccine in non-human primates SO VACCINE LA English DT Article DE Pandemic H1N1; Non-human primate; Influenza vaccine ID A H5N1 VIRUS; CYNOMOLGUS MACAQUES; RESPIRATORY-TRACT; INFECTION; PATHOLOGY; FERRETS; MODEL; MICE; STRAINS; MONKEYS AB We studied the replication of influenza A/California/07/09 (H1N1) wild type (CA09wt) virus in two non-human primate species and used one of these models to evaluate the immunogenicity and protective efficacy of a live attenuated cold-adapted vaccine, which contains the hemagglutinin and neuraminidase from the H1N1 wild type (wt) virus and six internal protein gene segments of the A/Ann Arbor/6/60 cold-adapted (Ca) master donor virus. We infected African green monkeys (AGMs) and rhesus macaques with 2 x 10(6) TCID50 of CA09wt and CA09ca influenza viruses. The virus CA09wt replicated in the upper respiratory tract of all animals but the titers in upper respiratory tract tissues of rhesus macaques were significant higher than in AGMs (mean peak titers 10(4.5) TCID50/g and 10(2.0) TCID50/g on days 4 and 2 post-infection, respectively: p<0.01). Virus replication was observed in the lungs of all rhesus macaques (10(2.0)-10(5.4) TCID50/g) whereas only 2 out of 4 AGMs had virus recovered from the lungs (10(2.5)-10(3.5) TCID50/g). The CA09ca vaccine virus was attenuated and highly restricted in replication in both AGMs and rhesus macaques. We evaluated the immunogenicity and protective efficacy of the CA09ca vaccine in rhesus macaques because CA09wt virus replicated more efficiently in this species. One or two doses of vaccine were administered intranasally and intratracheally to rhesus macaques. For the two-dose group, the vaccine was administered 4-weeks apart. Immunogenicity was assessed by measuring hemagglutination-inhibiting (HAI) antibodies in the serum and specific IgA antibodies to CA09wt virus in the nasal wash. One or two doses of the vaccine elicited a significant rise in HAI titers (range 40-320). Two doses of CA09ca elicited higher pH1N1-specific IgA titers than in the mock-immunized group (p<0.01). Vaccine efficacy was assessed by comparing titers of CA09wt challenge virus in the respiratory tract of mock-immunized and CA09ca vaccinated monkeys. Significantly lower virus titers were observed in the lungs of vaccinated animals than mock-immunized animals (p <= 0.01). Our results demonstrate that AGMs and rhesus macaques support the replication of pandemic H1N1 influenza virus to different degrees and a cold-adapted pH1N1 vaccine elicits protective immunity against pH1N1 virus infection in rhesus macaques. Published by Elsevier Ltd. C1 [Boonnak, Kobporn; Paskel, Myeisha; Matsuoka, Yumiko; Vogel, Leatrice; Subbarao, Kanta] NIAID, Emerging Resp Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Subbarao, K (reprint author), NIAID, Emerging Resp Viruses Sect, Infect Dis Lab, NIH, Bldg 33,Room 3E13C-1,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM KSUBBARAO@niaid.nih.gov FU Intramural Research Program of National Institute of Allergy and Infectious Diseases (NIAID), NIH FX This research was performed as part of a Cooperative Research and Development Agreement between the Laboratory of Infectious Diseases, NIAID and MedImmune. This work was supported in part by the Intramural Research Program of National Institute of Allergy and Infectious Diseases (NIAID), NIH. We would like to thank Jin Hong and George Kemble, MedImmune, Inc. for critical reading of this manuscript. NR 33 TC 11 Z9 11 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 17 PY 2012 VL 30 IS 38 BP 5603 EP 5610 DI 10.1016/j.vaccine.2012.06.088 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 000JF UT WOS:000308381900008 PM 22789506 ER PT J AU Patel, ES Okada, S Hachey, K Yang, LJ Durum, SK Moreb, JS Chang, LJ AF Patel, Ekta S. Okada, Starlyn Hachey, Kevin Yang, Li-jun Durum, Scott K. Moreb, Jan S. Chang, Lung-Ji TI Regulation of in vitro human T cell development through interleukin-7 deprivation and anti-CD3 stimulation SO BMC IMMUNOLOGY LA English DT Article DE T cell development; Interleukin-7; T cell receptor; Vbeta repertoire ID HEMATOPOIETIC STEM-CELLS; BLOOD CD34(+) CELLS; ALPHA-BETA CELLS; CORD BLOOD; BONE-MARROW; THYMOCYTE DIFFERENTIATION; PROGENITOR CELLS; GENE REARRANGEMENTS; FUNCTIONALLY MATURE; GROWTH-FACTOR AB Background: The role of IL-7 and pre-TCR signaling during T cell development has been well characterized in murine but not in human system. We and others have reported that human BM hematopoietic progenitor cells (HPCs) display poor proliferation, inefficient double negative (DN) to double positive (DP) transition and no functional maturation in the in vitro OP9-Delta-like 1 (DL1) culture system. Results: In this study, we investigated the importance of optimal IL-7 and pre-TCR signaling during adult human T cell development. Using a modified OP9-DL1 culture ectopically expressing IL-7 and Fms-like tyrosine kinase 3 ligand (Flt3L), we demonstrated enhanced T cell precursor expansion. IL-7 removal at various time points during T cell development promoted a slight increase of DP cells; however, these cells did not differentiate further and underwent cell death. As pre-TCR signaling rescues DN cells from programmed cell death, we treated the culture with anti-CD3 antibody. Upon pre-TCR stimulation, the IL-7 deprived T precursors differentiated into CD3(+)TCR alpha beta+DP cells and further matured into functional CD4 T cells, albeit displayed a skewed TCR V beta repertoire. Conclusions: Our study establishes for the first time a critical control for differentiation and maturation of adult human T cells from HPCs by concomitant regulation of IL-7 and pre-TCR signaling. C1 [Patel, Ekta S.; Okada, Starlyn; Hachey, Kevin; Chang, Lung-Ji] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. [Yang, Li-jun] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA. [Durum, Scott K.] NCI, Sect Cytokines & Immun, Gainesville, FL 32610 USA. [Moreb, Jan S.] Univ Florida, Coll Med, Dept Med, Gainesville, FL 32610 USA. RP Chang, LJ (reprint author), Univ Florida, Coll Med, Dept Mol Genet & Microbiol, 1600 SW Archer Rd,ARB R1-252, Gainesville, FL 32610 USA. EM lchang@mgm.ufl.edu FU NIH; amfAR grant [107768]; Yongling Foundation; flow cytometry fund of UF Shands Cancer Center FX We thank S. Williams, W. Chou, Dr. Shuhong Han and Yuling Yeh for technical assistance, Dr. Yung Chang and Dr. Lizi Wu for critical comments and reading the manuscript, and N. Benson for help with flow cytometry analysis. ESP was supported by NIH T32 graduate training grant. The study was supported by amfAR grant 107768, Yongling Foundation, and flow cytometry fund of UF Shands Cancer Center. NR 58 TC 2 Z9 3 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD AUG 16 PY 2012 VL 13 AR 46 DI 10.1186/1471-2172-13-46 PG 15 WC Immunology SC Immunology GA 037CB UT WOS:000311077500001 PM 22897934 ER PT J AU Lee, M Mandl, JN Germain, RN Yates, AJ AF Lee, Minyi Mandl, Judith N. Germain, Ronald N. Yates, Andrew J. TI The race for the prize: T-cell trafficking strategies for optimal surveillance SO BLOOD LA English DT Article ID LYMPH-NODES; DENDRITIC CELLS; RECIRCULATING LYMPHOCYTES; REPERTOIRE DIVERSITY; TCR REPERTOIRE; ANTIGEN; NAIVE; SURVIVAL; EGRESS; RECEPTOR AB The initiation of T-cell responses requires rare precursors to locate a draining lymph node (dLN) and encounter dendritic cells (DCs) presenting peptide-major histocompatibility complexes (pMHCs). To locate this needle in the haystack rapidly, T cells face an optimization problem-what is the most efficient trafficking strategy for surveillance and recirculation through blood? Two extremes are scanning low numbers of DCs per node with frequent recirculation, or meticulous surveillance with infrequent recirculation. Naive T cells also require stimulation by self-pMHCs. To enable efficient location of both foreign and self, has evolution settled on an optimum time for T cells to spend surveying each lymph node? Using a data-driven mathematical model, we show the most efficient strategy for detecting antigen in a dLN depends on its abundance. Detection of low-density antigen is optimized with systemically slow transit. In contrast, at high densities or if dLN egress is restricted, rapid transit through other nodes is optimal. We argue that blood-lymph recirculation dynamics facilitate a trade-off, and are consistent with dominant roles for the very early detection of rare foreign antigens in a dLN, and the efficient accumulation of signals from systemically distributed self-antigens. (Blood. 2012;120(7):1432-1438) C1 [Lee, Minyi; Yates, Andrew J.] Albert Einstein Coll Med, Dept Syst & Computat Biol, Bronx, NY 10461 USA. [Mandl, Judith N.; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Yates, Andrew J.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. RP Yates, AJ (reprint author), Albert Einstein Coll Med, Dept Syst & Computat Biol, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM andrew.yates@einstein.yu.edu FU National Institutes of Health [R01 AI093870-01] FX This study was supported by the National Institutes of Health (R01 AI093870-01 to A.J.Y.). NR 48 TC 11 Z9 11 U1 1 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 16 PY 2012 VL 120 IS 7 BP 1432 EP 1438 DI 10.1182/blood-2012-04-424655 PG 7 WC Hematology SC Hematology GA 009CA UT WOS:000309001900015 PM 22773385 ER PT J AU Backes, S Shapiro, JS Sabin, LR Pham, AM Reyes, I Moss, B Cherry, S tenOever, BR AF Backes, Simone Shapiro, Jillian S. Sabin, Leah R. Pham, Alissa M. Reyes, Ismarc Moss, Bernard Cherry, Sara tenOever, Benjamin R. TI Degradation of Host MicroRNAs by Poxvirus Poly(A) Polymerase Reveals Terminal RNA Methylation as a Protective Antiviral Mechanism SO CELL HOST & MICROBE LA English DT Article ID SMALL SILENCING RNAS; VACCINIA VIRUS; MESSENGER-RNAS; C-ELEGANS; 3' ENDS; BIOGENESIS; DROSOPHILA; MIRNAS; PROTEINS; SIRNAS AB The life cycle of several viruses involves host or virally encoded small noncoding RNAs, which play important roles in posttranscriptional regulation. Small noncoding RNAs include microRNAs (miRNAs), which modulate the transcriptome, and small interfering RNAs (siRNAs), which are involved in pathogen defense in plants, worms, and insects. We show that insect and mammalian poxviruses induce the degradation of host miRNAs. The virally encoded poly(A) polymerase, which polyadenylates viral transcripts, also mediates 3' polyadenylation of host miRNAs, resulting in their degradation by the host machinery. In contrast, siRNAs, which are protected by 2'O-methylation (2'OMe), were not targeted by poxviruses. These findings suggest that poxviruses may degrade host miRNAs to promote replication and that virus-mediated small RNA degradation likely contributed to 2'OMe evolution. C1 [Sabin, Leah R.; Cherry, Sara] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Backes, Simone; Shapiro, Jillian S.; Pham, Alissa M.; Reyes, Ismarc; tenOever, Benjamin R.] Mt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA. [Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Cherry, S (reprint author), Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. EM cherrys@mail.med.upenn.edu; benjamin.tenoever@mssm.edu OI Sabin, Leah/0000-0003-1757-7415 FU Burroughs Wellcome Fund; National Institutes of Health [R01AI074951, U54AI057168]; Army Research Office [59471LS] FX S.C. and B.R.t. acknowledge the gracious support of the Burroughs Wellcome Fund. This work was supported by grants from the National Institutes of Health (R01AI074951,U54AI057168) to S.C. and the Army Research Office (59471LS) to B.R.t. Additionally, we would like to thank Drs. G. Hannon (HHMI, Cold Spring Harbor Laboratories) for performing a subset of the deep sequencing, R. Condit (University of Florida, Gainesville) for the VACV E1L antibody, S.A. Perera (Great Lakes Forestry Centre, Ontario, Canada) for Amsacta moorei entomopoxvirus (AMEV), and R. Clem (Kansas State University, Manhattan, KS) for Amsacta moorei Ld652 cells. NR 75 TC 32 Z9 35 U1 1 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD AUG 16 PY 2012 VL 12 IS 2 BP 200 EP 210 DI 10.1016/j.chom.2012.05.019 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 998UM UT WOS:000308265900010 PM 22901540 ER PT J AU Grooman, B Fujiwara, I Otey, C Upadhyaya, A AF Grooman, Brian Fujiwara, Ikuko Otey, Carol Upadhyaya, Arpita TI Morphology and Viscoelasticity of Actin Networks Formed with the Mutually Interacting Crosslinkers: Palladin and Alpha-actinin SO PLOS ONE LA English DT Article ID CYTOSKELETAL POLYMER NETWORKS; F-ACTIN; MECHANICAL-PROPERTIES; FILAMENT NETWORKS; BINDING PROTEINS; CELL MECHANICS; GELS; DETERMINES; ELASTICITY; STIFFNESS AB Actin filaments and associated actin binding proteins play an essential role in governing the mechanical properties of eukaryotic cells. Even though cells have multiple actin binding proteins (ABPs) that exist simultaneously to maintain the structural and mechanical integrity of the cellular cytoskeleton, how these proteins work together to determine the properties of actin networks is not clearly understood. The ABP, palladin, is essential for the maintenance of cell morphology and the regulation of cell movement. Palladin coexists with alpha-actinin in stress fibers and focal adhesions and binds to both actin and alpha-actinin. To obtain insight into how mutually interacting actin crosslinking proteins modulate the properties of actin networks, we characterized the micro-structure and mechanics of actin networks crosslinked with palladin and alpha-actinin. We first showed that palladin crosslinks actin filaments into bundled networks which are viscoelastic in nature. Our studies also showed that composite networks of alpha-actinin/palladin/actin behave very similar to pure palladin or pure alpha-actinin networks. However, we found evidence that palladin and alpha-actinin synergistically modify network viscoelasticity. To our knowledge, this is the first quantitative characterization of the physical properties of actin networks crosslinked with two mutually interacting crosslinkers. C1 [Grooman, Brian] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Fujiwara, Ikuko] NHLBI, NIH, Bethesda, MD 20892 USA. [Otey, Carol] Univ N Carolina, Dept Cell & Mol Physiol, Chapel Hill, NC USA. [Upadhyaya, Arpita] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Upadhyaya, Arpita] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. RP Grooman, B (reprint author), Univ Maryland, Dept Phys, College Pk, MD 20742 USA. EM arpitau@umd.edu RI Fujiwara, Ikuko/H-5717-2016 OI Fujiwara, Ikuko/0000-0002-9361-636X FU Alfred P. Sloan Foundation; National Science Foundation [112170] FX This work has been supported by the Alfred P. Sloan Foundation and the National Science Foundation (Grant 112170). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 7 Z9 7 U1 1 U2 17 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 AUG 16 PY 2012 VL 7 IS 8 AR e42773 DI 10.1371/journal.pone.0042773 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 993AN UT WOS:000307824300015 PM 22916157 ER PT J AU Wang, XY Keefe, KM Jensen-Taubman, SM Yang, DL Yan, K Linnoila, RI AF Wang, Xiao-Yang Keefe, Kathleen M. Jensen-Taubman, Sandra M. Yang, Danlei Yan, Kai Linnoila, R. Ilona TI Novel Method for Isolation of Murine Clara Cell Secretory Protein-Expressing Cells with Traces of Stemness SO PLOS ONE LA English DT Article ID HUMAN AIRWAY EPITHELIUM; MOUSE LUNG; BRONCHIOLAR EPITHELIUM; IDENTIFICATION; DIFFERENTIATION; PROLIFERATION; DEFICIENCY; EXPOSURE; RENEWAL; NUMBER AB Clara cells are non-ciliated, secretory bronchiolar epithelial cells that serve to detoxify harmful inhaled substances. Clara cells also function as stem/progenitor cells for repair in the bronchioles. Clara cell secretory protein (CCSP) is specifically expressed in pulmonary Clara cells and is widely used as a Clara cell marker. In addition CCSP promoter is commonly used to direct gene expression into the lung in transgenic models. The discovery of CCSP immunoreactivity in plasma membranes of airway lining cells prompted us to explore the possibility of enriching Clara cells by flow cytometry. We established a novel and simple method for the isolation of CCSP-expressing cell Clara cells using a combination of mechanical and enzymatic dissociation followed by flow cytometry sorting technology. We showed that similar to 25% of dissociated cells from whole lung expressed CCSP. In the resulting preparation, up to 98% of cells expressed CCSP. Notably, we found that several common stem cell markers including CD44, CD133, Sca-1 and Sox2 were expressed in CCSP+ cells. Moreover, CCSP+ cells were able to form spheroid colonies in vitro with 0.97 parts per thousand efficiency. Parallel studies in vivo confirmed that a small population of CCSP- expressing cells in mouse airways also demonstrates stem cell-like properties such as label retention and harboring rare bronchioalveolar stem cells (BASCs) in terminal bronchioles (TBs). We conclude that CCSP+ cells exhibit a number of stem cell-like features including stem cell marker expression, bronchosphere colony formation and self-renewal ability. Clara cell isolation by flow cytometry sorting is a useful method for investigating the function of primary Clara cells in stem cell research and mouse models. C1 [Wang, Xiao-Yang; Keefe, Kathleen M.; Jensen-Taubman, Sandra M.; Yang, Danlei; Yan, Kai; Linnoila, R. Ilona] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wang, XY (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM xiaoyangwang@gmail.com; Linnoila@mail.nih.gov FU National Cancer Institute at the National Institutes of Health FX This study was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 3 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 AUG 16 PY 2012 VL 7 IS 8 AR e43008 DI 10.1371/journal.pone.0043008 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 993AN UT WOS:000307824300024 PM 22916196 ER PT J AU Ostrander, EA AF Ostrander, Elaine A. TI Both Ends of the Leash - The Human Links to Good Dogs with Bad Genes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID GENOME-WIDE ASSOCIATION; ROD-CONE DEGENERATION; LEBER CONGENITAL AMAUROSIS; HOGG-DUBE-SYNDROME; DOMESTIC DOG; RENAL CYSTADENOCARCINOMA; RETINITIS-PIGMENTOSA; CHILDHOOD BLINDNESS; HISTIOCYTIC SARCOMA; CANINE EPILEPSY C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Ostrander, EA (reprint author), NHGRI, NIH, 50 South Dr,Bldg 50,Rm 5351, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU Intramural NIH HHS [ZIA HG200377-01] NR 86 TC 28 Z9 28 U1 0 U2 43 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 AUG 16 PY 2012 VL 367 IS 7 BP 636 EP 646 DI 10.1056/NEJMra1204453 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 988NB UT WOS:000307496600007 PM 22894576 ER PT J AU Moore, HM Kelly, A McShane, LM Vaught, J AF Moore, Helen M. Kelly, Andrea McShane, Lisa M. Vaught, Jim TI Biospecimen reporting for improved study quality (BRISQ) SO CLINICA CHIMICA ACTA LA English DT Letter C1 [Moore, Helen M.; Vaught, Jim] NCI, Off Biorepositories & Biospecimen Res, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Kelly, Andrea] Rose Li & Associates Inc, Bethesda, MD USA. [McShane, Lisa M.] NCI, Biometr Res Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Moore, HM (reprint author), NCI, Off Biorepositories & Biospecimen Res, NIH, US Dept HHS, 11400 Rockville Pike,Suite 700, Bethesda, MD 20892 USA. EM moorehe@mail.nih.gov NR 4 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD AUG 16 PY 2012 VL 413 IS 15-16 BP 1305 EP 1305 DI 10.1016/j.cca.2012.04.013 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 960EH UT WOS:000305370300029 PM 22543057 ER PT J AU Sitaram, A Dennis, MK Chaudhuri, R De Jesus-Rojas, W Tenza, D Setty, SRG Wood, CS Sviderskaya, EV Bennett, DC Raposo, G Bonifacino, JS Marks, MS AF Sitaram, Anand Dennis, Megan K. Chaudhuri, Rittik De Jesus-Rojas, Wilfredo Tenza, Daniele Setty, Subba Rao Gangi Wood, Christopher S. Sviderskaya, Elena V. Bennett, Dorothy C. Raposo, Graca Bonifacino, Juan S. Marks, Michael S. TI Differential recognition of a dileucine-based sorting signal by AP-1 and AP-3 reveals a requirement for both BLOC-1 and AP-3 in delivery of OCA2 to melanosomes SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID LYSOSOME-RELATED ORGANELLES; HERMANSKY-PUDLAK-SYNDROME; SUSCEPTIBILITY FACTOR DYSBINDIN; VIRUS TYPE-1 NEF; DI-LEUCINE; PROTEIN TRAFFICKING; MEMBRANE-PROTEINS; SKIN PIGMENTATION; SYNAPTIC VESICLES; COMPLEX-1 BLOC-1 AB Cell types that generate unique lysosome-related organelles (LROs), such as melanosomes in melanocytes, populate nascent LROs with cargoes that are diverted from endosomes. Cargo sorting toward melanosomes correlates with binding via cytoplasmically exposed sorting signals to either heterotetrameric adaptor AP-1 or AP-3. Some cargoes bind both adaptors, but the relative contribution of each adaptor to cargo recognition and their functional interactions with other effectors during transport to melanosomes are not clear. Here we exploit targeted mutagenesis of the acidic dileucine-based sorting signal in the pigment cell-specific protein OCA2 to dissect the relative roles of AP-1 and AP-3 in transport to melanosomes. We show that binding to AP-1 or AP-3 depends on the primary sequence of the signal and not its position within the cytoplasmic domain. Mutants that preferentially bound either AP-1 or AP-3 each trafficked toward melanosomes and functionally complemented OCA2 deficiency, but AP-3 binding was necessary for steady-state melanosome localization. Unlike tyrosinase, which also engages AP-3 for optimal melanosomal delivery, both AP-1- and AP-3-favoring OCA2 variants required BLOC-1 for melanosomal transport. These data provide evidence for distinct roles of AP-1 and AP-3 in OCA2 transport to melanosomes and indicate that BLOC-1 can cooperate with either adaptor during cargo sorting to LROs. C1 [Sitaram, Anand; Dennis, Megan K.; De Jesus-Rojas, Wilfredo; Setty, Subba Rao Gangi; Wood, Christopher S.; Marks, Michael S.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Sitaram, Anand; Dennis, Megan K.; De Jesus-Rojas, Wilfredo; Setty, Subba Rao Gangi; Wood, Christopher S.; Marks, Michael S.] Univ Penn, Dept Physiol, Philadelphia, PA 19104 USA. [Sitaram, Anand] Univ Penn, Cell & Mol Biol Grad Grp, Philadelphia, PA 19104 USA. [Chaudhuri, Rittik; Bonifacino, Juan S.] NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. [Tenza, Daniele; Raposo, Graca] Inst Curie, Sect Rech, F-75005 Paris, France. [Tenza, Daniele; Raposo, Graca] CNRS, UMR 144, F-75005 Paris, France. [Sviderskaya, Elena V.; Bennett, Dorothy C.] Univ London, Biomed Sci Res Ctr, London SW17 0RE, England. RP Marks, MS (reprint author), Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM marksm@mail.med.upenn.edu RI Bennett, Dorothy/C-2418-2008; OI Bennett, Dorothy/0000-0002-3639-7527; Dennis, Megan/0000-0002-8986-5021; Marks, Michael/0000-0001-7435-7262; Bonifacino, Juan S./0000-0002-5673-6370 FU National Institutes of Health Grant from the National Eye Institute [R01 EY015625]; Institut Curie and Centre National de la Recherche Scientifique; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Wellcome Trust [078327]; [T32 GM007229]; [T32 HL007971]; [K12 GM081259] FX We thank Victor Faundez and Andrew Peden for generous gifts of antibodies. This work was supported by National Institutes of Health Grant R01 EY015625 from the National Eye Institute (to M.S.M.), Training Grants T32 GM007229 and T32 HL007971 (for A.S.) and K12 GM081259 (for M.K.D.), the Institut Curie and Centre National de la Recherche Scientifique (for G.R.), the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (for J.S.B.), and Wellcome Trust Grant 078327 (to E.V.S. and D.C.B.). NR 70 TC 19 Z9 21 U1 0 U2 7 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG 15 PY 2012 VL 23 IS 16 BP 3178 EP 3192 DI 10.1091/mbc.E11-06-0509 PG 15 WC Cell Biology SC Cell Biology GA 052SX UT WOS:000312219900015 PM 22718909 ER PT J AU Qiu, HF Hu, CH Gaur, NA Hinnebusch, AG AF Qiu, Hongfang Hu, Cuihua Gaur, Naseem A. Hinnebusch, Alan G. TI Pol II CTD kinases Bur1 and Kin28 promote Spt5 CTR-independent recruitment of Paf1 complex SO EMBO JOURNAL LA English DT Article DE CTD; Paf1C; Spt5; transcription elongation ID RNA-POLYMERASE-II; C-TERMINAL DOMAIN; COTRANSCRIPTIONAL HISTONE MODIFICATION; TRANSCRIPTION TERMINATION; H2B MONOUBIQUITINATION; ELONGATION; PHOSPHORYLATION; METHYLATION; ASSOCIATION; SUBUNIT AB Paf1 complex (Paf1C) is a transcription elongation factor whose recruitment is stimulated by Spt5 and the CDKs Kin28 and Bur1, which phosphorylate the Pol II C-terminal domain (CTD) on Serines 2, 5, and 7. Bur1 promotes Paf1C recruitment by phosphorylating C-terminal repeats (CTRs) in Spt5, and we show that Kin28 enhances Spt5 phosphorylation by promoting Bur1 recruitment. It was unclear, however, whether CTD phosphorylation by Kin28 or Bur1 also stimulates Paf1C recruitment. We find that Paf1C and its Cdc73 subunit bind diphosphorylated CTD repeats (pCTD) and phosphorylated Spt5 CTRs (pCTRs) in vitro, and that cdc73 mutations eliminating both activities reduce Paf1C recruitment in vivo. Phosphomimetic (acidic) substitutions in the Spt5 CTR sustain high-level Paf1C recruitment in otherwise wild-type cells, but not following inactivation of Bur1 or Kin28. Furthermore, inactivating the pCTD/pCTR-interaction domain (PCID) in Cdc73 decreases Paf1C-dependent histone methylation in cells containing non-phosphorylatable Spt5 CTRs. These results identify an Spt5 pCTR-independent pathway of Paf1C recruitment requiring Kin28, Bur1, and the Cdc73 PCID. We propose that pCTD repeats and Spt5 pCTRs provide separate interaction surfaces that cooperate to ensure high-level Paf1C recruitment. The EMBO Journal (2012) 31, 3494-3505. doi:10.1038/emboj.2012.188; Published online 13 July 2012 C1 [Qiu, Hongfang; Hu, Cuihua; Gaur, Naseem A.; Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, Bethesda, MD USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bldg 6,Room 230, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov OI Gaur, Naseem/0000-0002-1224-8789 FU Intramural Research Program of the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) FX We thank Tom Dever for excellent suggestions and advice; Fred Winston and Steven Hahn for plasmids; and Karen Arndt, Grant Hartzog, and Steven Hahn for antibodies. We also appreciate Kevan Shokat's kind gift of 3MB-PP1 at the outset of this study. We thank Andy VanDemark and Karen Arndt for critical reading of the manuscript and for communicating results prior to publication. This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH). NR 43 TC 28 Z9 28 U1 0 U2 9 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 AUG 15 PY 2012 VL 31 IS 16 BP 3494 EP 3505 DI 10.1038/emboj.2012.188 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 993SK UT WOS:000307879700013 PM 22796944 ER PT J AU Leandri, M Ghignotti, M Emionite, L Leandri, S Cilli, M AF Leandri, Massimo Ghignotti, Mariaisabella Emionite, Laura Leandri, Silia Cilli, Michele TI Electrophysiological features of the mouse tail nerves and their changes in chemotherapy induced peripheral neuropathy (CIPN) SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Tail nerve; Mouse; Compound action potential; Neuropathy; Chemotherapy ID SENSORY NEUROPATHY; AXONAL-TRANSPORT; RAT; CONDUCTION; MICE; TAXOL; IMPULSES; NEURONS AB Electrophysiology of tail nerves in rodents has been demonstrated a reliable method to investigate models of peripheral neuropathies. Nevertheless, data concerning mouse models are lacking. We assessed the normal features of sensory and motor conduction of tail nerves in adult mice. We found that, as in rats, a sensory compound action potential and motor responses could be recorded with the non invasive and highly reliable technique proposed, especially if bipolar derivations were used. We also investigated the changes related to chemotherapy induced peripheral neuropathy (CIPN) after paclitaxel treatment (times 1 and 2), compared to pre-treatment (time 0) and to controls. It was found that only the sensory compound action potential was involved in CIPN, with decrease in amplitude and conduction velocity, suggesting a significant reduction in number of fast conducting fibres and a correspondent increase in the number of slow conducting ones, although the total amount of active myelinated fibres was deemed to be unchanged through time 0, time 1 and time 2. The results obtained in CIPN provide new functional evidence about the involvement of sensory fibres and may help in better understanding the underlying mechanisms. (C) 2012 Elsevier B.V. All rights reserved. C1 [Leandri, Massimo; Ghignotti, Mariaisabella; Leandri, Silia] Univ Genoa, Interuniv Ctr Pain Neurophysiol, I-16146 Genoa, Italy. [Leandri, Massimo] Univ Genoa, Dept Neurosci Rehabil Ophtalmol & Genet, I-16132 Genoa, Italy. [Emionite, Laura; Cilli, Michele] Natl Canc Inst, Anim Facil, I-16132 Genoa, Italy. RP Leandri, M (reprint author), Univ Genoa, Interuniv Ctr Pain Neurophysiol, Via Dodecaneso 35, I-16146 Genoa, Italy. EM massimo.leandri@unige.it OI Leandri, Massimo/0000-0002-5197-7431 FU CIND; Italian Ministry of Health (OnRehab project) FX This work has been carried out at the Interuniversity Centre for Pain Neurophysiology (CIND), University of Genova, and at the Animal Facility, National Cancer Institute, Genova. Funding has been provided by CIND, with statutory funds, and by the Italian Ministry of Health (OnRehab project). NR 24 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD AUG 15 PY 2012 VL 209 IS 2 BP 403 EP 409 DI 10.1016/j.jneumeth.2012.07.005 PG 7 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 007OL UT WOS:000308897900018 PM 22800858 ER PT J AU Yin, JJ Liu, J Ehrenshaft, M Roberts, JE Fu, PP Mason, RP Zhao, BZ AF Yin, Jun-Jie Liu, Jun Ehrenshaft, Marilyn Roberts, Joan E. Fu, Peter P. Mason, Ronald P. Zhao, Baozhong TI Phototoxicity of nano titanium dioxides in HaCaT keratinocytes-Generation of reactive oxygen species and cell damage SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE TiO2 nanoparticles; Phototoxicity; Reactive oxygen species (ROS); Lipid peroxidation; Human HaCaT keratinocytes; ESR; Oximetry; Immuno-spin trapping ID PROTEIN RADICAL FORMATION; SINGLET OXYGEN; PHOTOCATALYTIC ACTIVITY; TIO2 NANOPARTICLES; OXIDATIVE STRESS; IN-VITRO; TOXICITY; EPR; UVA; CYTOTOXICITY AB Nano-sized titanium dioxide (TiO2) is among the top five widely used nanomaterials for various applications. In this study, we determine the phototoxicity of TiO2 nanoparticles (nano-TiO2) with different molecular sizes and crystal forms (anatase and rutile) in human skin keratinocytes under UVA irradiation. Our results show that all nano-TiO2 particles caused phototoxicity, as determined by the MIS assay and by cell membrane damage measured by the lactate dehydrogenase (LDH) assay, both of which were UVA dose- and nano-TiO2 dose-dependent. The smaller the particle size of the nano-TiO2 the higher the cell damage. The rutile form of nano-TiO2 showed less phototoxicity than anatase nano-TiO2. The level of photocytotoxicity and cell membrane damage is mainly dependent on the level of reactive oxygen species (ROS) production. Using polyunsaturated lipids in plasma membranes and human serum albumin as model targets, and employing electron spin resonance (ESR) oximetry and immuno-spin trapping as unique probing methods, we demonstrated that UVA irradiation of nano-TiO2 can induce significant cell damage, mediated by lipid and protein peroxidation. These overall results suggest that nano-TiO2 is phototoxic to human skin keratinocytes, and that this phototoxicity is mediated by ROS generated during UVA irradiation. (C) 2012 Elsevier Inc. All rights reserved. C1 [Liu, Jun; Zhao, Baozhong] Natl Ctr Nanosci & Technol, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100190, Peoples R China. [Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Ehrenshaft, Marilyn; Mason, Ronald P.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Roberts, Joan E.] Fordham Univ, New York, NY 10023 USA. [Fu, Peter P.] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Zhao, BZ (reprint author), Natl Ctr Nanosci & Technol, CAS Key Lab Biomed Effects Nanomat & Nanosafety, Beijing 100190, Peoples R China. EM zhaobz@nanoctr.cn RI Zhao, Baozhong/B-5865-2011; Yin, Jun Jie /E-5619-2014 FU FY11 FDA Nanotechnology CORES Program; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX This article is not an official US Food and Drug Administration (FDA) guidance or policy statement. No official support or endorsement by the US FDA is intended or should be inferred. This work was supported by a regulatory science grant under the FY11 FDA Nanotechnology CORES Program (JJ Yin) and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The authors are indebted to Dr. Jianxun Xu for his help in SEM image analysis, Dr. Zhanjun Gu, Yeteng Zhong for their help in XRD analysis, and Dr. Ann Motten, NIEHS, for critical reading of the manuscript. NR 42 TC 57 Z9 60 U1 4 U2 56 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 15 PY 2012 VL 263 IS 1 BP 81 EP 88 DI 10.1016/j.taap.2012.06.001 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 984RK UT WOS:000307208900011 PM 22705594 ER PT J AU Zhan, LJ Zhang, H Zhang, Q Woods, CG Chen, YY Xue, P Dong, J Tokar, EJ Xu, YY Hou, YY Fu, JQ Yarborough, K Wang, AP Qu, WD Waalkes, MP Andersen, ME Pi, JB AF Zhan, Lijuan Zhang, Hao Zhang, Qiang Woods, Courtney G. Chen, Yanyan Xue, Peng Dong, Jian Tokar, Erik J. Xu, Yuanyuan Hou, Yongyong Fu, Jingqi Yarborough, Kathy Wang, Aiping Qu, Weidong Waalkes, Michael P. Andersen, Melvin E. Pi, Jingbo TI Regulatory role of KEAP1 and NRF2 in PPAR gamma expression and chemoresistance in human non-small-cell lung carcinoma cells SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE NRF2; KEAP1; PPAR gamma; Arsenic trioxide; Chemoresistance; NSCLC; Lung cancer; Free radicals ID ACTIVATED RECEPTOR-GAMMA; INDUCED ANTIOXIDANT RESPONSE; ACUTE PROMYELOCYTIC LEUKEMIA; CANCER STEM-CELLS; IN-VITRO; A549 CELLS; HUMAN KERATINOCYTES; ADAPTIVE RESPONSE; ARSENIC TRIOXIDE; SIDE-POPULATION AB The nuclear factor-E2-related factor 2 (NRF2) serves as a master regulator in cellular defense against oxidative stress and chemical detoxification. However, persistent activation of NRF2 resulting from mutations in NRF2 and/or downregulation of or mutations in its suppressor, Kelch-like ECH-associated protein 1 (KEAP1), is associated with tumorigenicity and chemoresistance of non-small-cell lung carcinomas (NSCLCs). Thus, inhibiting the NRF2-mediated adaptive antioxidant response is widely considered a promising strategy to prevent tumor growth and reverse chemoresistance in NSCLCs. Unexpectedly, stable knockdown of KEAP1 by lentiviral shRNA sensitized three independent NSCLC cell lines (A549, HTB-178, and HTB-182) to multiple chemotherapeutic agents, including arsenic trioxide (As2O3), etoposide, and doxorubicin, despite moderately increased NRF2 levels. In lung adenocarcinoma epithelial A549 cells, silencing of KEAP1 augmented the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma) and genes associated with cell differentiation, including E-cadherin and gelsolin. In addition, KEAP1-knockdown A549 cells displayed attenuated expression of the proto-oncogene cyclin D1 and markers for cancer stem cells (CSCs) and reduced nonadherent sphere formation. Moreover, deficiency of KEAP1 led to elevated induction of PPAR gamma in response to As2O3. Pretreatment of A549 cells with PPAR gamma agonists activated PPAR gamma and augmented the cytotoxicity of As2O3. A mathematical model was formulated to advance a hypothesis that differential regulation of PPAR gamma and detoxification enzymes by KEAP1 and NRF2 may underpin the observed landscape changes in chemosensitivity. Collectively, suppression of KEAP1 expression in human NSCLC cells resulted in sensitization to chemotherapeutic agents, which may be attributed to activation of PPAR gamma and subsequent alterations in cell differentiation and CSC abundance. (C) 2012 Elsevier Inc. All rights reserved. C1 [Zhan, Lijuan; Zhang, Hao; Zhang, Qiang; Woods, Courtney G.; Chen, Yanyan; Xue, Peng; Dong, Jian; Hou, Yongyong; Fu, Jingqi; Yarborough, Kathy; Andersen, Melvin E.] Hamner Inst Hlth Sci, Inst Chem Safety Sci, Res Triangle Pk, NC 27709 USA. [Zhan, Lijuan; Wang, Aiping; Pi, Jingbo] Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China. [Zhan, Lijuan; Wang, Aiping; Pi, Jingbo] Peking Union Med Coll, Beijing 100021, Peoples R China. [Zhang, Hao; Qu, Weidong] Fudan Univ, Sch Publ Hlth, Shanghai 200433, Peoples R China. [Chen, Yanyan] China Med Univ, Sch Clin Sci 1, Shenyang, Peoples R China. [Tokar, Erik J.; Xu, Yuanyuan; Waalkes, Michael P.] NIEHS, Natl Toxicol Program Labs, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Zhang, Q (reprint author), Hamner Inst Hlth Sci, Inst Chem Safety Sci, Res Triangle Pk, NC 27709 USA. EM qzhang@thehamner.org; jpi@thehamner.org RI xue, peng/K-4159-2015; OI Andersen, Melvin/0000-0002-3894-4811 FU NIH [ES016005]; DOW Chemical Co.; Unilever; American Chemical Council FX This research was supported in part by the NIH Grant ES016005 (to J.P.), the DOW Chemical Co. (to M.E.A.), and Unilever (to M.E.A.). We are grateful for Drs. Bin Sun and Joe Trask for their technical assistance. The content is solely the responsibility of the authors. All authors have agreed to its content. M.E.A. received some funding from DOW Chemical Co. and Unilever. L.Z., HZ., Q.Z., C.G.W., P.X., Y.H., J.F., K.Y., M.E.A., and J.P. are employees of The Hamner Institutes for Health Sciences. The Hamner is a 501(c)3 not-for-profit organization that has a diverse research portfolio that includes funding from the American Chemical Council, a trade association that represents chemical manufacturers. 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 the NIEHS, the NIH, or the U.S. government. NR 54 TC 25 Z9 26 U1 2 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG 15 PY 2012 VL 53 IS 4 BP 758 EP 768 DI 10.1016/j.freeradbiomed.2012.05.041 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 994GY UT WOS:000307920100012 PM 22684020 ER PT J AU Tanaka, M Jaruga, P Kupfer, PA Leumann, CJ Dizdaroglu, M Sonntag, WE Chock, PB AF Tanaka, Mikiei Jaruga, Pawel Kuepfer, Pascal A. Leumann, Christian J. Dizdaroglu, Miral Sonntag, William E. Chock, P. Boon TI RNA oxidation catalyzed by cytochrome c leads to its depurination and cross-linking, which may facilitate cytochrome c release from mitochondria SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE RNA oxidation; Cytochrome c release; Cross-link; Abasic site; 8-Hydroxyguanosine; Free radicals ID MILD COGNITIVE IMPAIRMENT; DNA-POLYMERASE BETA; HYDROGEN-PEROXIDE; MESSENGER-RNA; MAMMALIAN CHROMATIN; INTERMEMBRANE SPACE; ALZHEIMERS-DISEASE; MASS-SPECTROMETRY; ABASIC SITES; EARLY EVENT AB Growing evidence indicates that RNA oxidation is correlated with a number of age-related neurodegenerative diseases, and RNA oxidation has also been shown to induce dysfunction in protein synthesis. Here we study in vitro RNA oxidation catalyzed by cytochrome c (cyt c)/H2O2 or by the Fe(II)/ascorbate/H2O2 system. Our results reveal that the products of RNA oxidation vary with the oxidant used. Guanosine residues are preferentially oxidized by cyt c/H2O2 relative to the Fe(II)/ascorbate/H2O2 system. GC/MS and LC/MS analyses demonstrated that the guanine base was not only oxidized but also depurinated to form an abasic sugar moiety. Results from gel electrophoresis and HPLC analyses show that RNA formed a crosslinked complex with cyt c in an H2O2 concentration-dependent manner. Furthermore, when cyt c was associated with liposomes composed of cardiolipin/phosphatidylcholine, and incubated with RNA and H2O2, it was found cross-linked with the oxidized RNA and dissociated from the liposome. Results of the quantitative analysis indicate that the release of the cyt c from the liposome is facilitated by the formation of an RNA-cyt c cross-linked complex. Thus, RNA oxidation may facilitate the release of cyt c from the mitochondrial membrane to induce apoptosis in response to oxidative stress. Published by Elsevier Inc. C1 [Tanaka, Mikiei; Chock, P. Boon] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. [Tanaka, Mikiei; Sonntag, William E.] Univ Oklahoma, Hlth Sci Ctr, Dept Geriatr Med, Reynolds Oklahoma Ctr Aging, Oklahoma City, OK 73104 USA. [Jaruga, Pawel; Dizdaroglu, Miral] NIST, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. [Kuepfer, Pascal A.; Leumann, Christian J.] Univ Bern, Dept Chem & Biochem, CH-3012 Bern, Switzerland. RP Chock, PB (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3, Bethesda, MD 20892 USA. EM mikiei.tanaka@usuhs.edu; bchock@nih.gov RI Jaruga, Pawel/M-4378-2015; OI Leumann, Christian/0000-0002-7996-7083 FU National Institutes of Health [AG11370, NS056218]; National Heart, Lung, and Blood Institute FX The authors acknowledge the late Dr. Earl R. Stadtman, an eminent scientist and a distinguished mentor, for his initiation and support of this project. This research was supported, in whole, by the Intramural Research Program of the National Institutes of Health; National Heart, Lung, and Blood Institute; and NIH Grants AG11370 and NS056218. Certain commercial equipment or materials are identified in this paper to specify the experimental procedure. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose. NR 56 TC 2 Z9 2 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG 15 PY 2012 VL 53 IS 4 BP 854 EP 862 DI 10.1016/j.freeradbiomed.2012.05.044 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 994GY UT WOS:000307920100022 PM 22683603 ER PT J AU Lok, B Khan, S Mutter, R Liu, J Fields, R Pulitzer, M Shi, WJ Zhang, ZG Kraus, D Pfister, D Busam, KJ Brownell, I Lee, N AF Lok, Benjamin Khan, Sabrina Mutter, Robert Liu, Jeffrey Fields, Ryan Pulitzer, Melissa Shi, Weiji Zhang, Zhigang Kraus, Dennis Pfister, David Busam, Klaus J. Brownell, Isaac Lee, Nancy TI Selective radiotherapy for the treatment of head and neck Merkel cell carcinoma SO CANCER LA English DT Article DE Merkel cell; carcinoma; radiotherapy; recurrence; survival; head and neck; radiation; neuroendocrine ID LYMPH-NODE BIOPSY; SINGLE INSTITUTION; SKIN; RADIATION; EXPERIENCE; PROGNOSIS; SURVIVAL; FEATURES; RISK AB BACKGROUND. The role of radiotherapy (RT) in the management of Merkel cell carcinoma (MCC) is controversial. The authors of this report evaluated the rates and patterns of failure in a selected group of patients who underwent RT for MCC of the head and neck (HN). METHODS. The records of 145 consecutive patients with MCC of the HN who presented to the authors' institution between 1988 and 2009 were reviewed. Only patients who received RT at the institution were included. The cumulative incidence of locoregional failure (LRF), distant metastatic failure (DMF), disease progression (DP) and disease-specific death (DSD) were estimated with death as a competing risk. RESULTS. Forty-eight patients were identified. The median follow-up was 51 months (range, 6-220 months) for living patients. LRF developed in 5 patients (10%), and those patients had a median time to recurrence of 3 months. Two of the 5 LRFs were local and developed at the edge of the treatment field; the remaining 3 LRFs were in lymph nodes and occurred outside the treatment field. DMF developed in 12 patients (25%). The estimated 5-year cumulative incidences of LRF, DP, and DSD were 10%, 30%, and 21%, respectively. Acute toxicities included 5 episodes (10%) of grade 3 dermatitis and 1 episode (2%) of grade 3 mucositis. CONCLUSIONS. The authors report a site-specific series of patients with HN MCC who received RT. In this group of patients with adverse features, RT was well tolerated, and LRF was low. The propensity for MCC to recur at the edge of the treatment field suggests that generous margins are appropriate when RT is administered. Cancer 2012. (c) 2011 American Cancer Society. C1 [Lok, Benjamin; Khan, Sabrina; Mutter, Robert; Lee, Nancy] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10065 USA. [Lok, Benjamin; Khan, Sabrina; Mutter, Robert; Lee, Nancy] NYU, Sch Med, New York, NY USA. [Liu, Jeffrey] Temple Univ, Dept Otolaryngol, Philadelphia, PA 19122 USA. [Fields, Ryan] Mem Sloan Kettering Canc Ctr, Dept Surg, Gastr & Mixed Tumor Serv, New York, NY 10065 USA. [Pulitzer, Melissa; Busam, Klaus J.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Shi, Weiji; Zhang, Zhigang] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Kraus, Dennis] Mem Sloan Kettering Canc Ctr, Head & Neck Serv, Dept Surg, New York, NY 10065 USA. [Pfister, David] Mem Sloan Kettering Canc Ctr, Head & Neck Med Oncol Serv, Dept Med, New York, NY 10065 USA. [Brownell, Isaac] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, N (reprint author), Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10065 USA. EM leen2@mskcc.org NR 24 TC 7 Z9 7 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2012 VL 118 IS 16 BP 3937 EP 3944 DI 10.1002/cncr.26738 PG 8 WC Oncology SC Oncology GA 983JZ UT WOS:000307116900011 PM 22180314 ER PT J AU Prickett, TD Samuels, Y AF Prickett, Todd D. Samuels, Yardena TI Molecular Pathways: Dysregulated Glutamatergic Signaling Pathways in Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID PROTEIN-COUPLED RECEPTORS; METASTATIC MELANOMA; NMDA RECEPTORS; GLIOMA-CELLS; IN-VIVO; METABOTROPIC GLUTAMATE-RECEPTOR-1; PHARMACOLOGICAL BLOCKADE; THERAPEUTIC TARGET; HUMAN MELANOCYTES; BRAF INHIBITORS AB The neurotransmitter glutamate interacts with glutamate receptor proteins, leading to the activation of multiple signaling pathways. Dysfunction in the glutamatergic signaling pathway is well established as a frequent player in diseases such as schizophrenia, Alzheimer disease, and brain tumors (gliomas). Recently, aberrant functioning of this pathway has also been shown in melanoma. In both glioma and melanoma, glutamate secretion stimulates tumor growth, proliferation, and survival through activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase/Akt pathways. In the future, extracellular glutamate levels and glutamatergic signaling may serve as biological markers for tumorigenicity and facilitate targeted therapy for melanoma. Clin Cancer Res; 18(16); 4240-6. (C) 2012 AACR. C1 [Prickett, Todd D.; Samuels, Yardena] NHGRI, NIH, Bethesda, MD 20892 USA. RP Samuels, Y (reprint author), NHGRI, NIH, Bldg 50,Room 5140,50 South Dr,MSC 8000, Bethesda, MD 20892 USA. EM samuelsy@mail.nih.gov FU National Human Genome Research Institute, National Institutes of Health FX Intramural Research Program, National Human Genome Research Institute, National Institutes of Health. NR 64 TC 34 Z9 34 U1 2 U2 6 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 AUG 15 PY 2012 VL 18 IS 16 BP 4240 EP 4246 DI 10.1158/1078-0432.CCR-11-1217 PG 7 WC Oncology SC Oncology GA 988PY UT WOS:000307504200005 PM 22648273 ER PT J AU Bates, SE AF Bates, Susan E. TI Pancreatic Cancer: Steps in the Right Direction SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Bethesda, MD 20892 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 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2012 VL 18 IS 16 BP 4248 EP 4248 DI 10.1158/1078-0432.CCR-12-2162 PG 1 WC Oncology SC Oncology GA 988PY UT WOS:000307504200006 PM 22896690 ER PT J AU Wei, CJ Yassine, HM McTamney, PM Gall, JGD Whittle, JRR Boyington, JC Nabel, GJ AF Wei, Chih-Jen Yassine, Hadi M. McTamney, Patrick M. Gall, Jason G. D. Whittle, James R. R. Boyington, Jeffrey C. Nabel, Gary J. TI Elicitation of Broadly Neutralizing Influenza Antibodies in Animals with Previous Influenza Exposure SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID MONOCLONAL-ANTIBODIES; PROTECTIVE IMMUNITY; A VIRUSES; VACCINE; HEMAGGLUTININS; INDUCTION; EPITOPE; CELLS AB The immune system responds to influenza infection by producing neutralizing antibodies to the viral surface protein, hemagglutinin (HA), which regularly changes its antigenic structure. Antibodies that target the highly conserved stem region of HA neutralize diverse influenza viruses and can be elicited through vaccination in animals and humans. Efforts to develop universal influenza vaccines have focused on strategies to elicit such antibodies; however, the concern has been raised that previous influenza immunity may abrogate the induction of such broadly protective antibodies. We show here that prime-boost immunization can induce broadly neutralizing antibody responses in influenza-immune mice and ferrets that were previously infected or vaccinated. HA stem-directed antibodies were elicited in mice primed with a DNA vaccine and boosted with inactivated vaccine from H1N1 A/New Caledonia/20/1999 (1999 NC) HA regardless of preexposure. Similarly, gene-based vaccination with replication-defective adenovirus 28 (rAd28) and 5 (rAd5) vectors encoding 1999 NC HA elicited stem-directed neutralizing antibodies and conferred protection against unmatched 1934 and 2007 H1N1 virus challenge in influenza-immune ferrets. Indeed, previous exposure to certain strains could enhance immunogenicity: The strongest HA stem-directed immune response was observed in ferrets previously infected with a divergent 1934 H1N1 virus. These findings suggest that broadly neutralizing antibodies against the conserved stem region of HA can be elicited through vaccination despite previous influenza exposure, which supports the feasibility of developing stem-directed universal influenza vaccines for humans. C1 [Wei, Chih-Jen; Yassine, Hadi M.; McTamney, Patrick M.; Whittle, James R. R.; Boyington, Jeffrey C.; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gall, Jason G. D.] GenVec Inc, Gaithersburg, MD 20878 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU Intramural Research Program of the VRC, National Institute of Allergy and Infectious Diseases (NIAID), NIH FX This research was supported by the Intramural Research Program of the VRC, National Institute of Allergy and Infectious Diseases (NIAID), NIH. The findings and conclusions in this report are those of the authors and do not necessarily reflect the views of the funding agency. NR 21 TC 29 Z9 30 U1 0 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD AUG 15 PY 2012 VL 4 IS 147 AR 147ra114 DI 10.1126/scitranslmed.3004273 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 994UR UT WOS:000307958800010 PM 22896678 ER PT J AU Oh, S Schwartz, RH Singh, NJ AF Oh, Soyoung Schwartz, Ronald H. Singh, Nevil J. TI Development and Tolerization of Hyperacute Rejection in a Transgenic Mouse Graft Versus Host Model SO TRANSPLANTATION LA English DT Article DE Hyperacute rejection; Tolerance; Cellular therapy; B-cell tolerance; T-cell activation ID XENOGRAFT REJECTION; T-CELLS; IN-VIVO; B-CELLS; TOLERANCE; XENOTRANSPLANTATION; ANTIBODY; PREVENTION; INDUCTION; BARRIERS AB Background. The hyperacute rejection mediated by preexisting antibodies is a major impediment to the success of transplants across allogeneic and xenogeneic barriers. We report a new mouse model that allows us to not only monitor the sensitization of B cells mediating the hyperacute response but also validate therapeutic strategies for tolerizing them. Model. The new model system uses 5C.C7,RAG2(-/-) T-cell receptor transgenic T cells and B10.S(9R),CD3 epsilon(-/-) hosts for adoptive transfer experiments. Results and Conclusions. In the allogeneic hosts, transgenic T cells expanded briefly before being chronically deleted. Once the deletion was initiated, a second graft of donor cells was used to assess a hyperacute response. The rapid rejection of the second cohort correlated with the appearance of donor-specific antibodies in the serum. Interestingly, chronically stimulated T cells were relatively resistant to hyperacute rejection, suggesting an explanation for the slower rejection kinetics of the first cohort even as the second cohort of identical donor cells was being hyperacutely rejected. Finally, we could tolerize the potential for a hyperacute response, by pretreating recipients with a single infusion of naive donor B cells before the first T-cell transfer. This treatment not only abrogated the development of a hyperacute response but also allowed the primary graft to survive in vivo for extended periods. C1 [Schwartz, Ronald H.; Singh, Nevil J.] NIAID, Lab Cellular & Mol Immunol, NIH, Bethesda, MD 20892 USA. [Oh, Soyoung] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY USA. RP Singh, NJ (reprint author), NIAID, Lab Cellular & Mol Immunol, NIH, Bldg 4,Room 211,4 Ctr Dr, Bethesda, MD 20892 USA. EM nevil@helix.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 22 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 15 PY 2012 VL 94 IS 3 BP 234 EP 240 DI 10.1097/TP.0b013e31825ccb91 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 988MN UT WOS:000307495200005 PM 22797707 ER PT J AU Desai, AA Zhou, T Ahmad, H Zhang, W Mu, WB Trevino, S Wade, MS Raghavachari, N Kato, GJ Peters-Lawrence, MH Thiruvoipati, T Turner, K Artz, N Huang, Y Patel, AR Yuan, JXJ Gordeuk, VR Lang, RM Garcia, JGN Machado, RF AF Desai, Ankit A. Zhou, Tong Ahmad, Homaa Zhang, Wei Mu, Wenbo Trevino, Sharon Wade, Michael S. Raghavachari, Nalini Kato, Gregory J. Peters-Lawrence, Marlene H. Thiruvoipati, Tejas Turner, Kristin Artz, Nicole Huang, Yong Patel, Amit R. Yuan, Jason X. -J. Gordeuk, Victor R. Lang, Roberto M. Garcia, Joe G. N. Machado, Roberto F. TI A Novel Molecular Signature for Elevated Tricuspid Regurgitation Velocity in Sickle Cell Disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE microarray; candidate gene approach; eQTL; pulmonary hypertension ID PULMONARY ARTERIAL-HYPERTENSION; POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE; ENDOTHELIAL-CELLS; EXPRESSION; RISK; IDENTIFICATION; POLYMORPHISMS; VASODILATION; HEMOGLOBIN; PRECURSORS AB Rationale: An increased tricuspid regurgitation jet velocity (TRV > 2.5 m/s) and pulmonary hypertension defined by right heart catheterization both independently confer increased mortality in sickle cell disease (SCD). Objectives: We explored the usefulness of peripheral blood mononuclear cell-derived gene signatures as biomarkers for an elevated TRV in SCD. Methods: Twenty-seven patients with SCD underwent echocardiography and peripheral blood mononuclear cell isolation for expression profiling and 112 patients with SCD were genotyped for single-nucleotide polymorphisms. Measurements and Main Results: Genome-wide gene and miRNA expression profiles were correlated against TRV, yielding 631 transcripts and 12 miRNAs. Support vector machine analysis identified a 10-gene signature including GALNT13 (encoding polypeptide N-acetylgalactosaminyltransferase 13) that discriminates patients with and without increased TRV with 100% accuracy. This finding was then validated in a cohort of patients with SCD without (n = 10) and with pulmonary hypertension (n = 10,90% accuracy). Increased TRV-related miRNAs revealed strong in silica binding predictions of miR-301a to GALNT13 corroborated by microarray analyses demonstrating an inverse correlation between their expression. A genetic association study comparing patients with an elevated (n = 49) versus normal (n = 63) TRV revealed five significant single-nucleotide polymorphisms within GALNT13 (P < 0.005), four trans-acting (P < 2.1 x 10(-7)) and one cis-acting (P = 0.6 x 10(-4)) expression quantitative trait locus upstream of the adenosine-A2B receptor gene (ADORA2B). Conclusions: These studies validate the clinical usefulness of genomic signatures as potential biomarkers and highlight ADORA2B and GALNT13 as potential candidate genes in SCD-associated elevated TRV. C1 [Machado, Roberto F.] Univ Illinois, Inst Personalized Resp Med, Sect Pulm Crit Care Med Sleep & Allergy, Chicago, IL 60612 USA. [Desai, Ankit A.] Univ Illinois, Cardiol Sect, Chicago, IL 60612 USA. [Zhang, Wei; Mu, Wenbo] Univ Illinois, Dept Pediat, Inst Human Genet, Ctr Canc, Chicago, IL 60612 USA. [Gordeuk, Victor R.] Univ Illinois, Dept Med, Ctr Comprehens Sickle Cell, Chicago, IL 60612 USA. [Ahmad, Homaa; Thiruvoipati, Tejas; Huang, Yong; Patel, Amit R.; Lang, Roberto M.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Raghavachari, Nalini] NHLBI, Genom Core Facil, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [Kato, Gregory J.; Peters-Lawrence, Marlene H.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Turner, Kristin; Artz, Nicole] Loyola Univ, Dept Med, Maywood, IL 60153 USA. RP Machado, RF (reprint author), Univ Illinois, Inst Personalized Resp Med, Sect Pulm Crit Care Med Sleep & Allergy, 840 S Wood St,Room 920-N,Clin Sci Bldg,MC 719, Chicago, IL 60612 USA. EM machador@uic.edu RI Patel, Amit/B-2464-2014; Kato, Gregory/I-7615-2014 OI Patel, Amit/0000-0001-7621-6463; Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [ZIA HL006013-04]; NCRR NIH HHS [UL1 RR029879, UL1RR029879]; NHLBI NIH HHS [K23HL098454, 1-R0 HL079912-02, F32 HL090359, F32HL090359, K23 HL098454, R01 HL079912] NR 44 TC 20 Z9 20 U1 0 U2 8 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG 15 PY 2012 VL 186 IS 4 BP 359 EP 368 DI 10.1164/rccm.201201-0057OC PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 989ZG UT WOS:000307600200011 PM 22679008 ER PT J AU Rudenko, IN Kaganovich, A Hauser, DN Beylina, A Chia, R Ding, JH Maric, D Jaffe, H Cookson, MR AF Rudenko, Iakov N. Kaganovich, Alice Hauser, David N. Beylina, Aleksandra Chia, Ruth Ding, Jinhui Maric, Dragan Jaffe, Howard Cookson, Mark R. TI The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation SO BIOCHEMICAL JOURNAL LA English DT Article DE gene mutation; Hsp90; inclusion body; kinase activity; neurite length; WD40 domain ID CYTOPLASMIC LOCALIZATION; 14-3-3 BINDING; LRRK2; LEUCINE-RICH-REPEAT-KINASE-2; STABILITY; INHIBITION; ARGININE; MUTANT; SUBSTITUTION; POPULATION AB Autosomal-dominant missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a common genetic cause of PD (Parkinson's disease). LRRK2 is a multidomain protein with kinase and GTPase activities. Dominant mutations are found in the domains that have these two enzyme activities, including the common G2019S mutation that increases kinase activity 2-3-fold. However, there is also a genetic variant in some populations, G2385R, that lies in a C-terminal WD40 domain of LRRK2 and acts as a risk factor for PD. In the present study we show that the G2385R mutation causes a partial loss of the kinase function of LRRK2 and deletion of the C-terminus completely abolishes kinase activity. This effect is strong enough to overcome the kinase-activating effects of the G2019S mutation in the kinase domain. Hsp90 (heat-shock protein of 90 kDa) has an increased affinity for the G2385R variant compared with WT (wild-type) LRRK2, and inhibition of the chaperone binding combined with proteasome inhibition leads to association of mutant LRRK2 with high molecular mass native fractions that probably represent proteasome degradation pathways. The loss-of-function of G2385R correlates with several cellular phenotypes that have been proposed to be kinase-dependent. These results suggest that the C-terminus of LRRK2 plays an important role in maintaining enzymatic function of the protein and that G2385R may be associated with PD in a way that is different from kinase-activating mutations. These results may be important in understanding the differing mechanism(s) by which mutations in LRRK2 act and may also have implications for therapeutic strategies for PD. C1 [Rudenko, Iakov N.; Kaganovich, Alice; Hauser, David N.; Beylina, Aleksandra; Chia, Ruth; Cookson, Mark R.] NIA, Cell Biol & Gene Express Sect, NIH, Bethesda, MD 20892 USA. [Hauser, David N.] Brown Univ, Natl Inst Hlth Grad Partnership Program, Dept Neurosci, Providence, RI 02912 USA. [Ding, Jinhui] NIA, Bioinformat Facil, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] Natl Inst Neurol Disorders & Stroke, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. [Jaffe, Howard] Natl Inst Neurol Disorders & Stroke, Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Sect, NIH, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov RI Hauser, David/I-4933-2012 OI Hauser, David/0000-0002-9500-5255 FU NIH, National Institute on Aging [AG000948]; National Institute of Neurological Diseases and Stroke FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging [project number AG000948] and by the National Institute of Neurological Diseases and Stroke. NR 38 TC 41 Z9 41 U1 2 U2 5 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 AUG 15 PY 2012 VL 446 BP 99 EP 111 DI 10.1042/BJ20120637 PN 1 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 990JH UT WOS:000307626300010 PM 22612223 ER PT J AU Zarate, CA Brutsche, N Laje, G Luckenbaugh, DA Venkata, SLV Ramamoorthy, A Moaddel, R Wainer, IW AF Zarate, Carlos A., Jr. Brutsche, Nancy Laje, Gonzalo Luckenbaugh, David A. Venkata, Swarajya L. Vattem Ramamoorthy, Anuradha Moaddel, Ruin Wainer, Irving W. TI Relationship of Ketamine's Plasma Metabolites with Response, Diagnosis, and Side Effects in Major Depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Bipolar disorder; dehydronorketamine; depression; hydroxynorketamine; norketamine; psychosis; response ID D-ASPARTATE ANTAGONIST; RAPID ANTIDEPRESSANT RESPONSE; HUMAN LIVER-MICROSOMES; COMPARATIVE PHARMACOLOGY; CYTOCHROME-P450 ENZYMES; HEALTHY-VOLUNTEERS; DRUG-METABOLISM; N-DEMETHYLATION; IN-VITRO; NORKETAMINE AB Background: Ketamine has rapid antidepressant effects lasting as long as 1 week in patients with major depressive disorder (MDD) and bipolar depression (BD). Ketamine is extensively metabolized. This study examined the relationship between ketamine metabolites and response, diagnosis, and psychotomimetic symptoms in MDD and BD patients. Methods: Following a 40-minute ketamine infusion (.5 mg/kg), plasma samples were collected at 40, 80, 110, and 230 minutes and day 1 postinfusion in 67 patients currently experiencing a major depressive episode (MDD, n = 45; BD, n = 22). Concentrations of ketamine, norketamine (NK), dehydronorketamine (DHNK), six hydroxynorketamine metabolites (HNK), and hydroxyketamine (HK) were measured. Plasma concentrations were analyzed by diagnostic group and correlated with patients' depressive, psychotic, and dissociative symptoms. The relationship between cytochrome P450 gene polymorphisms and metabolites, response, and diagnosis was also examined. Results: Ketamine, NK, DHNK, four of six HNKs, and HK were present during the first 230 minutes postinfusion. Patients with BD had higher plasma concentrations of DHNK, (2S,6S;2R,6R)-HNK, (2S,6R;2R,6S)-HNK, and (2S,5S;2R,5R)-HNK than patients with MDD, who, in turn, had higher concentrations of (2S,6S;2R,6R)-HK. Higher (2S,5S;2R,5R)-HNK concentrations were associated with nonresponse to ketamine in BD patients. Dehydronorketamine, HNK4c, and HNK4f levels were significantly negatively correlated with psychotic and dissociative symptoms at 40 minutes. No relationship was found between cytochrome P450 genes and any of the parameters examined. Conclusions: A diagnostic difference was observed in the metabolism and disposition of ketamine. Concentrations of (2S,5S;2R,5R)-HNK were related to nonresponse to ketamine in BD. Some hydroxylated metabolites of ketamine correlated with psychotic and dissociative symptoms. C1 [Zarate, Carlos A., Jr.; Brutsche, Nancy; Luckenbaugh, David A.] NIMH, NIH, Div Intramural Res Programs, Expt Therapeut & Pathophysiol Branch,CRC, Bethesda, MD 20892 USA. [Laje, Gonzalo] NIMH, Human Genet Branch, NIH, Bethesda, MD 20892 USA. [Laje, Gonzalo] NIMH, Genet Basis Mood & Anxiety Disorders Sect, NIH, Bethesda, MD 20892 USA. [Venkata, Swarajya L. Vattem; Ramamoorthy, Anuradha; Moaddel, Ruin; Wainer, Irving W.] NIA, Lab Clin Invest, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Zarate, CA (reprint author), NIMH, NIH, Div Intramural Res Programs, Expt Therapeut & Pathophysiol Branch,CRC, 10 Ctr Dr,Unit 7 SE,Room 7-3445, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov RI Laje, Gonzalo/L-2654-2014 OI Laje, Gonzalo/0000-0003-2763-3329 FU Intramural Research Programs of the National Institute of Aging, National Institutes of Health (NIH); National Institute of Mental Health, NIH; NIH [MH085098-01]; Brain & Behavior Research Foundation Bipolar Disorders Award FX This work was supported by the Intramural Research Programs of the National Institute of Aging, National Institutes of Health (NIH), and the National Institute of Mental Health, NIH, as well as NIH Grant MH085098-01 to GL, and the Brain & Behavior Research Foundation Bipolar Disorders Award (CAZ). NR 42 TC 63 Z9 63 U1 1 U2 20 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 AUG 15 PY 2012 VL 72 IS 4 BP 331 EP 338 DI 10.1016/j.biopsych.2012.03.004 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 980NA UT WOS:000306898800018 PM 22516044 ER PT J AU Shatz, M Menendez, D Resnick, MA AF Shatz, Maria Menendez, Daniel Resnick, Michael A. TI The Human TLR Innate Immune Gene Family Is Differentially Influenced by DNA Stress and p53 Status in Cancer Cells SO CANCER RESEARCH LA English DT Article ID TOLL-LIKE RECEPTORS; HUMAN-DISEASE; EXPRESSION; ACTIVATION; AGONISTS; CHEMOTHERAPY; MUTATIONS; INDUCTION; APOPTOSIS; THERAPY AB The transcription factor p53 regulates genes associated with a wide range of functions, including the Toll-like receptor (TLR) set of innate immunity genes, suggesting that p53 also modulates the human immune response. The TLR family comprises membrane glycoproteins that recognize pathogen-associated molecular patterns (PAMP) and mediate innate immune responses, and TLR agonists are being used as adjuvants in cancer treatments. Here, we show that doxorubicin, 5-fluorouracil, and UV and ionizing radiation elicit changes in TLR expression that are cell line-and damage-specific. Specifically, treatment-induced expression changes led to increased downstream cytokine expression in response to ligand stimulation. The effect of DNA stressors on TLR expression was mainly mediated by p53, and several p53 cancer-associated mutants dramatically altered the pattern of TLR gene expression. In all cell lines tested, TLR3 induction was p53-dependent, whereas induction of TLR9, the most stress-responsive family member, was less dependent on status of p53. In addition, each of the 10 members of the innate immune TLR gene family tested was differentially inducible. Our findings therefore show that the matrix of p53 status, chromosome stress, and responsiveness of individual TLRs should be considered in TLR-based cancer therapies. Cancer Res; 72(16); 3948-57. (C) 2012 AACR. C1 [Shatz, Maria; Menendez, Daniel; Resnick, Michael A.] NIEHS, NIH, Chromosome Stabil Grp, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Resnick, MA (reprint author), NIEHS, NIH, Chromosome Stabil Grp, Mol Genet Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov FU NIEHS [Z01-ES065079] FX The study was supported by NIEHS intramural research funds, project Z01-ES065079. NR 45 TC 39 Z9 41 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2012 VL 72 IS 16 BP 3948 EP 3957 DI 10.1158/0008-5472.CAN-11-4134 PG 10 WC Oncology SC Oncology GA 993SY UT WOS:000307881100008 PM 22673234 ER PT J AU Wu, J Li, JQ Salcedo, R Mivechi, NF Trinchieri, G Horuzsko, A AF Wu, Juan Li, Jiaqi Salcedo, Rosalba Mivechi, Nahid F. Trinchieri, Giorgio Horuzsko, Anatolij TI The Proinflammatory Myeloid Cell Receptor TREM-1 Controls Kupffer Cell Activation and Development of Hepatocellular Carcinoma SO CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; CHEMICAL HEPATOCARCINOGENESIS; FUNCTIONAL GENOMICS; CANCER DEVELOPMENT; INFLAMMATION; MACROPHAGES; PROLIFERATION; PROGRESSION; EXPRESSION; ENDOTOXIN AB Chronic inflammation drives liver cancer pathogenesis, invasion, and metastasis. Liver Kupffer cells have crucial roles in mediating the inflammatory processes that promote liver cancer, but the mechanistic basis for their contributions are not fully understood. Here we show that expression of the proinflammatory myeloid cell surface receptor TREM-1 expressed by Kupffer cells is a crucial factor in the development and progression of liver cancer. Deletion of the murine homolog Trem1 in mice attenuated hepatocellular carcinogenesis triggered by diethylnitrosamine (DEN). Trem1 deficiency attenuated Kupffer cell activation by downregulating transcription and protein expression of interleukin (IL)-6, IL-1 beta, TNF, CCL2, and CXCL10. In addition, Trem1 ablation diminished activation of the p38, extracellular regulated kinase 1/2, JNK, mitogen-activated protein kinase, and NF-kappa B signaling pathways in Kupffer cells, resulting in diminished liver injury after DEN exposure. Adoptive transfer of wild-type Kupffer cells to Trem1-deficient mice complemented these defects and reversed unresponsiveness to DEN-induced liver injury and malignant development. Together, our findings offer causal evidence that TREM-1 is a pivotal determinant of Kupffer cell activation in liver carcinogenesis, deepening mechanistic insights into how chronic inflammation underpins the development and progression of liver cancer. Cancer Res; 72(16); 3977-86. (C) 2012 AACR. C1 [Wu, Juan; Li, Jiaqi; Mivechi, Nahid F.; Horuzsko, Anatolij] Georgia Hlth Sci Univ, Ctr Mol Chaperone Radiobiol & Canc Virol, Dept Med, Augusta, GA 30912 USA. [Salcedo, Rosalba; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Salcedo, Rosalba] SAIC Frederick Inc, Frederick, MD USA. RP Horuzsko, A (reprint author), Georgia Hlth Sci Univ, Ctr Mol Chaperone Radiobiol & Canc Virol, Dept Med, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. EM ahoruzsko@georgiahealth.edu FU National Institutes of Health [AI055923, CA062130, CA132640] FX This work was supported by the National Institutes of Health grants AI055923 (A. Horuzsko) and CA062130 and CA132640 (N.F. Mivechi). NR 35 TC 57 Z9 61 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2012 VL 72 IS 16 BP 3977 EP 3986 DI 10.1158/0008-5472.CAN-12-0938 PG 10 WC Oncology SC Oncology GA 993SY UT WOS:000307881100011 PM 22719066 ER PT J AU Yaqoob, U Cao, S Shergill, U Jagavelu, K Geng, ZM Yin, M de Assuncao, TM Cao, Y Szabolcs, A Thorgeirsson, S Schwartz, M Yang, JD Ehman, R Roberts, L Mukhopadhyay, D Shah, VH AF Yaqoob, Usman Cao, Sheng Shergill, Uday Jagavelu, Kumaravelu Geng, Zhimin Yin, Meng de Assuncao, Thiago M. Cao, Ying Szabolcs, Anna Thorgeirsson, Snorri Schwartz, Martin Yang, Ju Dong Ehman, Richard Roberts, Lewis Mukhopadhyay, Debabrata Shah, Vijay H. TI Neuropilin-1 Stimulates Tumor Growth by Increasing Fibronectin Fibril Assembly in the Tumor Microenvironment SO CANCER RESEARCH LA English DT Article ID DOMAIN-CONTAINING PROTEIN; ENDOTHELIAL-CELLS; PROGENITOR CELLS; HUMAN GLIOMA; ACTIVATION; MATRIX; INTERACTS; CANCER; BETA; VEGF AB The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here, we report that neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin that promote alpha 5 beta 1 integrin-dependent fibronectin fibril assembly, matrix stiffness, and tumor growth. Tumor growth and fibronectin fibril assembly were reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo. Mechanistically, the increase in fibronectin fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl that augmented alpha 5 beta 1 fibronectin fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of fibronectin fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment. Cancer Res; 72(16); 4047-59. (C) 2012 AACR. C1 [Yaqoob, Usman; Cao, Sheng; Shergill, Uday; Jagavelu, Kumaravelu; Geng, Zhimin; de Assuncao, Thiago M.; Yang, Ju Dong; Roberts, Lewis; Shah, Vijay H.] Mayo Clin, Gastroenterol Res Unit, Rochester, MN 55905 USA. [Yaqoob, Usman; Cao, Sheng; Shergill, Uday; Jagavelu, Kumaravelu; Geng, Zhimin; de Assuncao, Thiago M.; Yang, Ju Dong; Roberts, Lewis; Shah, Vijay H.] Mayo Clin, Dept Internal Med, Rochester, MN 55905 USA. [Cao, Ying; Szabolcs, Anna; Mukhopadhyay, Debabrata] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. [Yin, Meng; Ehman, Richard] Mayo Clin, Dept Radiol, Rochester, MN 55905 USA. [Thorgeirsson, Snorri] NCI, Bethesda, MD 20892 USA. [Schwartz, Martin] Yale Univ, Div Cardiol, New Haven, CT USA. [Schwartz, Martin] Yale Univ, Dept Cell Biol, New Haven, CT USA. RP Shah, VH (reprint author), Mayo Clin, Gastroenterol Res Unit, 200 1st ST SW, Rochester, MN 55905 USA. EM cao.sheng@mayo.edu; shah.vijay@mayo.edu OI Yin, Meng/0000-0001-6778-192X; Roberts, Lewis/0000-0001-7885-8574 FU NIH [R01 DK 59615, R01 AA 021171, R01 HL 86990, P30 DK 084567] FX This work was supported by the grants from NIH R01 DK 59615 R01 AA 021171, and R01 HL 86990 (V. H. Shah), P30 DK 084567-Clinical Core and Cell Biology Core. NR 50 TC 36 Z9 43 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2012 VL 72 IS 16 BP 4047 EP 4059 DI 10.1158/0008-5472.CAN-11-3907 PG 13 WC Oncology SC Oncology GA 993SY UT WOS:000307881100018 PM 22738912 ER PT J AU Szabova, L Yin, CY Bupp, S Guerin, TM Schlomer, JJ Householder, DB Baran, ML Yi, M Song, YR Sun, WP McDunn, JE Martin, PL Van Dyke, T Difilippantonio, S AF Szabova, Ludmila Yin, Chaoying Bupp, Sujata Guerin, Theresa M. Schlomer, Jerome J. Householder, Deborah B. Baran, Maureen L. Yi, Ming Song, Yurong Sun, Wenping McDunn, Jonathan E. Martin, Philip L. Van Dyke, Terry Difilippantonio, Simone TI Perturbation of Rb, p53, and Brca1 or Brca2 Cooperate in Inducing Metastatic Serous Epithelial Ovarian Cancer SO CANCER RESEARCH LA English DT Article ID FALLOPIAN-TUBE; MOUSE MODEL; CONDITIONAL INACTIVATION; PERITONEAL MESOTHELIOMA; PAPILLARY CARCINOMA; SURFACE EPITHELIUM; DISTANT METASTASES; MUTATIONS; MICE; INDUCTION AB The majority of human high-grade serous epithelial ovarian cancer (SEOC) is characterized by frequent mutations in p53 and alterations in the RB and FOXM1 pathways. A subset of human SEOC harbors a combination of germline and somatic mutations as well as epigenetic dysfunction for BRCA1/2. Using Cre-conditional alleles and intrabursal induction by Cre-expressing adenovirus in genetically engineered mice, we analyzed the roles of pathway perturbations in epithelial ovarian cancer initiation and progression. Inactivation of RB-mediated tumor suppression induced surface epithelial proliferation with progression to stage I carcinoma. Additional biallelic inactivation and/or missense p53 mutation in the presence or absence of Brca1/2 caused progression to stage IV disease. As in human SEOC, mice developed peritoneal carcinomatosis, ascites, and distant metastases. Unbiased gene expression and metabolomic profiling confirmed that Rb, p53, and Brca1/2-triple mutant tumors aligned with human SEOC, and not with other intraperitoneal cancers. Together, our findings provide a novel resource for evaluating disease etiology and biomarkers, therapeutic evaluation, and improved imaging strategies in epithelial ovarian cancer. Cancer Res; 72(16); 4141-53. (C) 2012 AACR. C1 [Szabova, Ludmila; Bupp, Sujata; Guerin, Theresa M.; Schlomer, Jerome J.; Householder, Deborah B.; Baran, Maureen L.; Martin, Philip L.; Van Dyke, Terry; Difilippantonio, Simone] NCI Federick, Ctr Adv Preclin Res, SAIC, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Yi, Ming; Sun, Wenping] NCI Federick, Adv Biomed Comp Ctr, SAIC, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Song, Yurong; Van Dyke, Terry] NCI Frederick, Mouse Canc Genet Program, Frederick, MD USA. [Yin, Chaoying; Song, Yurong; Van Dyke, Terry] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [McDunn, Jonathan E.] Metabolon Inc, Durham, NC USA. RP Difilippantonio, S (reprint author), NCI Federick, Ctr Adv Preclin Res, SAIC, Frederick Natl Lab Canc Res, 1050 Boyles St,Bldg 539,Room 229, Frederick, MD 21702 USA. EM difilips@mail.nih.gov OI McDunn, Jonathan/0000-0001-8792-828X FU National Cancer Institute, Intramural Research Program, NIH [HHSN261200800001E] FX This research was supported with federal funds from the National Cancer Institute, Intramural Research Program, NIH under contract no. HHSN261200800001E. NR 49 TC 43 Z9 45 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2012 VL 72 IS 16 BP 4141 EP 4153 DI 10.1158/0008-5472.CAN-11-3834 PG 13 WC Oncology SC Oncology GA 993SY UT WOS:000307881100026 PM 22617326 ER PT J AU Zhang, M Mathur, A Zhang, YW Xi, SC Atay, S Hong, JA Datrice, N Upham, T Kemp, CD Ripley, RT Wiegand, G Avital, I Fetsch, P Mani, H Zlott, D Robey, R Bates, SE Li, XM Rao, M Schrump, DS AF Zhang, Mary Mathur, Aarti Zhang, Yuwei Xi, Sichuan Atay, Scott Hong, Julie A. Datrice, Nicole Upham, Trevor Kemp, Clinton D. Ripley, R. Taylor Wiegand, Gordon Avital, Itzak Fetsch, Patricia Mani, Haresh Zlott, Daniel Robey, Robert Bates, Susan E. Li, Xinmin Rao, Mahadev Schrump, David S. TI Mithramycin Represses Basal and Cigarette Smoke-Induced Expression of ABCG2 and Inhibits Stem Cell Signaling in Lung and Esophageal Cancer Cells SO CANCER RESEARCH LA English DT Article ID ARYL-HYDROCARBON RECEPTOR; SIDE POPULATION CELLS; TRANSCRIPTION FACTOR; ANTITUMOR-ACTIVITY; PROGNOSTIC-FACTOR; MAJOR MORBIDITY; CARCINOMA CELLS; BCRP/ABCG2; MORTALITY; BINDING AB Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell-related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies. Cancer Res; 72(16); 4178-92. (C) 2012 AACR. C1 [Zhang, Mary; Mathur, Aarti; Zhang, Yuwei; Xi, Sichuan; Atay, Scott; Hong, Julie A.; Datrice, Nicole; Upham, Trevor; Kemp, Clinton D.; Ripley, R. Taylor; Rao, Mahadev; Schrump, David S.] NCI, Thorac Oncol Sect, Surg Branch, Bethesda, MD 20892 USA. [Wiegand, Gordon; Avital, Itzak] NCI, Gastrointestinal & Hepatobiliary Malignancies Sec, Surg Branch, Bethesda, MD 20892 USA. [Fetsch, Patricia] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Zlott, Daniel] NCI, Dept Clin Pharm, Bethesda, MD 20892 USA. [Robey, Robert; Bates, Susan E.] NCI, Expt Therapeut Sect, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Mani, Haresh] Penn State Hershey, Med Ctr, Dept Pathol, Hershey, PA USA. [Li, Xinmin] Univ Calif Los Angeles, Clin Microarray Core, Los Angeles, CA USA. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, Bldg 10,4-3942,10 Ctr Dr, Bethesda, MD 20892 USA. EM David_Schrump@nih.gov NR 50 TC 33 Z9 36 U1 2 U2 12 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 AUG 15 PY 2012 VL 72 IS 16 BP 4178 EP 4192 DI 10.1158/0008-5472.CAN-11-3983 PG 15 WC Oncology SC Oncology GA 993SY UT WOS:000307881100029 PM 22751465 ER PT J AU Caceres, G Robey, RW Sokol, L McGraw, KL Clark, J Lawrence, NJ Sebti, SM Wiese, M List, AF AF Caceres, Gisela Robey, Robert W. Sokol, Lubomir McGraw, Kathy L. Clark, Justine Lawrence, Nicholas J. Sebti, Said M. Wiese, Michael List, Alan F. TI HG-829 Is a Potent Noncompetitive Inhibitor of the ATP-Binding Cassette Multidrug Resistance Transporter ABCB1 SO CANCER RESEARCH LA English DT Article ID ACUTE MYELOID-LEUKEMIA; P-GLYCOPROTEIN; DRUG-BINDING; PHASE-I; GROUP-B; CANCER; REVERSAL; MODULATOR; PSC-833; AGE AB Transmembrane drug export mediated by the ATP-binding cassette (ABC) transporter P-glycoprotein contributes to clinical resistance to antineoplastics. In this study, we identified the substituted quinoline HG-829 as a novel, noncompetitive, and potent P-glycoprotein inhibitor that overcomes in vitro and in vivo drug resistance. We found that nontoxic concentrations of HG-829 restored sensitivity to P-glycoprotein oncolytic substrates. In ABCB1-overexpressing cell lines, HG-829 significantly enhanced cytotoxicity to daunorubicin, paclitaxel, vinblastine, vincristine, and etoposide. Coadministration of HG-829 fully restored in vivo antitumor activity of daunorubicin in mice without added toxicity. Functional assays showed that HG-829 is not a Pgp substrate or competitive inhibitor of Pgp-mediated drug efflux but rather acts as a noncompetitive modulator of P-glycoprotein transport function. Taken together, our findings indicate that HG-829 is a potent, long-acting, and noncompetitive modulator of P-glycoprotein export function that may offer therapeutic promise for multidrug-resistant malignancies. Cancer Res; 72(16); 4204-13. (c) 2012 AACR. C1 [Lawrence, Nicholas J.; Sebti, Said M.] Univ S Florida, H Lee Moffitt Canc Ctr, Drug Discovery Program, Tampa, FL 33682 USA. [McGraw, Kathy L.] Univ S Florida, Canc Biol PhD Program, Tampa, FL USA. [Robey, Robert W.] NIH, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Wiese, Michael] Univ Bonn, Inst Pharm, Bonn, Germany. RP List, AF (reprint author), H Lee Moffitt Canc Ctr & Res Inst, MCC VP, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM alan.list@moffitt.org FU Procter and Gamble FX This work was supported by Procter and Gamble. NR 26 TC 5 Z9 6 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2012 VL 72 IS 16 BP 4204 EP 4213 DI 10.1158/0008-5472.CAN-12-0743 PG 10 WC Oncology SC Oncology GA 993SY UT WOS:000307881100031 PM 22761337 ER PT J AU Thiele, F Cohrs, CM Flor, A Lisse, TS Przemeck, GKH Horsch, M Schrewe, A Gailus-Durner, V Ivandic, B Katus, HA Wurst, W Reisenberg, C Chaney, H Fuchs, H Hans, W Beckers, J Marini, JC de Angelis, MH AF Thiele, Frank Cohrs, Christian M. Flor, Armando Lisse, Thomas S. Przemeck, Gerhard K. H. Horsch, Marion Schrewe, Anja Gailus-Durner, Valerie Ivandic, Boris Katus, Hugo A. Wurst, Wolfgang Reisenberg, Catherine Chaney, Hollis Fuchs, Helmut Hans, Wolfgang Beckers, Johannes Marini, Joan C. de Angelis, Martin Hrabe TI Cardiopulmonary dysfunction in the Osteogenesis imperfecta mouse model Aga2 and human patients are caused by bone-independent mechanisms SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENE-EXPRESSION; PULMONARY HYPOPLASIA; AORTIC DISSECTION; KAPPA-B; COLLAGEN; DISEASE; MICE; INVOLVEMENT; FIBROBLASTS; MATRIX AB Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with skeletal dysplasia of varying severity, predominantly caused by mutations in the collagen I genes (COL1A1/COL1A2). Extraskeletal findings such as cardiac and pulmonary complications are generally considered to be significant secondary features. Aga2, a murine model for human OI, was systemically analyzed in the German Mouse Clinic by means of in vivo and in vitro examinations of the cardiopulmonary system, to identify novel mechanisms accounting for perinatal lethality. Pulmonary and, especially, cardiac fibroblast of perinatal lethal Aga2/ animals display a strong down-regulation of Col1a1 transcripts in vivo and in vitro, resulting in a loss of extracellular matrix integrity. In addition, dysregulated gene expression of Nppa, different types of collagen and Agt in heart and lung tissue support a bone-independent vicious cycle of heart dysfunction, including hypertrophy, loss of myocardial matrix integrity, pulmonary hypertension, pneumonia and hypoxia leading to death in Aga2. These murine findings are corroborated by a pediatric OI cohort study, displaying significant progressive decline in pulmonary function and restrictive pulmonary disease independent of scoliosis. Most participants show mild cardiac valvular regurgitation, independent of pulmonary and skeletal findings. Data obtained from human OI patients and the mouse model Aga2 provide novel evidence for primary effects of type I collagen mutations on the heart and lung. The findings will have potential benefits of anticipatory clinical exams and early intervention in OI patients. C1 [Thiele, Frank; Cohrs, Christian M.; Lisse, Thomas S.; Przemeck, Gerhard K. H.; Horsch, Marion; Schrewe, Anja; Gailus-Durner, Valerie; Fuchs, Helmut; Hans, Wolfgang; Beckers, Johannes; de Angelis, Martin Hrabe] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Expt Genet, Neuherberg, Germany. [Flor, Armando; Reisenberg, Catherine; Marini, Joan C.] NICHHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. [Ivandic, Boris; Katus, Hugo A.] Heidelberg Univ, Dept Med 3, Div Cardiol, Heidelberg, Germany. [Wurst, Wolfgang] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Dev Genet, Neuherberg, Germany. [Wurst, Wolfgang] Tech Univ Munich, Ctr Life & Food Sci, Chair Dev Genet, Weihenstephan, Germany. [Chaney, Hollis] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Beckers, Johannes; de Angelis, Martin Hrabe] Tech Univ Munich, Ctr Life & Food Sci, Chair Expt Genet, Weihenstephan, Germany. RP de Angelis, MH (reprint author), German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Expt Genet, Neuherberg, Germany. EM hrabe@helmholtz-muenchen.de RI Przemeck, Gerhard/A-5991-2012; Cohrs, Christian/L-7336-2013; Beckers, Johannes/K-7237-2012; Gailus-Durner, Valerie/M-7337-2014; Hrabe de Angelis, Martin/F-5531-2012; Katus, Hugo/P-1712-2016; Fuchs, Helmut/M-7347-2014 OI Przemeck, Gerhard/0000-0003-3730-3454; Beckers, Johannes/0000-0001-7874-3822; Hrabe de Angelis, Martin/0000-0002-7898-2353; Fuchs, Helmut/0000-0002-5143-2677 FU Nationales Genomforschungs-netzwerk [01GS0850, 01GS0854]; National Institute of Child Health & Human Development Intramural Research Program; Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH) FX This work was supported by the Nationales Genomforschungs-netzwerk (01GS0850 to M. H. A., 01GS0854 H. A. K.). The clinical trial was supported by funds from the National Institute of Child Health & Human Development Intramural Research Program. Funding to pay the Open Access publication charges for this article was provided by Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH). NR 51 TC 13 Z9 13 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2012 VL 21 IS 16 BP 3535 EP 3545 DI 10.1093/hmg/dds183 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 981JX UT WOS:000306964700002 PM 22589248 ER PT J AU Renvoise, B Stadler, J Singh, R Bakowska, JC Blackstone, C AF Renvoise, Benoit Stadler, Julia Singh, Rajat Bakowska, Joanna C. Blackstone, Craig TI Spg20-/- mice reveal multimodal functions for Troyer syndrome protein spartin in lipid droplet maintenance, cytokinesis and BMP signaling SO HUMAN MOLECULAR GENETICS LA English DT Article ID HEREDITARY SPASTIC PARAPLEGIA; NEUROPATHY TARGET ESTERASE; UBIQUITIN LIGASES; SYNAPTIC GROWTH; IDENTIFICATION; DISEASE; LOCALIZATION; MECHANISMS; INTERACTS; MACHINERY AB Hereditary spastic paraplegias (HSPs; SPG1-48) are inherited neurological disorders characterized by lower extremity spasticity and weakness. Loss-of-function mutations in the SPG20 gene encoding spartin cause autosomal recessive Troyer syndrome (SPG20), which has additional features of short stature, cognitive deficits and distal amyotrophy. To identify cellular impairments underlying Troyer syndrome, we generated Spg20/ mice, which exhibit progressive gait defects. Although gross central nervous system pathology appeared largely normal, cerebral cortical neurons cultured from neonatal Spg20/ mice exhibited increased axon branching, a phenotype suppressed by reintroducing spartin and which required its interaction with the endosomal sorting complex required for transport (ESCRT)-III protein IST1. Analysis of the bone morphogenetic protein (BMP) signaling pathway in Spg20/ embryonic fibroblasts indicated that Smad1/5 phosphorylation is modestly elevated, possibly due to alterations in BMP receptor trafficking. Cytokinesis was impaired in embryonic fibroblasts cultured from Spg20/ mice, and binucleated chondrocytes were prominent in epiphyseal growth plates of bones in Spg20/ mice, perhaps explaining the short stature of patients. Finally, adipose tissue from Spg20/ female mice exhibited increased lipid droplet (LD) numbers and alterations in perilipin levels, supporting a role for spartin in LD maintenance. Taken together, our results support multimodal functions for spartin that provide important insights into HSP pathogenesis. C1 [Renvoise, Benoit; Stadler, Julia; Singh, Rajat; Blackstone, Craig] NINDS, Cell Biol Sect, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Bakowska, Joanna C.] Loyola Univ Chicago, Stritch Sch Med, Dept Pharmacol & Expt Therapeut, Maywood, IL 60153 USA. RP Bakowska, JC (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Pharmacol, 2160 S 1st Ave,Bldg 102,Room 3636, Maywood, IL 60153 USA. EM jbakowska@lumc.edu; blackstc@ninds.nih.gov OI Singh, Rajat/0000-0002-9542-1929 FU National Institute of Neurological Disorders and Stroke; NIH R01 grant [NS073967] FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (B. R., J.S., R. S. and C. B.), and NIH R01 grant NS073967 (to J.C.B.). NR 61 TC 19 Z9 20 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2012 VL 21 IS 16 BP 3604 EP 3618 DI 10.1093/hmg/dds191 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 981JX UT WOS:000306964700008 PM 22619377 ER PT J AU Cluzeau, CVM Watkins-Chow, DE Fu, R Borate, B Yanjanin, N Dail, MK Davidson, CD Walkley, SU Ory, DS Wassif, CA Pavan, WJ Porter, FD AF Cluzeau, Celine V. M. Watkins-Chow, Dawn E. Fu, Rao Borate, Bhavesh Yanjanin, Nicole Dail, Michelle K. Davidson, Cristin D. Walkley, Steven U. Ory, Daniel S. Wassif, Christopher A. Pavan, William J. Porter, Forbes D. TI Microarray expression analysis and identification of serum biomarkers for Niemann-Pick disease, type C1 SO HUMAN MOLECULAR GENETICS LA English DT Article ID LIVER-CELL DEATH; CATHEPSIN-D; GENE-EXPRESSION; CHOLESTEROL HOMEOSTASIS; UNESTERIFIED CHOLESTEROL; ALZHEIMERS-DISEASE; PLASMINOGEN-ACTIVATOR; OXIDATIVE STRESS; AMYLOID-BETA; EVERY ORGAN AB NiemannPick disease type C (NPC) is a lysosomal storage disorder characterized by liver disease and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation of cholesterol and glycosphingolipids in late endosomes and early lysosomes. In order to identify pathological mechanisms underlying NPC and uncover potential biomarkers, we characterized liver gene expression changes in an Npc1 mouse model at six ages spanning the pathological progression of the disease. We identified altered gene expression at all ages, including changes in asymptomatic, 1-week-old mice. Biological pathways showing early altered gene expression included: lipid metabolism, cytochrome P450 enzymes involved in arachidonic acid and drug metabolism, inflammation and immune responses, mitogen-activated protein kinase and G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, apoptosis and oxidative stress appeared to be late pathological processes. To identify potential biomarkers that could facilitate monitoring of disease progression, we focused on a subset of 103 differentially expressed genes that encode secreted proteins. Further analysis identified two secreted proteins with increased serum levels in NPC1 patients: galectin-3 (LGALS3), a pro-inflammatory molecule, and cathepsin D (CTSD), a lysosomal aspartic protease. Elevated serum levels of both proteins correlated with neurological disease severity and appeared to be specific for NPC1. Expression of Lgals3 and Ctsd was normalized following treatment with 2-hydroxypropyl--cyclodextrin, a therapy that reduces pathological findings and significantly increases Npc1(/) survival. Both LGALS3 and CTSD have the potential to aid in diagnosis and serve as biomarkers to monitor efficacy in therapeutic trials. C1 [Cluzeau, Celine V. M.; Fu, Rao; Yanjanin, Nicole; Dail, Michelle K.; Wassif, Christopher A.; Porter, Forbes D.] US Dept HHS, Program Dev Endocrinol & Genet, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Watkins-Chow, Dawn E.; Pavan, William J.] US Dept HHS, Genet Dis Res Branch, NHGRI, Bethesda, MD 20892 USA. [Borate, Bhavesh] US Dept HHS, Mol Genet Sect, Genome Technol Branch, NHGRI,NIH, Bethesda, MD 20892 USA. [Fu, Rao] Peking Univ, Hlth Sci Ctr, Beijing 100191, Peoples R China. [Davidson, Cristin D.; Walkley, Steven U.] Albert Einstein Coll Med, Rose F Kennedy Ctr, Dominick P Purpura Dept Neurosci, Bronx, NY 10461 USA. [Ory, Daniel S.] Washington Univ, Sch Med, Diabet Cardiovasc Dis Ctr, St Louis, MO 63110 USA. RP Pavan, WJ (reprint author), Bldg 49,Room 4A82,49 Convent Dr, Bethesda, MD 20892 USA. EM bpavan@nhgri.nih.gov; fdporter@mail.nih.gov RI Cluzeau, Celine/E-6873-2016; Davidson, Cristin/F-4889-2017; OI Cluzeau, Celine/0000-0002-7791-6223; Davidson, Cristin/0000-0002-5508-8113; Wassif, Christopher/0000-0002-2524-1420; Watkins-Chow, Dawn/0000-0002-4355-0868 FU Ara Parseghian Medical Research Foundation; Dana's Angels Research Trust; Therapeutics for Rare and Neglected Diseases program; NIH [NS053677]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Human Genome Research Institute; Office of Rare Diseases; National Institutes of Health Clinical Research Center FX The authors received support from the Ara Parseghian Medical Research Foundation (N.Y. and D.S.O.), Dana's Angels Research Trust (D.S.O. and S. U. W.), the Therapeutics for Rare and Neglected Diseases program, the NIH (grant number NS053677 to S. U. W.), the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the intramural research program of the National Human Genome Research Institute, a Bench to Bedside award from the Office of Rare Diseases and the National Institutes of Health Clinical Research Center. NR 92 TC 36 Z9 36 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2012 VL 21 IS 16 BP 3632 EP 3646 DI 10.1093/hmg/dds193 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 981JX UT WOS:000306964700010 PM 22619379 ER PT J AU Hutchinson, MR Northcutt, AL Hiranita, T Wang, X Lewis, SS Thomas, J van Steeg, K Kopajtic, TA Loram, LC Sfregola, C Galer, E Miles, NE Bland, ST Amat, J Rozeske, RR Maslanik, T Chapman, TR Strand, KA Fleshner, M Bachtell, RK Somogyi, AA Yin, H Katz, JL Rice, KC Maier, SF Watkins, LR AF Hutchinson, M. R. Northcutt, A. L. Hiranita, T. Wang, X. Lewis, S. S. Thomas, J. van Steeg, K. Kopajtic, T. A. Loram, L. C. Sfregola, C. Galer, E. Miles, N. E. Bland, S. T. Amat, J. Rozeske, R. R. Maslanik, T. Chapman, T. R. Strand, K. A. Fleshner, M. Bachtell, R. K. Somogyi, A. A. Yin, H. Katz, J. L. Rice, K. C. Maier, S. F. Watkins, L. R. TI Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement SO JOURNAL OF NEUROSCIENCE LA English DT Article ID NECROSIS-FACTOR-ALPHA; MICROGLIAL ACTIVATION; AV411 IBUDILAST; MORPHINE; EXPRESSION; ANALGESIA; REWARD; RAT; LIPOPOLYSACCHARIDE; MECHANISMS AB Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4(-/-) mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward. C1 [Hutchinson, M. R.; Northcutt, A. L.; Wang, X.; Lewis, S. S.; Loram, L. C.; Sfregola, C.; Galer, E.; Miles, N. E.; Amat, J.; Rozeske, R. R.; Chapman, T. R.; Strand, K. A.; Bachtell, R. K.; Maier, S. F.; Watkins, L. R.] Univ Colorado Boulder, Dept Psychol & Neurosci, Ctr Neurosci, Boulder, CO 80309 USA. [Maslanik, T.; Fleshner, M.] Univ Colorado Boulder, Dept Integrat Physiol, Ctr Neurosci, Boulder, CO 80309 USA. [Wang, X.; Yin, H.] Univ Colorado Boulder, Dept Chem & Biochem, Ctr Neurosci, Boulder, CO 80309 USA. [Wang, X.; Yin, H.] Univ Colorado Boulder, Biofrontiers Inst, Boulder, CO 80309 USA. [van Steeg, K.] Univ Adelaide, Sch Med Sci, Discipline Physiol, Adelaide, SA 5005, Australia. [Thomas, J.; Somogyi, A. A.] Univ Adelaide, Sch Med Sci, Discipline Pharmacol, Adelaide, SA 5005, Australia. [van Steeg, K.] Univ Utrecht, Fac Sci, Div Pharmacol, NL-3805 TD Utrecht, Netherlands. [Kopajtic, T. A.; Katz, J. L.] NIDA, Dept Hlth & Human Serv, NIH, Intramural Res Program,Biomed Res Ctr MDRB, Baltimore, MD 21224 USA. [Bland, S. T.] Univ Colorado Denver, Dept Psychol, Denver, CO 80217 USA. [Rice, K. C.] NIDA, Chem Biol Res Branch, NIH, Bethesda, MD 20892 USA. [Rice, K. C.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Watkins, LR (reprint author), Univ Colorado Boulder, Dept Psychol & Neurosci, Ctr Neurosci, Campus Box 345, Boulder, CO 80309 USA. EM linda.watkins@colorado.edu RI Hiranita, Takato/G-6567-2011; Bachtell, Ryan/H-7436-2013; Hutchinson, Mark/G-4147-2014; YIN, HANG/O-2097-2014; Wang, Xiaohui/B-8126-2011; OI Bachtell, Ryan/0000-0001-5268-5927; Hutchinson, Mark/0000-0003-2154-5950; YIN, HANG/0000-0002-9762-4818; Wang, Xiaohui/0000-0002-3415-5612; Strand, Keith/0000-0001-8885-0162; Katz, Jonathan/0000-0002-1068-1159 FU NIH [DA024044, DE017782, DA023132, DA025740, NS067425, DA027977, DA026950]; NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism; International Association for the Study of Pain international collaborative research grant; American Australian Association Merck Company Foundation Fellowship; National Health and Medical Research Council CJ Martin Fellowship [ID 465423]; Australian Research Council Research Fellowship [DP110100297]; Australian Postgraduate Award; Danone Research for Specialised Nutrition (The Netherlands) (K.vS) FX This research was supported by NIH Grants DA024044, DE017782, DA023132, DA025740, NS067425, DA027977, and DA026950 and by the NIH Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. Support was also provided by an International Association for the Study of Pain international collaborative research grant, an American Australian Association Merck Company Foundation Fellowship, a National Health and Medical Research Council CJ Martin Fellowship (ID 465423; M.R.H. 2007-2010), Australian Research Council Research Fellowship (DP110100297; M.R.H. 2011), and Australian Postgraduate Award (J.T.) and Danone Research for Specialised Nutrition (The Netherlands) (K.vS). We thank Dr. David White and the NIDA Addiction Treatment Discovery Program (NIDA ATDP) for the NovaScreen data generated through a contract with Caliper Life Sciences as well as for the biogenic amine transporter data generated through a contract with Research Service (R&D-22), Department of Veterans Affairs Medical Center, Portland, OR. NR 63 TC 76 Z9 76 U1 1 U2 29 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 AUG 15 PY 2012 VL 32 IS 33 BP 11187 EP 11200 DI 10.1523/JNEUROSCI.0684-12.2012 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 994OJ UT WOS:000307940000004 PM 22895704 ER PT J AU Setiawan, VW Pike, MC Karageorgi, S Deming, SL Anderson, K Bernstein, L Brinton, LA Cai, H Cerhan, JR Cozen, W Chen, C Doherty, J Freudenheim, JL Goodman, MT Hankinson, SE Lacey, JV Liang, XL Lissowska, J Lu, LG Lurie, G Mack, T Matsuno, RK McCann, S Moysich, KB Olson, SH Rastogi, R Rebbeck, TR Risch, H Robien, K Schairer, C Shu, XO Spurdle, AB Strom, BL Thompson, PJ Ursin, G Webb, PM Weiss, NS Wentzensen, N Xiang, YB Yang, HP Yu, H Horn-Ross, PL De Vivo, I AF Setiawan, Veronica Wendy Pike, Malcolm C. Karageorgi, Stalo Deming, Sandra L. Anderson, Kristin Bernstein, Leslie Brinton, Louise A. Cai, Hui Cerhan, James R. Cozen, Wendy Chen, Chu Doherty, Jennifer Freudenheim, Jo L. Goodman, Marc T. Hankinson, Susan E. Lacey, James V., Jr. Liang, Xiaolin Lissowska, Jolanta Lu, Lingeng Lurie, Galina Mack, Thomas Matsuno, Rayna K. McCann, Susan Moysich, Kirsten B. Olson, Sara H. Rastogi, Radhai Rebbeck, Timothy R. Risch, Harvey Robien, Kim Schairer, Catherine Shu, Xiao-Ou Spurdle, Amanda B. Strom, Brian L. Thompson, Pamela J. Ursin, Giske Webb, Penelope M. Weiss, Noel S. Wentzensen, Nicolas Xiang, Yong-Bing Yang, Hannah P. Yu, Herbert Horn-Ross, Pamela L. De Vivo, Immaculata CA Australian Natl Endometrial Canc S TI Age at Last Birth in Relation to Risk of Endometrial Cancer: Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE endometrial neoplasms; parity; reproductive history ID REPRODUCTIVE FACTORS; POSTMENOPAUSAL WOMEN; REPLACEMENT THERAPY; POPULATION; COHORT; ASSOCIATION; CONSUMPTION; PROGESTIN; CARCINOMA; PREGNANCY AB Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (P-trend 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95 confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44 decreased risk compared with women who had their last birth under the age of 25 years (95 confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years. C1 [Setiawan, Veronica Wendy; Pike, Malcolm C.; Cozen, Wendy; Mack, Thomas] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90033 USA. [Pike, Malcolm C.; Liang, Xiaolin; Olson, Sara H.; Rastogi, Radhai] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Karageorgi, Stalo; De Vivo, Immaculata] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Deming, Sandra L.; Cai, Hui; Shu, Xiao-Ou] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Anderson, Kristin; Robien, Kim] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Bernstein, Leslie; Lacey, James V., Jr.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA. [Brinton, Louise A.; Schairer, Catherine; Wentzensen, Nicolas; Yang, Hannah P.] NCI, Bethesda, MD 20892 USA. [Cerhan, James R.] Mayo Clin, Rochester, MN USA. [Chen, Chu; Doherty, Jennifer] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Freudenheim, Jo L.] SUNY Buffalo, Sch Publ Hlth & Hlth Profess, Buffalo, NY 14260 USA. [Goodman, Marc T.; Lurie, Galina; Matsuno, Rayna K.; Thompson, Pamela J.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Lu, Lingeng; Risch, Harvey; Yu, Herbert] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Hankinson, Susan E.; De Vivo, Immaculata] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hankinson, Susan E.; De Vivo, Immaculata] Harvard Univ, Sch Med, Boston, MA USA. [McCann, Susan; Moysich, Kirsten B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Rebbeck, Timothy R.; Strom, Brian L.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Spurdle, Amanda B.; Webb, Penelope M.] Queensland Inst Med Res, Div Genet & Populat Hlth, Brisbane, Qld 4006, Australia. [Ursin, Giske] Canc Registry Norway, Oslo, Norway. [Ursin, Giske] Univ Oslo, Dept Nutr, N-0316 Oslo, Norway. [Weiss, Noel S.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Xiang, Yong-Bing] Shanghai Canc Inst, Shanghai, Peoples R China. [Horn-Ross, Pamela L.] Canc Prevent Inst Calif, Fremont, CA USA. RP Setiawan, VW (reprint author), Univ So Calif, Dept Prevent Med, Keck Sch Med, 1450 Biggy St,Room 1517G, Los Angeles, CA 90033 USA. EM vsetiawa@usc.edu RI Brinton, Louise/G-7486-2015; Spurdle, Amanda/A-4978-2011; OI Brinton, Louise/0000-0003-3853-8562; Cerhan, James/0000-0002-7482-178X; Webb, Penelope/0000-0003-0733-5930; Spurdle, Amanda/0000-0003-1337-7897; Lissowska, Jolanta/0000-0003-2695-5799; Robien, Kim/0000-0002-2120-2280 FU National Cancer Institute (NCI) of the National Institutes of Health (NIH) [R03 CA135632]; National Cancer Institute [CA116543]; National Health and Medical Research Council of Australia (NHMRC); NHMRC [339435]; Cancer Council of Queensland; Cancer Council of Tasmania; NIH [R01 CA58598, N01 CN67001, N01 PC35137, R01 CA39742, P01 CA87262, R01 CA082838, R01 CA092585, R01 CA48774, P30 CA14089, P01 CA77596, CA11535]; U.S. Army Medical Research Program DAMD [17-96-607]; California Breast Cancer Research Program (CBCRP) [4JB-1106]; Department of Health and Human Services, NCI, NIH; CBCRP fund; California Department of Public Health [103885]; NCI; Public Health Institute, University of Southern California; Centers for Disease Control and Prevention FX This work was supported by a grant from the National Cancer Institute (NCI) of the National Institutes of Health (NIH) (grant R03 CA135632 to V. W. S.). V. W. S is supported in part by a National Cancer Institute K07 Career Development Award (CA116543). P. M. W. and A. B. S. are supported by fellowships from the National Health and Medical Research Council of Australia (NHMRC). The individual studies were funded by the following grants and agencies: Australian National Endometrial Cancer Study: NHMRC grant 339435 and the Cancer Councils of Queensland and Tasmania; Bay Area Women's Health Study: NIH grant R01 CA74877; controls were collected under NIH grant R01 63446, U.S. Army Medical Research Program DAMD grant 17-96-607, and California Breast Cancer Research Program (CBCRP) grant 4JB-1106; Breast Cancer Detection Demonstration Project: Intramural Research Programs of the Department of Health and Human Services, NCI, NIH; Connecticut Endometrial Cancer Study: NIH grant R01 CA098346; California Teachers Study: NIH grant R01CA77398 and the CBCRP fund; the collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885, the NCI's Surveillance, Epidemiology, and End Results Program awarded to the Cancer Prevention Institute of California, the Public Health Institute, University of Southern California, and the Centers for Disease Control and Prevention's National Program of Cancer Registries; Estrogen, Diet, Genetics, and Endometrial Cancer Study: NIH grant R01 CA83918; Fred Hutchinson Cancer Research Center: NIH grants R35 CA39779, R01 CA75977, N01 HD23166, K05 CA92002, R01 CA105212, and R01 CA87538; Hawaii Endometrial Cancer Study: NIH grants P01 CA33619, R01 CA58598, N01 CN67001, and N01 PC35137; Iowa Women's Health Study: NIH grant R01 CA39742; Nurses' Health Study: NIH grants P01 CA87262 and R01 CA082838; Polish Endometrial Cancer Study: Intramural Research Funds of the Department of Health and Human Services, NCI, NIH; Shanghai Endometrial Cancer Study: NIH grant R01 CA092585; US Endometrial Cancer Study: Intramural Research Funds of the Department of Health and Human Services, NCI, NIH; case-control study conducted by USC: NIH grants R01 CA48774 and P30 CA14089; Women's Insight and Shared Experience Study: NIH grant P01 CA77596; and Western New York Diet Study: NIH grant CA11535. NR 40 TC 16 Z9 16 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2012 VL 176 IS 4 BP 269 EP 278 DI 10.1093/aje/kws129 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 988ON UT WOS:000307500500001 PM 22831825 ER PT J AU Howlader, N Noone, AM Yu, MD Cronin, KA AF Howlader, Nadia Noone, Anne-Michelle Yu, Mandi Cronin, Kathleen A. TI Use of Imputed Population-based Cancer Registry Data as a Method of Accounting for Missing Information: Application to Estrogen Receptor Status for Breast Cancer SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast neoplasms; imputation; incidence; missing data; receptors; estrogen ID UNITED-STATES; AMERICAN SOCIETY; INCIDENCE RATES; TRENDS; WOMEN; RECOMMENDATIONS AB The National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) Program provides a rich source of data stratified according to tumor biomarkers that play an important role in cancer surveillance research. These data are useful for analyzing trends in cancer incidence and survival. These tumor markers, however, are often prone to missing observations. To address the problem of missing data, the authors employed sequential regression multivariate imputation for breast cancer variables, with a particular focus on estrogen receptor status, using data from 13 SEER registries covering the period 19922007. In this paper, they present an approach to accounting for missing information through the creation of imputed data sets that can be analyzed using existing software (e.g., SEERStat) developed for analyzing cancer registry data. Bias in age-adjusted trends in female breast cancer incidence is shown graphically before and after imputation of estrogen receptor status, stratified by age and race. The imputed data set will be made available in SEERStat (http://seer.cancer.gov/analysis/index.html) to facilitate accurate estimation of breast cancer incidence trends. To ensure that the imputed data set is used correctly, the authors provide detailed, step-by-step instructions for conducting analyses. This is the first time that a nationally representative, population-based cancer registry data set has been imputed and made available to researchers for conducting a variety of analyses of breast cancer incidence trends. C1 [Howlader, Nadia; Noone, Anne-Michelle; Yu, Mandi; Cronin, Kathleen A.] NCI, Data Anal & Interpretat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Howlader, N (reprint author), NCI, Data Anal & Interpretat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, 6116 Execut Blvd,Suite 504, Bethesda, MD 20892 USA. EM howladern@mail.nih.gov FU Division of Cancer Control and Population Sciences, National Cancer Institute FX This work was supported by the Surveillance Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute. NR 26 TC 25 Z9 26 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2012 VL 176 IS 4 BP 347 EP 356 DI 10.1093/aje/kwr512 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 988ON UT WOS:000307500500009 PM 22842721 ER PT J AU Cho, Y Kim, MS Kim, HS Ann, J Lee, J Pearce, LV Pavlyukovets, VA Morgan, MA Blumberg, PM Lee, J AF Cho, Yongsung Kim, Myeong Seop Kim, Ho Shin Ann, Jihyae Lee, Jiyoun Pearce, Larry V. Pavlyukovets, Vladimir A. Morgan, Matthew A. Blumberg, Peter M. Lee, Jeewoo TI The SAR analysis of TRPV1 agonists with the alpha-methylated B-region SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Vanilloid receptor 1; TRPV1 agonist; Capsaicin ID VANILLOID RECEPTOR TRPV1; CAPSAICIN RECEPTOR; A-REGION; ANTAGONISTS; PAIN; CHANNEL; ANALGESICS; MECHANISMS; ANALOGS AB A series of TRPV1 agonists with amide, reverse amide, and thiourea groups in the B-region and their corresponding alpha-methylated analogues were investigated. Whereas the alpha-methylation of the amide B-region enhanced the binding affinities and potencies as agonists, that of the reverse amide and thiourea led to a reduction in receptor affinity. The analysis indicated that proper hydrogen bonding as well as steric effects in the B-region are critical for receptor binding. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Cho, Yongsung; Kim, Myeong Seop; Kim, Ho Shin; Ann, Jihyae; Lee, Jeewoo] Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. [Lee, Jiyoun] Sungshin Womens Univ, Dept Global Med Sci, Seoul 142732, South Korea. [Pearce, Larry V.; Pavlyukovets, Vladimir A.; Morgan, Matthew 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, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr; jeewoo@snu.ac.kr FU NRF [R11-2007-107-02001-0]; Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z1A BC 005270] FX This research was supported by Grants R11-2007-107-02001-0 from the NRF and was supported in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Project Z1A BC 005270). We thank other members of the Blumberg group for assistance with some of the assays. NR 22 TC 2 Z9 2 U1 3 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 15 PY 2012 VL 22 IS 16 BP 5227 EP 5231 DI 10.1016/j.bmcl.2012.06.059 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 981JJ UT WOS:000306962800014 PM 22796184 ER PT J AU Falade-Nwulia, O Seaberg, EC Rinaldo, CR Badri, S Witt, M Thio, CL AF Falade-Nwulia, Oluwaseun Seaberg, Eric C. Rinaldo, Charles R. Badri, Sheila Witt, Mallory Thio, Chloe L. TI Comparative Risk of Liver-Related Mortality From Chronic Hepatitis B Versus Chronic Hepatitis C Virus Infection SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; OPPORTUNISTIC INFECTIONS; ANTIRETROVIRAL THERAPY; VIRAL-HEPATITIS; NATURAL-HISTORY; HIV-INFECTION; DISEASE; COHORT; DEATH; AIDS AB Background. It is not known whether chronic hepatitis B (CH-B) or chronic hepatitis C (CH-C) carries a greater risk of liver-related mortality. This study compared rates of liver-related mortality between these 2 groups in the Multicenter AIDS Cohort Study (MACS). Methods. Six hundred eighty men with CH-B (n = 337) or CH-C (n = 343) at study entry into the MACS were prospectively followed to death, last follow-up visit, or 30 March 2010, whichever came first. Four hundred seventy-two (69.4%) of these men were infected with human immunodeficiency virus type 1 (HIV-1). Causes of death were obtained from death registry matching and death certificates. Liver-related and all-cause mortality rates (MRs) were compared between groups using Poisson regression and adjusted for potential confounders and competing risks. Results. In 6728 person-years (PYs) of follow-up, there were 293 deaths from all causes (43.5 per 1000 PYs), of which 51 were liver-related (7.6 per 1000 PYs). The all-cause MR was similar between those with CH-B and CH-C; however, the liver-related MR was significantly higher in those with CH-B (9.6 per 1000 PYs; 95% confidence interval [CI], 6.9-13.2) than those with CH-C (5.0 per 1000 PYs; 95% CI, 3.0-8.4). In the HIV-infected subgroup, which had 46 (90.2%) of the liver-related deaths, the liver-related MR remained higher from CH-B after adjusting for potential confounders (incidence rate ratio, 2.2; P = .03) and competing risks (subhazard rate ratio, 2.4; P = .02). Furthermore, among HIV-infected subjects, CD4 cell counts <200 cells/mm(3) were associated with a 16.2-fold (95% CI, 6.1-42.8) increased risk of liver-related death compared with CD4 cell counts >350 cell/mm(3). Conclusions. Chronic hepatitis B carries a higher risk of death from liver disease than does CH-C, especially in HIV-infected men with greater immunosuppression. C1 [Falade-Nwulia, Oluwaseun; Thio, Chloe L.] Johns Hopkins Univ, Div Infect Dis, Baltimore, MD 21287 USA. [Falade-Nwulia, Oluwaseun] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Seaberg, Eric C.] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21287 USA. [Rinaldo, Charles R.] Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA 15260 USA. Rush Univ, Med Ctr, Div Infect Dis, John H Stroger Jr Hosp Cook Cty, Chicago, IL 60612 USA. [Badri, Sheila; Witt, Mallory] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA. [Badri, Sheila; Witt, Mallory] Harbor UCLA Med Ctr, Div HIV Med, Torrance, CA 90509 USA. RP Falade-Nwulia, O (reprint author), Johns Hopkins Univ, Div Infect Dis, 1830 E Monument St,Rm 420, Baltimore, MD 21287 USA. EM ofalade1@jhmi.edu FU National Institute of Allergy and Infectious Diseases; National Cancer Institute [UO1-AI-35042, UL1-RR025005, UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041] FX The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (UO1-AI-35042, UL1-RR025005 [GCRC], UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, and UO1-AI-35041). NR 26 TC 18 Z9 18 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2012 VL 55 IS 4 BP 507 EP 513 DI 10.1093/cid/cis432 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 977RQ UT WOS:000306682500008 PM 22523269 ER PT J AU Dooley, KE Mitnick, CD DeGroote, MA Obuku, E Belitsky, V Hamilton, CD Makhene, M Shah, S Brust, JCM Durakovic, N Nuermberger, E AF Dooley, Kelly E. Mitnick, Carole D. DeGroote, Mary Ann Obuku, Ekwaro Belitsky, Vera Hamilton, Carol D. Makhene, Mamodikoe Shah, Sarita Brust, James C. M. Durakovic, Nadza Nuermberger, Eric CA RESIST-TB TI Old Drugs, New Purpose: Retooling Existing Drugs for Optimized Treatment of Resistant Tuberculosis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID EARLY BACTERICIDAL ACTIVITY; MYCOBACTERIUM-TUBERCULOSIS; MULTIDRUG-RESISTANT; PULMONARY TUBERCULOSIS; ANTITUBERCULOSIS DRUGS; ETHAMBUTOL RESISTANCE; THERAPY; CYCLOSERINE; AMIKACIN; CAPREOMYCIN AB Treatment of drug-resistant tuberculosis is hindered by the high toxicity and poor efficacy of second-line drugs. New compounds must be used together with existing drugs, yet clinical trials to optimize combinations of drugs for drug-resistant tuberculosis are lacking. We conducted an extensive review of existing in vitro, animal, and clinical studies involving World Health Organization-defined group 1, 2, and 4 drugs used in drug-resistant tuberculosis regimens to inform clinical trials and identify critical research questions. Results suggest that optimizing the dosing of pyrazinamide, the injectables, and isoniazid for drug-resistant tuberculosis is a high priority. Additional pharmacokinetic, pharmacodynamic, and toxicodynamic studies are needed for pyrazinamide and ethionamide. Clinical trials of the comparative efficacy and appropriate treatment duration of injectables are recommended. For isoniazid, rapid genotypic tests for Mycobacterium tuberculosis mutations should be nested in clinical trials. Further research focusing on optimization of dose and duration of drugs with activity against drug-resistant tuberculosis is paramount. C1 [Dooley, Kelly E.] Johns Hopkins Univ, Sch Med, Div Clin Pharmacol, Baltimore, MD 21287 USA. [Mitnick, Carole D.] Harvard Univ, Sch Med, Boston, MA USA. [DeGroote, Mary Ann] Colorado State Univ, Mycobacterial Res Labs, Ft Collins, CO 80523 USA. [Obuku, Ekwaro] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Obuku, Ekwaro] AIDS Relief Programme & Joint Clin Res Ctr, Kampala, Uganda. [Belitsky, Vera; Durakovic, Nadza] Partners Hlth, Boston, MA USA. [Hamilton, Carol D.] Family Hlth Int, Durham, NC USA. [Makhene, Mamodikoe] NIH, Bethesda, MD 20892 USA. [Shah, Sarita; Brust, James C. M.] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Dooley, KE (reprint author), Johns Hopkins Univ, Sch Med, Div Clin Pharmacol, 600 N Wolfe St,Osler 527, Baltimore, MD 21287 USA. EM kdooley1@jhmi.edu FU National Institutes of Health [K23AI080842, K23AI083088]; Doris Duke Charitable Foundation [2007071] FX This work was supported by the National Institutes of Health (grant K23AI080842 to K. E. D. and K23AI083088 to J. C. M. B.) and the Doris Duke Charitable Foundation (Clinical Scientist Development Award 2007071 to S. S.). NR 45 TC 28 Z9 31 U1 2 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2012 VL 55 IS 4 BP 572 EP 581 DI 10.1093/cid/cis487 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 977RQ UT WOS:000306682500018 PM 22615332 ER PT J AU Chi, BH Adler, MR Bolu, O Mbori-Ngacha, D Ekouevi, DK Gieselman, A Chipato, T Luo, CW Phelps, BR McClure, C Mofenson, LM Stringer, JSA AF Chi, Benjamin H. Adler, Michelle R. Bolu, Omotayo Mbori-Ngacha, Dorothy Ekouevi, Didier K. Gieselman, Anna Chipato, Tsungai Luo, Chewe Phelps, B. Ryan McClure, Craig Mofenson, Lynne M. Stringer, Jeffrey S. A. TI Progress, Challenges, and New Opportunities for the Prevention of Mother-to-Child Transmission of HIV Under the US President's Emergency Plan for AIDS Relief SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE prevention of mother-to-child HIV transmission; MTCT; PEPFAR; global response; HIV ID EARLY ANTIRETROVIRAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; PROSPECTIVE COHORT; SOUTH-AFRICA; PREGNANT-WOMEN; MALE CIRCUMCISION; INFECTED INFANTS; INCOME COUNTRIES; DOSE NEVIRAPINE; PROGRAMS AB In June 2011, the Joint United Nations Programme on HIV/AIDS, the US President's Emergency Plan for AIDS Relief (PEPFAR), and other collaborators outlined a transformative plan to virtually eliminate pediatric AIDS worldwide. The ambitious targets of this initiative included a 90% reduction in new pediatric HIV infections and a 50% reduction in HIV-related maternal mortality-all by 2015. PEPFAR has made an unprecedented commitment to the expansion and improvement of prevention of mother-to-child HIV transmission (PMTCT) services globally and is expected to play a critical role in reaching the virtual elimination target. To date, PEPFAR has been instrumental in the success of many national programs, including expanded coverage of PMTCT services, an enhanced continuum of care between PMTCT and HIV care and treatment, provision of more efficacious regimens for antiretroviral prophylaxis, design of innovative but simplified PMTCT approaches, and development of new strategies to evaluate program effectiveness. These accomplishments have been made through collaborative efforts with host governments, United Nations agencies, other donors (eg, the Global Fund for AIDS, Tuberculosis, and Malaria), nongovernmental organizations, and private sector partners. To successfully meet the ambitious global targets to prevent new infant HIV infections, PEPFAR must continue to leverage the existing PMTCT platform, while developing innovative approaches to rapidly expand quality HIV services. PEPFAR must also carefully integrate PMTCT into the broader combination prevention agenda for HIV, so that real progress can be made toward an "AIDS-free generation" worldwide. C1 [Chi, Benjamin H.; Stringer, Jeffrey S. A.] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Chi, Benjamin H.; Stringer, Jeffrey S. A.] Univ N Carolina, Chapel Hill, NC USA. [Adler, Michelle R.; Bolu, Omotayo] Ctr Dis Control & Prevent, Global AIDS Program, Atlanta, GA USA. [Adler, Michelle R.; Gieselman, Anna] Off Global AIDS Coordinator, Washington, DC USA. [Mbori-Ngacha, Dorothy] UNICEF, Johannesburg, South Africa. [Ekouevi, Didier K.] Univ Bordeaux Segalen, INSERM, U897, Bordeaux, France. [Ekouevi, Didier K.] Programme PAC CI, Abidjan, Cote Ivoire. [Chipato, Tsungai] Univ Zimbabwe, Harare, Zimbabwe. [Luo, Chewe; McClure, Craig] UNICEF, New York, NY USA. [Phelps, B. Ryan] US Agcy Int Dev, Washington, DC 20523 USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD USA. RP Chi, BH (reprint author), Plot 1275 Lubutu Rd,POB 34681, Lusaka, Zambia. EM bchi@cidrz.org RI EKOUEVI, Didier/E-7960-2014; OI Mofenson, Lynne/0000-0002-2818-9808 NR 82 TC 31 Z9 31 U1 1 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2012 VL 60 SU 3 BP S78 EP S87 DI 10.1097/QAI.0b013e31825f3284 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 981TR UT WOS:000306994100006 PM 22797744 ER PT J AU El-Sadr, WM Morrison, JS Quinn, T Volberding, P AF El-Sadr, Wafaa M. Morrison, J. Stephen Quinn, Thomas Volberding, Paul TI A Chronicle of Hope and Promise: The World As It Was, As It Is, and As It Can Be SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article C1 [El-Sadr, Wafaa M.] Columbia Univ, ICAP, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Morrison, J. Stephen] Ctr Strateg & Int Studies, Washington, DC 20006 USA. [Quinn, Thomas] NIAID, Div Intramural Res, Bethesda, MD 20892 USA. [Volberding, Paul] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP El-Sadr, WM (reprint author), Columbia Univ, ICAP, Mailman Sch Publ Hlth, 722 W 168th St,13th Floor, New York, NY 10032 USA. EM wme1@columbia.edu FU NIAID NIH HHS [P30 AI027763] 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 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2012 VL 60 SU 3 BP S49 EP S50 DI 10.1097/QAI.0b013e31825c78bb PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 981TR UT WOS:000306994100001 PM 22797739 ER PT J AU Goosby, E Dybul, M Fauci, AA Fu, J Walsh, T Needle, R Bouey, P AF Goosby, Eric Dybul, Mark Fauci, Anthony A. Fu, Joe Walsh, Thomas Needle, Richard Bouey, Paul TI The United States President's Emergency Plan for AIDS Relief: A Story of Partnerships and Smart Investments to Turn the Tide of the Global AIDS Pandemic SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE PEPFAR; HIV prevention; care; treatment AB The United States President's Emergency Plan for AIDS Relief (PEPFAR) has played a key leadership role in the global response to the HIV/AIDS pandemic. PEPFAR was inspired by the principles of the historic Monterrey Consensus (United Nations. Monterrey Consensus on Financing for Development, Monterrey, Mexico, March 18-22, 2002. New York: United Nations; 2002. Available at: http://www.un.org/esa/ffd/monterrey/MonterreyConsensus.pdf. Accessed April 21, 2012), which changed the underlying conceptual framework for international development, and therefore global health-a shift from paternalism to partnership that begins with country ownership and requires good governance, a results-based approach, and engagement of all sectors of society. PEPFAR began with a focus on the growing emergency of the HIV/AIDS pandemic by rapidly expanding HIV services, building clinical capacity, implementing strategic information systems, and building a coalition of partners to lead the response. Within the first years of implementation, there was a shift to sustainability, including the advent of Partnership Frameworks. The PEPFAR reauthorization in 2008 codified into law, the evolution in policies and programs for the next phase of implementation. In 2011 alone, PEPFAR supported nearly 4 million people on treatment, supported programs that provided more than 1.5 million HIV-positive pregnant women with antiretroviral drugs to prevent HIV transmission to their children, and supported HIV testing for more than 40 million people. This article provides an overview of how smart investments and partnerships across sectors and US agencies have helped achieve unprecedented results in increasing HIV/AIDS services and engaging partner countries and organizations in sharing the responsibility for an AIDS-free generation. C1 [Goosby, Eric; Fu, Joe; Walsh, Thomas; Needle, Richard; Bouey, Paul] Off US Global AIDS Coordinator, Washington, DC 20522 USA. [Dybul, Mark] Georgetown Univ, ONeill Inst Natl & Global Hlth Law, Washington, DC USA. [Fauci, Anthony A.] NIAID, NIH, Bethesda, MD 20892 USA. RP Fu, J (reprint author), Off US Global AIDS Coordinator, 301 4th St SW,700, Washington, DC 20522 USA. EM fujkh@state.gov NR 19 TC 17 Z9 18 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2012 VL 60 SU 3 BP S51 EP S56 DI 10.1097/QAI.0b013e31825ca721 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 981TR UT WOS:000306994100002 PM 22797740 ER PT J AU Reed, JB Njeuhmeli, E Thomas, AG Bacon, MC Bailey, R Cherutich, P Curran, K Dickson, K Farley, T Hankins, C Hatzold, K Justman, J Mwandi, Z Nkinsi, L Ridzon, R Ryan, C Bock, N AF Reed, Jason Bailey Njeuhmeli, Emmanuel Thomas, Anne Goldzier Bacon, Melanie C. Bailey, Robert Cherutich, Peter Curran, Kelly Dickson, Kim Farley, Tim Hankins, Catherine Hatzold, Karin Justman, Jessica Mwandi, Zebedee Nkinsi, Luke Ridzon, Renee Ryan, Caroline Bock, Naomi TI Voluntary Medical Male Circumcision: An HIV Prevention Priority for PEPFAR SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE male circumcision; HIV prevention; PEPFAR ID RANDOMIZED CONTROLLED-TRIAL; IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN-PAPILLOMAVIRUS; FEMALE PARTNERS; TARGET-CELLS; YOUNG MEN; INFECTION; RISK; TRANSMISSION; KISUMU AB As the science demonstrating strong evidence for voluntary medical male circumcision (VMMC) for HIV prevention has evolved, the President's Emergency Plan for AIDS Relief (PEPFAR) has collaborated with international agencies, donors, and partner country governments supporting VMMC programming. Mathematical models forecast that quickly reaching a large number of uncircumcised men with VMMC in strategically chosen populations may dramatically reduce community-level HIV incidence and save billions of dollars in HIV care and treatment costs. Because VMMC is a 1-time procedure that confers life-long partial protection against HIV, programs for adult men are vital short-term investments with long-term benefits. VMMC also provides a unique opportunity to reach boys and men with HIV testing and counseling services and referrals for other HIV services, including treatment. After formal recommendations by WHO in 2007, priority countries have pursued expansion of VMMC. More than 1 million males have received VMMC thus far, with the most notable successes coming from Kenya's Nyanza Province. However, a myriad of necessary cultural, political, and ethical considerations have moderated the pace of overall success. Because many millions more uncircumcised men would benefit from VMMC services now, US President Barack Obama committed PEPFAR to provide 4.7 million males with VMMC by 2014. Innovative circumcision methods-such as medical devices that remove the foreskin without injected anesthesia and/or sutures-are being rigorously evaluated. Incorporation of safe innovations into surgical VMMC programs may provide the opportunity to reach more men more quickly with services and dramatically reduce HIV incidence for all. C1 [Reed, Jason Bailey; Bock, Naomi] US Ctr Dis Control & Prevent, Atlanta, GA USA. [Njeuhmeli, Emmanuel] US Agcy Int Dev, Washington, DC 20523 USA. [Thomas, Anne Goldzier] USN, Hlth Res Ctr, Dept Def HIV AIDS Program, San Diego, CA 92152 USA. [Bacon, Melanie C.] US Natl Inst Hlth, Bethesda, MD USA. [Bailey, Robert] Univ Illinois, Sch Publ Hlth, Chicago, IL USA. [Curran, Kelly] Johns Hopkins Bloomberg Sch Publ Hlth, Jhpiego, Baltimore, MD USA. [Dickson, Kim] UNICEF, Hlth Sect, New York, NY USA. [Farley, Tim] WHO, Sigma3 Serv, Nyon, Switzerland. [Hankins, Catherine] London Sch Hyg & Trop Med, Geneva, Switzerland. [Hankins, Catherine] Joint United Nations Programme HIV AIDS, Geneva, Switzerland. [Justman, Jessica] Columbia Univ, Mailman Sch Publ Hlth, Int Ctr AIDS Care & Treatment Programs, New York, NY USA. [Mwandi, Zebedee] US Ctr Dis Control & Prevent Kenya, Nairobi, Kenya. [Ridzon, Renee] Bill & Melinda Gates Fdn, Ahimsa Grp LLC, Seattle, WA USA. [Ryan, Caroline] Off Global AIDS Coordinator, Washington, DC USA. RP Reed, JB (reprint author), 1600 Clifton Rd NE,MS E-04, Atlanta, GA 30333 USA. EM jreed1@cdc.gov OI Hankins, Catherine/0000-0002-1642-8592 FU PEPFAR FX Various authors receive financial support or have professional relationships from PEPFAR (either as employees of PEPFAR-supported US Government agencies or as grantees/contractors) as outlined in the Copyright Transfer Agreement Forms. NR 54 TC 15 Z9 15 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2012 VL 60 SU 3 BP S88 EP S95 DI 10.1097/QAI.0b013e31825cac4e PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 981TR UT WOS:000306994100007 PM 22797745 ER PT J AU Qian, Y Jeong, JS Maldonado, M Valenzuela, JG Gomes, R Teixeira, C Evangelista, F Qaqish, B Aoki, V Hans, G Rivitti, EA Eaton, D Diaz, LA AF Qian, Ye Jeong, Joseph S. Maldonado, Mike Valenzuela, Jesus G. Gomes, Regis Teixeira, Clarissa Evangelista, Flor Qaqish, Bahjat Aoki, Valeria Hans, Gunter, Jr. Rivitti, Evandro A. Eaton, Donald Diaz, Luis A. TI Cutting Edge: Brazilian Pemphigus Foliaceus Anti-Desmoglein 1 Autoantibodies Cross-React with Sand Fly Salivary LJM11 Antigen SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FOGO SELVAGEM; LUTZOMYIA-LONGIPALPIS; IMMUNOTHERAPY; ANTIBODIES; VULGARIS; CHAGASI; DISEASE; EPITOPE; VECTOR; VITRO AB The environmental factors that contribute to the development of autoimmune diseases are largely unknown. Endemic pemphigus foliaceus in humans, known as Fogo Selvagem (FS) in Brazil, is mediated by pathogenic IgG4 autoantibodies against desmoglein 1 (Dsg1). Clusters of FS overlap with those of leishmaniasis, a disease transmitted by sand fly (Lutzomyia longipalpis) bites. In this study, we show that salivary Ags from the sand fly, and specifically the LJM11 salivary protein, are recognized by FS Abs. Anti-Dsg1 monoclonal autoantibodies derived from FS patients also cross-react with LJM11. Mice immunized with LJM11 generate anti-Dsg1 Abs. Thus, insect bites may deliver salivary Ags that initiate a cross-reactive IgG4 Ab response in genetically susceptible individuals and lead to subsequent FS. Our findings establish a clear relationship between an environmental, noninfectious Ag and the development of potentially pathogenic autoantibodies in an autoimmune disease. The Journal of Immunology, 2012, 189: 1535-1539. C1 [Qian, Ye; Jeong, Joseph S.; Maldonado, Mike; Evangelista, Flor; Diaz, Luis A.] Univ N Carolina, Dept Dermatol, Chapel Hill, NC 27599 USA. [Valenzuela, Jesus G.; Gomes, Regis; Teixeira, Clarissa] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Qaqish, Bahjat] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Aoki, Valeria; Rivitti, Evandro A.] Univ Sao Paulo, Dept Dermatol, BR-05508 Sao Paulo, Brazil. [Hans, Gunter, Jr.; Eaton, Donald] Univ Fed Mato Grosso do Sul, Dept Dermatol, BR-79070900 Mato Grosso, Brazil. RP Diaz, LA (reprint author), Univ N Carolina, Dept Dermatol, CB 7287, Chapel Hill, NC 27599 USA. EM luis_diaz@med.unc.edu RI Aoki, Valeria/H-1415-2012 FU National Institutes of Health [R01 AR30281, R01 AR32599, K01 AR056378]; Dermatology Foundation research award; American Skin Association Alice P. Melly research grant FX This work was supported in part by National Institutes of Health Grants R01 AR30281, R01 AR32599 (to L.A.D.), and K01 AR056378 (to Y.Q.). Y.Q. was also supported by a Dermatology Foundation research award and an American Skin Association Alice P. Melly research grant. NR 23 TC 18 Z9 18 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2012 VL 189 IS 4 BP 1535 EP 1539 DI 10.4049/jimmunol.1200842 PG 5 WC Immunology SC Immunology GA 984TW UT WOS:000307216000002 PM 22798673 ER PT J AU Vargas-Inchaustegui, DA Xiao, P Tuero, I Patterson, LJ Robert-Guroff, M AF Vargas-Inchaustegui, Diego A. Xiao, Peng Tuero, Iskra Patterson, L. Jean Robert-Guroff, Marjorie TI NK and CD4(+) T Cell Cooperative Immune Responses Correlate with Control of Disease in a Macaque Simian Immunodeficiency Virus Infection Model SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; ACUTE HIV-1 INFECTION; INNATE IMMUNITY; RHESUS MACAQUES; SIV INFECTION; ELITE CONTROLLERS; DENDRITIC CELLS; IFN-GAMMA; MUCOSAL; REPLICATION AB Control of infectious disease may be accomplished by successful vaccination or by complex immunologic and genetic factors favoring Ag-specific multicellular immune responses. Using a rhesus macaque model, we evaluated Ag-specific T cell-dependent NK cell immune responses in SIV-infected macaques, designated "controlling" or "noncontrolling" based on long-term chronic viremia levels, to determine whether NK cell effector functions contribute to control of SIV infection. We observed that Gag stimulation of macaque PBMCs induced subset-specific NK cell responses in SIV-controlling but not SIV-noncontrolling animals, as well as that circulatory NK cell responses were dependent on Ag-specific IL-2 production by CD4(+) central memory T cells. NK cell activation was blocked by anti-IL-2-neutralizing Ab and by CD4(+) T cell depletion, which abrogated the Gag-specific responses. Among tissue-resident cells, splenic and circulatory NK cells displayed similar activation profiles, whereas liver and mucosal NK cells displayed a decreased activation profile, similar in SIV-controlling and -noncontrolling macaques. Lack of T cell-dependent NK cell function was rescued in SIV-noncontrolling macaques through drug-mediated control of viremia. Our results indicate that control of disease progression in SIV-controlling macaques is associated with cooperation between Ag-specific CD4(+) T cells and NK cell effector function, which highlight the importance of such cell-to-cell cooperativity in adaptive immunity and suggest that this interaction should be further investigated in HIV vaccine development and other prophylactic vaccine approaches. The Journal of Immunology, 2012, 189: 1878-1885. C1 [Vargas-Inchaustegui, Diego A.; Xiao, Peng; Tuero, Iskra; Patterson, L. Jean; Robert-Guroff, Marjorie] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, NIH, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 47 TC 16 Z9 16 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2012 VL 189 IS 4 BP 1878 EP 1885 DI 10.4049/jimmunol.1201026 PG 8 WC Immunology SC Immunology GA 984TW UT WOS:000307216000040 PM 22798665 ER PT J AU Sarkar, T Nguyen, TL Su, ZW Hao, J Bai, RL Gussio, R Qiu, SX Hamel, E AF Sarkar, Taradas Tam Luong Nguyen Su, Zhi-Wei Hao, Jun Bai, Ruoli Gussio, Rick Qiu, Samuel X. Hamel, Ernest TI Interaction of pseudolaric acid B with the colchicine site of tubulin SO BIOCHEMICAL PHARMACOLOGY LA English DT Article ID BETA-TUBULIN; ANTIMITOTIC AGENTS; BINDING; THIOCOLCHICINE; POLYMERIZATION; FLUORESCENCE; INHIBITORS; MECHANISM; KINETICS; ISOTYPES AB We purified pseudolaric acid B (PAB) from the root and stem bark of Pseudolarix kaempferi (Lindl.) Gorden. Confirming previous findings, we found that the compound had high nanomolar IC50 antiproliferative effects in several cultured cell lines, causing mitotic arrest and the disappearance of intracellular microtubules. PAB strongly inhibited tubulin assembly (IC50, 1.1 mu M) but weakly inhibited the binding of colchicine to tubulin, as demonstrated by fluorescence and with [H-3]-colchicine. Kinetic analysis demonstrated that the mechanism of inhibition was competitive, with an apparent K-i of 12-15 mu M. Indirect studies demonstrated that PAB bound rapidly to tubulin and dissociated more rapidly from tubulin than the colchicine analog 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone, whose complex with tubulin is known to have a half-life of 17 s at 37 degrees C. We modeled PAB into the colchicine site of tubulin, using the crystal structure 1SA0 that contains two alpha beta-tubulin heterodimers, both bound to a colchicinoid and to a stathmin fragment. The binding model of PAB revealed common pharmacophoric features between PAB and colchicinoids, not readily apparent from their chemical structures. Published by Elsevier Inc. C1 [Su, Zhi-Wei; Hao, Jun; Qiu, Samuel X.] Chinese Acad Sci, S China Bot Garden, Key Lab Plant Resources Conservat & Sustainable U, Program Nat Prod Med Chem & Drug Discovery, Guangzhou 510650, Peoples R China. [Sarkar, Taradas; Bai, Ruoli; Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Su, Zhi-Wei; Hao, Jun; Qiu, Samuel X.] NCI, Informat Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Tam Luong Nguyen] NCI, Target Struct Based Drug Discovery Grp, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Qiu, SX (reprint author), Chinese Acad Sci, S China Bot Garden, Key Lab Plant Resources Conservat & Sustainable U, Program Nat Prod Med Chem & Drug Discovery, 723 Xingke Ave, Guangzhou 510650, Peoples R China. EM sxqiu@scbg.ac.cn; hamele@mail.nih.gov FU Chinese National Science and Technology Major Project [2009ZX09103-436]; Guangzhou Municipal Science and Technology Major Project [2009A1-E011]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This work was partially supported by the following awards to SXQ: Chinese National Science and Technology Major Project (No. 2009ZX09103-436) and Guangzhou Municipal Science and Technology Major Project (No. 2009A1-E011). This work has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. We also thank Drs. John J. Correia (University of Mississippi Medical Center) and Richard F. Luduena (University of Texas Health Science Center) for their assistance and advice on beta-tubulin isotypes. NR 27 TC 11 Z9 11 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 15 PY 2012 VL 84 IS 4 BP 444 EP 450 DI 10.1016/j.bcp.2012.05.014 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 983RE UT WOS:000307135600005 PM 22634405 ER PT J AU Fogel, JM Taha, TE Sun, J Hoover, DR Parsons, TL Kumwenda, JJ Mofenson, LM Fowler, MG Hendrix, CW Kumwenda, NI Eshleman, SH Mirochnick, M AF Fogel, Jessica M. Taha, Taha E. Sun, Jin Hoover, Donald R. Parsons, Teresa L. Kumwenda, Johnstone J. Mofenson, Lynne M. Fowler, Mary Glenn Hendrix, Craig W. Kumwenda, Newton I. Eshleman, Susan H. Mirochnick, Mark TI Stavudine Concentrations in Women Receiving Postpartum Antiretroviral Treatment and Their Breastfeeding Infants SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE stavudine concentrations; breast milk; mother-to-child transmission; HIV ID MILK; 2',3'-DIDEHYDRO-3'-DEOXYTHYMIDINE; MOTHERS AB First-line antiretroviral treatment regimens in resource-limited settings used in breastfeeding mothers often include stavudine (d4T). Limited data describing d4T concentrations in breast milk are available. We analyzed d4T concentrations in 52 mother-infant pairs using ultra-performance liquid chromatography-tandem mass spectrometry (lower limit of quantification: 5 ng/mL in plasma, 20 ng/mL in breast milk). Median (interquartile range) d4T concentrations were 86 (36-191) ng/mL in maternal plasma, 151 (48-259) ng/mL in whole milk, 190 (58-296) ng/mL in skim milk, and <5 (<5 to <5) ng/mL in infant plasma. Although d4T is concentrated in breast milk relative to maternal plasma, the infant d4T dose received from breast milk is very small and not clinically significant. C1 [Fogel, Jessica M.] Johns Hopkins Univ, Sch Med, Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Taha, Taha E.; Sun, Jin; Kumwenda, Newton I.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Hoover, Donald R.] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Hoover, Donald R.] Rutgers State Univ, Inst Hlth Hlth Care Policy & Aging Res, Piscataway, NJ USA. [Parsons, Teresa L.; Hendrix, Craig W.] Johns Hopkins Univ, Sch Med, Dept Med Clin Pharmacol, Baltimore, MD 21205 USA. [Kumwenda, Johnstone J.] Univ Malawi, Coll Med, Dept Med, Blantyre, Malawi. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Rockville, MD USA. [Mirochnick, Mark] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. RP Fogel, JM (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Med Inst, Dept Pathol, Ross Bldg,Room 646,720 Rutland Ave, Baltimore, MD 21205 USA. EM jfogel@jhmi.edu RI Hendrix, Craig/G-4182-2014; OI Hendrix, Craig/0000-0002-5696-8665; Mofenson, Lynne/0000-0002-2818-9808 FU National Institute of Allergy and Infectious Diseases (NIAID/NIH) [R01-AI087139]; International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network [UM1-AI068632]; HIV Prevention Trials Network (HPTN); NIAID; National Institute on Drug Abuse; National Institute of Mental Health; Office of AIDS Research, of the NIH, Department of Health and Human Services [UM1-AI068613] FX Supported by (1) the National Institute of Allergy and Infectious Diseases (NIAID/NIH) R01-AI087139 (to S.H.E); (2) the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network (UM1-AI068632); and (3) the HIV Prevention Trials Network (HPTN) sponsored by NIAID, the National Institute on Drug Abuse, the National Institute of Mental Health, and the Office of AIDS Research, of the NIH, Department of Health and Human Services (UM1-AI068613). NR 17 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2012 VL 60 IS 5 BP 462 EP 465 DI 10.1097/QAI.0b013e31825ddcfa PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 981TV UT WOS:000306994500005 PM 22614899 ER PT J AU Wilkin, TJ Lalama, CM McKinnon, J Gandhi, RT Lin, NN Landay, A Ribaudo, H Fox, L Currier, JS Mellors, JW Gulick, R Tenorio, AR AF Wilkin, Timothy J. Lalama, Christina M. McKinnon, John Gandhi, Rajesh T. Lin, Nina Landay, Alan Ribaudo, Heather Fox, Lawrence Currier, Judith S. Mellors, John W. Gulick, Roy Tenorio, Allan R. TI A Pilot Trial of Adding Maraviroc to Suppressive Antiretroviral Therapy for Suboptimal CD4(+) T-Cell Recovery Despite Sustained Virologic Suppression: ACTG A5256 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; LYMPHOCYTE ACTIVATION; CORECEPTOR USAGE; HAART ERA; COUNT; COMBINATION; CCR5; DEATH; AIDS AB Background. Despite viral suppression, antiretroviral therapy (ART) does not restore CD4(+) T-cell counts in many patients infected with human immunodeficiency virus type 1 (HIV-1). Methods. In a single-arm pilot trial involving ART recipients with suppressed plasma levels of HIV-1 RNA for at least 48 weeks and stable suboptimal CD4(+) T-cell recovery, subjects added maraviroc, a CCR5 antagonist, to their existing ART for 24 weeks. After stopping maraviroc, they were followed for an additional 24 weeks. A Wilcoxon signed-rank test was used to evaluate whether maraviroc was associated with an increase of at least 20 cells/mu L in the CD4(+) T-cell count. Results. A total of 34 subjects were enrolled. The median age was 50 years, and the median baseline CD4(+) T-cell count was 153 cells/mu L. The median increase in CD4(+) T-cell count from baseline to week 22/24 was 12 cells/mu L (90% confidence interval, 1-22). A CD4(+) T-cell count increase of at least 20 cells/mu L was not detected (P = .97). Markers of immune activation and apoptosis decreased during maraviroc intensification; this decline partially reversed after discontinuing maraviroc. Conclusions. Adding maraviroc to suppressive ART for 24 weeks was not associated with an increase in CD4(+) T-cell counts of at least 20 cells/mu L. Further studies of CCR5 antagonists in the dampening of immune activation associated with HIV infection are warranted. C1 [Wilkin, Timothy J.; Gulick, Roy] Weill Cornell Med Coll, Div Infect Dis, New York, NY 10011 USA. [Lalama, Christina M.; Ribaudo, Heather] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [McKinnon, John; Mellors, John W.] Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA 15260 USA. [Gandhi, Rajesh T.; Lin, Nina] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Gandhi, Rajesh T.] Ragon Inst, Boston, MA USA. [Lin, Nina] Harvard Univ, Sch Med, Boston, MA USA. [Landay, Alan] Rush Univ, Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. [Fox, Lawrence] NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. [Currier, Judith S.] Univ Calif Los Angeles, Div Infect Dis, Los Angeles, CA USA. [Tenorio, Allan R.] Rush Univ, Med Ctr, Infect Dis Sect, Chicago, IL 60612 USA. [Tenorio, Allan R.] Univ Philippines, Coll Med, Manila, Philippines. RP Wilkin, TJ (reprint author), Weill Cornell Med Coll, Div Infect Dis, 119 W 24th St, New York, NY 10011 USA. EM tiw2001@med.cornell.edu FU National Institute of Allergy and Infectious Diseases [U01 AI68636, AI068634, AI045008, AI050409, AI050410, AI060354, AI082151, K24 AI51966, R01 AI066992-04A1]; National Institute of Allergy and Infectious Diseases (Virology Support Laboratory) [204VC009]; National Institute of Allergy and Infectious Diseases (Statistical and Data Analysis Center) [AI069418, AI069419, AI069423, AI069424, AI069432, AI069439, AI069447, AI069452, AI069465, AI069471, AI069472, AI069474, AI069477, AI069484, AI069494, AI069495, AI69501, AI069502, AI069503, AI069511, AI069532, AI069556]; National Center for Research Resources [RR023561, RR024160, RR 025747, RR024975, RR024996]; National Library of Medicine [G08LM008830-01]; Pfizer; Tibotec; Gilead Sciences; Merck; ViiV FX National Institute of Allergy and Infectious Diseases (grant U01 AI68636 to the AIDS Clinical Trials Group; Virology Support Laboratory subcontract 204VC009 to the University of Pittsburgh; grant AI068634 to the Statistical and Data Analysis Center; grants AI069418, AI069419, AI069423, AI069424, AI069432, AI069439, AI069447, AI069452, AI069465, AI069471, AI069472, AI069474, AI069477, AI069484, AI069494, AI069495, AI69501, AI069502, AI069503, AI069511, AI069532, and AI069556 to participating clinical trial units; grants AI045008, AI050409, AI050410, AI060354, and AI082151 to the Centers for AIDS Research; grant K24 AI51966 to R. M. G.; and grant R01 AI066992-04A1 to R. T. G.); National Center for Research Resources (grants RR023561, RR024160, RR 025747, RR024975, and RR024996 to the Clinical and Translational Science Centers); National Library of Medicine (grant G08LM008830-01 to R. T. G.); and Pfizer Investigator-Initiated Research Grant (funds for assays and supply of maraviroc).; T. J. W. has served as an ad hoc consultant to Pfizer and Quest Diagnostics and as site principal investigator for research grants (to Weill Cornell Medical College) for Tibotec and GlaxoSmithKline. R. T. G. has received grant support from Tibotec and Gilead Sciences. A. L. receives research grants from Merck and Tobira and has served as a consultant to Merck. J. S. C. has served as the principal investigator for research grants (to UCLA) for Merck and Tibotec. J. W. M. is a consultant for Gilead Sciences, Merck, and RFS Pharma and owns share options in RFS Pharma. R. M. G. served as an ad hoc consultant for Bristol-Myers, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, ViiV, and Virostatics and as site principal investigator for research grants (to Weill Cornell Medical College) for Merck, Pfizer, and ViiV. A. R. T. has served as an ad hoc consultant to Johnson & Johnson and as principal investigator for research grants from Abbott and Gilead Sciences. All other authors report no potential conflicts. NR 35 TC 45 Z9 45 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 AUG 15 PY 2012 VL 206 IS 4 BP 534 EP 542 DI 10.1093/infdis/jis376 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 977MQ UT WOS:000306667000011 PM 22740718 ER PT J AU Corton, JC Bushel, PR Fostel, J O'Lone, RB AF Corton, J. Christopher Bushel, Pierre R. Fostel, Jennifer O'Lone, Raegan B. TI Sources of variance in baseline gene expression in the rodent liver SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Review DE Toxicogenomics; Baseline expression; Microarray; Fasting; Sex; Circadian rhythm; Microbiota; Life stage; Diet ID MOUSE-LIVER; RAT-LIVER; MICROARRAY ANALYSIS; DRUG-METABOLISM; SUPRACHIASMATIC NUCLEUS; COPPER DISTRIBUTION; NEWBORN LIVER; SEX; ENZYMES; FEMALE AB The use of gene expression profiling in both clinical and laboratory settings would be enhanced by better characterization of variation due to individual, environmental, and technical factors. Analysis of microarray data from untreated or vehicle-treated animals within the control arm of toxicogenomics studies has yielded useful information on baseline fluctuations in liver gene expression in the rodent. Here, studies which highlight contributions of different factors to gene expression variability in the rodent liver are discussed including a large meta-analysis of rat liver, which identified genes that vary in control animals in the absence of chemical treatment. Genes and their pathways that are the most and least variable were identified in a number of these studies. Life stage, fasting, sex, diet, circadian rhythm and liver lobe source can profoundly influence gene expression in the liver. Recognition of biological and technical factors that contribute to variability of background gene expression can help the investigator in the design of an experiment that maximizes sensitivity and reduces the influence of confounders that may lead to misinterpretation of genomic changes. The factors that contribute to variability in liver gene expression in rodents are likely analogous to those contributing to human interindividual variability in drug response and chemical toxicity. Identification of batteries of genes that are altered in a variety of background conditions could be used to predict responses to drugs and chemicals in appropriate models of the human liver. Published by Elsevier B.V. C1 [Corton, J. Christopher] US EPA, Integrated Syst Toxicol Div, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Bushel, Pierre R.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC USA. [Fostel, Jennifer] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Res Triangle Pk, NC USA. [O'Lone, Raegan B.] ILSI Hlth & Environm Sci Inst, Washington, DC USA. RP Corton, JC (reprint author), US EPA, Integrated Syst Toxicol Div, Natl Hlth & Environm Effects Res Lab, 109 TW Alexander Dr,MD-B143-06, Res Triangle Pk, NC 27711 USA. EM corton.chris@epa.gov FU HESI Genomics Technical Committee; ILSI HESI; Division of the National Toxicology Program; Intramural Research Program of the National Institutes of Health (NIH); National Institute of Environmental Health Sciences (NIEHS) [Z01 ES102345-04]; U.S. Environmental Protection Agency FX We would like to thank Drs. Brian Chorley and Mitch Rosen for their critical review, the HESI Genomics Technical Committee for supporting the work, and to members of the committee who contributed microarray data for this and on-going analyses. Some of the work described was carried out by a subgroup of the HESI Application of Genomics to Mechanism-Based Risk Assessment Technical Committee, funded through ILSI HESI. This research was supported by the Division of the National Toxicology Program, the Intramural Research Program of the National Institutes of Health (NIH) and National Institute of Environmental Health Sciences (NIEHS) [Z01 ES102345-04]. The information in this document has been supported by the U.S. Environmental Protection Agency. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. NR 79 TC 8 Z9 8 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 EI 1879-3592 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD AUG 15 PY 2012 VL 746 IS 2 SI SI BP 104 EP 112 DI 10.1016/j.mrgentox.2011.12.017 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 972TW UT WOS:000306304400003 PM 22230429 ER PT J AU Bandettini, PA AF Bandettini, Peter A. TI Twenty years of functional MRI: The science and the stories SO NEUROIMAGE LA English DT Review DE fMRI; Functional MRI; Brain imaging; Brain; MRI; Blood; High field; Cognitive neuroscience; Neuroscience; Hemoglobin; Neurovascular coupling; Brain function ID CEREBRAL-BLOOD-FLOW; HUMAN VISUAL-CORTEX; EVENT-RELATED FMRI; BOLD POSTSTIMULUS UNDERSHOOT; TRANSVERSE RELAXATION-TIME; NUCLEAR MAGNETIC-RESONANCE; HIGH-RESOLUTION FMRI; HUMAN BRAIN ACTIVITY; 1ST ADVANCING FMRI; ULTRA-HIGH FIELD AB Since its inception over twenty years ago, the field of functional magnetic resonance imaging (fMRI) has grown in usage, sophistication, range of applications, and impact. After twenty years, it's useful to briefly look back as well as forward to size up just how far we have come and speculate just how far we may go. This is an introduction to the special issue of "Twenty years of fMRI: the science and the stories." The one-hundred and three papers in this special issue highlight the major methodological developments and controversies of fMRI from a first person perspective over the past twenty years. The growth of this field is not just fascinating from a science and technology perspective, but also from a human perspective. Most who were fortunate enough to be part of this effort at the beginning, as well as those who jumped in along the way have their fair share of interesting stories consisting of top rate science as well as intense thought and effort, good or bad fortune, and some claim to a contribution. These stories are in the following papers, written by the current leaders in the field and the innovators throughout the twenty year history. The categories, designed to cover every aspect of the emergence and development of fMRI, include: pre-fMRI: the first BOLD brain activation results; developments in pulse sequences, imaging methods, and hardware for fMRI; methodological developments, issues, and mechanisms; new paradigm designs; education; and the future. Within this issue, we have a collage of overlapping, complementary, yet sometimes contradictory accounts of what happened during the breathtakingly diverse and intense development of this still growing field over the past twenty years. (C) 2012 Published by Elsevier Inc. C1 NIMH, Sect Funct Imaging Methods & Funct MRI Facil, Bethesda, MD 20892 USA. RP Bandettini, PA (reprint author), NIMH, Sect Funct Imaging Methods & Funct MRI Facil, Bldg 10,Room 1D80,10 Ctr Dr MSC 1148, Bethesda, MD 20892 USA. EM bandettini@nih.gov FU Intramural NIH HHS NR 185 TC 40 Z9 41 U1 3 U2 79 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 AUG 15 PY 2012 VL 62 IS 2 SI SI BP 575 EP 588 DI 10.1016/j.neuroimage.2012.04.026 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600001 PM 22542637 ER PT J AU Koretsky, AP AF Koretsky, Alan P. TI Early development of arterial spin labeling to measure regional brain blood flow by MRI SO NEUROIMAGE LA English DT Review DE Perfusion MRI; Magnetization transfer; Functional MRI; Blood flow tracers ID NUCLEAR-MAGNETIC-RESONANCE; FREE-INDUCTION DECAYS; RAT-BRAIN; CONTRAST AGENTS; AMPHETAMINE STIMULATION; SENSORY STIMULATION; EXCHANGE-REACTIONS; NMR-SPECTROSCOPY; RADIO-FREQUENCY; PERFUSION MRI AB Two major avenues of work converged in the late 1980's and early 1990's to give rise to brain perfusion MRI. The development of anatomical brain MRI quickly had as a major goal the generation of angiograms using tricks to label flowing blood in macroscopic vessels. These ideas were aimed at getting information about microcirculatory flow as well. Over the same time course the development of in vivo magnetic resonance spectroscopy had as its primary goal the assessment of tissue function and in particular, tissue energetics. For this the measurement of the delivery of water to tissue was critical for assessing tissue oxygenation and viability. The measurement of the washin/washout of "freely" diffusible tracers by spectroscopic based techniques pointed the way for quantitative approaches to measure regional blood flow by MRI. These two avenues came together in the development of arterial spin labeling (ASL) MRI techniques to measure regional cerebral blood flow. The early use of ASL to measure brain activation to help verify BOLD fMRI led to a rapid development of ASL based perfusion MRI. Today development and applications of regional brain blood flow measurements with ASL continues to be a major area of activity. (C) 2012 Published by Elsevier Inc. C1 NINDS, LFMI, NIH, Bethesda, MD 20892 USA. RP Koretsky, AP (reprint author), NINDS, LFMI, NIH, Bldg 10,Rm B1D728,10 Ctr Dr, Bethesda, MD 20892 USA. EM koretskya@ninds.nih.gov RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU NINDS, NIH FX I would like to acknowledge Don Williams, John Detre, Afonso Silva, Lalith Talagala, and Jeff Duyn for their careful reading of the manuscript. Lalith Talagala supplied the images in Fig. 1. I would also like to acknowledge Peter Bandettini for the kind invitation to describe the early history of ASL from my own perspective. A nice opportunity to be self-indulgent, I ask the readers for their forgiveness. Dr. Koretsky is supported by the intramural research program of NINDS, NIH. NR 93 TC 7 Z9 7 U1 2 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 602 EP 607 DI 10.1016/j.neuroimage.2012.01.005 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600004 PM 22245338 ER PT J AU Bandettini, PA AF Bandettini, Peter A. TI Sewer pipe, wire, epoxy, and finger tapping: The start of fMRI at the Medical College of Wisconsin SO NEUROIMAGE LA English DT Review ID HUMAN VISUAL-CORTEX; NUCLEAR MAGNETIC-RESONANCE; HUMAN BRAIN ACTIVATION; FUNCTIONAL MRI; SENSORY STIMULATION; HIGH-RESOLUTION; SPIN-ECHO; 1.5 T; BLOOD; TIME AB In 1991, the Biophysics Research Institute at the Medical College of Wisconsin was among the first groups to develop functional Magnetic Resonance Imaging (fMRI). Our story is unique on a few levels: We didn't have knowledge of the ability to image human brain activation with MRI using blood oxygenation dependent (BOLD) contrast until early August of 1991 when we attended the Society for Magnetic Resonance in Medicine (SMRM) meeting in San Francisco, yet we produced our first BOLD-based maps of motor cortex activation about a month later. The effort started with two graduate students, Eric Wong and myself. Only a few days prior to that extremely important SMRM meeting, we had developed human echo planar imaging (EPI) capability in-house. Wong designed, built, and interfaced a head gradient coil made out of sewer pipe, wire, and epoxy to a standard GE 1.5 T MRI scanner. Also, a few months prior to building this human head gradient coil he developed the EPI pulse sequences and image reconstruction. All of these efforts were towards a different goal for demonstration of Wong's novel approach to perfusion imaging in the human brain. Following SMRM, where a plenary lecture by Tom Brady from MGH opened our eyes to human brain activation imaging using BOLD contrast, and where we learned that EPI was extremely helpful if not critical to its success, we worked quickly to achieve our first results on September 14, 1991. The story is also unique in that Jim Hyde had set up the Biophysics Research Institute to be optimal for just this type of rapidly advancing basic technology research. It was well equipped for hardware development, had open and dynamic collaborative relationships with other departments, hospitals on campus, and GE, and had a relatively flat hierarchy and relaxed, flexible, collegial atmosphere internally. Since these first brain activation results, MCW Biophysics has continued to be at the forefront of functional MRI innovation, having helped to pioneer real time fMRI, high-resolution fMRI, and functional connectivity mapping. Published by Elsevier Inc. C1 [Bandettini, Peter A.] NIMH, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. [Bandettini, Peter A.] NIMH, Funct MRI Core Facil, Bethesda, MD USA. RP Bandettini, PA (reprint author), NIMH, Sect Funct Imaging Methods, Bethesda, MD 20892 USA. EM pab.neuroimage@gmail.com FU NIH; NINDS; NIMH FX I would like to thank Patricia Bandettini, Scott Hinks, Jim Hyde, and Eric Wong for help in the proofreading of this document. The NIH intramural programs, NINDS and NIMH, support Peter Bandettini. NR 50 TC 3 Z9 3 U1 3 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 620 EP 631 DI 10.1016/j.neuroimage.2011.10.044 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600008 PM 22044784 ER PT J AU van Gelderen, P Duyn, JH Ramsey, NF Liu, G Moonen, CTW AF van Gelderen, P. Duyn, J. H. Ramsey, N. F. Liu, G. Moonen, C. T. W. TI The PRESTO technique for fMRI SO NEUROIMAGE LA English DT Review DE Functional magnetic resonance imaging (fMRI); Blood oxygenation level dependent (BOLD); contrast; PRESTO (Principles of Echo-Shifting with a Train of Observation); Echo shifting ID GRADIENT-RECALLED MRI; HUMAN VISUAL-CORTEX; FUNCTIONAL MRI; HUMAN BRAIN; CONTRAST AGENT; LANGUAGE LATERALIZATION; TIME-SERIES; ECHO; SENSE; EPI AB In the early days of BOLD fMRI, the acquisition of T-2* weighted data was greatly facilitated by rapid scan techniques such as EPI. The latter, however, was only available on a few MRI systems that were equipped with specialized hardware that allowed rapid switching of the imaging gradients. For this reason, soon after the invention of fMRI, the scan technique PRESTO was developed to make rapid T-2* weighted scanning available on standard clinical scanners. This method combined echo shifting, which allows for echo times longer than the sequence repetition time, with acquisition of multiple k-space lines per excitation. These two concepts were combined in order to achieve a method fast enough for fMRI, while maintaining a sufficiently long echo time for optimal contrast. PRESTO has been primarily used for 3D scanning, which minimized the contribution of large vessels due to inflow effects. Although PRESTO is still being used today, its appeal has lessened somewhat due to increased gradient performance of modern MRI scanners. Compared to 2D EPI, PRESTO may have somewhat reduced temporal stability, which is a disadvantage for fMRI that may not outweigh the advantage of reduced inflow effects provided by 3D scanning. In this overview, the history of the development of the PRESTO is presented, followed by a qualitative comparison with EPI. Published by Elsevier Inc. C1 [van Gelderen, P.; Duyn, J. H.] NINDS, NIH, Adv Magnet Resonance Imaging sect, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. [Ramsey, N. F.] Univ Med Ctr Utrecht, Div Neurosci, Rudolf Magnus Inst Neurosci, Utrecht, Netherlands. [Liu, G.] Natl Inst Biomed Imaging & Bioengn, Div Appl Sci & Technol, Bethesda, MD USA. [Moonen, C. T. W.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. RP van Gelderen, P (reprint author), NINDS, NIH, Adv Magnet Resonance Imaging sect, Lab Funct & Mol Imaging, Bld 10,Rm B1 D-725,10 Ctr Dr, Bethesda, MD 20892 USA. EM gelderen@nih.gov RI Moonen, Chrit/K-4434-2016 OI Moonen, Chrit/0000-0001-5593-3121 FU National Institute of Neurological Disorders and Stroke, NIH FX This work was funded (in part) by the intramural program of the National Institute of Neurological Disorders and Stroke, NIH. NR 51 TC 9 Z9 9 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 676 EP 681 DI 10.1016/j.neuroimage.2012.01.017 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600017 PM 22245350 ER PT J AU Cox, RW AF Cox, Robert W. TI AFNI: What a long strange trip it's been SO NEUROIMAGE LA English DT Review DE Functional data analysis; 3D registration; FMRI group analysis; FMRI connectivity; FMRI software ID HUMAN BRAIN-FUNCTION; FUNCTIONAL MRI; FMRI AB AFNI is an open source software package for the analysis and display of functional MRI data. It originated in 1994 to meet the specific needs of researchers at the Medical College of Wisconsin, in particular the mapping of activation maps to Talairach-Tournoux space, but has been expanded steadily since then into a wide-ranging set of tool for FMRI data analyses. AFNI was the first platform for real-time 3D functional activation and registration calculations. One of AFNI's main strengths is,its flexibility and transparency. In recent years, significant efforts have been made to increase the user-friendliness of AFNI's FMRI processing stream, with the introduction of "super-scripts" to setup the entire analysis, and graphical front-ends for these managers. Published by Elsevier Inc. C1 NIMH, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Cox, RW (reprint author), NIMH, NIH, Dept Hlth & Human Serv, 10 Ctr Dr, Room 1D80, Bethesda, MD 20892 USA. EM robertcox@mail.nih.gov FU NIMH; NINDS FX Without the efforts of these people (and others), AFNI would not have "grown up" as well has it has thank you all. The development of AFNI has been supported over the years by the American people: when I was at MCW, via grants from the NIMH and NINDS extramural programs, and currently via the NIMH and NINDS intramural programs. NR 15 TC 64 Z9 64 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 743 EP 747 DI 10.1016/j.neuroimage.2011.08.056 PG 5 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600026 PM 21889996 ER PT J AU Saad, ZS Reynolds, RC AF Saad, Ziad S. Reynolds, Richard C. TI SUMA SO NEUROIMAGE LA English DT Review DE Cortical surface models; Cortical thickness; FMRI retinotopy; Surface ROI drawing; Surface-based smoothing; Surface-based group analysis; Interactive FMRI resting state analysis ID SURFACE-BASED ANALYSIS; CORTICAL SURFACE; COORDINATE SYSTEM; CEREBRAL-CORTEX; MRI; REGISTRATION; SOFTWARE AB Surface-based brain imaging analysis offers the advantages of preserving the topology of cortical activation, increasing statistical power of group-level statistics, estimating cortical thickness, and visualizing with ease the pattern of activation across the whole cortex. SUMA is an open-source suite of programs for performing surface-based analysis and visualization. It was designed since its inception to allow for a fine control over the mapping between volume and surface domains, and for very fast and simultaneous display of multiple surface models and corresponding multitudes of datasets, all while maintaining a direct two-way link to volumetric data from which surface models and data originated. SUMA provides tools for performing spatial operations such as controlled smoothing, clustering, and interactive ROI drawing on folded surfaces in 3D, in addition to the various level-1 and level-2 FMRI statistics including FOR and FWE correction for multiple comparisons. In our contribution to this commemorative issue of Neuroimage we touch on the importance of surface-based analysis and provide a historic backdrop that motivated the creation of SUMA. We also highlight features that are particular to SUMA, notably the standardization procedure of meshes to greatly facilitate group-level analyses, and the ability to control SUMA's graphical interface from external programs making it possible to handle large collections of data with relative ease. Published by Elsevier Inc. C1 [Saad, Ziad S.; Reynolds, Richard C.] NIMH, NIH, Bethesda, MD 20892 USA. RP Saad, ZS (reprint author), NIMH, NIH, 10 Ctr DR,Room 1080, Bethesda, MD 20892 USA. EM saadz@mail.nih.gov FU NIMH of NIH; NINDS of NIH FX Much of the utility and speed of SUMA (and for better or worse, the first author's) is due to the leveraging of AFNI's libraries, interface, and most importantly the vast and generous mind of AFNI's creator, Robert W. Cox. The authors are particularly grateful to Michael S. Beauchamp for feedback and support, and to all users with encouraging messages and thoughtful suggestions. Credit is also due to Edgar A. DeYoe whose early ideas for a good surface-mapping interface shaped many of SUMA's features years later. This research was supported by the NIMH and NINDS Intramural Research Programs of the NIH. NR 19 TC 40 Z9 42 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 768 EP 773 DI 10.1016/j.neuroimage.2011.09.016 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600030 PM 21945692 ER PT J AU Silva, AC AF Silva, Afonso C. TI Using manganese-enhanced MRI to understand BOLD SO NEUROIMAGE LA English DT Review DE Animal models; Blood-brain barrier; Brain; Cerebral blood flow; Functional magnetic resonance imaging; Manganese; Neural activity ID RESONANCE-IMAGING MEMRI; NUCLEAR-MAGNETIC-RESONANCE; CEREBRAL-BLOOD-FLOW; RAT-BRAIN; FOREPAW STIMULATION; FUNCTIONAL MRI; IN-VIVO; DEPENDENT CONTRAST; SENSORY STIMULATION; NEGATIVE RESPONSE AB The 1990s were designated "The Decade of the Brain" by U.S. Congress, perhaps in great anticipation of the impact that functional neuroimaging techniques would have on advancing our understanding of how the brain is functionally organized. While it is impossible to overestimate the impact of functional MRI in neuroscience, many aspects of the blood oxygenation level-dependent (BOLD) contrast remain poorly understood, in great part due to the complex relationship between neural activity and hemodynamic changes. To better understand such relationship, it is important to probe neural activity independently. Manganese-enhanced MRI (MEMRI), when used to monitor neural activity, is a technique that uses the divalent manganese ion, Mn2+, as a surrogate measure of calcium influx. A major advantage of using Mn2+ as a functional marker is that the contrast obtained is directly related to the accumulation of the ion in excitable cells in an activity dependent manner. As such, the contrast in MEMRI is more directly related to neural activity then hemodynamic-based fMRI techniques. In the present work, the early conceptualization of MEMRI is reviewed, and the comparative experiments that have helped provide a better understanding of the spatial specificity of BOLD signal changes in the cortex is discussed. Published by Elsevier Inc. C1 NINDS, Cerebral Microcirculat Unit, NIH, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. RP Silva, AC (reprint author), NINDS, Cerebral Microcirculat Unit, NIH, Lab Funct & Mol Imaging, 10 Ctr Dr,MSC 1065,Bldg 10,Room B1D106, Bethesda, MD 20892 USA. EM SilvaA@ninds.nih.gov FU Intramural Research Program of the NIH, NINDS FX I am most grateful to Alan P. Koretsky for critical reading of the manuscript. This research was supported by the Intramural Research Program of the NIH, NINDS. NR 68 TC 7 Z9 7 U1 1 U2 21 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 AUG 15 PY 2012 VL 62 IS 2 SI SI BP 1009 EP 1013 DI 10.1016/j.neuroimage.2012.01.008 PG 5 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600059 PM 22245640 ER PT J AU Handwerker, DA Gonzalez-Castillo, J D'Esposito, M Bandettini, PA AF Handwerker, Daniel A. Gonzalez-Castillo, Javier D'Esposito, Mark Bandettini, Peter A. TI The continuing challenge of understanding and modeling hemodynamic variation in fMRI SO NEUROIMAGE LA English DT Review DE BOLD; fMRI; Hemodynamic response; Population studies; Regional variation; Blood vessels ID CEREBRAL-BLOOD-FLOW; VISUAL BOLD RESPONSE; EVENT-RELATED FMRI; FUNCTIONAL MRI; HUMAN BRAIN; OXYGEN-METABOLISM; BASE-LINE; STIMULATION; ACTIVATION; CAFFEINE AB Interpretation of fMRI data depends on our ability to understand or model the shape of the hemodynamic response (HR) to a neural event. Although the HR has been studied almost since the beginning of fMRI, we are still far from having robust methods to account for the full range of known HR variation in typical fMRI analyses. This paper reviews how the authors and others contributed to our understanding of HR variation. We present an overview of studies that describe HR variation across voxels, healthy volunteers, populations, and dietary or pharmaceutical modulations. We also describe efforts to minimize the effects of HR variation in intrasubject, group, population, and connectivity analyses and the limits of these methods. Published by Elsevier Inc. C1 [Handwerker, Daniel A.; Gonzalez-Castillo, Javier; Bandettini, Peter A.] NIMH, Lab Brain & Cognit, Sect Funct Imaging Methods, Bethesda, MD 20814 USA. [Bandettini, Peter A.] NIMH, Funct MRI Facil, Bethesda, MD 20892 USA. [D'Esposito, Mark] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [D'Esposito, Mark] Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. RP Handwerker, DA (reprint author), Bldg 10,Rm 1080,10 Ctr Dr MSC 1148, Bethesda, MD 20892 USA. EM handwerkerd@mail.nih.gov OI Gonzalez-Castillo, Javier/0000-0002-6520-5125 FU NIMH Intramural research program FX Supported by the NIMH Intramural research program. Carlton Chu helped make sure the DCM analyses were properly run. NR 55 TC 41 Z9 41 U1 3 U2 24 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 AUG 15 PY 2012 VL 62 IS 2 SI SI BP 1017 EP 1023 DI 10.1016/j.neuroimage.2012.02.015 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600061 PM 22366081 ER PT J AU Koretsky, AP AF Koretsky, Alan P. TI Is there a path beyond BOLD? Molecular imaging of brain function SO NEUROIMAGE LA English DT Review DE Manganese enhanced MRI; MRI calcium indicators; MRI gene expression reporters; MRI detection of neurotransmitters; MRI detection of membrane potential ID MANGANESE-ENHANCED MRI; NUCLEAR-MAGNETIC-RESONANCE; CENTRAL-NERVOUS-SYSTEM; IN-VIVO DETECTION; GENE-EXPRESSION; CONTRAST AGENT; CREATINE-KINASE; BETA-GALACTOSIDASE; REPORTER GENE; RAT-BRAIN AB The dependence of BOLD on neuro-vascular coupling leaves it many biological steps removed from direct monitoring of neural function. MRI based approaches have been developed aimed at reporting more directly on brain function. These include: manganese enhanced MRI as a surrogate for calcium ion influx; agents responsive to calcium concentrations; approaches to measure membrane potential; agents to measure neurotransmitters; and strategies to measure gene expression. This work has led to clever design of molecular imaging tools and many contributions to studies of brain function in animal models. However, a robust approach that has potential to get MRI closer to neurons in the human brain has not yet emerged. (C) 2012 Published by Elsevier Inc. C1 NINDS, LFMI, NIH, Bethesda, MD 20892 USA. RP Koretsky, AP (reprint author), NINDS, LFMI, NIH, Bldg 10,Rm B1D728,10 Ctr Dr, Bethesda, MD 20892 USA. EM koretskya@ninds.nih.gov RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU National Institute of Neurological Disorders and Stroke, NIH FX Alan Koretsky is supported by the intramural research program of the National Institute of Neurological Disorders and Stroke, NIH. The author acknowledges the kind invitation from Peter Bandettini to write this article and thanks Afonso Silva for encouragement and comments. NR 139 TC 16 Z9 16 U1 1 U2 28 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 AUG 15 PY 2012 VL 62 IS 2 SI SI BP 1208 EP 1215 DI 10.1016/j.neuroimage.2012.02.076 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600088 PM 22406355 ER PT J AU Duyn, JH AF Duyn, Jeff H. TI The future of ultra-high field MRI and fMRI for study of the human brain SO NEUROIMAGE LA English DT Review DE High field MRI; Magnet technology; RF coils; Resolution; Contrast; Brain function; Brain structure; Myelin; Cortex ID HIGH-RESOLUTION MRI; TO-NOISE RATIO; VIVO H-1-NMR SPECTROSCOPY; HIGH MAGNETIC-FIELD; ARRAY HEAD COIL; IN-VIVO; MULTIPLE-SCLEROSIS; WHITE-MATTER; 3 TESLA; ORIENTATION COLUMNS AB MRI and fMRI have been used for about three and two decades respectively and much has changed over this time period, both in the quality of the data and in the range of applications for studying the brain. Apart from resolution improvements from around 4 mm in the early days to below 0.5 mm with modern technology, novel uses of contrast have led to the ability to sensitize images to some of the brain's structural properties at the cellular scale as well as study the localization and organization of brain function at the level of cortical columns. These developments have in part been facilitated by a continuing drive to increase the magnetic field strength. Will the next few decades see similar improvements? Here we will discuss current state of high field MRI, expected further increases in field strength, and improvements expected with these increases. (C) 2011 Elsevier Inc. All rights reserved. C1 NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Duyn, JH (reprint author), NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bldg 10,Room B1D724,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jhd@helix.nih.gov FU National Institute of Neurological Disorders and Stroke, National Institutes of Health FX Alan Koretsky and Peter van Gelderen of the Laboratory of Functional and Molecular imaging at NIH are acknowledged for helpful discussions and suggestions. This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 104 TC 58 Z9 59 U1 3 U2 42 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 AUG 15 PY 2012 VL 62 IS 2 SI SI BP 1241 EP 1248 DI 10.1016/j.neuroimage.2011.10.065 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600093 PM 22063093 ER PT J AU Del Brutto, OH Nash, TE Garcia, HH AF Del Brutto, Oscar H. Nash, Theodore E. Garcia, Hector H. TI Cysticerci-related single parenchymal brain enhancing lesions in non-endemic countries SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Cysticercosis; Neurocysticercosis; Single cysticercus granuloma ID TAENIA-SOLIUM; SOLITARY NEUROCYSTICERCOSIS; FOLLOW-UP; SEIZURES; GRANULOMA; DIAGNOSIS; EDEMA; FEATURES; MASS; UK AB Objective: Review of case reports and case series of patients with single cysticercus granulomas in non-endemic countries to determine the characteristics of this form of neurocysticercosis in these regions. Methods: MEDLINE and manual search of patients with single cysticercus granulomas diagnosed in non-endemic countries from 1991 to 2011. Abstracted data included: demographic profile, clinical manifestations, form of neurocysticercosis, and whether the disease occurred in immigrants, international travelers, or citizens from non-endemic countries who had never been abroad. Results: A total of 77 patients were found. Of these, 61 (79%) were diagnosed since the year 2000. Thirty-four patients (44%) patients were immigrants from endemic countries, 18 (23%) were international travelers returning from disease-endemic areas, and the remaining 25 (33%) were citizens from non-endemic countries who had never been abroad. Most immigrants and international travelers became symptomatic two or more years after returning home. Countries with the most reported patients were Kuwait (n = 18), UK (n = 11), Australia (n = 8), USA (n = 7), Japan (n = 6), and Israel (n = 5). Conclusions: A single cerebral cysticercus granuloma in a non-endemic country is not a rare event. As seen in endemic regions, these cases have a good prognosis although more surgical procedures are performed in non-endemic countries, likely reflecting a decrease of diagnostic suspicion for cysticercosis and an increased availability of surgical options. The mean age of the reported cases was 25 years, and immigrants most often developed the disease greater than two years after arrival into a non-endemic area, suggesting a significant delay between infection and symptoms. However, some may have been infected and developed the disease while residing in non-endemic countries. (C) 2012 Elsevier B.V. All rights reserved. C1 [Del Brutto, Oscar H.] Hosp Clin Kennedy, Dept Neurol Sci, Guayaquil, Ecuador. [Nash, Theodore E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Garcia, Hector H.] Univ Peruana Cayetano Heredia, Ctr Global Hlth, Lima, Peru. [Garcia, Hector H.] Univ Peruana Cayetano Heredia, Dept Microbiol, Sch Sci, Lima, Peru. [Garcia, Hector H.] Inst Nacl Ciencias Neurol, Cysticercosis Unit, Lima, Peru. RP Del Brutto, OH (reprint author), Air Ctr 3542,POB 522970, Miami, FL 33152 USA. EM oscardelbrutto@hotmail.com FU Division of Intramural Research, National Institutes of Allergy and Infectious Diseases; Wellcome Trust FX Funding for this work was provided in part by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases (Dr. Nash). Dr. Garcia is supported by a Wellcome Trust International Senior Fellowship in Public Health and Tropical Medicine. NR 70 TC 10 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD AUG 15 PY 2012 VL 319 IS 1-2 BP 32 EP 36 DI 10.1016/j.jns.2012.05.027 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 971ZS UT WOS:000306246900007 PM 22658897 ER PT J AU Campa, D Butterbach, K Slager, SL Skibola, CF de Sanjose, S Benavente, Y Becker, N Foretova, L Maynadie, M Cocco, P Staines, A Kaaks, R Boffetta, P Brennan, P Conde, L Bracci, PM Caporaso, NE Strom, SS Camp, NJ Cerhan, JR Canzian, F Nieters, A AF Campa, Daniele Butterbach, Katja Slager, Susan L. Skibola, Christine F. de Sanjose, Silvia Benavente, Yolanda Becker, Nikolaus Foretova, Lenka Maynadie, Marc Cocco, Pierluigi Staines, Anthony Kaaks, Rudolf Boffetta, Paolo Brennan, Paul Conde, Lucia Bracci, Paige M. Caporaso, Neil E. Strom, Sara S. Camp, Nicola J. Cerhan, James R. Canzian, Federico Nieters, Alexandra CA GEC Consortium TI A comprehensive study of polymorphisms in the ABCB1, ABCC2, ABCG2, NR1I2 genes and lymphoma risk SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE lymphoma; multidrug resistance 1; multidrug resistance protein 2; breast cancer resistance protein; pregnane x receptor ID SINGLE NUCLEOTIDE POLYMORPHISMS; ACUTE LYMPHOBLASTIC-LEUKEMIA; GENOME-WIDE ASSOCIATION; NON-HODGKIN-LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; CANCER RESISTANCE PROTEIN; B-CELL LYMPHOMA; C421A POLYMORPHISM; EPIDEMIOLOGY CONSORTIUM; TISSUE DEFENSE AB Owing to their role in controlling the efflux of toxic compounds, transporters are central players in the process of detoxification and elimination of xenobiotics, which in turn is related to cancer risk. Among these transporters, ATP-binding cassette B1/multidrug resistance 1 (ABCB1/MDR1), ABCC2/multidrug resistance protein 2 (MRP2) and ABCG2/breast cancer resistance protein (BCRP) affect susceptibility to many hematopoietic malignancies. The maintenance of regulated expression of these transporters is governed through the activation of intracellular xenosensors like the nuclear receptor 1I2/pregnane X receptor (NR1I2/PXR). SNPs in genes encoding these regulators have also been implicated in the risk of several cancers. Using a tagging approach, we tested the hypothesis that common polymorphisms in the transporter genes ABCB1, ABCC2, ABCG2 and the regulator gene NR1I2 could be implicated in lymphoma risk. We selected 68 SNPs in the four genes, and we genotyped them in 1,481 lymphoma cases and 1,491 controls of the European casecontrol study (EpiLymph) using the Illumina GoldenGate (TM) assay technology. Carriers of the SNP rs6857600 minor allele in ABCG2 was associated with a decrease in risk of B-cell lymphoma (B-NHL) overall (p < 0.001). Furthermore, a decreased risk of chronic lymphocytic leukemia (CLL) was associated with the ABCG2 rs2231142 variant (p = 0.0004), which could be replicated in an independent population. These results suggest a role for this gene in B-NHL susceptibility, especially for CLL. C1 [Nieters, Alexandra] Univ Med Ctr, Ctr Chron Immunodeficiency, D-79106 Freiburg, Germany. [Campa, Daniele; Canzian, Federico] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Butterbach, Katja; Becker, Nikolaus; Kaaks, Rudolf] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Slager, Susan L.] Mayo Clin, Coll Med, Div Biomed Stat & Informat, Rochester, MN USA. [Skibola, Christine F.; Conde, Lucia] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [de Sanjose, Silvia; Benavente, Yolanda] Catalan Inst Oncol, Unit Infect & Canc, Barcelona, Spain. [de Sanjose, Silvia; Benavente, Yolanda] CIBERESP, Madrid, Spain. [Foretova, Lenka] Masaryk Mem Canc Inst, Brno, Czech Republic. [Maynadie, Marc] Univ Burgundy, CHU Dijon, EA 4184, Serv Hematol Biol, Dijon, France. [Cocco, Pierluigi] Univ Cagliari, Occupat Hlth Sect, Dept Publ Hlth, Cagliari, Italy. [Staines, Anthony] Dublin City Univ, Sch Nursing, Dublin 9, Ireland. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Bracci, Paige M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Caporaso, Neil E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Strom, Sara S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Camp, Nicola J.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Cerhan, James R.] Mayo Clin, Coll Med, Div Epidemiol, Rochester, MN USA. [Nieters, Alexandra] Univ Med Ctr, Inst Med Biostat & Med Informat, D-79106 Freiburg, Germany. [Nieters, Alexandra] Univ Freiburg, D-79106 Freiburg, Germany. RP Nieters, A (reprint author), Univ Med Ctr, Ctr Chron Immunodeficiency, Breisacher Str 117, D-79106 Freiburg, Germany. EM alexandra.nieters@uniklinik-freiburg.de RI Conde, Lucia/D-9295-2011; de Sanjose Llongueras, Silvia/H-6339-2014; Benavente, Yolanda/H-9810-2014; Campa, Daniele/K-1617-2016; OI Campa, Daniele/0000-0003-3220-9944; Cerhan, James/0000-0002-7482-178X; Staines, Anthony/0000-0001-9161-1357 FU German Jose Carreras Leukemia Foundation [DJCLS_R04/08]; EC [QLK4-CT-2000-00422, FP6-2003-FOOD-2-B]; Federal Office for Radiation Protection (Germany) [StSch4261, StSch4420]; Spanish Ministry of Health grants CIBERESP (Spain) [06/02/0073, FIS 08-1555 1, Marato V3 (051210)]; La Fondation de France; Compagnia di San Paolo di Torino, Programma Oncologia; Health Research Board, Ireland FX Grant sponsor: German Jose Carreras Leukemia Foundation; Grant number: DJCLS_R04/08; Grant sponsor: EC 5th Framework Program Quality of Life; Grant number: QLK4-CT-2000-00422; Grant sponsor: EC 6th Framework Program; Grant number: FP6-2003-FOOD-2-B; Grant sponsor: Federal Office for Radiation Protection; Grant numbers: StSch4261, StSch4420 (Germany); Grant sponsor: Spanish Ministry of Health grants CIBERESP; Grant numbers: 06/02/0073, FIS 08-1555 1 and Marato V3 (051210) (Spain); Grant sponsor: La Fondation de France; Grant sponsor: Compagnia di San Paolo di Torino, Programma Oncologia; Grant sponsor: Health Research Board, Ireland starD.C. and K.B. contributed equally to this work. NR 50 TC 12 Z9 12 U1 0 U2 8 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 AUG 15 PY 2012 VL 131 IS 4 BP 803 EP 812 DI 10.1002/ijc.26436 PG 10 WC Oncology SC Oncology GA 961GD UT WOS:000305451300031 PM 21918980 ER PT J AU Yang, HP Trabert, B Murphy, MA Sherman, ME Sampson, JN Brinton, LA Hartge, P Hollenbeck, A Park, Y Wentzensen, N AF Yang, Hannah P. Trabert, Britton Murphy, Megan A. Sherman, Mark E. Sampson, Joshua N. Brinton, Louise A. Hartge, Patricia Hollenbeck, Albert Park, Yikyung Wentzensen, Nicolas TI Ovarian cancer risk factors by histologic subtypes in the NIH-AARP diet and health study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE reproductive factors; non-reproductive factors; histology; ovarian cancer; prospective study ID BODY-MASS INDEX; FALLOPIAN-TUBE; CIGARETTE-SMOKING; ENDOMETRIAL CANCER; GENE-EXPRESSION; POSTMENOPAUSAL WOMEN; COLORECTAL-CANCER; POOLED ANALYSIS; CARCINOMA; CARCINOGENESIS AB Data suggest that risk factors for ovarian carcinoma vary by histologic type, but findings are inconsistent. We prospectively evaluated risk factors by histological subtypes of incident ovarian cancer (n = 849) in a cohort of 169,391 women in the NIH-AARP Diet and Health Study. We constructed Cox models of individual exposures by comparing case subtypes to the entire non-case group and assessed p-heterogeneity in casecase comparisons using serous as the reference category. Substantial risk differences between histologic subtypes were observed for menopausal hormone therapy (MHT) use, oral contraceptive (OC) use, parity and body mass index (p-heterogeneity = 0.01, 0.03, 0.05, 0.03, respectively). MHT users were at increased risk for all histologic subtypes except for mucinous carcinomas, where risk was reduced (relative risk (RR) = 0.37; 95% confidence interval (CI): 0.18, 0.80). OC users were only at significantly decreased risk for serous cancers (RR = 0.69; 95% CI: 0.55, 0.85). Although parity was inversely associated with risk of all subtypes, the RRs ranged from 0.28 (clear cell) to 0.83 (serous). Obesity was a significant risk factor only for endometrioid cancers (RR = 1.64; 95% CI: 1.00, 2.70). Our findings support a link between etiological factors and histological heterogeneity in ovarian carcinoma. C1 [Yang, Hannah P.; Trabert, Britton; Murphy, Megan A.; Sherman, Mark E.; Brinton, Louise A.; Wentzensen, Nicolas] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Rockville, MD 20852 USA. [Sampson, Joshua N.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Rockville, MD 20852 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. [Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Rockville, MD 20852 USA. RP Yang, HP (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, 6120 Execut Blvd,EPS-5102, Rockville, MD 20852 USA. EM yanghan@mail.nih.gov RI Brinton, Louise/G-7486-2015; Trabert, Britton/F-8051-2015; OI Brinton, Louise/0000-0003-3853-8562; Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of the NIH; National Cancer Institute; NIH [5 T32 CA09001-35] FX Grant sponsors: Intramural Research Program of the NIH, National Cancer Institute, Grant sponsor: NIH; Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System under contract to the Department of Health (DOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the contractor or DOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. Authors are indebted to the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation. Authors thank Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcomes ascertainment and management and Leslie Carroll at Information Management Services for data support and analysis. Megan A Murphy is supported in part by training grant NIH 5 T32 CA09001-35. In memory of Dr. Arthur Schatzkin, visionary investigator who founded the NIH-AARP Diet and Health Study. NR 51 TC 35 Z9 35 U1 0 U2 2 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 AUG 15 PY 2012 VL 131 IS 4 BP 938 EP 948 DI 10.1002/ijc.26469 PG 11 WC Oncology SC Oncology GA 961GD UT WOS:000305451300045 PM 21960414 ER PT J AU Tatokoro, M Koga, F Yoshida, S Kawakami, S Fujii, Y Neckers, L Kihara, K AF Tatokoro, Manabu Koga, Fumitaka Yoshida, Soichiro Kawakami, Satoru Fujii, Yasuhisa Neckers, Len Kihara, Kazunori TI Potential role of Hsp90 inhibitors in overcoming cisplatin resistance of bladder cancer-initiating cells SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE bladder cancer; tumor-initiating cell; Hsp90 inhibitors; cisplatin resistance ID SHOCK-PROTEIN 90; STEM-CELLS; UROTHELIAL CARCINOMA; GROWTH-FACTOR; TUMOR-GROWTH; IDENTIFICATION; HYALURONAN; APOPTOSIS; LEUKEMIA; INVASION AB For metastatic bladder cancer patients, systemic cisplatin (CDDP)-based combination chemotherapy is the first-line choice of treatment. Although up to 70% of advanced bladder cancer patients initially show good tumor response to this form of combination chemotherapy, over 90% of good responders relapse and eventually die of the disease. According to the cancer stem cell theory, this phenomenon is attributable to the re-growth of bladder cancer-initiating cells (BCICs) that have survived chemotherapy. In this study, the authors have isolated BCICs from cultured human bladder cancer cells to analyze their sensitivity to CDDP and to investigate whether heat-shock protein 90 (Hsp90) inhibitors potentiate the cytotoxicity of CDDP on BCICs. First, the authors have confirmed that a CD44+ subpopulation of 5637 cells met the requirements to be considered tumor-initiating cells. These BCICs were more resistant to CDDP and exhibited more activity in the Akt and ERK oncogenic signaling pathways when compared with their CD44- counterparts. The Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), which simultaneously inactivated both Akt and ERK signaling at noncytocidal concentrations, synergistically potentiated the cytotoxicity of CDDP against BCICs by enhancing CDDP-induced apoptosis in vitro. The potentiating effect of 17-DMAG was more effective than a combination of the two inhibitors specific for the Akt and ERK pathways. Finally, the authors have confirmed that, though human BCIC xenografts exhibited resistance to a single administration of CDDP and the Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), 17-AAG sensitized them to CDDP in a mouse model. These data encourage clinical trials of Hsp90 inhibitors as they may improve therapeutic outcomes of CDDP-based combination chemotherapy against advanced bladder cancer. C1 [Tatokoro, Manabu; Koga, Fumitaka; Yoshida, Soichiro; Kawakami, Satoru; Fujii, Yasuhisa; Kihara, Kazunori] Tokyo Med & Dent Univ, Grad Sch, Dept Urol, Bunkyo Ku, Tokyo 1138519, Japan. [Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Koga, F (reprint author), Tokyo Med & Dent Univ, Grad Sch, Dept Urol, Bunkyo Ku, 1-5-45 Yushima, Tokyo 1138519, Japan. EM f-koga.uro@tmd.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan [23791744, 23501266] FX This work was supported, in part, by grants-in-aids for Scientific research 23791744 (Manabu Tatokoro), 23501266 (Fumitaka Koga), from the Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 50 TC 28 Z9 30 U1 0 U2 9 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 AUG 15 PY 2012 VL 131 IS 4 BP 987 EP 996 DI 10.1002/ijc.26475 PG 10 WC Oncology SC Oncology GA 961GD UT WOS:000305451300050 PM 21964864 ER PT J AU Gunter, MJ Schaub, JA Xue, XN Freedman, ND Gaudet, MM Rohan, TE Hollenbeck, AR Sinha, R AF Gunter, Marc J. Schaub, Jennifer A. Xue, Xiaonan Freedman, Neal D. Gaudet, Mia M. Rohan, Thomas E. Hollenbeck, Albert R. Sinha, Rashmi TI A prospective investigation of coffee drinking and endometrial cancer incidence SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE coffee; endometrial cancer; chemoprevention ID CIGARETTE-SMOKING; RISK; INSULIN; GROWTH; CONSUMPTION; CAFFEINE; COHORT; WOMEN AB Coffee drinking may be associated with reduced risk of endometrial cancer; however, prospective data are limited. Further, it is not clear whether any association between coffee and endometrial cancer differs according to coffee caffeine content. The association of coffee drinking with incidence of endometrial cancer was evaluated among 226,732 women, aged 5071, enrolled in the NIH-AARP Diet and Health Study who completed a baseline epidemiologic questionnaire. Following a mean 9.3 years of follow-up, data were available for 1,486 incident endometrial cancer cases. Cox proportional hazards models were used to estimate associations of coffee with endometrial cancer incidence. Sub-group analyses were performed according to smoking status, hormone therapy use (HT) and body habitus. Coffee drinking was inversely related to incidence of endometrial cancer (hazard ratio [HR] comparing drinking of >3 cups/day versus no cups = 0.64, 95% CI, 0.510.80; Ptrend = 0.0004). The association of coffee with endometrial cancer risk was apparent for consumption of both regular (HR per cup = 0.90, 95% CI, 0.860.95) and decaffeinated coffee (HR per cup = 0.93, 95% CI, 0.870.99). The relation of coffee with endometrial cancer incidence varied significantly by HT use (Pinteraction = 0.03) with an association only apparent among HT-never users (HR comparing drinking >3 cups/day versus no cups = 0.54, 95% CI, 0.410.72; Ptrend = 0.0005). Endometrial cancer incidence appears to be reduced among women that habitually drink coffee, an association that does not differ according to caffeine content. C1 [Gunter, Marc J.; Schaub, Jennifer A.; Xue, Xiaonan; Rohan, Thomas E.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London W2 1PG, England. [Gunter, Marc J.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Freedman, Neal D.; Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Gunter, MJ (reprint author), Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, Norfolk Pl, London W2 1PG, England. EM m.gunter@imperial.ac.uk RI Sinha, Rashmi/G-7446-2015; Freedman, Neal/B-9741-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Freedman, Neal/0000-0003-0074-1098; Schaub, Jennifer/0000-0001-8788-239X FU Intramural Research Program of National Cancer Institute, NIH; Florida Cancer Data System FX Grant sponsor: Intramural Research Program of National Cancer Institute, NIH; We thank the participants in the NIH-AARP Diet and Health Study for their outstanding cooperation, Adam Risch from Information Management Services for data support and analysis, Sigurd Hermansen and Kerry Grace Morrissey from Westat for study outcome ascertainment and management. Cancer incidence data from the Atlanta metropolitan area were collected by Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by Florida Cancer Data System under contract to Department of Health (DOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the contractor or DOH. Cancer incidence data from Louisiana were collected by Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. NR 18 TC 18 Z9 19 U1 1 U2 13 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 AUG 15 PY 2012 VL 131 IS 4 BP E530 EP E536 DI 10.1002/ijc.26482 PG 7 WC Oncology SC Oncology GA 961GD UT WOS:000305451300020 PM 22021096 ER PT J AU Becker, D Sfakianakis, I Krupp, M Staib, F Gerhold-Ay, A Victor, A Binder, H Blettner, M Maass, T Thorgeirsson, S Galle, PR Teufel, A AF Becker, Diana Sfakianakis, Ioannis Krupp, Markus Staib, Frank Gerhold-Ay, Aslihan Victor, Anja Binder, Harald Blettner, Maria Maass, Thorsten Thorgeirsson, Snorri Galle, Peter R. Teufel, Andreas TI Genetic signatures shared in embryonic liver development and liver cancer define prognostically relevant subgroups in HCC SO MOLECULAR CANCER LA English DT Article ID HEPATOCELLULAR-CARCINOMA CELLS; BETA-CATENIN; TRANSCRIPTION FACTORS; PROGENITOR CELLS; EXPRESSION; PROLIFERATION; MORPHOGENESIS; GROWTH; DIFFERENTIATION; EPIDEMIOLOGY AB Multiple activations of individual genes during embryonic liver and HCC development have repeatedly prompted speculations about conserved embryonic signatures driving cancer development. Recently, the emerging discussion on cancer stem cells and the appreciation that generally tumors may develop from progenitor cells of diverse stages of cellular differentiation has shed increasing light on the overlapping genetic signatures between embryonic liver development and HCC. However there is still a lack of systematic studies investigating this area. We therefore performed a comprehensive analysis of differentially regulated genetic signaling pathways in embryonic and liver cancer development and investigated their biological relevance. Genetic signaling pathways were investigated on several publically available genome wide microarray experiments on liver development and HCC. Differentially expressed genes were investigated for pathway enrichment or underrepresentation compared to KEGG annotated pathways by Fisher exact evaluation. The comparative analysis of enrichment and under representation of differentially regulated genes in liver development and HCC demonstrated a significant overlap between multiple pathways. Most strikingly we demonstrated a significant overlap not only in pathways expected to be relevant to both conditions such as cell cycle or apoptosis but also metabolic pathways associated with carbohydrate and lipid metabolism. Furthermore, we demonstrated the clinical significance of these findings as unsupervised clustering of HCC patients on the basis of these metabolic pathways displayed significant differences in survival. These results indicate that liver development and liver cancer share similar alterations in multiple genetic signaling pathways. Several pathways with markedly similar patterns of enrichment or underrepresentation of various regulated genes between liver development and HCC are of prognostic relevance in HCC. In particular, the metabolic pathways were identified as novel prognostically relevant players in HCC development. C1 [Becker, Diana; Sfakianakis, Ioannis; Krupp, Markus; Staib, Frank; Maass, Thorsten; Galle, Peter R.; Teufel, Andreas] Johannes Gutenberg Univ Mainz, Dept Med 1, D-55101 Mainz, Germany. [Gerhold-Ay, Aslihan; Victor, Anja; Binder, Harald; Blettner, Maria] Johannes Gutenberg Univ Mainz, Inst Med Biostat Epidemiol & Informat, D-55101 Mainz, Germany. [Thorgeirsson, Snorri] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Teufel, A (reprint author), Johannes Gutenberg Univ Mainz, Dept Med 1, Bldg 605,Langenbeckstr 1, D-55101 Mainz, Germany. EM teufel@uni-mainz.de RI Binder, Harald/C-7413-2009 OI Binder, Harald/0000-0002-5666-8662 NR 43 TC 13 Z9 14 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD AUG 14 PY 2012 VL 11 AR 55 DI 10.1186/1476-4598-11-55 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 068BM UT WOS:000313339500001 PM 22891627 ER PT J AU Huang, ZJ Das, A Qiu, YL Tatem, AJ AF Huang, Zhuojie Das, Anirrudha Qiu, Youliang Tatem, Andrew J. TI Web-based GIS: the vector-borne disease airline importation risk (VBD-AIR) tool SO INTERNATIONAL JOURNAL OF HEALTH GEOGRAPHICS LA English DT Article DE Infectious disease; Air transport network; Imported disease; Web GIS; Malaria; Dengue; Yellow fever; Chikungunya; Mosquito ID DOMINANT ANOPHELES VECTORS; INFECTIOUS-DISEASE; DISTRIBUTION MAPS; BIONOMIC PRECIS; HUMAN MALARIA; TRANSPORTATION NETWORK; AEDES-ALBOPICTUS; YELLOW-FEVER; SPREAD; WORLDWIDE AB Background: Over the past century, the size and complexity of the air travel network has increased dramatically. Nowadays, there are 29.6 million scheduled flights per year and around 2.7 billion passengers are transported annually. The rapid expansion of the network increasingly connects regions of endemic vector-borne disease with the rest of the world, resulting in challenges to health systems worldwide in terms of vector-borne pathogen importation and disease vector invasion events. Here we describe the development of a user-friendly Web-based GIS tool: the Vector-Borne Disease Airline Importation Risk Tool (VBD-AIR), to help better define the roles of airports and airlines in the transmission and spread of vector-borne diseases. Methods: Spatial datasets on modeled global disease and vector distributions, as well as climatic and air network traffic data were assembled. These were combined to derive relative risk metrics via air travel for imported infections, imported vectors and onward transmission, and incorporated into a three-tier server architecture in a Model-View-Controller framework with distributed GIS components. A user-friendly web-portal was built that enables dynamic querying of the spatial databases to provide relevant information. Results: The VBD-AIR tool constructed enables the user to explore the interrelationships among modeled global distributions of vector-borne infectious diseases (malaria. dengue, yellow fever and chikungunya) and international air service routes to quantify seasonally changing risks of vector and vector-borne disease importation and spread by air travel, forming an evidence base to help plan mitigation strategies. The VBD-AIR tool is available at www.vbd-air.com. Conclusions: VBD-AIR supports a data flow that generates analytical results from disparate but complementary datasets into an organized cartographical presentation on a web map for the assessment of vector-borne disease movements on the air travel network. The framework built provides a flexible and robust informatics infrastructure by separating the modules of functionality through an ontological model for vector-borne disease. The VBD-AIR tool is designed as an evidence base for visualizing the risks of vector-borne disease by air travel for a wide range of users, including planners and decisions makers based in state and local government, and in particular, those at international and domestic airports tasked with planning for health risks and allocating limited resources. C1 [Huang, Zhuojie; Qiu, Youliang; Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Huang, Zhuojie; Das, Anirrudha; Qiu, Youliang; Tatem, Andrew J.] Univ Florida, Emerging Pathogen Inst, Gainesville, FL 32611 USA. [Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Huang, ZJ (reprint author), Univ Florida, Dept Geog, Gainesville, FL 32611 USA. EM seenhzj@gmail.com FU NCATS NIH HHS [UL1 TR000064] NR 51 TC 19 Z9 19 U1 2 U2 46 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-072X J9 INT J HEALTH GEOGR JI Int. J. Health Geogr. PD AUG 14 PY 2012 VL 11 AR 33 DI 10.1186/1476-072X-11-33 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 044NL UT WOS:000311626600001 PM 22892045 ER PT J AU Yutin, N Koonin, EV AF Yutin, Natalya Koonin, Eugene V. TI Hidden evolutionary complexity of Nucleo-Cytoplasmic Large DNA viruses of eukaryotes SO VIROLOGY JOURNAL LA English DT Article ID HORIZONTAL GENE-TRANSFER; GIANT VIRUSES; MELTING-POT; GENOME; MIMIVIRUS; SEQUENCE; AMEBAS; ORIGIN; MICROORGANISMS; PHYLOGENIES AB Background: The Nucleo-Cytoplasmic Large DNA Viruses (NCLDV) constitute an apparently monophyletic group that consists of at least 6 families of viruses infecting a broad variety of eukaryotic hosts. A comprehensive genome comparison and maximum-likelihood reconstruction of the NCLDV evolution revealed a set of approximately 50 conserved, core genes that could be mapped to the genome of the common ancestor of this class of eukaryotic viruses. Results: We performed a detailed phylogenetic analysis of these core NCLDV genes and applied the constrained tree approach to show that the majority of the core genes are unlikely to be monophyletic. Several of the core genes have been independently acquired from different sources by different NCLDV lineages whereas for the majority of these genes displacement by homologs from cellular organisms in one or more groups of the NCLDV was demonstrated. Conclusions: A detailed study of the evolution of the genomic core of the NCLDV reveals substantial complexity and diversity of evolutionary scenarios that was largely unsuspected previously. The phylogenetic coherence between the core genes is sufficient to validate the hypothesis on the evolution of all NCLDV from a common ancestral virus although the set of ancestral genes might be smaller than previously inferred from patterns of gene presence-absence. 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 DHHS intramural program (NIH, national Library of Medicine) FX The authors' research is supported by the DHHS intramural program (NIH, national Library of Medicine). NR 40 TC 54 Z9 55 U1 0 U2 20 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 AUG 14 PY 2012 VL 9 AR 161 DI 10.1186/1743-422X-9-161 PG 18 WC Virology SC Virology GA 037RE UT WOS:000311123400001 PM 22891861 ER PT J AU Berezhkovskii, AM AF Berezhkovskii, Alexander M. TI Note: Aris-Taylor dispersion from single-particle point of view SO JOURNAL OF CHEMICAL PHYSICS LA English DT Letter C1 NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, 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. FU Intramural NIH HHS NR 3 TC 3 Z9 3 U1 0 U2 3 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD AUG 14 PY 2012 VL 137 IS 6 AR 066101 DI 10.1063/1.4746027 PG 2 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 995XN UT WOS:000308048700067 PM 22897315 ER PT J AU Dorjgochoo, T Shu, XO Xiang, YB Yang, G Cai, QY Li, HL Ji, BT Cai, H Gao, YT Zheng, W AF Dorjgochoo, Tsogzolmaa Shu, Xiao Ou Xiang, Yong-Bing Yang, Gong Cai, Qiuyin Li, Honglan Ji, Bu-Tian Cai, Hui Gao, Yu-Tang Zheng, Wei TI Circulating 25-hydroxyvitamin D levels in relation to blood pressure parameters and hypertension in the Shanghai Women's and Men's Health Studies SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Blood pressure parameters; Hypertension; 25-Hydroxyvitamin D; Sex differences; China ID NUTRITION EXAMINATION SURVEY; CARDIOVASCULAR RISK-FACTORS; PARATHYROID-HORMONE LEVELS; RENIN-ANGIOTENSIN SYSTEM; VITAMIN-D ALPHACALCIDOL; 3RD NATIONAL-HEALTH; LONG-TERM TREATMENT; DOUBLE-BLIND; INSULIN SENSITIVITY; METABOLIC SYNDROME AB Little is known about the association of circulating 25-hydroxyvitamin D (25(OH) D) and blood pressure (BP) parameters, including systolic and diastolic BP, pulse pressure (PP), mean arterial pressure (MAP) and hypertension in non-Western populations that have not yet been exposed to foods fortified with vitamins and seldom use vitamin D supplements. A cross-sectional analysis of plasma 25(OH) D levels in association with BP measures was performed for 1460 participants (1055 women and 405 men, aged 40-74 years) of two large cohort studies in Shanghai. Multivariable linear and logistic regressions were conducted. Overall, the prevalence of vitamin D deficiency was 55.8% using National Health and Nutrition Examination Survey, USA criteria and 29.9% using WHO criteria. The median plasma 25(OH)D level in the population was 38.0 nmol/l for men and 33.6 nmol/l for women (P<0.01) among participants who were not on antihypertensive drugs. Among men, BP parameters (systolic BP, diastolic BP and MAP) were significantly and inversely associated with higher quintiles of 25(OH)D compared with the lowest quintile (P-trend < 0.05 for all). Vitamin D non-deficient status (WHO criteria) was inversely associated with hypertension (ORadjusted = 0.29; 95% CI 0.10, 0.82). An inverse association was also found between hypertension and the highest quintile of 25(OH)D (ORadjusted = 0.16; 95% CI 0.04, 0.65 for >= 50.6 nmol/l; Ptrend 0.02). Among women, no significant associations were found for BP parameters and hypertension. The present study shows that vitamin D deficiency is common among adults in urban China. Circulating 25(OH)D levels were inversely related to the levels of individual BP parameters and hypertension among middle-aged and elderly men but not among women. More research is needed to investigate the potential sex differential associations. C1 [Dorjgochoo, Tsogzolmaa; Shu, Xiao Ou; Yang, Gong; Cai, Qiuyin; Cai, Hui; Zheng, Wei] Vanderbilt Univ, Sch Med, IMPH, Div Epidemiol,Dept Med, Nashville, TN 37203 USA. [Dorjgochoo, Tsogzolmaa; Shu, Xiao Ou; Yang, Gong; Cai, Qiuyin; Cai, Hui; Zheng, Wei] Vanderbilt Univ, Sch Med, IMPH, Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Xiang, Yong-Bing; Li, Honglan; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai 200032, Peoples R China. [Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Shu, XO (reprint author), Vanderbilt Univ, Sch Med, IMPH, Div Epidemiol,Dept Med, 2525 W End Ave,Suite 600, Nashville, TN 37203 USA. EM xiao-ou.shu@vanderbilt.edu FU National Cancer Institute at the National Institutes of Health, USA [R37 CA070867, R01 CA082729, R01 HL079123] FX The contributions of the authors were as follows: T. D. analysed the data and drafted the manuscript. X. O. S. and W. Z. designed and directed the study, obtained funding for the parent studies and provided critical review of the manuscript. Y.-B. X., G. Y., H. L. and Y.-T. G. directed and supervised the field operations of the parent studies, data cleaning and reviewed the manuscript. B.-T. J., G. Y. and Q. C. contributed to critical review of the paper. H. C. contributed to the statistical analysis and reviewed the paper. The authors thank the Shanghai residents who participated in the studies and the research staff of the Shanghai Women's Health Study (SWHS) and the Shanghai Men's Health Study (SMHS) for their dedication and contributions to the present study. The authors also thank Bethanie Rammer and Jacqueline Stern for their editorial assistance. This work was supported by the National Cancer Institute at the National Institutes of Health, USA (R37 CA070867, R01 CA082729, R01 HL079123). The authors declare that they have no conflicts of interest. NR 47 TC 15 Z9 17 U1 0 U2 10 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD AUG 14 PY 2012 VL 108 IS 3 BP 449 EP 458 DI 10.1017/S0007114511005745 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 999JC UT WOS:000308304700011 PM 22365135 ER PT J AU Murphy, TP Cerezo, J Cutlip, DE Reynolds, MR Regensteiner, JG Mohler, ER Cohen, DJ Massaro, JM Lewis, BA Oldenburg, NC Steffes, MW Hirsch, AT Thum, CC Goldberg, S Jaff, MR Comerota, AJ Ehrman, J Treat-Jacobson, D Bronas, U Walsh, ME Badenhop, DT Collins, T AF Murphy, Timothy P. Cerezo, Joselyn Cutlip, Donald E. Reynolds, Matthew R. Regensteiner, Judith G. Mohler, Emile R. Cohen, David J. Massaro, Joseph M. Lewis, Beth A. Oldenburg, Niki C. Steffes, Michael W. Hirsch, Alan T. Thum, Claudia C. Goldberg, Suzanne Jaff, Michael R. Comerota, Anthony J. Ehrman, Jonathan Treat-Jacobson, Diane Bronas, Ulf Walsh, M. Eileen Badenhop, Dalynn T. Collins, Tracie TI Response to Letters Regarding Article, "Supervised Exercise Versus Primary Stenting for Claudication Resulting From Aortoiliac Peripheral Artery Disease: Six-Month Outcomes From the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) Study" SO CIRCULATION LA English DT Letter C1 [Murphy, Timothy P.; Cerezo, Joselyn] Rhode Isl Hosp, Providence, RI 02903 USA. [Cutlip, Donald E.; Reynolds, Matthew R.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Regensteiner, Judith G.] Univ Colorado, Sch Med, Aurora, CO USA. [Mohler, Emile R.] Univ Penn, Philadelphia, PA 19104 USA. [Cohen, David J.] Univ Missouri, Kansas City, MO 64110 USA. [Massaro, Joseph M.] Boston Univ, Boston, MA 02215 USA. [Lewis, Beth A.] Univ Minnesota, Sch Kinesiol, Minneapolis, MN USA. [Oldenburg, Niki C.; Steffes, Michael W.; Hirsch, Alan T.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Thum, Claudia C.] Harvard Clin Res Inst, Boston, MA USA. [Goldberg, Suzanne] NHLBI, Bethesda, MD 20892 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Comerota, Anthony J.] Jobst Vasc Ctr, Toledo, OH USA. [Ehrman, Jonathan] Henry Ford Hosp, Detroit, MI 48202 USA. [Treat-Jacobson, Diane; Bronas, Ulf] Univ Minnesota, Sch Nursing, Minneapolis, MN 55455 USA. [Walsh, M. Eileen] Univ Toledo, Coll Nursing, Toledo, OH 43606 USA. [Collins, Tracie] Univ Kansas, Sch Med, Witchita Dept Prevent Med & Publ Hlth, Wichita, KS USA. RP Murphy, TP (reprint author), Rhode Isl Hosp, Providence, RI 02903 USA. NR 1 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 14 PY 2012 VL 126 IS 7 BP E102 EP E103 DI 10.1161/CIRCULATIONAHA.112.113704 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 993TQ UT WOS:000307882900006 ER PT J AU Roberts, KG Morin, RD Zhang, JH Hirst, M Zhao, YJ Su, XP Chen, SC Payne-Turner, D Churchman, ML Harvey, RC Chen, X Kasap, C Yan, CH Becksfort, J Finney, RP Teachey, DT Maude, SL Tse, K Moore, R Jones, S Mungall, K Birol, I Edmonson, MN Hu, Y Buetow, KE Chen, IM Carroll, WL Wei, L Ma, J Kleppe, M Levine, RL Garcia-Manero, G Larsen, E Shah, NP Devidas, M Reaman, G Smith, M Paugh, SW Evans, WE Grupp, SA Jeha, S Pui, CH Gerhard, DS Downing, JR Willman, CL Loh, M Hunger, SP Marra, MA Mullighan, CG AF Roberts, Kathryn G. Morin, Ryan D. Zhang, Jinghui Hirst, Martin Zhao, Yongjun Su, Xiaoping Chen, Shann-Ching Payne-Turner, Debbie Churchman, Michelle L. Harvey, Richard C. Chen, Xiang Kasap, Corynn Yan, Chunhua Becksfort, Jared Finney, Richard P. Teachey, David T. Maude, Shannon L. Tse, Kane Moore, Richard Jones, Steven Mungall, Karen Birol, Inanc Edmonson, Michael N. Hu, Ying Buetow, Kenneth E. Chen, I-Ming Carroll, William L. Wei, Lei Ma, Jing Kleppe, Maria Levine, Ross L. Garcia-Manero, Guillermo Larsen, Eric Shah, Neil P. Devidas, Meenakshi Reaman, Gregory Smith, Malcolm Paugh, Steven W. Evans, William E. Grupp, Stephan A. Jeha, Sima Pui, Ching-Hon Gerhard, Daniela S. Downing, James R. Willman, Cheryl L. Loh, Mignon Hunger, Stephen P. Marra, Marco A. Mullighan, Charles G. TI Genetic Alterations Activating Kinase and Cytokine Receptor Signaling in High-Risk Acute Lymphoblastic Leukemia SO CANCER CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; CHRONIC MYELOMONOCYTIC LEUKEMIA; GROWTH-FACTOR RECEPTOR; OF-FUNCTION MUTATIONS; BCR-JAK2 FUSION GENE; MYELOPROLIFERATIVE NEOPLASMS; FLT3 MUTATIONS; NUCLEAR-PORE; B-PROGENITOR; CHILDHOOD AB Genomic profiling has identified a subtype of high-risk B-progenitor acute lymphoblastic leukemia (B-ALL) with alteration of IKZF1, a gene expression profile similar to BCR-ABL1-positive ALL and poor outcome (Ph-like ALL). The genetic alterations that activate kinase signaling in Ph-like ALL are poorly understood. We performed transcriptome and whole genome sequencing on 15 cases of Ph-like ALL and identified rearrangements involving ABL1, JAK2, PDGFRB, CRLF2, and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, which encodes the JAK2-negative regulator LNK. Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy. C1 [Hunger, Stephen P.] Univ Colorado, Sch Med, Aurora, CO 80045 USA. [Roberts, Kathryn G.; Su, Xiaoping; Chen, Shann-Ching; Payne-Turner, Debbie; Churchman, Michelle L.; Wei, Lei; Ma, Jing; Downing, James R.; Mullighan, Charles G.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [Zhang, Jinghui; Chen, Xiang] St Jude Childrens Res Hosp, Dept Computat Biol & Bioinformat, Memphis, TN 38105 USA. [Becksfort, Jared] St Jude Childrens Res Hosp, Dept Informat Sci, Memphis, TN 38105 USA. [Jeha, Sima; Pui, Ching-Hon] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Paugh, Steven W.; Evans, William E.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Morin, Ryan D.; Hirst, Martin; Zhao, Yongjun; Tse, Kane; Moore, Richard; Jones, Steven; Mungall, Karen; Birol, Inanc; Marra, Marco A.] BC Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada. [Harvey, Richard C.; Chen, I-Ming; Willman, Cheryl L.] Univ New Mexico, Canc Res & Treatment Ctr, Albuquerque, NM 87131 USA. [Kasap, Corynn; Shah, Neil P.] Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. [Loh, Mignon] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Yan, Chunhua; Finney, Richard P.] NCI, Ctr Bioinformat & Informat Technol, NIH, Bethesda, MD 20892 USA. [Edmonson, Michael N.; Hu, Ying; Buetow, Kenneth E.] NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. [Smith, Malcolm] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. [Gerhard, Daniela S.] NCI, Off Canc Genom, NIH, Bethesda, MD 20892 USA. [Teachey, David T.; Maude, Shannon L.; Grupp, Stephan A.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Carroll, William L.] NYU, Inst Canc, New York, NY 10016 USA. [Kleppe, Maria; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Garcia-Manero, Guillermo] Univ Texas Houston, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Larsen, Eric] Maine Childrens Canc Program, Scarborough, ME 04074 USA. [Devidas, Meenakshi] Univ Florida, Gainesville, FL 32601 USA. [Reaman, Gregory] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Marra, Marco A.] Univ British Columbia, Dept Med Genet, Vancouver, BC VSZ 1L3, Canada. [Hunger, Stephen P.] Childrens Hosp Colorado, Aurora, CO 80045 USA. RP Hunger, SP (reprint author), Univ Colorado, Sch Med, Aurora, CO 80045 USA. EM stephen.hunger@childrenscolorado.org; mmarra@bcgsc.ca; charles.mullighan@stjude.org RI Paugh, Steven/A-7739-2008; Kleppe, Maria/C-6341-2014; Tang, Macy/B-9798-2014; Hirst, Martin/B-7684-2016; Jones, Steven/C-3621-2009; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011; OI Paugh, Steven/0000-0001-5697-9228; Kleppe, Maria/0000-0002-4372-6704; Birol, Inanc/0000-0003-0950-7839; Harvey, Richard/0000-0002-4904-9767; Mullighan, Charles/0000-0002-1871-1850 FU NCI; NIH, Therapeutically Applicable Research to Generate Effective Treatments initiative [N01-C0-12400]; Children's Oncology Group Chair's award [CA098543]; National Cancer Institute Strategic Partnering to Evaluate Cancer Signatures Program [CA114762]; NIH Cancer Center Core Grant [CA21765]; St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project; Stand Up To Cancer Innovative Research Grant; American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital; National Health and Medical Research Council (Australia); Haematology Society of Australia; New Zealand Novartis New Investigator Scholarship; MSFHR; [U10 CA98543]; [U10 CA98413]; [U24 CA114766] FX We thank M. Tomasson and J. Cools for providing the MSCV-ETV6-PDGFRB-IRES-GFP and MSCV-NUP214-ABL1-IRES-GFP constructs, respectively; D. Pei and C. Cheng for statistical analyses of cell line proliferation data; Garry Nolan for providing the Phoenix cell line (http://www.stanford.edu/group/nolan/retroviral_systems/phx.html); Beckman Coulter Genomics for Sanger Sequencing; and the Flow Cytometry Core Facility, Tissue Resources Core Facility, and Clinical Application of Core Technology (Affymetrix) Laboratory of the Hartwell Center for Bioinformatics and Biotechnology of St. Jude Children's Research Hospital. The correlative biology studies described in this manuscript were funded by grants from the National Institutes of Health (NIH) and philanthropic funds of the Children's Oncology Group and not a commercial entity. The sequencing was part-funded with Federal funds from the NCI and NIH under Contract No. N01-C0-12400 as part of the Therapeutically Applicable Research to Generate Effective Treatments initiative. This work was supported by funds provided as a supplement to the Children's Oncology Group Chair's award (CA098543, G.R.); grants to the COG, including U10 CA98543 (COG Chair's grant), U10 CA98413 (COG Statistical Center), and U24 CA114766 (COG Specimen Banking); a National Cancer Institute Strategic Partnering to Evaluate Cancer Signatures Program award CA114762 (W.L.C., I-M.C., R.C.H., and C.L.W.); NIH Cancer Center Core Grant CA21765 (J.R.D., C.G.M., W.E.E., C.-H.P., and S.J.); St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project; a Stand Up To Cancer Innovative Research Grant (C.G.M.); and the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital. K.G.R. is supported by a National Health and Medical Research Council (Australia) Overseas Training Fellowship and a Haematology Society of Australia and New Zealand Novartis New Investigator Scholarship. R.D.M. is a Vanier Scholar (CIHR) and holds a MSFHR senior graduate studentship. M.A.M. is a UBC Canada Research Chair in Genome Science and a Michael Smith Senior Research Scholar. S.P.H. is the Ergen Family Chair in Pediatric Cancer. C.G.M. is a Pew Scholar in the Biomedical Sciences and a St. Baldrick's Scholar. S.P.H. is a member of the Bristol Myers Squibb pediatric dasatinib advisory board. NR 62 TC 225 Z9 231 U1 5 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG 14 PY 2012 VL 22 IS 2 BP 153 EP 166 DI 10.1016/j.ccr.2012.06.005 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 991FD UT WOS:000307686000005 PM 22897847 ER PT J AU Sanda, T Lawton, LN Barrasa, MI Fan, ZP Kohlhammer, H Gutierrez, A Ma, WX Tatarek, J Ahn, Y Kelliher, MA Jamieson, CHM Staudt, LM Young, RA Look, AT AF Sanda, Takaomi Lawton, Lee N. Barrasa, M. Inmaculada Fan, Zi Peng Kohlhammer, Holger Gutierrez, Alejandro Ma, Wenxue Tatarek, Jessica Ahn, Yebin Kelliher, Michelle A. Jamieson, Catriona H. M. Staudt, Louis M. Young, Richard A. Look, A. Thomas TI Core Transcriptional Regulatory Circuit Controlled by the TAL1 Complex in Human T Cell Acute Lymphoblastic Leukemia SO CANCER CELL LA English DT Article ID GENOME-WIDE ANALYSIS; GENE-EXPRESSION; TARGET GENE; PROTEINS; BINDING; DIFFERENTIATION; ALPHA; E2A; SCL; ONCOGENE AB The oncogenic transcription factor TAL1/SCL is aberrantly expressed in over 40% of cases of human T cell acute lymphoblastic leukemia (T-ALL), emphasizing its importance in the molecular pathogenesis of T-ALL. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. We show that TAL1 forms a positive interconnected autoregulatory loop with GATA3 and RUNX1 and that the TAL1 complex directly activates the MYB oncogene, forming a positive feed-forward regulatory loop that reinforces and stabilizes the TAL1-regulated oncogenic program. One of the critical downstream targets in this circuitry is the TRIB2 gene, which is oppositely regulated by TAL1 and E2A/HEB and is essential for the survival of T-ALL cells. C1 [Sanda, Takaomi; Gutierrez, Alejandro; Ahn, Yebin; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Lawton, Lee N.; Barrasa, M. Inmaculada; Fan, Zi Peng; Young, Richard A.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Fan, Zi Peng] MIT, Computat & Syst Biol Program, Cambridge, MA 02142 USA. [Young, Richard A.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Kohlhammer, Holger; Staudt, Louis M.] NCI, Metab Branch, Bethesda, MD 20892 USA. [Gutierrez, Alejandro; Look, A. Thomas] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Ma, Wenxue; Kelliher, Michelle A.; Jamieson, Catriona H. M.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Ma, Wenxue; Kelliher, Michelle A.; Jamieson, Catriona H. M.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Tatarek, Jessica] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. RP Look, AT (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM thomas_look@dfci.harvard.edu RI Young, Richard/F-6495-2012; OI Young, Richard/0000-0001-8855-8647; Gutierrez, Alejandro/0000-0002-0249-9007 FU National Cancer Institute [5P01CA109901, 5P01CA68484, 1K99CA157951]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; William Lawrence and Blanche Hughes Foundation; Children's Leukemia Research Association; Japan Society for the Promotion of Science; California Institute for Regenerative Medicine Leukemia Team FX We thank the members of the Look and Young laboratories for discussions and critical review and Jennifer O'Neil for initial experimentation and TAL1 plasmids. We are grateful to Garrett Frampton and Dave Orlando for the development of ChIP-seq analysis tools and continued support with the analysis. We are also grateful to the Whitehead Genome Technology Core (V. Dhanapal, J.-A. Kwon, J. Love, S. Gupta, and T. Volkert) for assistance with ChIP-Seq and expression array hybridization and to Bingbing Yuan from BaRC for developing the phenotype ontology analysis. We acknowledge the RNAi Consortium for providing lentivirus shRNA constructs, and we thank John R. Gilbert for editing and critical review of the manuscript. This research was supported by grants (5P01CA109901, 5P01CA68484, and 1K99CA157951) from the National Cancer Institute and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. T.S. is supported by grants from the William Lawrence and Blanche Hughes Foundation, the Children's Leukemia Research Association, and the Japan Society for the Promotion of Science. W.M. and C.J. are supported by the California Institute for Regenerative Medicine Leukemia Team grant. NR 61 TC 66 Z9 67 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG 14 PY 2012 VL 22 IS 2 BP 209 EP 221 DI 10.1016/j.ccr.2012.06.007 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 991FD UT WOS:000307686000009 PM 22897851 ER PT J AU Cecchi, F Pajalunga, D Fowler, CA Uren, A Rabe, DC Peruzzi, B MacDonald, NJ Blackman, DK Stahl, SJ Byrd, RA Bottaro, DP AF Cecchi, Fabiola Pajalunga, Deborah Fowler, C. Andrew Ueren, Aykut Rabe, Daniel C. Peruzzi, Benedetta MacDonald, Nicholas J. Blackman, Davida K. Stahl, Stephen J. Byrd, R. Andrew Bottaro, Donald P. TI Targeted Disruption of Heparan Sulfate Interaction with Hepatocyte and Vascular Endothelial Growth Factors Blocks Normal and Oncogenic Signaling SO CANCER CELL LA English DT Article ID FACTOR/SCATTER FACTOR; CRYSTAL-STRUCTURE; C-MET; FACTOR ISOFORMS; NK1 FRAGMENT; FUNCTIONAL-CHARACTERIZATION; RECEPTOR ACTIVATION; PROVIDE INSIGHTS; STRUCTURAL BASIS; DOMAIN RECEPTOR AB Hepatocyte growth factor (HGF) and vascular endothelial cell growth factor (VEGF) regulate normal development and homeostasis and drive disease progression in many forms of cancer. Both proteins signal by binding to receptor tyrosine kinases and heparan sulfate (HS) proteoglycans on target cell surfaces. Basic residues comprising the primary HS binding sites on HGF and VEGF provide similar surface charge distributions without underlying structural similarity. Combining three acidic amino acid substitutions in these sites in the HGF isoform NK1 or the VEGF isoform VEGF165 transformed each into potent, selective competitive antagonists of their respective normal and oncogenic signaling pathways. Our findings illustrate the importance of HS in growth factor driven cancer progression and reveal an efficient strategy for therapeutic antagonist development. C1 [Cecchi, Fabiola; Rabe, Daniel C.; Peruzzi, Benedetta; Bottaro, Donald P.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Pajalunga, Deborah; Fowler, C. Andrew; Byrd, R. Andrew] Frederick Natl Lab Canc Res, Macromol NMR Sect, Struct Biophys Lab, Frederick, MD 21702 USA. [Pajalunga, Deborah; MacDonald, Nicholas J.; Blackman, Davida K.] EntreMed Inc, Rockville, MD 20850 USA. [Ueren, Aykut] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Stahl, Stephen J.] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. RP Bottaro, DP (reprint author), NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. EM dbottaro@helix.nih.gov RI Bottaro, Donald/F-8550-2010; Byrd, R. Andrew/F-8042-2015; OI Fowler, Andrew/0000-0001-5646-5307; Bottaro, Donald/0000-0002-5057-5334; Byrd, R. Andrew/0000-0003-3625-4232; Cecchi, Franco/0000-0002-2035-5621 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank the late Dr. Ralph Schwall for recombinant Met-Ig fusion protein; Dr. Jeffrey Esko for CHO 745 cells; Drs. Dominic Esposito, Troy Taylor, and William Gillette for plasmid and protein production and purification; and Drs. Miriam Anver, Lawrence Sternberg, and Roberta Smith for pathology, immunohistochemistry analysis, and clinical chemistry analyses. NR 50 TC 14 Z9 14 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG 14 PY 2012 VL 22 IS 2 BP 250 EP 262 DI 10.1016/j.ccr.2012.06.029 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 991FD UT WOS:000307686000012 PM 22897854 ER PT J AU Endo, Y Ishiwata-Endo, H Yamada, KM AF Endo, Yukinori Ishiwata-Endo, Hiroko Yamada, Kenneth M. TI Extracellular Matrix Protein Anosmin Promotes Neural Crest Formation and Regulates FGF, BMP, and WNT Activities SO DEVELOPMENTAL CELL LA English DT Article ID LINKED KALLMANN-SYNDROME; CELL FATE SPECIFICATION; TRANSCRIPTION FACTOR; PARAXIAL MESODERM; INDUCTION; GASTRULATION; CHICK; GENE; DIFFERENTIATION; REQUIRES AB Neural crest cells are a transient stem cell-like population appearing during vertebrate embryonic development. Generation of the cranial neural crest is known to require a balanced combination of FGF and BMP levels. However, it is poorly understood how the functions of such growth factors are controlled in the extracellular space. Anosmin is an extracellular matrix protein implicated in FGF signaling and mutated in Kallmann syndrome. Here, we demonstrate that anosmin is synthesized locally in the cranial neural crest of chicken embryos and is essential for cranial neural crest formation. Anosmin upregulates FGF8 and BMP5 gene expression; it also enhances FGF8 activity while inhibiting BMP5 and WNT3a signaling. Taken together, our data establish that the matrix protein anosmin is required for cranial neural crest formation, with functional modulation of FGF, BMP, and WNT. C1 [Endo, Yukinori; Ishiwata-Endo, Hiroko; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Endo, Y (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 OI Yamada, Kenneth/0000-0003-1512-6805 FU National Institute of Dental and Craniofacial Research, National Institutes of Health; Japan Society for the Promotion of Science Research FX We thank Dr. Woei-Jer Chuang for valuable advice on anosmin protein purification, members of the Yamada laboratory for comments, and Shelagh Johnson for proofreading. We especially thank Drs. Daniel Rifkin, Dwight Towler, and Angela Nieto for kindly providing C2C12-BRA cells, 7xOCFRE, and 3xOCFRE plasmids and chicken SNAI2 plasmid, respectively. Supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health. Y.E. was partially supported by the Japan Society for the Promotion of Science Research. NR 54 TC 27 Z9 27 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD AUG 14 PY 2012 VL 23 IS 2 BP 305 EP 316 DI 10.1016/j.devcel.2012.07.006 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 991IU UT WOS:000307695500010 PM 22898776 ER PT J AU Frontini, M Kukalev, A Leo, E Ng, YM Cervantes, M Cheng, CW Holic, R Dormann, D Tse, E Pommier, Y Yu, V AF Frontini, Mattia Kukalev, Alexander Leo, Elisabetta Yiu-Ming Ng Cervantes, Marcella Cheng, Chi-Wai Holic, Roman Dormann, Dirk Tse, Eric Pommier, Yves Yu, Veronica TI The CDK Subunit CKS2 Counteracts CKS1 to Control Cyclin A/CDK2 Activity in Maintaining Replicative Fidelity and Neurodevelopment SO DEVELOPMENTAL CELL LA English DT Article ID DNA-DAMAGE RESPONSE; S-PHASE CHECKPOINT; CELL-CYCLE; NEURONAL DIFFERENTIATION; INDEPENDENT FUNCTION; EARLY EMBRYOGENESIS; DEPENDENT KINASES; PROGENITOR CELLS; MAMMALIAN-CELLS; CEREBRAL-CORTEX AB CKS proteins are evolutionarily conserved cyclin-dependent kinase (CDK) subunits whose functions are incompletely understood. Mammals have two CKS proteins. CKS1 acts as a cofactor to the ubiquitin ligase complex SCFSKP2 to promote degradation of CDK inhibitors, such as p27. Little is known about the role of the closely related CKS2. Using a Cks2(-/-) knockout mouse model, we show that CKS2 counteracts CKS1 and stabilizes p27. Unopposed CKS1 activity in Cks2-/- cells leads to loss of p27. The resulting unrestricted cyclin A/CDK2 activity is accompanied by shortening of the cell cycle, increased replication fork velocity, and DNA damage. In vivo, Cks2(-/-) cortical progenitor cells are limited in their capacity to differentiate into mature neurons, a phenotype akin to animals lacking p27. We propose that the balance between CKS2 and CKS1 modulates p27 degradation, and with it cyclin A/CDK2 activity, to safeguard replicative fidelity and control neuronal differentiation. C1 [Frontini, Mattia; Kukalev, Alexander; Cervantes, Marcella; Holic, Roman; Yu, Veronica] Univ London Imperial Coll Sci Technol & Med, MRC Clin Sci Ctr, Eukaryot Chromatin Dynam Grp, London W12 0NN, England. [Dormann, Dirk] Univ London Imperial Coll Sci Technol & Med, MRC Clin Sci Ctr, Microscopy Facil, London W12 0NN, England. [Kukalev, Alexander; Yiu-Ming Ng; Yu, Veronica] Kings Coll London, Sch Med, Guys Hosp, Dept Med & Mol Genet, London SE1 9RT, England. [Leo, Elisabetta; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yiu-Ming Ng; Cheng, Chi-Wai; Tse, Eric] Univ Hong Kong, Dept Med, Div Haematol, Hong Kong, Hong Kong, Peoples R China. [Holic, Roman] Slovak Acad Sci, Inst Anim Biochem & Genet, Ivanka Pri Dunaji 90028, Slovakia. RP Yu, V (reprint author), Univ London Imperial Coll Sci Technol & Med, MRC Clin Sci Ctr, Eukaryot Chromatin Dynam Grp, Hammersmith Campus,Du Cane Rd, London W12 0NN, England. EM veronica.yu@kcl.ac.uk OI Holic, Roman/0000-0003-1347-4785 FU Medical Research Council; Cancer Research UK; Generation Trust; Academy of Medical Sciences; Wellcome Trust; British Heart Foundation; National Institute for Health Research at Guy's NHS Foundation Trust; National Institute for Health Research at St. Thomas' NHS Foundation Trust; King's College London; Outstanding Young Researcher Award, University of Hong Kong; National Institutes of Health Intramural Program, Center for Cancer Research, National Cancer Institute FX We thank V. de Paola and H. Dewchand for kind assistance and expertise in preparation of mouse brains. The Yu laboratory is funded by the Medical Research Council, Cancer Research UK, the Generation Trust, the Academy of Medical Sciences, the Wellcome Trust, and the British Heart Foundation. V.Y. is supported by a fellowship from the National Institute for Health Research at Guy's and St. Thomas' NHS Foundation Trust in partnership with King's College London. E.T. is a recipient of the Outstanding Young Researcher Award 2010, University of Hong Kong. The Pommier laboratory is funded by the National Institutes of Health Intramural Program, Center for Cancer Research, National Cancer Institute. NR 50 TC 11 Z9 11 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD AUG 14 PY 2012 VL 23 IS 2 BP 356 EP 370 DI 10.1016/j.devcel.2012.06.018 PG 15 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 991IU UT WOS:000307695500014 PM 22898779 ER PT J AU Hlatky, MA Douglas, PS Cook, NL Wells, B Benjamin, EJ Dickersin, K Goff, DC Hirsch, AT Hylek, EM Peterson, ED Roger, VL Selby, JV Udelson, JE Lauer, MS AF Hlatky, Mark A. Douglas, Pamela S. Cook, Nakela L. Wells, Barbara Benjamin, Emelia J. Dickersin, Kay Goff, David C. Hirsch, Alan T. Hylek, Elaine M. Peterson, Eric D. Roger, Veronique L. Selby, Joseph V. Udelson, James E. Lauer, Michael S. TI Future Directions for Cardiovascular Disease Comparative Effectiveness Research Report of a Workshop Sponsored by the National Heart, Lung, and Blood Institute SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE clinical trials; comparative effectiveness; research methods ID 10-YEAR FOLLOW-UP; MYOCARDIAL-INFARCTION; ATRIAL-FIBRILLATION; CLINICAL-TRIALS; GLUCOSE CONTROL; BYPASS SURGERY; OUTCOMES; RISK; SURVIVAL; INTERVENTION AB Comparative effectiveness research (CER) aims to provide decision makers with the evidence needed to evaluate the benefits and harms of alternative clinical management strategies. CER has become a national priority, with considerable new research funding allocated. Cardiovascular disease is a priority area for CER. This workshop report provides an overview of CER methods, with an emphasis on practical clinical trials and observational treatment comparisons. The report also details recommendations to the National Heart, Lung, and Blood Institute for a new framework for evidence development to foster cardiovascular CER, and specific studies to address 8 clinical issues identified by the Institute of Medicine as high priorities for cardiovascular CER. (J Am Coll Cardiol 2012; 60: 569-80) (C) 2012 by the American College of Cardiology Foundation C1 [Hlatky, Mark A.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Douglas, Pamela S.; Lauer, Michael S.] Duke Univ, Med Ctr, Durham, NC USA. [Cook, Nakela L.; Wells, Barbara; Lauer, Michael S.] NHLBI, Bethesda, MD 20892 USA. [Benjamin, Emelia J.; Hylek, Elaine M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Dickersin, Kay] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Goff, David C.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Hirsch, Alan T.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Roger, Veronique L.] Mayo Clin, Rochester, MN USA. [Udelson, James E.] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Hlatky, MA (reprint author), Stanford Univ, Sch Med, HRP Redwood Bldg,Room T150,259 Campus Dr, Stanford, CA 94305 USA. EM hlatky@stanford.edu RI Lauer, Michael/L-9656-2013; OI Lauer, Michael/0000-0002-9217-8177; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI FX From the *Stanford University School of Medicine, Stanford, California; dagger Duke University Medical Center, Durham, North Carolina; National Heart, Lung, and Blood Institute, Bethesda, Maryland; Boston University School of Medicine, Boston, Massachusetts; parallel to Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Wake Forest University Health Sciences, Winston-Salem, North Carolina; #University of Minnesota Medical School, Minneapolis, Minnesota; and the **Mayo Clinic, Rochester, Minnesota. dagger dagger Division of Research, Kaiser Permanente of Northern California, Oakland, California; and the Tufts University School for Medicine, Boston, Massachusetts. Drs. Cook, Wells, and Lauer are full-time employees of the National Heart, Lung, and Blood Institute (NHLBI). The views expressed in this manuscript do not necessarily represent the views of the NHLBI, National Institutes of Health, or any other government entity. Dr. Goff is a research consultant for and a data and safety monitoring board member for a clinical trial of a glucose-lowering medication marketed by Merck and Takeda. Dr. Hirsch has relationships with Pozen Medical, Merck, AstraZeneca, Abbott Vascular, Viromed, Summit Doppler, Novartis, and Cytokinetics. Dr. Hylek is on the scientific advisory board of Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Merck, Ortho-McNeil, and Pfizer. Dr. Selby was employed by Kaiser Permanente and is currently the Executive Director of the Patient Centered Outcomes Research Institute (PCORI); the opinions expressed in this paper do not necessarily reflect those of PCORI. Dr. Udelson has received research funding from the NHLBI. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Hlatky and Douglas cochaired the workshop. NR 40 TC 22 Z9 22 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 14 PY 2012 VL 60 IS 7 BP 569 EP 580 DI 10.1016/j.jacc.2011.12.057 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 988BR UT WOS:000307463700002 PM 22796257 ER PT J AU Ishida, K Nishizuka, SS Chiba, T Ikeda, M Kume, K Endo, F Katagiri, H Matsuo, T Noda, H Iwaya, T Yamada, N Fujiwara, H Takahashi, M Itabashi, T Uesugi, N Maesawa, C Tamura, G Sugai, T Otsuka, K Koeda, K Wakabayashi, G AF Ishida, Kazushige Nishizuka, Satoshi S. Chiba, Takehiro Ikeda, Miyuki Kume, Kohei Endo, Fumitaka Katagiri, Hirokatsu Matsuo, Teppei Noda, Hironobu Iwaya, Takeshi Yamada, Noriyuki Fujiwara, Hisataka Takahashi, Masanori Itabashi, Tetsuya Uesugi, Noriyuki Maesawa, Chihaya Tamura, Gen Sugai, Tamotsu Otsuka, Koki Koeda, Keisuke Wakabayashi, Go TI Molecular Marker Identification for Relapse Prediction in 5-FU-Based Adjuvant Chemotherapy in Gastric and Colorectal Cancers SO PLOS ONE LA English DT Article ID NF-KAPPA-B; LYSATE MICROARRAYS; GENE-EXPRESSION; JNK ACTIVATION; COLON-CANCER; CELL-LINES; CARCINOMA; INHIBITION; ALPHA; CHEMORESISTANCE AB To confirm the clinical significance of NF-kappa B and JNK protein expression from experimentally identified candidates for predicting prognosis for patients with 5-FU treatment, we evaluated the protein expression of surgically removed specimens. A total of 79 specimens were obtained from 30 gastric and 49 colorectal cancer patients who underwent R0 resection followed by postoperative 5-FU based adjuvant chemotherapy. Immunohistochemical examinations of NF-kappa B and JNK on tissue microarrays (TMAs) revealed that significantly shorter time-to-relapse (TTR) in both NF-kappa B(+) and JNK(-) subgroups in both gastric (NF-kappa B(+), p = 0.0002, HR11.7. 95% CI3 3.2-43.4; JNK(-), p = 0.0302, HR4.4, 95% CI 1.2-16.6) and colon (NF-kappa B(+), p = 0.0038, HR36.9, 95% CI 3.2-426.0; JNK(-), p = 0.0098, HR3.2, 95% CI 1.3-7.7) cancers. These protein expression patterns also show strong discriminately power in gastric cancer patients for overall survival rate, suggesting a potential utility as prognostic or chemosensitivity markers. Baseline expression of these proteins using gastric cancer cell lines demonstrated the reciprocal patterns between NF-kappa B and JNK, while 5-FU exposure of these cell lines only induced NF-kappa B, suggesting that NF-kappa B plays a dominant role in the response to 5-FU. Subsequent siRNA experiments confirmed that gene knockdown of NF-kappa B increased 5-FU-specific sensitivity, whereas that of JNK did not affect the chemosensitivity. These results suggest that the expression of these proteins may aid in the decisions involved with adjuvant chemotherapy for gastrointestinal tract cancers. C1 [Ishida, Kazushige; Nishizuka, Satoshi S.; Chiba, Takehiro; Ikeda, Miyuki; Kume, Kohei; Endo, Fumitaka; Katagiri, Hirokatsu; Matsuo, Teppei; Noda, Hironobu; Iwaya, Takeshi; Fujiwara, Hisataka; Takahashi, Masanori; Itabashi, Tetsuya; Otsuka, Koki; Koeda, Keisuke; Wakabayashi, Go] Iwate Med Univ, Sch Med, Dept Surg, Morioka, Iwate 020, Japan. [Nishizuka, Satoshi S.; Kume, Kohei; Uesugi, Noriyuki; Maesawa, Chihaya; Wakabayashi, Go] Iwate Med Univ, MIAST, Morioka, Iwate 020, Japan. [Iwaya, Takeshi] Kyushu Univ, Med Inst Bioregulat, Dept Surg, Beppu, Oita, Japan. [Kume, Kohei; Maesawa, Chihaya] Iwate Med Univ, Ctr Adv Med Sci, Dept Tumor Biol, Yahaba, Iwate, Japan. [Yamada, Noriyuki; Uesugi, Noriyuki; Sugai, Tamotsu] Iwate Med Univ, Sch Med, Dept Pathol, Div Diagnost Mol Pathol, Morioka, Iwate 020, Japan. [Tamura, Gen] Yamagata Prefectural Cent Hosp, Dept Pathol & Lab Med, Yamagata, Japan. RP Ishida, K (reprint author), NCI, Chem Immunol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM snishizu@iwate-med.ac.jp FU Keiryokai Research Foundation [101]; KAKENHI [21591676]; MIAST (Medical Innovation by Advanced Science and Technology) project of the Ministry of Education, Culture, Sports, Science and Technology, JAPAN FX This work was supported by: Keiryokai Research Foundation (101) by S.S.N.; KAKENHI (21591676); Grant-in-Aid for Scientific Research(C) by S.S.N; and MIAST (Medical Innovation by Advanced Science and Technology) project of the Ministry of Education, Culture, Sports, Science and Technology, JAPAN by S.S.N, K. K, N.U., C. M., T. S., and G. W. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 6 Z9 7 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2012 VL 7 IS 8 AR e43236 DI 10.1371/journal.pone.0043236 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 988OQ UT WOS:000307500800062 PM 22905237 ER PT J AU Gaspar, D Veiga, AS Sinthuvanich, C Schneider, JP Castanho, MARB AF Gaspar, Diana Veiga, Ana Salome Sinthuvanich, Chomdao Schneider, Joel P. Castanho, Miguel A. R. B. TI Anticancer Peptide SVS-1: Efficacy Precedes Membrane Neutralization SO BIOCHEMISTRY LA English DT Article ID HOST-DEFENSE PEPTIDES; ANTIMICROBIAL PEPTIDES; CANCER-TREATMENT; CHARGE AB Anticancer peptides are polycationic amphiphiles capable of preferentially killing a wide spectrum of cancer cells relative to noncancerous cells. Their primary mode of action is an interaction with the cell membrane and subsequent activation of lytic effects; however, the exact mechanism responsible for this mode of action remains controversial. Using zeta potential analyses we demonstrate the interaction of a small anticancer peptide with membrane model systems and cancer cells. Electrostatic interactions have a pivotal role in the cell killing process, and in contrast to the antimicrobial peptides action cell death occurs without achieving full neutralization of the membrane charge. C1 [Gaspar, Diana; Veiga, Ana Salome; Castanho, Miguel A. R. B.] Univ Lisbon, Fac Med, Inst Mol Med, P-1649028 Lisbon, Portugal. [Sinthuvanich, Chomdao; Schneider, Joel P.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Sinthuvanich, Chomdao] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. RP Castanho, MARB (reprint author), Univ Lisbon, Fac Med, Inst Mol Med, Av Prof Egas Moniz, P-1649028 Lisbon, Portugal. EM macastanho@fm.ul.pt RI Schneider, Joel/N-2610-2014; Gaspar, Diana/M-9562-2015; OI Gaspar, Diana/0000-0002-9602-567X; Veiga, Ana Salome/0000-0002-9892-2243; Castanho, Miguel/0000-0001-7891-7562 FU Fundacao para a Ciencia e a Tecnologia (Ministerio da Educacao e Ciencia, Portugal) [SFRH/BPD/73500/2010]; Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme [PIOF-GA-2009-235154]; Office of the Higher Education Commission, Ministry of Education, Thailand FX D.G. acknowledges Fundacao para a Ciencia e a Tecnologia (Ministerio da Educacao e Ciencia, Portugal) for Fellowship SFRH/BPD/73500/2010. A.S.V. acknowledges a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (PIOF-GA-2009-235154). C.S. acknowledges the Strategic Scholarship for Frontier Research Network (SFR) from Office of the Higher Education Commission, Ministry of Education, Thailand. NR 18 TC 14 Z9 14 U1 2 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 14 PY 2012 VL 51 IS 32 BP 6263 EP 6265 DI 10.1021/bi300836r PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 988GY UT WOS:000307478700001 PM 22839778 ER PT J AU Shukla, H Vaitiekunas, P Majumdar, AK Dragan, AI Dimitriadis, EK Kotova, S Crane-Robinson, C Privalov, PL AF Shukla, Hem Vaitiekunas, Paulius Majumdar, Ananya K. Dragan, Anatoly I. Dimitriadis, Emilios K. Kotova, Svetlana Crane-Robinson, Colyn Privalov, Peter L. TI The Linker of the Interferon Response Factor 3 Transcription Factor Is Not Unfolded SO BIOCHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURE; PROTEIN LIGATION; BETA ENHANCER; DNA-BINDING; IRF-3; DOMAINS; NMR; PHOSPHORYLATION; TRANSACTIVATION; ACTIVATION AB Interferon response factor 3 (IRF-3) is a transcription factor that plays an essential role in controlling the synthesis of interferon-beta (IFN-beta) and is a protein consisting of two well-defined domains, the N-terminal DNA-binding and the C-terminal dimerization domains, connected by a 75-residue linker, supposedly unfolded. However, it was not clear whether in intact IRF-3 this linker segment of the chain, which carries the nuclear export signal and includes a region of high helical propensity, remains unfolded. This has been investigated using nuclear magnetic resonance by ligating the N-15-labeled linker to the unlabeled N-terminal and C-terminal domains. It was found that, while the linker alone is indeed in a completely unfolded state, when ligated to the C-terminal domain it shows some ordering, and this ordering becomes much more pronounced when the linker is also ligated to the N-terminal domain. Thus, in intact IRF-3, the linker represents a folded structural domain; i.e., IRF-3 is a three-domain globular protein. Light scattering studies of wild-type IRF-3 showed that these three domains are tightly packed, and therefore, the dimer of IRF-3, which is formed upon phosphorylation of its C-terminal domains following virus invasion, must be a rather rigid and compact construction. One would then expect that binding of such a dimer to its tandem recognition sites PRDIII and PRDI, which are located on opposing faces of the IFN-beta enhancer DNA, should result in deformation of the DNA. Analysis of the characteristics of binding of the monomeric and dimeric IRF-3 to the enhancer DNA indeed showed that formation of this complex requires considerable work for deformation of its components, most likely bending of the DNA. Such bending was confirmed by atomic force microscopy of dimeric IRF-3 bound to the PRDII-PRDI tandem recognition sites placed at the middle of a 300 bp DNA probe. Bending of DNA by IRF-3 must be significant in the assembly and function of the IFN-beta enhancer. C1 [Shukla, Hem; Vaitiekunas, Paulius; Majumdar, Ananya K.; Dragan, Anatoly I.; Crane-Robinson, Colyn; Privalov, Peter L.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Dragan, Anatoly I.] Univ Maryland, Inst Fluorescence, Baltimore, MD 21201 USA. [Dimitriadis, Emilios K.; Kotova, Svetlana] NIH, Bethesda, MD 20892 USA. [Crane-Robinson, Colyn] Univ Portsmouth, Sch Biol Sci, Biophys Grp, Portsmouth, Hants, England. RP Crane-Robinson, C (reprint author), Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. EM colyn.crane-robinson@port.ac.uk FU NIH [105365] FX The authors wish to acknowledge NIH grant 105365, entitled "The mechanism of Interferon Regulatory Factor (IRF) Activation". NR 27 TC 4 Z9 4 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 14 PY 2012 VL 51 IS 32 BP 6320 EP 6327 DI 10.1021/bi300260s PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 988GY UT WOS:000307478700005 PM 22812703 ER PT J AU Coon, SL Munson, PJ Cherukuri, PF Sugden, D Rath, MF Moller, M Clokie, SJH Fu, C Olanich, ME Rangel, Z Werner, T Mullikin, JC Klein, DC AF Coon, Steven L. Munson, Peter J. Cherukuri, Praveen F. Sugden, David Rath, Martin F. Moller, Morten Clokie, Samuel J. H. Fu, Cong Olanich, Mary E. Rangel, Zoila Werner, Thomas Mullikin, James C. Klein, David C. CA NISC Comparative Sequencing Progra TI Circadian changes in long noncoding RNAs in the pineal gland SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE RNA sequencing; neuroendocrine regulation; differential expression; chronobiology ID RAT PINEALOCYTES; GENE-EXPRESSION; ADENOSINE-3',5'-MONOPHOSPHATE; TRANSCRIPTION; REVEALS; DIFFERENTIATION; COMPLEXES; MECHANISM; MELATONIN; RHYTHMS AB Long noncoding RNAs (lncRNAs) play a broad range of biological roles, including regulation of expression of genes and chromosomes. Here, we present evidence that lncRNAs are involved in vertebrate circadian biology. Differential night/day expression of 112 lncRNAs (0.3 to >50 kb) occurs in the rat pineal gland, which is the source of melatonin, the hormone of the night. Approximately one-half of these changes reflect nocturnal increases. Studies of eight lncRNAs with 2- to >100-fold daily rhythms indicate that, in most cases, the change results from neural stimulation from the central circadian oscillator in the suprachiasmatic nucleus (doubling time = 0.5-1.3 h). Light exposure at night rapidly reverses (halving time = 9-32 min) levels of some of these lncRNAs. Organ culture studies indicate that expression of these lncRNAs is regulated by norepinephrine acting through cAMP. These findings point to a dynamic role of lncRNAs in the circadian system. C1 [Coon, Steven L.; Clokie, Samuel J. H.; Fu, Cong; Olanich, Mary E.; Klein, David C.] NHGRI, Sect Neuroendocrinol, Program Dev Endocrinol & Genet,NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Munson, Peter J.; Rangel, Zoila] NHGRI, Math & Stat Comp Lab, Ctr Informat Technol, NIH, Bethesda, MD 20892 USA. [Cherukuri, Praveen F.; Mullikin, James C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Cherukuri, Praveen F.; Mullikin, James C.; NISC Comparative Sequencing Progra] NHGRI, Intramural Sequencing Ctr, NIH, Bethesda, MD 20852 USA. [Sugden, David] Kings Coll London, Sch Med, Div Womens Hlth, London SE1 1UL, England. [Rath, Martin F.; Moller, Morten] Univ Copenhagen, Panum Inst, Dept Neurosci & Pharmacol, DK-2200 Copenhagen, Denmark. [Werner, Thomas] Genomatix Software GmbH, D-80335 Munich, Germany. [Werner, Thomas] Univ Michigan, Ann Arbor, MI 48109 USA. RP Klein, DC (reprint author), NHGRI, Sect Neuroendocrinol, Program Dev Endocrinol & Genet,NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. EM klein@helix.nih.gov OI Clokie, Samuel/0000-0002-0025-3652; Rath, Martin/0000-0002-4047-6324 FU National Institute of Child Health and Human Development, National Institutes of Health; Center for Information Technology, National Institutes of Health; National Human Genome Research Institute, National Institutes of Health; Biotechnology and Biological Sciences Research Council United Kingdom; Danish Medical Research Council; Lundbeck Foundation; Novo Nordisk Foundation; Carlsberg Foundation; Simon Fougner Hartmanns Familiefond FX We thank Ms. Tine Thorup Mellergaard for expert technical assistance. This work was supported, in whole or in part, by the Intramural Research Programs of the National Institute of Child Health and Human Development, National Institutes of Health (S. L. C., S.J.H.C., C. F., M.E.O. and D. C. K.), the Center for Information Technology, National Institutes of Health (P.J.M. and Z.R.), and the National Human Genome Research Institute, National Institutes of Health (P. F. C. and J.C. M.); the Biotechnology and Biological Sciences Research Council United Kingdom (D. S.); the Danish Medical Research Council (M. F. R.); the Lundbeck Foundation (M. F. R. and M. M.); and the Novo Nordisk Foundation, the Carlsberg Foundation, and the Simon Fougner Hartmanns Familiefond (M. M.). NR 46 TC 28 Z9 33 U1 2 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 AUG 14 PY 2012 VL 109 IS 33 BP 13319 EP 13324 DI 10.1073/pnas.1207748109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992VC UT WOS:000307807000043 PM 22864914 ER PT J AU Qin, LZ Liu, XB Sun, QF Fan, ZP Xia, DS Ding, G Ong, HL Adams, D Gahl, WA Zheng, CY Qi, SR Jin, LY Zhang, CM Gu, LK He, JQ Deng, DJ Ambudkar, IS Wang, SL AF Qin, Lizheng Liu, Xibao Sun, Qifei Fan, Zhipeng Xia, Dengsheng Ding, Gang Ong, Hwei Ling Adams, David Gahl, William A. Zheng, Changyu Qi, Senrong Jin, Luyuan Zhang, Chunmei Gu, Liankun He, Junqi Deng, Dajun Ambudkar, Indu S. Wang, Songlin TI Sialin (SLC17A5) functions as a nitrate transporter in the plasma membrane SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pH; proton ID ACID STORAGE DISORDERS; NITRIC-OXIDE; ANION TRANSPORTER; HUMAN CIRCULATION; DIETARY NITRATE; EXPRESSION; METABOLISM; CHL1; SALIVARY; DISEASES AB In vivo recycling of nitrate (NO3-) and nitrite (NO2-) is an important alternative pathway for the generation of nitric oxide (NO) and maintenance of systemic nitrate-nitrite-NO balance. More than 25% of the circulating NO3- is actively removed and secreted by salivary glands. Oral commensal bacteria convert salivary NO3- to NO2-, which enters circulation and leads to NO generation. The transporters for NO3- in salivary glands have not yet been identified. Here we report that sialin (SLC17A5), mutations in which cause Salla disease and infantile sialic acid storage disorder (ISSD), functions as an electrogenic 2NO(3)(-)/H+ cotransporter in the plasma membrane of salivary gland acinar cells. We have identified an extracellular pH-dependent anion current that is carried by NO3- or sialic acid (SA), but not by Br-, and is accompanied by intracellular acidification. Both responses were reduced by knockdown of sialin expression and increased by the plasma membrane-targeted sialin mutant (L22A-L23A). Fibroblasts from patients with ISSD displayed reduced SA- and NO3--induced currents compared with healthy controls. Furthermore, expression of disease-associated sialin mutants in fibroblasts and salivary gland cells suppressed the H+-dependent NO3- conductance. Importantly, adenovirus-dependent expression of the sialinH183R mutant in vivo in pig salivary glands decreased NO3- secretion in saliva after intake of a NO3--rich diet. Taken together, these data demonstrate that sialin mediates nitrate influx into salivary gland and other cell types. We suggest that the 2NO(3)(-)/H+ transport function of sialin in salivary glands can contribute significantly to clearance of serum nitrate, as well as nitrate recycling and physiological nitrite-NO homeostasis. C1 [Gu, Liankun; Deng, Dajun] Peking Univ, Canc Hosp & Inst, Key Lab Carcinogenesis & Translat Res, Beijing 100142, Peoples R China. [Qin, Lizheng; Sun, Qifei; Fan, Zhipeng; Xia, Dengsheng; Ding, Gang; Qi, Senrong; Jin, Luyuan; Zhang, Chunmei; Wang, Songlin] Capital Med Univ, Sch Stomatol, Salivary Gland Dis Ctr, Beijing 100050, Peoples R China. [Qin, Lizheng; Sun, Qifei; Fan, Zhipeng; Xia, Dengsheng; Ding, Gang; Qi, Senrong; Jin, Luyuan; Zhang, Chunmei; Wang, Songlin] Capital Med Univ, Sch Stomatol, Beijing Key Lab Tooth Regenerat & Funct Reconstru, Beijing 100050, Peoples R China. [Liu, Xibao; Ong, Hwei Ling; Zheng, Changyu; Ambudkar, Indu S.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, Bethesda, MD 20892 USA. [Adams, David; Gahl, William A.] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [He, Junqi; Wang, Songlin] Capital Med Univ, Sch Basic Med, Dept Biochem & Mol Biol, Beijing 100069, Peoples R China. RP Deng, DJ (reprint author), Peking Univ, Canc Hosp & Inst, Key Lab Carcinogenesis & Translat Res, Beijing 100142, Peoples R China. EM dengdajun@bjmu.edu.cn; iambudkar@dir.nidcr.nih.gov; slwang@ccmu.edu.cn RI Deng, Dajun/D-4605-2009 OI Deng, Dajun/0000-0001-5161-5943 FU National Nature Science Foundation of China [30430690, 30125042, 81170975]; National Basic Research Program of China [2007CB947304, 2010CB944801]; Division of Intramural Research of the National Institute of Dental and Craniofacial Research; Division of Intramural Research of the National Human Genome Research Institute FX We thank Dr. Jim Turner, Dr. Shmuel Muallem, Dr. Jing Jiang, and Professor Liangbiao Chen for their invaluable help during the course of this work. This study was supported by the National Nature Science Foundation of China (Grants 30430690, 30125042, and 81170975), the National Basic Research Program of China (Grants 2007CB947304 and 2010CB944801), and the Divisions of Intramural Research of the National Institute of Dental and Craniofacial Research and the National Human Genome Research Institute. NR 30 TC 36 Z9 37 U1 3 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 AUG 14 PY 2012 VL 109 IS 33 BP 13434 EP 13439 DI 10.1073/pnas.1116633109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992VC UT WOS:000307807000063 PM 22778404 ER PT J AU Ozen, E Gozukizil, A Erdal, E Uren, A Bottaro, DP Atabey, N AF Ozen, Evin Gozukizil, Aysim Erdal, Esra Uren, Aykut Bottaro, Donald P. Atabey, Nese TI Heparin Inhibits Hepatocyte Growth Factor Induced Motility and Invasion of Hepatocellular Carcinoma Cells through Early Growth Response Protein 1 SO PLOS ONE LA English DT Article ID TRANSCRIPTION FACTOR EGR-1; FACTOR SCATTER FACTOR; C-MET; FACTOR/SCATTER FACTOR; SIGNALING PATHWAY; IN-VIVO; MELANOMA-CELLS; UP-REGULATION; GENE-THERAPY; EXPRESSION AB The Hepatocyte Growth Factor (HGF)/c-Met signaling pathway regulates hepatocyte proliferation, and pathway aberrations are implicated in the invasive and metastatic behaviors of hepatocellular carcinoma (HCC). In addition to c-Met, heparin acts as a co-receptor to modulate pathway activity. Recently, anti-metastatic and anti-cancer effects of heparin have been reported. However, the role of heparin in the regulation of HGF signaling remains controversial and the effects of heparin on HGF-induced biological responses during hepatocarcinogenesis is not yet defined. In this study we determined the effects of heparin on HGF-induced activities of HCC cells and the underlying molecular mechanisms. Here, we report for the first time that heparin inhibits HGF-induced adhesion, motility and invasion of HCC cells. In addition, heparin reduced HGF-induced activation of c-Met and MAPK in a dose-dependent manner, as well as decreased transcriptional activation and expression of Early growth response factor 1 (Egr1). HGF-induced MMP-2 and MMP-9 activation, and MT1-MMP expression, also were inhibited by heparin. Stable knockdown of Egr1 caused a significant decrease in HGF-induced invasion, as well as the activation and expression of MMPs. Parallel to these findings, the overexpression of Egr1 increased the invasiveness of HCC cells. Our results suggest that Egr1 activates HGF-induced cell invasion through the regulation of MMPs in HCC cells and heparin inhibits HGF-induced cellular invasion via the downregulation of Egr1. Therefore, heparin treatment might be a therapeutic approach to inhibit invasion and metastasis of HCC, especially for patients with active HGF/c-Met signaling. C1 [Ozen, Evin; Gozukizil, Aysim; Erdal, Esra; Atabey, Nese] Dokuz Eylul Univ, Dept Med Biol & Genet, Sch Med, Izmir, Turkey. [Uren, Aykut] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Bottaro, Donald P.] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ozen, E (reprint author), Dokuz Eylul Univ, Dept Med Biol & Genet, Sch Med, Izmir, Turkey. EM nese.atabey@deu.edu.tr RI Bottaro, Donald/F-8550-2010 OI Bottaro, Donald/0000-0002-5057-5334 FU Turkish Scientific and Technological Research Council (TUBITAK) [SBAG - 110S349]; Dokuz Eylul University Research Foundation [2008-KB-SAG-02]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Cancer Center Support Grant from NIH/NCI [P30 CA051008] FX This project was funded by grants to Prof. Dr. Atabey from Turkish Scientific and Technological Research Council (TUBITAK, SBAG - 110S349) and Dokuz Eylul University Research Foundation (2008-KB-SAG-02). This work was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by the Cancer Center Support Grant (P30 CA051008) from NIH/NCI for the use of Biacore Molecular Interaction Shared Resource. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 12 Z9 12 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 AUG 13 PY 2012 VL 7 IS 8 AR e42717 DI 10.1371/journal.pone.0042717 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 988OJ UT WOS:000307500100023 PM 22912725 ER PT J AU Pitzer, VE Atkins, KE de Blasio, BF Van Effelterre, T Atchison, CJ Harris, JP Shim, E Galvani, AP Edmunds, WJ Viboud, C Patel, MM Grenfell, BT Parashar, UD Lopman, BA AF Pitzer, Virginia E. Atkins, Katherine E. de Blasio, Birgitte Freiesleben Van Effelterre, Thierry Atchison, Christina J. Harris, John P. Shim, Eunha Galvani, Alison P. Edmunds, W. John Viboud, Cecile Patel, Manish M. Grenfell, Bryan T. Parashar, Umesh D. Lopman, Ben A. TI Direct and Indirect Effects of Rotavirus Vaccination: Comparing Predictions from Transmission Dynamic Models SO PLOS ONE LA English DT Article ID INFECTIOUS INTESTINAL DISEASE; 1ST 2 YEARS; UNITED-STATES; GENERAL-PRACTICE; DOUBLE-BLIND; IMPACT; GASTROENTERITIS; EFFICACY; PROTECTION; CHILDREN AB Early observations from countries that have introduced rotavirus vaccination suggest that there may be indirect protection for unvaccinated individuals, but it is unclear whether these benefits will extend to the long term. Transmission dynamic models have attempted to quantify the indirect protection that might be expected from rotavirus vaccination in developed countries, but results have varied. To better understand the magnitude and sources of variability in model projections, we undertook a comparative analysis of transmission dynamic models for rotavirus. We fit five models to reported rotavirus gastroenteritis (RVGE) data from England and Wales, and evaluated outcomes for short- and long-term vaccination effects. All of our models reproduced the important features of rotavirus epidemics in England and Wales. Models predicted that during the initial year after vaccine introduction, incidence of severe RVGE would be reduced 1.8-2.9 times more than expected from the direct effects of the vaccine alone (28-50% at 90% coverage), but over a 5-year period following vaccine introduction severe RVGE would be reduced only by 1.1-1.7 times more than expected from the direct effects (54-90% at 90% coverage). Projections for the long-term reduction of severe RVGE ranged from a 55% reduction at full coverage to elimination with at least 80% coverage. Our models predicted short-term reductions in the incidence of RVGE that exceeded estimates of the direct effects, consistent with observations from the United States and other countries. Some of the models predicted that the short-term indirect benefits may be offset by a partial shifting of the burden of RVGE to older unvaccinated individuals. Nonetheless, even when such a shift occurs, the overall reduction in severe RVGE is considerable. Discrepancies among model predictions reflect uncertainties about age variation in the risk and reporting of RVGE, and the duration of natural and vaccine-induced immunity, highlighting important questions for future research. C1 [Pitzer, Virginia E.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Pitzer, Virginia E.; Viboud, Cecile; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Pitzer, Virginia E.; Atkins, Katherine E.; Galvani, Alison P.] Yale Univ, Dept Epidemiol Microbial Dis, Sch Publ Hlth, New Haven, CT 06520 USA. [de Blasio, Birgitte Freiesleben] Univ Oslo, Dept Biostat, Inst Basic Med Sci, Oslo, Norway. [de Blasio, Birgitte Freiesleben] Norwegian Inst Publ Hlth, Dept Infect Dis Epidemiol, Oslo, Norway. [Van Effelterre, Thierry] GlaxoSmithKline Biol, Global Vaccine Dev, Wavre, Belgium. [Atchison, Christina J.; Edmunds, W. John] London Sch Hyg & Trop Med, Infect Dis Epidemiol Unit, Dept Epidemiol & Populat Hlth, London WC1, England. [Harris, John P.] Hlth Protect Agcy, Ctr Infect, Dept Gastrointestinal Emerging & Zoonot Infect, London, England. [Shim, Eunha] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Patel, Manish M.; Parashar, Umesh D.; Lopman, Ben A.] Ctr Dis Control & Prevent, Epidemiol Branch, Div Viral Dis, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. RP Pitzer, VE (reprint author), Yale Univ, Dept Epidemiol Microbial Dis, Sch Publ Hlth, New Haven, CT 06520 USA. EM virginia.pitzer@yale.edu OI Atchison, Christina/0000-0001-8304-7389; Pitzer, Virginia/0000-0003-1015-2289 FU National Institutes of Health [R01 GM083983-01]; Bill and Melinda Gates Foundation; Miriam Weston Trust; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health; GAVI Alliance under a collaborative agreement with the Program for Appropriate Technology in Health (PATH) FX This work was supported by the National Institutes of Health (R01 GM083983-01) (V.E.P. and B.T.G.), the Bill and Melinda Gates Foundation (V.E.P. and B.T.G.), Miriam Weston Trust (K.E.A. and A.P.G.), the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health (V.E.P, B.T.G., K.E.A., and B.F.B.), and the GAVI Alliance under a collaborative agreement with the Program for Appropriate Technology in Health (PATH) (M.M.P., U.D.P., and B.A.L.). The findings and conclusions in this report are those of the authors and do not necessarily represent